chronic kidney disease 1-3 stages

EditorsAlthea MahonKaren Jenkins

Project Co-ordinatorMaría Cruz Casal

Chronic Kidney DiseaseA Guide to Clinical Practice

This handbook is an initiative of EDTNA/ERCA

Chronic Kidney Disease (CKD) Interest Group

A limited edition will be available in the followinglanguages: English, Spanish, Greek, Czech,

Hebrew, Portuguese and Turkish

All rights are reserved by the author and publisher, including the rights ofreprinting, reproduction in any form and translation. No part of this book maybe reproduced, stored in a retrieval system or transmitted, in any form or bymeans, electronic, mechanical, photocopying, recording, or otherwise, withoutthe prior written permission of the publisher.

First edition: July 2007

European Dialysis and Transplant Nurses Association/ European Renal CareAssociation (EDTNA/ERCA)Pilatrustrasse 35, Postfach 3052, 6002 Luzern, Switzerlandwww.edtnaerca.org

ISBN: 978-84-611-8259-6

D.L.: M-34351-2007

Layout, Binding and Printing: Imprenta Tomás HermanosC/Río Manzanares, 42-44 · E28970 Humanes de MadridMadrid - Spainwww.tomashermanos.com

6

Chronic Kidney Disease: A Guide to Clinical Practice (Stages 1-3)

Acknowledgments

This book is an initiative of EDTNA/ERCACKD Interest Group. A considerable contribution has been made by all Interest Group Members: Karen Jenkins, Anastasia Liossatou, Sue Teasdale, Tai Mooi Ho Wong and Nurit Cohen in the production of this publication. I would like to take this opportunity to thank all ofthem. A special mention goes to Althea Mahon, Immediate Past President of EDTNA/ERCA for her support in all phases of this project: as Author, Editor and for Proof Reading. Along with Karen Jenkins they have assumed all of these roles in order to complete this book, and it has been greatly appreciated.

The EDTNA/ERCA would like to thank all authors of each chapter

Editors:Althea Mahon, RN, BSc Nursing, MSc NursingBarts and The London NHS Trust, London, UK

Karen Jenkins, RN PG Dip HE. MSc NursingDepartment of Renal Medicine, East Kent Hospitals NHS Trust, Canterbury, UK

Co-ordinatorMaria Cruz Casal RN, DUELaboratory of Nephrology, Hospital Universitario 12 de Octubre,Madrid, Spain

7

Acknowledgments

Reviewers:Annemarie Visser, BSc, Dietetics Diploma in Hospital Dietetics Barts and The London NHS Trust, London, UKLesley Bennett BA, RN, RM, Renal CertOxford Radcliffe NHS Trust, Churchill Hospital, Oxford, UKDiane Green BSc (Hons), RDSalford Royal Hospitals NHS Trust, Manchester, UKDr Cordelia Ashwanden, PhD, MSc, BSc (Hons),Adult Ed. Cert, RGNEditor of the EDTNA/ERCA Journal of Renal CareRay James, BSc, MScSub-editor of the EDTNA/ERCA Journal of Renal Care

Translators:Thanks to Spanish, Greek, Czech, Israeli, Portuguese and Turkish colleagues for their collaboration in the translation ofthis book.

Sponsor:The printing of the English version of this book has been sponsored by an education grant from Roche Products Ltd (UK)

Finally thanks go to the EDTNA/ERCA Executive Committee for their support of the Chronic Kidney Disease Interest Group

Maria Cruz CasalCKD Interest Group Chair

10


Preface .............................................................................................................. 15

Althea Mahon, RN, BSc Nursing, MSc NursingBarts and The London NHS Trust, London, UK

1. Anatomy and Physiologyof the Kidney ............................................................................................ 21

Melissa Chamney, RN, BN, MN, PG Dip Academic Practice, City University, London, UK

2. Assessment, Diagnosis and Management of ChronicKidney Disease ........................................................................................ 33

Karen Jenkins, RN, PG Dip HE, MSc NursingDepartment of Renal Medicine, East Kent Hospitals NHS Trust, Canterbury, UK

3. Diagnostic Investigations inChronic Kidney Disease ................................................................ 53

Tai Mooi Ho Wong, RN, RM, DUE,Hypertension Unit, Hospital del Mar, Barcelona, Spain

María Cruz Casal, RN, DUELaboratory of Nephrology. Hospital Universitario 12 de Octubre,Madrid, Spain

11

Table of contents

4. Management of Anaemia in Chronic Kidney Disease ................................................................ 85

Anastasia Liossatou, RN, BN, MScNephrology Department, General Hospital of Kefalonia, Argostoli, Kefalonia, Greece

Karen Jenkins, RN, PG Dip HE, MSc NursingDepartment of Renal Medicine. East Kent Hospitals NHS Trust,Canterbury, UK

5. Nutrition and Chronic Kidney Disease ...................................................................................... 105

Nurit Cohen, RN, BN, Master of Public Health (MPH),Nephrology Department, Soroka University Medical Center, Beer-Sheva, Israel

Lina Schwarz, RN, BNNephrology Department. Soroka University Medical Center, Beer-Sheva, Israel

Diane Green, BSc (Hons), RDSalford Royal Hospitals NHS Trust, Manchester, UK

6. The Effect of Diabetes Mellitus on Chronic Kidney DiseaseProgression ............................................................................................... 119

Sue Teasdale, RN, MA, BSc (Hons)Salford Royal Hospitals NHS Trust, Manchester, UK

12


7. Cardiovascular Risk in ChronicKidney Disease ...................................................................................... 135

Sue Teasdale, RN, MA, BSc (Hons)Salford Royal Hospitals NHS Trust, Manchester, UK

8. Management of Hypertensionin Chronic Kidney Disease ...................................................... 149

María Luisa Fernandez, RN, DUE Hypertension Unit. Hospital Universitario 12 de Octubre,Madrid, Spain

Julián Segura Consultant Nephrologist, Hypertension Unit. Hospital Universitario 12 de Octubre, Madrid, Spain

9. Patient Information ........................................................................... 165

Althea Mahon, RN, BSc, MSc NursingBarts and The London NHS Trust, London, UK

13

Table of contents

16


PrefaceThe early detection of chronic kidney disease (CKD) is important as it provides the best opportunity to modify the disease and reduce the associated cardiovascular risk. CKDaffects approximately 10% of the population1,2. Slowing the progression of the disease has a major impact on reducing the number of patients requiring renal replacement therapy and improving the quality of life and outcomes for patients. It is important to remember that, of those diagnosed with CKD, onlya small minority will reach end stage renal failure. This pocket guide focuses on CKD stages 1-3 which has become a majorhealth concern as a result of early detection programmes.

The US NHANES study found the prevalence of stage3 CKD and higher (i.e. a glomerular fi ltration rate of�60ml/min/1.73m2)1 in US adults in the unselected adult population was 4.7%. This has been supported by a largesurvey of 112,215 people from 12 general practice surgeriesin the UK where they found the prevalence to be 4.9%3. Theprevalence of CKD amongst people with other co-morbidities such as diabetes, hypertension, and coronary heart diseasewill be considerably higher than 4.9%.

The rise in diagnosis of CKD is multifactorial and, in part, is associated with the ageing population. In addition to people living longer, there have been improvements in chronicdisease management. Another important factor is the rise in the incidence of type 2 diabetes, which is expected to double in the next 25 years4. This in turn will lead to an increasedincidence of diabetic nephropathy, with approximately 30%progressing to Stage 5 CKD. Other factors include an increase in CKD prevalence with age5. Men with CKD have a more rapid decline in renal function and progression of their renal disease than women6. Some ethnic populations have a higher

17

Preface

prevalence of CKD such as South Asians in the UK7 and Afro-Caribbean’s8. People from South Asia are at higher risk of CKDlinked to diabetes as there is a higher incidence of diabetes in this community9. Afro-Caribbean’s and Africans are at greaterrisk of CKD due to their higher prevalence of hypertension10.

The reality is that the majority of the CKD population have one or more co-morbid condition, with a known higher prevalence in ethnic minorities and lower socio-economic groups; combine this with the increase in childhood obesity and prevalence ofdiabetes and it is clear why we have an epidemic of CKDand that, without effective prevention and early detection programmes, this will continue to rise. Lastly the rise may alsobe due to the development of guidelines such as KDOQI11 andalso nationally agreed CKD guidelines such as the UK CKDguidelines12, along with the implementation of a simple blood test-based formulae (e.g. GFR) that allows for easier and earlier diagnosis of CKD and therefore increased reporting.

Whilst acknowledging that CKD is progressive, with goodmanagement, mainly focusing on lowering blood pressure, maximizing lipid control, lowering salt intake, encouragingregular exercise and weight reduction, maintaining tightdiabetic control, giving smoking cessation advice and avoidingnephrotoxic drugs this progression can be slowed. Earlydetection and management of CKD stages 1-3 can be and should be undertaken in primary care. Healthcare professionals have a responsibility to understand the classifi cation systemof CKD, its assessment process and treatment. It is hoped that this pocket guide will be a useful tool in the assessment, diagnosis, management and treatment of the early stages ofCKD.

18


References1. Coresh J, Astor BC, Greene T, Eknoyan G, Levey A. Prevalence of

chronic kidney disease and decreased kidney function in the adult US population: Third national health and nutrition survey. Am J KidneyDis, 2003; 41, (1): 1-12.

2. John R, Webb M, Young A, Stevens PE. Unreferredchronic kidney disease: a longitudinal study.Am J Kidney Dis 2004; 43: 825-835.

3. de Lusignan S, Chan T, Stevens P, O’Donoghue D, Hague N, DzregahB et al. Identifying patients with chronic kidney disease from generalpractice computer records. Fam Pract 2005; 22, (3): 234-241.

4. Atkins R. The epidemiology of chronic kidney disease. Kidney Int2005; 67, (Supp 94): S14-S18.

5. Rodriguez-Puyol D. Aging kidney. Kidney Int 1998; 54: 2247-2265.6. Neugarten J, Acharya A, Silbiger SR. Effect of gender on the

progression of nondiabetic renal disease: a meta-analysis. J Am Soc Nephrol 2000; 11(2):319-329.

7. Buck K, Feehally J. Diabetes and renal failure in Indo-Asians in the UK: a paradigm for the study of disease susceptibility. Nephrol DialTransplant 1999; 23: 1555-1557.

8. United States Renal Data System. Annual data report: incidence and prevalence of ESRD (2003).Am J Kidney Dis 2003; 42 (Suppl 5): S37-41.

9. Lightstone L. Preventing kidney disease: the ethnic challenge. The National Kidney Research Fund: Peterborough. 2001.

10. Raleigh VS. Diabetes and hypertension in Britain’s ethnic minorities: implications for the future of renal services. BMJ 1997; 313:209-215.

11. National Kidney Foundation. Clinical practice guidelinesfor chronic kidney disease: evaluation classifi cation and stratification. Am J Kidney Dis 2002; 39 (Supp 1):S1-266.

12. Chronic Kidney Disease in Adults: UK CKD Guidelines for Identifi cation, Management and Referral of adults (2005). Available from: http//www.renal.org/CKDguide/ckd.html

19

Preface

22


Learning Outcomes

• Review knowledge and understanding of the normal anatomy and physiology of the kidney

• An understanding of the pathophysiology of chronic kidney disease (CKD) and the most common causes of CKD

• Knowledge of the signs and symptoms of CKD

Introduction:The kidneys perform a number of important regulatory, excretoryand hormonal functions that will be discussed in this chapter. The most signifi cant role of the kidneys is to appropriatelyfi lter waste products from the blood excreting them in the urine. The kidneys process the blood to form urine, which serves several important functions.

• Waste products from cell activity are excreted• Fluid that accumulates in the body from ingestion of food

and water is removed• The concentration of many substances within the body is

maintained within limits

The kidneys typically produce 180L of fi ltrate from the blood per day; however the vast majority of the fi ltered fl uid is reabsorbed into the bloodstream. Approximately 2 litres offl uid is fi nally excreted as urine. The remaining 178 litres of

23

Anatomy and Physiology of the Kidney

fluid are reabsorbed back into the blood stream so that normalmetabolite concentration and homeostasis are maintained1.Large molecules such as red blood cells and protein are retained within the blood and smaller molecules enter thefi ltrate. Only excess fl uid and metabolic waste and toxic products are removed from the body. Kidneys play a crucial role in maintaining water and electrolyte balance. Kidneys also regulate acid base balance within a narrow range2.

The purpose of this chapter is to identify the main parts of the kidney and describe their basic function.

Normal Anatomy and PhysiologyThe kidneys lie on either side of the spine, just below the ribs at the back of the body and each kidney is approximately10 - 15 cms in length and shaped like a bean, this is proportional to the size of the individual. The right kidney is slightly lower than the left kidney due to the existence of the liver on that side3. Approximately 20% of cardiac output passes through the kidneys per minute. Under normal physiologicalconditions this blood fl ow is autoregulated, ensuringacceptable Glomerular Filtration Rate (GFR), ultrafi ltration, selective secretion and excretion of substances whichcontribute to the production of urine and elimination ofmetabolic waste products4. A high rate of blood fl ow and normal blood pressure within the kidneys is essential for the formation of urine2. The kidneys receive a constant supply ofblood which needs to be fi ltered in order to remove the excesswater and waste. In this manner the kidneys also regulate theamount of various substances in the blood stream, so that homeostasis is maintained.

So how does it all work?The functional unit of the kidney is called the nephron and is able to create urine by itself. Therefore it is not necessary to

24


describe the entire kidney, but merely the operation of one nephron to explain the function of the kidney5. Each kidneycontains approximately one million nephrons, each one ofwhich has it’s own glomerulus. Infl ammation, damage and destruction of the glomerulus will adversely affect it’s capacityto fi lter blood and this in turn will reduce the scope of the nephron to process the fi ltrate and produce urine. Sincethe glomeruli fi lter waste products and water from the blood any glomerular damage will adverely affect the person’s homeostasis. The kidney also contains a system of collectingducts that carry urine through the renal pyramids into the calyces, in the renal pelvis to the ureter. The systemic blood pressure determines if blood enters the glomerulus from the afferent arteriole. Holes in the capillary lining allow small particles to pass into the renal tubule and larger proteins are retained as they cannot pass through the glomerularfi ltration barrier8.

Glomerular fi ltration is the process by which fi ltrate is produced and it is the fi rst phase in urine production. The fi ltrate produced consists of virtually all blood components except larger molecules such as protein and red blood cells.However, many of the smaller substances that pass freelythrough the glomerulus are vital for normal body function. A process called tubular reabsorption is the second phase which selects certain substances from the fi ltrate and returnsthem to the blood via the peritubular capillaries, thus avoidingloss into the urine. Tubular secretion is the third phase where substances which are not fi ltered are secreted into the tubuleand excreted. By the time the fi nal excretory product (urine)drains from the collecting duct into the renal pelvis it is greatlyreduced in volume. The urine removes toxic waste products from the body as well as excess salt and water4rr .

The glomerulus is a high pressure capillary bed which causes fl uid to be fi ltered out of the blood. By contrast the peritubular capillary bed has low pressure which allows fl uid

25


to be reabsorbed back into the blood from the tubules. Assolutes are transported out of the proximal tubules in particularby the reassertion process, an osmotic gradient is establishedcausing water to be absorbed. Consequently over 65% of the glomerular fi ltrate is reabsorbed before entering the Loop ofHenle. Progressively lower fractions of water are reabsorbed as the fi ltrate passes through the tubular system. By varyingthe rate of reabsorption, large and small volumes of urine can be generated allowing extracellular fl uid volume in the body to be maintained which in turn is of importance in the control ofblood pressure9. In addition to water, a number of substances of nutritional importance are reabsorbed such as glucose,proteins and amino acids. The vasa recta are involved in the very important task of concentrating the urine. Without the ability of the kidneys to concentrate urine, a great deal more water would be needed to remove solutes from the blood3.

Glomerulus

Bowman'scapsule

Juxtaglomerularapparatus

Proximaltubule

Distaltubule Collecting

tubule

Collectingduct

Afferent arterioleEfferent arteriole

Loop ofHenle

Artery

Vein

Vasarecta

Peritubularcapillary network

Diagram 1: The Nephron.

26


This would require very regular drinking and result in a highurine output.

The glomerular capillaries have very high permeability, 100 to 500 times greater than the permeability of capillaries in other body tissues. When blood enters the glomerulus largequantities of fl uid are fi ltered from the blood forming the glomerular fi ltrate which then enters the Bowman’s capsule. Although the glomerular membrane is highly permeable, it is also selective, depending on the molecular size of a given substance. The permeability to large molecules suchas proteins is very low and thus these are confi ned to the blood. For all practical purposes the glomerular fi ltrate has virtually the same composition as blood plasma (containingall dissolved solutes) with the exception of proteins. The rate at which fi ltrate is generated is called the glomerular fi ltration rate (GFR).

It is important that the GFR is tightly controlled. Any disparitywould otherwise upset the fi ne balance between fi ltration and reabsorption, which controls the volume of urine produced. An increase in GFR would cause the fi ltrate to pass more rapidly through the tubules at a rate exceeding reabsorption.Similarly if the GFR decreases, all fl uid entering the tubules would be reabsorbed and there would be no urine output. A mechanism called auto regulation ensures that the GFRis tightly controlled. This is achieved by vasodilation of the afferent arteriole and vasoconstriction of the efferent arteriole.Although the GFR is maintained relatively constant, extremes of mean arterial pressure ultimately cause some effect in urine output. High arterial pressure leads to increase urine output whereas at pressures below 50 mmHg urine output virtuallyceases. This link between arterial pressure and urine output is called pressure diuresis.

A person’s bladder can hold on average 400 mls of urine before they will feel the need to urinate and most people pass two litres of urine per day. The kidneys are able to vary this

27


output of urine between 400 - 1500 mls to maintain a constant fluid volume3. Usually when these processes failurine production may cease altogether severely limiting theremoval of waste products and excess water from the body.Some aspects of renal function are assessed by measuringthe concentrations of metabolites such as urea and creatinine, both of which are excreted by the kidney. The glomerularfi ltration rate (GFR) is also a measure of renal function and will be discussed further in the CKD chapter.

Functions of the KidneyAs discussed above, the functions of the kidney include the production of urine via fi ltration of the blood, reabsorption of necessary electrolytes and excretion of waste products. This way the kidneys control homeostasis and fl uid balance as well as acid-base and electrolyte balance.

Excretory• Excretion of metabolic waste products, e.g. urea and f

creatinine

RegulatoryRegulation of:

• Body water volume• Body fl uid osmolality• Electrolyte balance• Acid-base balance• Blood pressure

Metabolic• Activation of vitamin D• Production of Renin• Production of Erythropoietin

(From Thomas, N (2002) Renal Nursing (2nd Ed), Bailliere Tindall, London, with permission of Elsevier Publications).

Table 1: The functions of the kidney3

28


They also control hormonal functions of renin production to control blood pressure, erythropoietin production to stimulate red cell production, and synthesis of vitamin D to assist with intestinal absorption of calcium.

A number of hormones influence renal function and theregulation of various substances:

• The Renin Angiotensin Aldosterone System maintains blood pressure

• Aldosterone contributes to the control of sodium andpotassium by stimulating sodium re-absorption in the distal tubules and collecting ducts

• Anti-Diuretic Hormone increases the absorption of water• Erythropoietin is produced primarily by the kidneys and

is essential for haemoglobin production• Vitamin D and Vitamin D3 are essential to form active

Vitamin D to maintain calcium balance• Parathyroid Hormone is released by the parathyroid

glands to maintain calcium and phosphate levels• Calcitonin affects plasma Ca+ levels

What happens in Chronic Kidney DiseaseCKD is a progression from health to illness which results in a permanent failure of the excretory, regulatory and hormonal (metabolic) functions of the kidney. CKD can be a slowlyprogressive disease over many months or years which results from the gradual loss of nephrons. The function maybe stable for prolonged periods of time and can be managedwith conservative management strategies. CKD is often asymptomatic in the early stages and is often not diagnoseduntil suffi cient impairment exists to retain uraemic toxins in the blood. Unfortunately the damage caused by CKD is irreversible and so unless the patient is managed appropriately,particularly at the early stages, it can then be impossible to delay or even stop their CKD progressing to later stages ofestablished renal failure where the person will require Renal Replacement Therapy (RRT) of some form to maintain life.

29


Renal Problems:There are many presentations of CKD; it is not a disease itselfbut the result of a number of disease processes which mayaffect renal function such as:

• Glomerular diseases (Glomerulonephritis)• Cystic diseases (Adult Polycystic Disease)• Systemic diseases (Multiple Myeloma)• Vascular diseases (Hypertension)• Obstructive disorders (Renal Stones)• Drug related reactions (Paracetamol, NSAIDS)

Diabetes is the fastest growing risk for renal failure in the western world and hypertension is the second leading cause of CKD. People with a family history of renal failure or a person’s age are factors that cannot be controlled, but other factorssuch as controlling blood glucose levels and blood pressure can help renal function to be maintained for longer. The KDOQI guidelines 200310 recommend a target blood pressure should be <130 / 80 mmHg for patients with CKD, regardlessof the degree of proteinuria.

Signs and Symptoms of CKD:In the early stages of CKD the remaining healthy nephrons compensate for the destroyed nephrons by increasing in size and working harder. Over time their ability to adapt to the loss of nephrons fails and it is then that the signs and symptoms ofCKD start to become evident. Most substances are eliminated from the body as they are produced, primarily by way of the kidneys. When these cannot be removed from the body due to renal failure this will account for some of the disordered bodyfunctions11.

Since patients with CKD stages 1 to 3 rarely have symptomsthey may be unaware that they have a problem with their kidneys and are often diagnosed after blood tests are

30


performed for other reasons. Waste products build up at later stages of CKD, which can cause symptoms such as nausea, vomiting, itchy skin, shortness of breath, oedema and symptoms of anaemia and renal bone disease. These symptoms affect people differently, but their overall qualityof life is diminished and appropriate treatment is needed to assist them. People who have diabetes and/or hypertensionusually have their kidney function checked annually. This type of screening can often identify early changes in kidneyfunction.

SummaryCKD is a common problem and improved detection and classifi cation using standardized criteria is needed to improve patient outcomes12. Understanding of the anatomyand physiology of the workings of the kidneys are important to be aware of if we are to make progress and advances in this specialism.

References1. Al-Khader A and Al-Jondeby M. Handbook for Dialysis Nurses

(2nd Ed). Al Sayyari: Saudi Arabia, 2006.2. Thibodeau G and Patton K. The Human Body in Health & Disease

(4th Ed). Elsevier Mosby: Missouri, 2005.3. Thomas N. Renal Nursing (2nd Ed). Bailliere Tindall: London, 2002.4. Montague S, Watson R and Herbert R. Physiology for Nursing

Practice (3rd Ed). Elsevier: Edinburgh, 2005. 5. Guyton A. Human Physiology and Mechanisms of disease (5th Ed).

W.B. Saunders Company: Philadelphia, 1992.6. Ind D. Nephrology Nursing Practice Student Notes. The Queen

Elizabeth Hospital: Adelaide, 2004.7. Stein A and Wild J. Kidney Dialysis and Transplants. Class

Publishing: London. 2004.8. Steggall M. in Brooker C and Waugh A. Foundations of Nursing

Practice, Fundamentals of Holistic Care. Mosby Elsevier: Philadelphia. 2007.

31


9. Seeley R, Stephens T and Tate P. Anatomy and Physiology (7th Ed).McGraw Hill: New York, 2006.

10. US National Kidney Foundation. Kidney Disease Outcomes QualityInitiative (KDOQI), www.kdoqi.org, accessed 15th March 2007.

11. Vander A. Renal Physiology (3rd Ed). McGraw Hill: New York. 1985.12. Coresh J, Astor B, Greene T, Eknoyan G, Levy A. Prevalence of

chronic kidney disease and decreased kidney function in the adult US population: third national health and nutrition examination survey,Am J of Kidney Dis 2003; 41 (1): 1-12.

34


Learning Outcomes

• To gain knowledge and understanding of the risk factors and prevalence of Chronic Kidney Disease (CKD)

• To understand how kidney function is measured• To gain knowledge and understanding of the

classifi cation of CKD• To gain insight into the referral process and

management of CKD

IntroductionChronic kidney disease (CKD) is now recognised as a major health problem. Studies carried out both in the United States1 and the United Kingdom2 to investigate the prevalence, progression and referral rates of CKD in the general adult population, have shown that older age, diabetesand hypertension are strongly associated with moderate or severely decreased renal function. The growing prevalence of CKD means that measures need to be taken to accuratelymeasure kidney function, stage of kidney disease, devise referral criteria and develop clear management plans.

Epidemiology of CKDThe number of patients with chronic kidney disease (CKD),and the subsequent need for renal replacement therapy (RRT),has reached epidemic proportion and is anticipated to rise further. CKD affects approximately 10% of the population

35

Assessment, Diagnosis and Management of CKD

worldwide1 and it is estimated that over 1.1 million patients with end stage renal disease (ESRD) currently require maintenance dialysis. A figure which is increasing at a rate of 7% per year3. If the trend continues, by 2010 the number will exceed 2 million4. This figure excludes third world countries, where there is less availability of, and access to, dialysis services, and is, therefore, an underestimate of the true demand. In the UK the incidence of ESRD has doubled over the last ten years and has now reached 101 patients per million of population (pmp)5. This is below the Europeanand USA averages of approximately 135 and 336 pmp respectively6. Studies such as the NHANES (National Health and Nutrition Examination Survey) which provided data on the adult unselected population estimated that 4.7% of USadults had CKD stage 3 or higher (defi ned as estimated glomerular fi ltration rate (eGFR) <60ml/min/1.73m2). Theyalso estimated that up to 11% of the general population (19.2 million) has some degree of CKD1.

Risk Factors of CKDRisk factors for CKD include:

• Diabetes• Cardiovascular disease• Smoking• Obesity• Sedentary lifestyle• Low socio-economic status

UK studies have shown a higher incidence of CKD in deprived areas7,8 consistent with both USA and Swedish studies9.Obesityhas become a global issue in developed countries adding to thepopulation of people with chronic disease. Those with diabetes and hypertension are at greatest risk and have a higher rate of renal problems than those in the normal population10. Thereality is that the majority of the CKD population have one or

36


more co-morbid conditions with a known higher prevalence in ethnic minorities and lower socio-economic groups. This along with the increase in childhood obesity and prevalence ofdiabetes make it clear why there is becoming an epidemic ofCKD and that, without effective prevention and early detection of CKD this will continue to rise.

Measurement of kidney functionTraditionally kidney function has been determined bymeasuring serum creatinine alone. However, serum creatinine alone is not an accurate index of the level of kidney function as there is not a direct relationship between glomerular fi ltration rate (GFR) and serum creatinine. By the time the creatinine becomes elevated, there may already be a 50% reduction in kidney function.

The use of the serum level of creatinine as an index ofGlomerular Filtration Rate (GFR) to measure kidney functionrests on three important assumptions:

• Creatinine is an ideal fi ltration marker whose clearance approximates GFR

• Creatinine excretion rate is constant among individuals and over time

• Measurement of serum creatinine is accurate andreproducible across clinical laboratories

Although the serum creatinine concentration can provide a rough index of the level of GFR, none of these assumptions is strictly true, and numerous factors can lead to errors in estimation of the level of GFR from the serum creatinine concentration alone.

Factors other than the level of GFR can also infl uence creatinine secretion include11:

• Kidney disease• Reduced muscle mass

37


• Malnutrition• Ingestion of cooked meat• Trimethoprim; Cimetidine• Ketoacidosis

Creatinine is mainly derived from the metabolism of creatine in muscle, and its generation is proportional to the total muscle mass. As a result, mean creatinine generation is higher in men than in women, in younger than in older individuals, andin blacks than in whites. This leads to differences in serumcreatinine concentration according to age, gender, and race, even after adjusting for GFR12.

In addition, measurement of creatinine clearance is not easy. Urinary clearance measurements require timed urinecollections, which are diffi cult to obtain and often involve errors in collection. Furthermore, day-to-day variation in creatinineexcretion exists, making estimation of GFR, even from a valid 24-hour urine collection, imprecise.

Therefore it is recommended that kidney function should be assessed by an estimation of glomerular fi ltration rate (eGFR)not creatinine alone. To do this there are specifi c formulae available. The most widely used are:

• Modifi cation of Diet in Renal Disease (MDRD)• Cockcroft Gault

Equations estimating GFR based on serum creatinine are more accurate and precise than estimates of GFR from measurement of serum creatinine alone. Studies havedocumented that creatinine production varies substantiallyacross sex, age, and ethnicity12.

Equations have the advantage of providing an estimate of GFRwhich empirically combine all of these average effects while allowing for the marked differences in creatinine production between individuals13.

38


Modifi cation of Diet in Renal Disease (MDRD)The four-variable Modification of Diet in Renal Disease(MDRD) formula is used to estimate GFR in mls per minute11.The formula requires the gender, age, serum creatinine and ethnicity (black/non-black) of the patient. Assumption of Caucasian ethnicity can be made when using MDRD ifethnicity is unknown.

MDRD calculation:The 4-variable Modifi cation of Diet in Renal Disease (MDRD)equation:

GFR (ml/min/1.73 m2) = 186 x {[Serum Creatinine �mol/l/88.4]2

-1.154} x {age (years) -0.203} x 0.742 if female and x 1.21 ifAfrican American.

Cockcroft Gault (1976) calculation14

The formula takes into consideration: weight, genderserum creatinine and age. However this technique tends to underestimate creatinine clearance in obese patients andoverestimates it in patients who may be on a low protein diet.

Cockcroft Gault equation

In men:(140-age) x weight in kg

Creatinine clearance = -------------------------------------------------· 1 72 x serum creatinine

In women:(140-age) x weight in kg

Creatinine clearance = ------------------------------------------------- · 0.8572 x serum creatinine

39


The eGFR can be related to percentage of kidney function.For example, an eGFR 20mls/min/1.73m2 = 20% kidneyfunction. A normal eGFR is considered to be more than 90mls/min/1.73m2.

How often should eGFR be measured?eGFR should be measured at initial assessment and then at least annually in all adult patients with:

1. Previously diagnosed CKD including:• Identifi ed renal pathology (e.g. polycystic kidney, biopsy

proven glomerular nephritis, refl ux nephropathy)• Persistent proteinuria• Urologically unexplained haematuria

2. Conditions associated with a high risk of silent development of obstructive kidney disease:• Bladder voiding dysfunction (outfl ow obstruction,

neurogenic bladder)• Urinary diversion surgery• Urinary stone disease (more than one episode/year)

3. Conditions associated with a high risk of silent development of parenchymal kidney disease:• Hypertension, diabetes mellitus, heart failure• Atherosclerotic coronary, cerebral, or peripheral

vascular disease

4. Conditions requiring long-term treatment with potentially nephrotoxic drugs• For example: ACE inhibitors (ACEI) Angiotensin

Receptor Blockers (ARB’s), Non steroidal anti-

40


infl ammatory Drugs (NSAIDs), Lithium, Mesalazine, Cyclosporin, Tacrolimus

5. Multi-system diseases that may involve the kidney• For example systemic lupus erythematosus (SLE),

vasculitis, myeloma, rheumatoid arthritis

In summary, a normal range for serum creatinine should no longer be given and management of the patient needs to be based on eGFR. Until laboratories are able to report eGFR MDRD and Cockcroft Gaultcalculators can be downloaded from www.renal.org orwww.nephron.com.

Should you rely on eGFR for acute renal failure patients?No, the eGFR is not appropriate for a patient with acute renal failure, as it relies on a stable serum creatinine for its predictive accuracy. eGFR cannot be used in children.

Staging of kidney diseaseThe presence of chronic kidney disease should be established, based on presence of kidney damage and level of kidney function (glomerular fi ltration rate - GFR),irrespective of diagnosis.

Among patients with chronic kidney disease, the stageof disease should be assigned based on the level ofkidney function, irrespective of diagnosis, according to the K/DOQI CKD classifi cation13 (Table 1).

41


Defi nition of Chronic Kidney DiseaseCKD is defi ned as either evidence of kidney damage or an eGFR <60ml/min/1.73m2 for � 3 months.

Kidney damage is defi ned as pathological abnormalities or markers of damage including abnormal blood or urine tests or imaging studies13,15.

K/DOQI suggests that:• All individuals with eGFR <60 ml/min/1.73 m2 for �3

months are classifi ed as having chronic kidney disease, irrespective of the presence or absence of kidneydamage. The rationale for including these individuals is that reduction in kidney function to this level or lower represents loss of half or more of the adult level of normal kidney function

• All individuals with kidney damage are classifi ed as having chronic kidney disease, irrespective of the level of eGFR. The rationale for including individuals with eGFR �60 ml/min/1.73 m2 is that eGFR may be sustained at normal or increased levels despitesubstantial kidney damage and that patients with kidney

Stage Description eGFR(ml/min/1.73m²)

1 Kidney Damage withNormal or � eGFR �90

2 Kidney Damage withmild � eGFR 60-89

3 Moderate � eGFR 30-59

4 Severe � eGFR 15-29

5 Kidney Failure < 15 (or dialysis)

Table 1: Classifi cation of CKD

42


damage are at increased risk of the two major outcomes of chronic kidney disease: loss of kidney function and development of cardiovascular disease

Other markers of kidney damage:• Persistent microalbuminuria (measured by an albumin

creatinine ratio)• Persistent proteinuria (after exclusion of other causes

e.g. urological)• Persistent haematuria• Structural abnormalities of the kidney• Biopsy proven chronic glomerulonephritis

Patients found to have eGFR 60-89ml/min/1.73m2 without oneof these markers should not be considered to have CKD or be subject to further investigation. Rate of change of eGFR is important when considering disease progression and needfor referral. eGFR is considered stable if there is <2ml/min/1.73m2 fall over 6 months or more.

Referral criteriaThe changes in reporting of kidney function are alreadyhaving an effect on the number of referrals to nephrologists.To provide guidance for referral the UK renal association have drafted a set of referral guidelines which are available from www.renal.org. Of course referral criteria may differamongst European countries and guidelines relevant to thelocal area of practice should be considered. Table 2 shows UK recommendations15 for referral as an example.

43


Table 2: UK Recommendations

Estimated GFR Referral criteria

<15ml/min/1.73m2

Immediate referralExceptions may include: patients inwhom CKD supervenes as part ofanother terminal illness; patients in whomfurther investigation and treatment isinappropriate; those who have stablefunction and appropriate investigationsand management interventions havebeen performed and have an agreed carepathway

15-29 ml/min/1.73m2 Urgent referral - routine if known to be stable

30-59 ml/min/1.73m2

Routine referral if:Progressive fall in eGFR/increase in creatinine, microscopic haematuriaUrinary PCR >45mg/mmolUnexplained anaemia (Hb,11g/dl)abnormal calcium, phosphate, or potassiumUncontrolled BP >150/90 on 3 agents

60-89 ml/min/1.73m2 Referral not required

Renal problemsirrespective of eGFR

Immediate referral for• Malignant hypertension• Hyperkalaemia (potassium >7.0mmol/L)

Urgent referral for:• Proteinuria with oedema and low

serum albumin (Nephrotic syndrome)

Routine referral for:• Dipstick proteinuria and urine PCR

>100mg/mmol• Dipstick proteinuria and microscopic

haematuria• Macroscopic haematuria but urological

tests negative

44


Management of CKDThe KDOQI guidelines13,16 suggest that patients with chronic kidney disease should be evaluated to determine:

• Diagnosis (Type of kidney disease)• Co-morbid conditions• Severity assessed by level of kidney function• Complications related to level of kidney function

e.g. anaemia• Risk for loss of kidney function• Risk for cardiovascular disease

Treatment of CKD should include:• Specifi c therapy, based on diagnosis• Evaluation and management of co-morbid conditions• Slowing the loss of kidney function• Prevention and treatment of cardiovascular disease• Prevention and treatment of complications of decreased

kidney function• Preparation for kidney failure and renal

replacement therapy• Replacement of kidney function by dialysis and

transplantation, if signs and symptoms of uraemia are present

A clinical action plan should be developed for each patient, based on the stage of disease as defi ned by the K/DOQI CKD classification13 (Table 3).

Provision should be made for the implementation of care plans for all adult patients with CKD irrespective of age and should be shared between primary, secondary and tertiary care.

The progression of CKD can be slowed down by focusing on:• Blood pressure control• Lipid control

45


• Glycaemic control• Healthy living - exercise• Smoking cessation• Avoiding nephrotoxic drugs

Both the UKPDS17 and DCCT18 study groups have shownthat good glycaemic control can decrease macrovasculardisease in type I and type II diabetes as well as slowing the progression from albuminuria to microalbuminuria.

Table 3: K/DOQI CKD classifi cation13

Description eGFR(ml/min/1.73m2) Action

1Kidney damagewith normal or

� GFR�90

Diagnosis and treatmentTreatment of co-morbidconditionsSlowing progressionCardiovascular risk reduction

2 Kidney damagewith mild � GFR 60-89 Estimating process

3 Moderate � GFR 30-59 Evaluate and treatcomplications

4 Severe � GFR 15-29 Preparation for kidneyreplacement therapy

5 Kidney failure < 15(or dialysis)

Replacement therapy orconservative management

46


The use of angiotensin-converting enzyme (ACE inhibitors)or angiotensin receptor blockers (ARBs) are effective at reducing progression when there is concurrent proteinuria.Target blood pressure may vary across Europe but inthe UK, one study19 showed that maintaining a blood pressure below 130/75 mmHg, correlated to a reduction in the progression of renal disease in people with type 2 diabetics with albuminuria.

It is essential that robust mechanisms are put in place inboth primary and secondary care for the early detection and management of CKD. Education is of great importance forboth health care professionals and patients.

There are many challenges ahead for educating patients about CKD. Perhaps the most important issue is how to avoid labeling of patients and how to reduce anxiety when patients are fi rst told that they have kidney disease. Prevention ofkidney disease is crucial - but essentially the managementis the same for renal disease, diabetes and cardiovascular disease - the priority is reducing cardiovascular risk.

The latest initiative in Europe is the forming of the European Kidney Health Alliance (EKHA) which is aims to raise the awareness of CKD on a European Union level. There are four major stakeholders, ISN,ERA-EDTA, EDTNA/ERCA and CEAPIR representing the multidisciplinary team and patients.

SummaryStrategies for the management of people with chronic kidneydisease need to be in place to aid the prevention and help slow down the progression of the disease. The International Society of Nephrology (ISN) has for some time had a focus on prevention and the COMGAN group believe in improving globaloutcomes of kidney disease20. The new initiative by the KidneyDisease: Improving Global Outcomes (KDIGO) group aims to

47


develop a global approach to managing the CKD epidemic. Their mission statement is “Improve the care and outcomes of kidney disease patients worldwide through promotingcoordination, collaboration and integration of initiatives to develop and implement clinical practice guidelines”. KDIGOand the ISN are now working together on developing a CKDstrategy21.

Nephrology services need to adapt to cope with the increasein the number of referrals which have been evident sincethe introduction of eGFR reporting. Renal disease is a chronic disease and as such needs a multi-disciplinaryapproach in order to manage not only the renal disease but also its cardiac and diabetic complications. This will involve the education and training of general practitioners who are the main contact point for many patients in the communityso that they feel confi dent in managing CKD stages1, 2 & 3 (without risk factors) in the community and thereby reduce the burden of referrals to the nephrology units. Developingguidelines is pivotal in addressing the current problem; however the key to success lies in the implementation process. Nurses are in a good position to take on this roleas there are clear guidelines available for managing CKD. For example in the UK, the Renal Association in collaboration with the Royal College of Physicians and GeneralPractitioners have provided a comprehensive document to support both nephrology units and community services. Many UK units have adapted these guidelines to meet thelocal community needs and demands. The introductionof such guidelines is also supported by renal teams providing education to community physicians and nurses, advising them when and how refer patients with CKD. Joint working with renal units, community health care providers, specialist service providers and patient groups is raising the awareness of CKD and removing barriers which have previously stood in the way of providing holistic patient care.

48


Within Europe there are differences in roles and responsibilities of nurses as was seen in the data from the European Network of Renal Care Associations (ENRCA) project. This group in 2004 is made up of 10 National Associations (UK, Spain, Israel, Croatia, Slovenia, Turkey, Greece, Belgium (Flanders),Italy, Portugal and Cyprus) and the EDTNA/ERCA. Theysurveyed 10% of renal units in each country to identify the task portfolio and responsibilities of nurses and allied healthcare professionals. They found that, for instance, the UK and Israel had many nurse-led services in place whilst pre-dialysis care was not usually performed by nurses in Spain. What will become evident is how CKD is managed in the future within these countries. Although many roles and responsibilities have been physician-led in the past, this is an ideal opportunity for nurses to review their way of thinkingthroughout Europe and diversify the skills of healthcare professionals.

Management of CKD requires a collaborative approach and there is a need to be creative to enable patients to receive a seamless journey of care.

Frequently asked Questions

1. Why is serum creatinine alone not a goodmeasurement of kidney function?A: Serum creatinine is affected by the level of GFR

and by factors independent of GFR, including age,gender, race, body size, diet, certain drugs, andlaboratory analytical methods

2. What is GFR?A: GFR is glomerular fi ltration rate

3. What is a normal GFR?A: More than 90 mls/min

49


4. How can I calculate eGFR?A: Laboratory measurement or download a calculator

from www.renal.orgg/ or/ www.nephron.cop m5. How does eGFR relate to kidney function?

A: It corresponds with percentage of kidney function i.e. eGFR 20mls/min = 20% kidney function

6. What is staging of CKD?A: It is defi ned by the eGFR e.g. Stage 3 kidney disease

refers to an eGFR between 30-59 mls/min7. At what stage should a patient be referred to a

Nephrologist?A: This will depend on local guidelines but generally at

stages 3-58. Where should patients referred to a Nephrologist be

managed?A: This will depend on the individual health care

system, but often it shared by the family doctor and Nephrologist

References1. Coresh J, Astor BC, Greene T, Eknoyan G, Levey A. Prevalence of

chronic kidney disease and decreased kidney function in the adult US population: Third national health and nutrition examination survey.Am J Kidney Dis 2003; 41, (1): 1-12.

2. John R, M Webb, Young A, Stevens PE. Unreferred chronic kidneydisease: A longitudinal study. Am J Kidney Dis 2004; 43; (5):825-835.

3. Lysaght MJ. Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol 2002; 13: 37-40.

4. Xue J, Ma J et al. A forecast of the number of patients with end-stage renal disease in the United States to the year 2010. J Am Soc Nephrol 2001; 12:2753-2758.

5. The Renal Association. UK Renal Registry. The sixth annual report 2004. Available at www.renalreg.com/home.htm

50


6. Anandarajah S, Tai T, de Lusignan S, Stevens P, O’Donoghue D, Walker M, Hilton S. The validity of searching routinely collected general practice computer data to identify patients with chronic kidneydisease (CKD) : a manual review of 500 medical records. NephrolDial Transplant 2005; 20, (10) :2089-2096.

7. Roderick P et al. What determines geographical variation rates of acceptance onto renal replacement therapy in England?J Health Serv Res Policy 1999; 4, (3): 139-146.

8. Drey N. The epidemiology of diagnosed chronic renal failure in Southampton in South West Hampshire Health Authority. PhD Thesis Southampton: University of Southampton, 2000.

9. Young EW, Mauger EA, Jiang KH, Port FK and Wolfe RA. Socioeconomic status and end-stage renal disease in the United States. Kidney Int 1994; 45, (3): 907-911.

10. Kissmeyer L, Kong C, Cohen J, Unwin RJ, Woolfson RG and Neld GH. Community Nephrology : audit of screening for renal insuffi ciencyin a high risk population. Nephrol Dial Transplant 1999; 14: 2150-2155.

11. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N and Roth D. more accurate method to estimate glomerular fi ltration rate from serum creatinine: a new prediction equation. Modifi cation of Diet in Renal Disease Study Group Ann Intern Med 1999;130 (6):461-79.

12. Perrone RD, Madias NE and Levey AS. Serum creatinine as an index of renal function: New insights into old concepts. Clin Chem 1992; 38:1993-1953.

13. National Kidney Foundation. K/DOQI clinical practice guidelines forchronic kidney disease: evaluation, classifi cation, and stratifi cation. Am J Kidney Dis 2002; 39 (Suppl 2):S1–246.

14. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.

15. Chronic Kidney Disease in Adults: UK CKD Guidelines for Identifi cation, Management and Referral of Adults. 2005. Available from:http//.www.renal.org/CKDguide/ckd.html

16. Levey AS, Coresh J, Balk E et al. National Kidney Foundation Practice Guidelines for chronic kidney disease: evaluation, classifi cation and stratification. Ann Intern Med 2003;139: 137–147.

17. UK Prospective Diabetes Study Group. Intensive blood –glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352 :837-853.

18. The DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med 1993; 329: 977-986.

51


19. McIntosh A, Hutchinson A, Marshall S, Barnes S, Brown V, Hooper S et al. Clinical Guidelines and Evidence Review for Type 2 Diabetes. Renal Disease: Prevention and Early Management. Sheffi eld: ScHARR, University of Sheffi eld, 2002. http://www.nice.org.uk

20. Kam-Tao Li P, Weening J, Dirks J et al. A report with consensus statements of the International Society of Nephrology 2004 Consensus Workshop on Prevention of Progression of Renal Disease, Hong Kong, June 29, 2004. Kidney Int 2005; 67 (Supp 94): S2-S7. 2005.

21. Eknoyan G, Lameire N, Barsoum R, Eckardt K, Levin A et al. The burden of kidney disease: Improving global outcomes. Kidney Int 2004; 66: 1310-1314.

54


Learning Outcomes

• To demonstrate an understanding of the different types of diagnostic investigations including urine, blood, imaging and renal biopsy tests

• To interpret results within the clinical setting

IntroductionRoutine clinical assessment involves undertakingin-depth physical examination, social, medical and medication histories. Diagnostic investigations play an important role in the assessment of the cause and severity of kidney disease. Chronic Kidney Disease (CKD) is characterised by the gradual and progressive loss of functioning nephrons and, as discussed in chapter 1, has various causes. Damage to the kidneys is usually irreversible and is often insidious in nature, taking place over many years depending on the aetiology. In most cases there are no signs or symptoms in the early stagesof CKD. However, with the introduction of routine estimated glomerular function rate (eGFR) measurement, CKD is often uncovered as an incidental fi nding during routine blood tests.

Blood TestsThe normal function of the kidneys is to excrete waste products which are a by-product of metabolism and there are various blood tests that can yield a wealth of information. The followingtable provides a guide to the normal range, an explanation about the test and how to interpret the results1,2,3,4. The normalrange for tests will vary in different countries and hospitals.

55

Diagnostic Investigations in CKD

Blo

odTe

stE

xpla

natio

n an

dIn

terp

reta

tion

of R

esul

tN

orm

alR

ange

Fast

ing

gluc

ose

Use

d to

det

ect u

ndia

gnos

ed d

iabe

tes

or a

sses

s di

abet

es c

ontro

l70

-110

mg /

dl(3

.9-5

.5 m

mol/

L)

Ure

ani

troge

n(B

UN

)

Incr

ease

d bl

ood

urea

may

indi

cate

kid

ney

dam

age.

Nor

mal

ly, u

rea

rises

in

conj

unct

ion

with

cre

atin

ine

leve

ls in

CK

D, b

ut a

t tim

es le

vels

may

rem

ain

with

in n

orm

al l

imits

whe

n th

e cr

eatin

ine

leve

ls a

re h

i gh.

A s

igni

fi can

t el

evat

ed u

rea

in a

pre

viou

sly

heal

thy

pers

on c

an o

ccur

in a

cute

ren

alfa

ilure

due

to s

ever

e in

fect

ion

or m

ajor

cru

sh in

jurie

s

Som

e ca

uses

of n

on-k

idne

y re

late

d hi

gh u

rea

leve

ls:

• H

igh

prot

ein

diet

and

/or s

trenu

ous

exer

cise

•C

erta

in d

rugs

(e.g

. cor

ticos

tero

ids,

tetra

cycl

ine)

•G

astro

inte

stin

al tr

act h

aem

orrh

age

• P

rolo

nged

mal

nutri

tion

and/

or d

ehyd

ratio

n

Adu

lt:

8-18

mg/

dl(2

.5-6

.4 m

mol/

L)

Cre

atin

ine

Cre

atin

ine

is n

ot a

goo

d m

arke

r ofC

KD

as

a 50

% lo

ss o

f kid

ney

func

tion

occu

rs b

e for

e an

y ev

iden

ce o

f an

elev

ated

cre

atin

ine

is s

een

Oth

er c

ause

s of

ele

vate

d cr

eatin

ine:

• A

gein

g pr

oces

s as

the

kidn

eyfu

nctio

n de

clin

es b

y 10

% p

er d

ecad

efro

m th

e ag

e of

40

• H

igh

mea

t con

tent

die

ts•

Peo

ple

with

a la

rge

mus

cle

mas

s

Adu

lt:

0,6 - 1

.2 mg

/dl(5

0 - 11

0 �mo

l/L)

Sligh

t var

iation

isex

pecte

d betw

een

m ale

and f

emale

56


Blo

odTe

stE

xpla

natio

n an

dIn

terp

reta

tion

of R

esul

tN

orm

alR

ange

Pot

assi

umH

yper

kala

emia

yp, m

ay o

ccur

in:

•K

idne

ydi

seas

e•

Bur

ns•

Insu

lin d

efi c

ienc

y•

Pos

t-tra

umat

ic c

ondi

tions

(sur

gica

l and

acc

iden

tal)

• D

isse

min

ated

intra

vasc

ular

coa

gula

tion

(DIC

)•

Dia

bete

s m

ellit

us•

Sid

e ef

fect

of s

ome

med

icat

ions

e.g

. AC

E in

hibi

tors

Hyp

okal

aem

iayp

may

occ

ur in

:•

Per

sist

ent v

omiti

ng a

nd d

iarr

hoea

•R

enal

tubu

lara

cido

sis

• D

iure

tic tr

eatm

ent

• E

xces

s in

sulin

(cau

ses

an in

crea

se u

ptak

e of

pot

assi

um)

3.5 -

5.0 m

Eq/L

(3.5

- 5.0

mmol/

L)

Sod

ium

Hyp

erna

trem

iayp

can

occu

r in:

• R

educ

ed fl

uid

inta

ke a

nd d

ehyd

ratio

n•

Dia

bete

sin

sipi

dus

• M

etab

olic

acid

osis

• E

xces

sive

infu

sion

of i

soto

nic

fl uid

s in

rena

l im

pairm

ent

Hyp

onat

rem

iayp

can

occu

rin:

• C

ases

of e

xces

s bo

dyfl u

id•

Bur

ns•

Vom

iting

, and

diar

rhoe

a•

Nep

hriti

s•

Dia

betic

acid

osis

135 -

145 m

Eq/L

(135 -

145 m

mol/L

)

57


Arte

rial p

HTh

e pH

is m

easu

red

via

arte

rial b

lood

and

is a

mea

sure

of t

he n

umbe

r of

hydr

ogen

ions

and

indi

cate

s th

e ac

idity

or a

lkal

inity

of t

he b

lood

7.35 -

7.45

pH un

its

Bica

rbon

ateB

uffe

rs a

re c

hem

ical

sub

stan

ces

that

kee

p th

e pH

of b

lood

with

in a

nor

mal

ra

nge.

Bic

arbo

nate

is th

e m

ost i

mpo

rtant

buf

fer i

n th

e bl

ood

22 -

30 m

Eq/L

(22 - 3

0 mmo

l/L)

Uric

aci

dE

leva

ted

uric

aci

d m

aybe

see

n in

:•

Gou

t•

Arth

ritis

• K

idne

y di

seas

e•

Cer

tain

diu

retic

s•

Acu

te s

hock

and

pre

-ecl

amps

ia

2.0 -

7.0 m

g /dl

(120 -

420 �

mol/L

)Sl

ight v

ariat

ion is

expe

cted b

etwee

n m a

lean

dfem

ale

Tota

lpr

otei

nsH

yper

prot

eina

emia

ypp

with

a n

orm

al a

lbum

in/g

lobu

lin r

atio

may

occ

ur i

n hy

povo

laem

ia

Hyp

erpr

otei

naem

iayp

pw

ith a

low

alb

umin

/glo

bulin

rat

io m

ay s

ugge

st a

n au

toim

mun

e di

seas

e (e

.g.

SLE

, sh

ock,

lon

g-te

rm i

nfec

tion

or m

ultip

le

mye

lom

a)

Hyp

opro

tein

aem

iayp

pre

late

d w

ith lo

w a

lbum

in le

vels

of <

35 g

/l m

ay b

e se

en

in p

atie

nts

who

are

mal

nour

ishe

d an

d in

nep

hrot

ic s

yndr

ome

whe

re la

rge

amou

nt o

f pro

tein

leak

s in

to th

e ur

ine.

It is

als

o pr

esen

t in

liver

dis

ease

, bu

rns

and

haem

orrh

age

6.0 -

8.0 g /

dl(6

0 - 80

g/L)

58


Blo

odTe

stE

xpla

natio

n an

dIn

terp

reta

tion

of R

esul

tN

orm

alR

ange

Alb

umin

Hyp

eral

bum

inae

mia

ypm

ay b

e as

soci

ated

with

hyp

ovol

aem

ia

Hyp

oalb

umin

aem

iayp

is fr

eque

nt in

ren

al p

atie

nts

with

poo

r di

etar

y in

take

, on

per

itone

al d

ialy

sis

due

to p

rote

in l

oss

in d

ialy

sate

. It

is a

com

mon

fe

atur

e in

nep

hrot

ic s

yndr

ome

4.0 -

6.0 g/

dl40

- 60

g/L

Tota

lca

lciu

mH

yper

calc

aem

iayp

may

ind

icat

e hy

perp

arat

hyro

idis

m,

or m

ay b

e du

e to

di

uret

ics

(thia

zide

s).

Its h

igh

leve

l can

res

ult

in r

enal

cal

culi

and

rena

l t u

bula

rdis

ease

Hyp

ocal

caem

iayp

may

occ

ur in

cer

tain

met

abol

ic d

isor

ders

(e.

g. d

efi c

ient

pa

rath

yroi

d ho

rmon

e) a

nd m

ay b

e du

e to

pho

spha

te re

tent

ion

in c

hron

ic

rena

l fai

lure

8.8 -

10.3

mg/dl

2.20 -

2.58

mmo

l/L

Phos

phor

ous

Hyp

erph

osph

atae

mia

ypp

pca

n be

see

n in

con

junc

tion

with

hyp

ocal

caem

ia in

va

rious

type

s of

rena

l fai

lure

Hyp

opho

spha

taem

iayp

pp

occu

rs

in

rena

l tu

bula

r di

seas

e re

sulti

ng

in

oste

omal

acia

2.4 -

4.1 m

g/dl

(0.8 -

1.4 m

mol/L

)

Alka

line

p hos

phata

seLe

vels

are

rais

ed w

hen

bone

dis

ease

dev

elop

s in

CK

D. I

t var

ies

with

age

and

gend

er

Oth

er c

ondi

tions

ass

ocia

ted

with

ele

vate

d le

vels

are

see

n in

you

ngch

ildre

n ex

perie

ncin

g ra

pid

grow

th,

in p

regn

ancy

,liv

er a

ndin

test

inal

ulce

rativ

edi

seas

e

30 -

120 (

37ºC

)Un

its/L

59


Para

thyr

oidho

rmon

e(P

TH)

PTH

is

prod

uced

in

the

para

thyr

oid

glan

d an

d re

gula

tes

extra

cellu

lar

calc

ium

It ris

es p

rogr

essi

vely

with

dec

linin

g ki

dney

func

tion

Varie

s acc

ordin

g to

assa

y meth

od

Lipids

and

tri glyc

eride

sD

yslip

idae

mia

is c

omm

on in

CK

D,

espe

cial

ly in

pat

ient

s w

ith n

ephr

otic

sy

ndro

me

or a

kid

ney

trans

plan

t. Th

e 3

maj

or ty

pes

of c

hole

ster

ol a

re L

ow

Den

sit y

Lip

opro

tein

(LD

L), H

igh

Den

sity

Lip

opro

tein

(HD

L) a

nd V

ery

Low

D

ensi

t y L

ipop

rote

in (V

LDL)

Ele

vate

d le

vels

(exc

ept H

DL)

are

ass

ocia

ted

with

car

diov

ascu

lar e

vent

s,

a m

a jor

cau

se o

f mor

bidi

ty a

nd m

orta

lity

Tota

l cho

leste

rol:

< 20

0 mg/d

l(d

esira

ble)

LDL:

<130

mg/d

l(d

esira

ble)

HDL:

>60 m

g/dl

(des

irable

)

Trig

lycer

ides

:<1

50 m

g/dl

(des

irable

)

CR

PTh

e pr

esen

ce o

fCR

P us

ually

indi

cate

s ac

ute

infl a

mm

atio

n. P

ositi

ve re

sults

m

ay a

lso

occu

r in

late

pre

gnan

cy o

r with

the

use

of o

ral c

ontra

cept

ives

Nor

mal

val

ueis

<5m

g /L

Ser

umel

ectro

-ph

ores

is

The

fi ve

prot

ein

grou

ps m

ove

at d

iffer

ent s

peed

s in

an

elec

trica

l fi e

ld a

nd

this

tes

t m

easu

res

the

rate

of

mov

emen

t. It

is m

ost

com

mon

ly u

sed

to

dete

ct m

ultip

le m

yelo

ma

Nor

mal

pat

tern

60


Full Blood Count (FBC) / Complete Blood Count (CBC)

count /White bloodcell count

(WBC)

Leukocytosis, (high WBC count)is associated with:

• Leukaemia• Infectious diseases• Infl ammatory disease (allergy

or rheumatoid arthritis)

Leukopenia (low WBC count) canbe due to:

• Systemic lupuserythematosus

• Bone marrow failure• Liver and spleen diseases

4,500 - 10,000 / mm3

Haemoglobin(Hb)

The RBCs should be normocytic(normal shape) and normochromic(normal colour). However iniron defi ciency anaemia theyare microcytic (small) andhypochromic (pale)See chapter 4 on anaemiamanagement

Male:14.5 - 16.0 g/dl

Female:13.0 - 15.5 g/dl

Hb level in CKD7should be > 11 g/dl in

all patients

Haematocrit(HCT)

The haematocrit will be low inrenal anaemia, in conjunction witha low haemoglobin level

Male:39 - 49 %Female:33 - 43 %

Ferritin In renal failure, levels should bemaintained above 100 ng/mL -see Chapter 4

18 - 300 ng/mL(18 - 300 �g/L)

Vitamin B12 Its defi ciency causes macrocyticanaemia

150 - 1000 ng/L

61


Coagulation screeningsBleeding

timeProlongation occurs in patientswith vascular abnormalities,thrombocytopenia andthromboasthenia

3 - 6 minutes(Ivy method)

ActivatedPartial

ThromboPlastin Time

(APTT)

A prolonged APTT occurs in avariety of disorders (e.g.liver cirrhosis, disseminatedintravascular coagulation (DIC).Patient on anticoagulant therapymay have an APTT time of 1.5 to2.5 times control values

22 - 37 seconds(Values vary

between labs.)

Plateletcount /

thrombocytecount

Use to check for any clottingabnormality

130,000 - 400,000/mm3

62


SerologyAuto

antibodies egantinuclearantibodies:ANA/ANCAAnti-GBM

The measurement of abnormalantinuclear antibodies amount andpattern provides a diagnosis forcertain diseasesPositive anti-nuclear antibodiesare seen in systemic lupuserythromatosus or sclerodermaPositive anti-neutrophil cytoplasmicantibodies (ANCA): seen in systemicand renal vasculitisPositive anti-glomerular basementmembrane (Anti-GBM): verysuggestive of Goodpasture’ssyndrome

Negative isnormal

HBsAg, HIVHCV

Routine performed as part of renalscreening

Negative isnormal

Immuno-globulins

These are commonly referred to asantibodies and IgG, IgM and IgAare measured to identify certainautoimmune diseases and allergiese.g. IgA nephropathy, Multiplemyeloma etc

IgG 5.5 - 16.5 g/L

IgA 0.8 - 4 g/LIgM 0.4 - 2 g/L

Urine TestsUrinalysis plays an essential part in the assessment of anypatient with CKD. The assessment should include observation of the physical appearance of the urine together with dipstick testing and further laboratory analysis. Dipstick tests have mostly replaced cumbersome laboratory testing for routine rapid clinical work, however, machines are also available to

63


perform urinalysis with good reliability. A laboratory microscopy,culture and sensitivity (MC&S) test can identify and detect the presence of any cells, casts, crystals or bacteria in the urine.

Why is urinalysis important?

• To aid in the diagnosis of kidney disease• To screen a population for asymptomatic kidney

disease• To monitor the progression of disease• To monitor the effectiveness or complications of therapy• To detect diabetes, urine infection and other urinary tract

problems such as calculi or cancers5

When undertaking a urine assessment it is important to observe the appearance, smell and to undertake a dipstick urinalysis. In some situations it may be necessary to measure the volume of urine produced over a 24 hour period. The following provides a brief overview of normal and abnormal fi ndings when undertaking a urinalysis.

Observational AssessmentOdour: Abnormal odour occurs most often due toincorrect handling and storage or if there is an infection. However, eating certain foods can also cause an abnormal and distinctive odour e.g. asparagus. In the presence ofexcess ketones in the blood (ketotic state), the urine will have a distinctive sweet or fruity smell (although a sizeable percentage of the population is unable to detect this smell).This is especially important in the diagnosis of patients with diabetic ketoacidosis, a life threatening condition.

Colour: Urine normally appears pale to dark yellow dependingon its concentration, however it can appear darker if left to stand for too long.

64


Table 1: Urine colour6,7

Colour CausesPale • High fl uid intake

• Polyuria (renal tubules cannot reabsorb fl uid)• Diabetes insipidus• Diabetes mellitus

Turbid/cloudy • Bacterial infection/pus• Crystallization of salts e.g. calcium, urate

and oxalate

Red or darkurine.

Blood inthe urine

(haematuria)- vary from

smoky to teacolour and varyin strength e.g.bright or dark

• Urinary tract infections• Trauma to the kidney• Internal damage to the glomeruli in the

kidney• Smoky: Can indicate bleeding from the

kidney• Eating beetroot or other vegetable dyes.• Porphyria• Menstruation• Medications e.g. rifampicin

Foam or frothNormal urine

will foam slightlywhen stored ina container and

shaken

• Heavy proteinuria (lots of white foam whencontainer shaken)

65


Volume::The normal amount of urine collected within a 24 hour period of time can range from 500mls/day to 1500mls/day. Abnormal amounts are as follows:

Anuria: failure or inability of the kidneys to produce urine: <50-100 ml per dayOliguria: where <400 ml of urine is produced per dayPolyuria: is a condition of excessive production of urine >2.5L/day

Dipstick/UrinalysisDipstick tests provide a cheap and simple way to assess various substances in the urine. They are only reliable when the manufacturer’s instructions are followed e.g. length of time dipping in urine, leaving to stand before reading the result, keeping the lid on when not in use. Inaccuracies may also be caused by patient factors such as:

• Menstruation e.g. positive result for blood• Medications, such as diuretics or high doses of vitamin

C (ascorbic acid) taken with certain antibiotics (such as tetracycline)

• Some antibiotics, such as erythromycin and trimethoprim. Radiological contrast material6,7

Normal urine is made up of 95% water and 5% solids, mainly urea and sodium chloride. It is slightly acidic, with a pH of 6.0 and the normal specifi c gravity is 1.010-1.030 g/ml.

66


Tabl

e 2:

Dip

stic

k te

st6,

7

Sub

stan

ceIn

terp

reta

tion

pH(a

cidity

or a

lkalin

ity o

f the

urin

e)

The

norm

al ra

nge

is 4

.5 -

8.0

depe

nden

t on

die t

Infl u

ence

d by

die

t, re

cent

eat

ing,

bac

teria

l in

fect

ion

and

stor

age

time. •

Aci

dic

p HpH

< 5

= ri

sk o

f uric

aci

d st

ones

• A

lkal

ine

p HpH

> 7

= c

omm

only

foun

d in

veg

etar

ians

pH>

8 =

rena

l tub

ular

aci

dosi

s or

urin

e in

fect

ion

Spe

cifi c

Gra

vity

(SG

)(g/

ml)

Mea

sure

sso

lute

load

in th

eur

ine.

Isa

usef

ul in

dica

toro

fre

nal c

once

ntra

ting

abili

ty

>1.0

30(n

o pr

otei

nuria

or g

lyco

suria

) - ra

diog

raph

ic c

ontra

st>1

.020

Usu

ally

in v

olum

e de

plet

ion

1.00

0 - 1

005

(fi xe

d S

G) -

occ

urs

in d

iabe

tic in

sipi

dus

May

be

unre

alia

ble

if:•

Wat

er a

nd e

lect

roly

te im

bala

nce

is p

rese

nt•

Low

pro

tein

diet

s•

Chr

onic

live

r dis

ease

•P

regn

ancy

Glu

cose

A po

sitiv

e re

sult

is in

dica

tive

of h

yper

glyc

aem

ia o

r a lo

w re

nal g

luco

set h

resh

old

67


Pro

tein

• N

orm

al u

rine

shou

ld n

ot c

onta

in m

ore

than

a tr

ace

of p

rote

in. I

tis

pos

sibl

e fo

r lev

els

of p

rote

inur

ia u

p to

150

mg/

24 h

our b

efor

ean

y pr

otei

n sh

ows

up o

n a

dips

tick

• P

ersi

sten

t sm

all i

ncre

ases

in p

rote

in o

r alb

umin

in th

e ur

ine

are

an e

arly

sig

n of

kid

ney

inju

ry a

nd o

ften

prec

ede

any

dete

ctab

le

chan

ge in

the

seru

m c

reat

inin

e co

ncen

tratio

n or

eG

FR•

Per

sist

ently

hig

h le

vels

of p

rote

in d

amag

e th

e ki

dney

and

cont

ribut

e to

pro

gres

sive

loss

of k

idne

yfu

nctio

n; th

is is

parti

cula

rl y e

vide

nt in

pat

ient

s w

ith p

rote

inur

ia le

vels

gre

ater

than

1gm

/day

• H

i gh

leve

ls o

f pro

tein

uria

are

alw

ays

impo

rtant

; how

ever

in

term

itten

t low

leve

ls o

f pro

tein

uria

ma y

not

be

as s

igni

fi can

t. S

ome

exam

ples

of c

ause

s of

inte

rmitt

ent p

rote

inur

ia a

re:

• D

ehyd

ratio

n•

Em

otio

nals

tress

•Fe

ver

•H

eati

njur

y•

Infl a

mm

ator

y pr

oces

s•

Inte

nse

activ

ity•

Mos

tacu

te il

lnes

ses

•O

rthos

tatic

(pos

tura

l) di

sord

er

68


Nitr

ites

The

pres

ence

of n

itrite

s us

ually

indi

cate

s an

infe

ctio

n.

Ket

ones

The

pres

ence

of k

eton

es m

ay b

e se

en in

hyp

erem

esis

of p

regn

ancy

,st

arva

tion

orke

toac

idos

is

Bili

rubi

nU

rine

does

not

nor

mal

ly c

onta

in a

ny b

iliru

bin,

onl

y sm

all a

mou

nt a

s ur

obili

noge

n. It

app

ears

in th

e pr

esen

ce o

f liv

er d

isea

se o

r bi

le d

uct

obst

ruct

ion

Blo

od•

A po

sitiv

e te

st in

dica

tes

haem

atur

ia, h

aem

oglo

binu

ria o

r m

yogl

obin

uria

•Fa

lse

posi

tive

read

ings

may

bedu

e to

con

tam

inat

ion

with

men

stru

albl

ood

• H

aem

atur

ia is

defi

ned

as

>3 R

BC

/hpf

of c

entri

fuge

d se

dim

ent

unde

r mic

rosc

ope

• Fa

lse

posi

tives

can

be

incr

ease

d by

deh

ydra

tion

whi

chco

ncen

trate

s th

e nu

mbe

r of R

BC

s pr

oduc

ed a

nd e

xerc

ise

•Fa

lse

nega

tives

may

occ

ur if

the

urin

e is

left

to s

tand

for s

ever

al

hour

s pr

ior t

o m

icro

scop

y as

dur

ing

this

tim

e th

e re

d bl

ood

cells

m

a y ly

se

Sub

stan

ceIn

terp

reta

tion

69


Mic

roal

bum

in•

The

pres

ence

of s

mal

l am

ount

s of

alb

umin

is o

f im

porta

nce

as

a pr

edic

tor o

f kid

ney

dam

age

and

is th

e fi r

st in

dica

tor o

f kid

ney

dise

ase

in d

iabe

tics

• M

icro

albu

min

uria

is d

efi n

ed a

s pe

rsis

tent

alb

umin

/cre

atin

ine

ratio

s >2

.5m

g/m

mol

(mal

e) o

r >3.

5mg/

mm

ol(fe

mal

e) o

n 2-

3 oc

casi

ons

or u

rinar

y al

bum

in e

xcre

tion

of20

-200

� g/m

in•

Test

ing

shou

ldbe

avo

ided

durin

g ac

ute

illne

ss o

r men

stru

atio

nto

redu

ce th

e in

cide

nce

o ffa

lse

read

ings

8,9

Mic

roal

bum

inur

ia m

ay in

dica

te th

e fo

llow

ing:

•su

b-cl

inic

alca

rdio

vasc

ular

dise

ase

• va

scul

ar e

ndot

helia

l dys

func

tion

• pr

o gno

stic

mar

ker f

or k

idne

y di

seas

e:-

in d

iabe

tes

mel

litus

- in

hyp

erte

nsio

n8,9

70


Other specifi c urine testsOsmolality: normal range 500-800 mosmolkg1.This provides an indication of the kidneys’ ability to concentrate and dilute the urine and provides a more accurate assessment of renal tubular concentrating ability than the specifi c gravity.A urine osmolality test should preferably be done on an earlymorning urine sample as water depletion during the nightshould concentrate the urine.

Protein/Creatinine Ratio (PCR)Assessment of urinary protein can be carried out on a single,preferably early morning, urine sample. Several studies have shown that, as patients fi nd the accurate provision of a 24-hour urine collection very diffi cult, the PCR to be more accurate than the “gold standard” of the 24-hour urine protein measurement. The PCR will not detect microalbuminuria. A PCR >100 mg/mmol (1g/day) requires specialist renal management and these patients should be referred to a nephrologist. Likewise ifthe PCR is >45 mg/mmol but the patient also has microscopic haematuria they should also be referred10.

It is important to note that in nephrotic syndrome, heavyproteinuria is a main clinical feature with proteinuria >3.5 g/day (150 mg/24 hr). Other features are:

• Peripheral oedema, especially around the eyes, feet, and hands

• Hypoalbuminaemia: low levels of protein in the blood <30 g/l

• Hypercholesterolemia, specifi cally elevated low densitylipoproteins

• Coagulation abnormalities

Bence-Jones Protein analysisThis is ideally tested on an early morning urine sample. Apositive result may indicate the presence of multiple myeloma

71


in 70-80% of cases and is a useful diagnostic tool. It can also be seen in amyloidosis, Waldenstrom’s macroglobulinaemia,cryoglobulinaemia and chronic lymphocytic leukaemia6.

Myoglobin levelsThis is ideally tested on an early morning urine sample. Myoglobin in the urine is found in conditions such as rhabdomyolysis, the breakdown of muscle tissue usually due to a crush injury or trauma to the area, seizures or severe exercise. The myoglobin is released from the muscle tissue into the bloodstream and is nephrotoxic as when it is fi ltered by the kidneys it causes blockages in the renal tubules and leads to acute tubular necrosis6.

Urinary CatecholaminesUrinary catecholamines such as adrenaline or noradrenaline or their metabolites such as vanylmandelic acid (VMA) can be tested for in a 24-urine sample. A level twice the upper limit of normal is virtually diagnostic of phaeochromocytoma,however several 24-hour samples may be needed if there is clinical suspicion of this tumour as levels fl uctuate greatly.Hypertension may cause mildly elevated results. When collecting the samples it is necessary to keep the container refrigerated. Certain foods including coffee, tea, bananas, chocolate, cocoa, citrus fruits, and vanilla can increase urinarycatecholamine and these should be avoided for several daysprior to the test. Centrally acting sympathomimetic drugs such as methyl dopa will also affect the results as may acute stress and vigorous exercise8.

Microscopy, Culture and SensitivityMicroscopy of the centrifuged urinary sediment will show up bacteria, blood cells, casts and crystals. Urinary culture will

72


identify bacterial and fungal urinary infection which can then be tested for sensitivity to various antibiotic and antifungalagents.

Bacteria: Bacterial urinary tract infections are common. Predisposing factors include:

• Gender - women have a shorter urethra and are more susceptible to urinary tract infections (UTI)

• Sexually active women• Pregnancy• Incomplete emptying of the bladder• Immunosuppression

e.g. HIV patients, transplant patients• Diabetes mellitus• Vesico-ureteral reflux• Urethral catheterisation

A signifi cant fi nding is bacteria >100 000 / ml. If multiple organisms are seen, then a contaminated sample is likely.

Table 3: Most common causes of UTIs11

Bacteria Normally present in

Escherichia coli (E. Coli) GI tract, faeces

Staphylococcusepidermis (S. epidermis) Skin, external genital tract

Proteus species GI tract, faeces, hospital environment

Klebsiella species GI tract, faeces, external genital tract

Pseudomonasaeruginosa

GI tract, faeces (rare), hospital environment

73


Blood cells (erythrocytes)When intact, they are biconcave disks with smooth appearance. Abnormal is to fi nd >3 per high power fi eld. When the erythrocytes are distorted, irregular or misshaped, they are know as dysmorphic blood cells and usually suggest glomerulardisease, especially when accompanied by proteinuria and blood casts. Red blood cells may be seen in the following:

• Acute tubular necrosis• Upper and lower urinary tract infections• Nephrotoxicity• Tumours• Kidney trauma• Renal calculi• Renal infarcts• Physical stress

Other causes not kidney related are:• Trauma from urinary catherization• Menstruation• Excessive exercise can cause microscopic haemeturia

and is common, it is advisable to re-test in 48-72 hrs

White cells (leukocytes)These are disks with granular cytoplasm and nucleus. Pathological fi ndings are indicated if white cells are >5 per high power fi eld. The presence of increased white cells in the urine is termed pyuria and indicates infl ammation or infectionof the urinary tract. The presence of eosinophils may indicate an allergic interstitial nephritis. White cells can be presents as a result of a contaminant from the vagina or urethral meatus.

74


Epithelial cellsThese cells line all of the urinary and genital tracts. The presence of squamous epithelial cells implies contamination, transitional epithelial cells are normal.

Renal Epithelial cellsThey are the most clinically important of the epithelial cells that may be found in urine and result from a variety of disorders, especially acute tubular necrosis, viral infections involving the kidney and in renal transplant rejection.

CastsThe discovery of casts in the urine sediment is the result ofsolidifi cation of protein within the lumen of the kidneys tubules. At the time of cast formation, any material present within the tubule e.g. cells, fat, or bacteria is trapped within the cast matrix7,11.

Type Cause

Hyaline castsalso known asTamm-Horsfall

proteins

These come from the renal tubules and are theleast important of casts. They may be seen without signifi cant proteinuria. They are often found in people who undertake strenuous exercise, feverand the use of diuretics. Large numbers are related with moderate or severe renal disease andmay be seen in pyelonephritis

Granular orcellular

May be seen in renal parenchymal disease. Their quantifi cation and progression are of greatimportance in diagnosis

Red BloodCells

Indicates bleeding of renal origin oftenglomerulonephritis. However are also seen in patients who participate in contact sports

Leukocyte Their fi nding indicates infl ammation/ infection. Maybe indicative of interstitial nephritis, pyelonephritisor glomerulonephritis

75


CrystalsIt is important to interpret the presence of crystals in conjunctionwith urinary pH and concentration.

Abnormal forms may indicate metabolic disorders, such as the presence of cystine crystals in the urine of people with cystinuria, an inherited metabolic condition. In acidic uric the presence of uric acid crystals and elevated serum uric acid may be associated with gout. Triple phosphate crystals are associated with an alkaline pH and infection.

CultureMicrooganisms are identifi ed after culturing the urine for 24/48 hours. A gram stain will determine the exact organisim and alsowhich antibiotics the organism is sensitive and resistent to.

CytologyA cytology exam of urine is used to detect cancer and infl ammatory diseases of the urinary tract. Collection of a “clean-catch” (midstream) urine sample is required.

Kidney Function Tests

EstimatedGlomerular

fi ltrationrate

(eGFR)(GFR) /

In healthy individuals, from 40 years of ageonwards, GFR diminishes at about 10 ml/min per decade

• eGFR should not be used as a marker of kidney function in acute renalfailure patients

Non-renal causes of increased eGFR:• High protein diet• Diurnal variation• Pregnancy

Non-renal causes of decreased eGFR:• Low protein diet• Liver disease• Ageing

See Chapter 2 for eGFR calculation and classifi cations of CKD

70 -125 ml/min

76


Imaging TestsThey are diagnostic methods in medicine that use certain techniques to produce internal images of the body. The techniques employed are:

• X-rays• Sound waves• Magnetic fi elds• Radioactive particles

These techniques work on the principle that rays, sound waves and particles interact differently with various types of tissues. They are detected and converted into images after passingthrough body tissues. Contrast agents are sometimes used in conjunction with X-ray tests to enhance better images. In nephrology practice, imaging tests are employed accordingto their specifi c capability to detect structural or functionalproblems. However, when there is renal damage, caution istaken in choosing the type of imaging test to confi rm diagnosis.This is because the contrast agent used in some of these tests may further worsen the already impaired renal function.Caution should be taken in all investigations involving x-raysand contrast media if a woman is possibly pregnant and all patients should be asked if they suffer from any allergies (e.g.iodine) or asthma.

77


Des

crip

tion

and

Obj

ectiv

e of

Use

: Im

agin

gTes

ts6,

8,12

,13

Test

Indi

catio

nsP

reca

utio

ns

X-r

ay /

radi

ogra

phP

lain

abd

omin

al x

-ray

s ca

n sh

ow th

e co

ntou

r of

kid

neys

, ure

ters

and

bla

dder

(K

UB

). It

is

usef

ul in

the

initi

al a

sses

smen

t of

the

siz

e,

shap

e, p

ositi

on a

nd th

e pr

esen

ce o

f one

or

two

kidn

eys.

Lik

ewis

e, o

f any

abn

orm

aliti

es,

espe

cial

ly k

idne

y ca

lcul

i

• All

wom

en s

houl

d be

ask

ed if

they

are

pr

egna

nt o

r cou

ld b

e pr

egna

nt

Intra

veno

uspy

elog

raph

y(IV

P)/

Intra

veno

usur

ogra

phy

(IVU

)

A co

ntra

st m

ediu

m (u

sual

ly io

dine

bas

ed) i

s in

ject

ed in

to t

he v

ein

and

ente

rs t

he b

lood

st

ream

. It

colle

cts

in t

he k

idne

ys a

nd t

he

urin

ary

tract

ou

tlini

ng

the

who

le

urin

ary

colle

ctin

g sy

stem

. X-r

ayfi l

ms

are

then

take

n at

inte

rval

s an

d th

e pr

ogre

ss o

f the

con

trast

dy

e is

obs

erve

d. U

sed

to s

tudy

the

kidn

eys

(cal

yces

and

pel

vis)

, the

ure

ters

and

urin

ary

blad

der

•Che

ckfo

r alle

rgie

s to

con

trast

age

nt,

as th

ere

is a

pot

entia

l for

an

alle

rgic

anap

hyla

ctic

reac

tion

• Cau

tion

is ta

ken

in w

omen

who

may

be p

regn

ant;

they

mus

t not

ify th

era

diol

ogis

t• C

ontra

st m

edia

is n

ephr

otox

ic. I

n th

ose

with

kno

wn

CK

D, k

idne

yfu

nctio

n sh

ould

be

che

cked

pos

t pro

cedu

re. A

cute

rena

lfa

ilure

may

resu

lt af

ter t

he p

roce

dure

. If

poss

ible

patie

nts

shou

ld in

crea

se o

ral

fl uid

inta

ke a

nd u

rinar

y ou

tput

sho

uld

bem

onito

red

78


Test

Indi

catio

nsP

reca

utio

nsU

sefu

l to

dete

ct:

• re

nalc

alcu

li•

enla

r ged

pro

stat

e•

tum

ours

in th

eki

dney

, ure

ters

or u

rinar

ybl

adde

r

• Fol

low

loca

l pol

icie

s fo

rfas

ting

and

bow

el p

repa

ratio

n. U

sual

l y in

clud

esa

mild

laxa

tive

to b

e ta

ken

the

nigh

tbe

fore

the

test

tocl

ear t

hebo

wel

whi

chw

ill a

llow

for a

dequ

ate

visi

bilit

y of

the

urin

ary

syst

em

Ret

rogr

ade

p yel

ogra

phy

A cy

stos

cope

is

inse

rted

into

the

ure

thra

an

d a

smal

l ure

teric

cat

hete

r is

pas

sed

in a

re

trogr

ade

man

ner

into

the

kidn

ey. C

ontra

st

me d

iais

the

nin

ject

ed t

hrou

gh t

he c

athe

ter

into

the

pel

vis

o f t

he k

idne

ys a

nd u

rete

r. X

-ra y

s ar

e th

en ta

ken.

Use

d to

out

line

calc

uli,

cal y

ceal

def

ects

and

tum

ours

in th

e ur

eter

or

rena

l pel

vis

Itca

nal

sobe

done

a fte

ran

IV

P or

ultra

soun

d to

defi n

ede

form

ities

such

ashy

dron

ephr

osis

• The

pat

ient

nee

ds to

be

nil b

y m

outh

fo

r 6 h

ours

(che

ck lo

cal p

olic

y) a

s it

is

usua

llydo

ne u

nder

gene

ral a

naes

thet

icin

an

oper

atin

g th

eatre

.Writ

ten

cons

ent

is re

quire

d• A

fter t

he p

roce

dure

, pat

ient

s sh

ould

be

advi

sed

toch

eck

thei

rurin

e fo

rsi

gns

o f a

ny b

lood

(hae

mat

uria

), an

dno

ti fy

if th

ey h

ave

a fe

ver o

r pai

n. If

not

cont

rain

dica

ted,

the

patie

nt s

houl

d be

enco

ura g

ed to

drin

k pl

enty

of w

ater

to

avoi

d ur

inar

y in

fect

ion.

Pro

phyl

actic

ant ib

iotic

may

be o

rder

ed•C

ontra

st m

edia

is n

ephr

otox

ic. I

n th

ose

with

kno

wn

CK

D, k

idne

yfu

nctio

n sh

ould

be c

heck

ed p

ost p

roce

dure

. Acu

te re

nal

failu

re m

a y re

sult

afte

r the

pro

cedu

re. I

fpo

ssib

le p

atie

nts

shou

ldin

crea

se o

ral

fl uid

inta

ke a

nd u

rinar

y ou

tput

sho

uld

be

mon

itore

d

79


Ren

alar

terio

-gr

aphy

/ ren

al

ang i

ogra

m

Ang

iogr

am in

volv

es th

e in

ject

ion

of c

ontra

st

me d

ium

into

a b

lood

ves

sel t

o ca

rry

out

X-

ray

exam

inat

ion.

Use

ful i

n di

agno

sing

ren

al

arte

r y

sten

osis

, tu

mou

rs

and

inju

ries

o fv e

ssel

s

• Prio

r to

the

test

, ant

icoa

gula

nt th

erap

ysh

ould

be w

ithhe

ld a

ccor

ding

to m

edic

alin

stru

ctio

n•W

ritte

n co

nsen

t is

nece

ssar

y.P

atie

ntsh

ould

be

info

rmed

of a

ny re

stric

ted

activ

ity a

fter t

he p

roce

dure

and

to

repo

rt of

any

hae

mat

oma

at th

e si

te o

fpu

nctu

re o

r any

hae

mat

uria

• Con

trast

med

ia is

nep

hrot

oxic

. In

thos

ew

ith k

now

n C

KD

, kid

ney

func

tion

shou

ld

be c

heck

edpo

stpr

oced

ure.

Acu

te re

nal

failu

re m

ay re

sult

afte

r the

pro

cedu

re. I

fpo

ssib

le p

atie

nts

shou

ldin

crea

se o

ral

fl uid

inta

ke a

nd u

rinar

y ou

tput

sho

uld

bem

onito

red

Abd

omin

alU

ltras

ound

scan

/so

nogr

aphy

Aid

s in

the

dia

gnos

is o

f ki

dney

dis

ease

by

defi n

ing

the

kidn

eys

size

, ec

hoge

nici

ty,

pres

ence

or

ab

senc

e of

h y

dron

ephr

osis

,le

sion

s an

d c y

sts.

It is

als

o us

ed to

gui

de th

e op

erat

or in

rena

l bio

psy

Non

e

80


Test

Indi

catio

nsP

reca

utio

nsC

ompu

ted

Tom

ogra

phy

(CT)

sca

n /

com

pute

d ax

ial

tom

ogra

phy

(CAT

) sca

n

Sho

ws

in d

etai

l th

e re

nal

anat

omy

and

itsad

jace

nt

stru

ctur

es.

The

use

of

cont

rast

enha

nces

the

vis

ibili

ty o

f th

e re

nal

corte

xfro

m t

he m

edul

la.

It is

the

tes

tof

choi

ce in

the

stud

y of

rena

l mas

s an

d re

nal t

raum

a

• If c

ontra

st m

edia

use

d , th

ose

with

kno

wn

CK

D, k

idne

y fu

nctio

n sh

ould

be

chec

ked

post

pro

cedu

re. A

cute

ren

al f

ailu

re m

ayre

sult

afte

r th

e pr

oced

ure.

If

poss

ible

patie

nts

shou

ld in

crea

se o

ral fl

uid

inta

ke

and

urin

ary

outp

ut s

houl

dbe

mon

itore

d

Mag

netic

Res

onan

ceIm

age

(MR

I)sc

an

Pro

duce

s cr

oss-

sect

iona

l imag

es o

f the

bod

y.G

adol

iniu

m,

a no

n-ne

phro

toxi

c co

ntra

stag

ent,

may

be

used

intra

veno

usly.

MR

I giv

esve

ry c

lear

and

det

aile

d im

ages

of s

oft-t

issu

est

ruct

ures

. H

ence

, it

is u

sefu

l in

rev

ealin

gm

ass

lesi

ons,

rena

l vei

n th

rom

bosi

s, e

tc

Non

e if

non-

toxi

cco

ntra

st m

edia

used

•Ren

ogra

m

• Ren

al S

can

Reno

gram

: a

rena

l sc

intig

raph

yin

wh

ichdy

nam

ic an

d ra

pid

seria

lim

agin

gis

done

follo

wing

th

e in

trave

nous

in

ject

ion

of

aniso

tope

(e.g

.99MTc

-MAG

3, a

n id

eal r

adio

isoto

pedu

e to

its

fi lt

ratio

n by

glom

erul

i an

del

imin

atio

n ex

clusiv

ely

by t

ubul

ar s

ecre

tion)

.It

is us

ed to

eva

luat

e re

nal f

unct

ion,

e.g

. in

the

oftra

nspl

ante

dkid

neys

Rena

lSca

n:

a re

nal s

cintig

raph

y in

whi

ch tw

oto

four

hou

rs p

rior

to th

e te

st, a

sm

all a

mou

ntof

rad

ioiso

tope

(e.

g.99

MTc

-DM

SA)

is in

ject

edin

trave

nous

ly.Va

rious

sta

ticim

ages

are

the

nta

ken.

It is

ofte

nus

ed to

eval

uate

rena

lcor

tical

lesio

ns

Non

e

81


Ren

alB

iops

yP

ercu

tane

ous

rena

lbio

psy

An

inva

sive

pro

cedu

reby

whi

ch a

spe

cial

need

le is

intro

duce

d in

to t

he lo

wer

pol

e of

the

kidn

ey(p

refe

rabl

y th

e le

ft as

it is

mor

eea

sily

acc

essi

ble

and

not

near

the

live

r) t

oob

tain

a p

iece

of t

issu

e sp

ecim

en fo

r st

udy.

It is

use

d to

est

ablis

h di

agno

sis,

to o

rient

ate

treat

men

t reg

ime

and

to c

lass

ify p

rogn

osis

Indi

cate

d in

CK

D:

•C

onse

rved

kid

ney

size

(> 9

cm

)•

Pro

tein

uria

• M

icro

scop

ic h

aem

atur

ia

Con

train

dica

ted:

• S

ingl

e ki

dney

(exc

ept t

rans

plan

ted)

• G

ross

obe

sity

• U

ncon

trolle

d hy

perte

nsio

n•

Sev

ere

anae

mia

•U

ncon

trolle

d co

agul

opat

hy•

Kid

ney

with

hydr

onep

hros

is o

r cys

ts•

Red

uced

siz

e ki

dney

(< 9

cm

)

•Prio

r to

the

proc

edur

e, p

atie

nt s

houl

dha

ve h

is/h

er b

lood

coa

gula

tion

chec

ked

•Writ

ten

cons

ent n

eede

d• P

atie

ntsh

ould

be in

form

edof

24h

co

mpl

ete

bed-

rest

afte

r nat

ive

biop

syor

acc

ordi

ng to

uni

t pol

icy

and

obse

rve

punc

ture

site

for s

igns

of b

leed

ing

and

chec

k ur

ine

for s

igns

of h

aem

atur

ia

82


References1. Mahon, A. Investigations in Renal Failure. EDTNA ERCA J. 2004

Jan-Mar; 30(1): 4-8.2. Laposata M. SI Unit Conversion Guide. The New England Journal of

Medicine. NEJM Books: Boston. 1992.3. http://www.nlm.nih.gov/medlineplus/encyclopedia.html4. Locatelli F et al. Revised European Best Practice Guidelines for

the Management of Anemia in Patients with Chronic Renal Failure. Nephrol Dial Transplant 2004; 19 (suppl 2): 1-47.

5. Munson K and Jorgenson Linne J. Urinalysis and Body Fluids. A color Text and Atlas. Chapters 2, 3, 4. Elsevier: Toronto. 1995.

6. Thomas, N Renal Nursing (2nd Edition). BaillièreTindall: Edinburgh.2002.

7. French TW and Blue JT. Urine Sediment Atlas. Cornell University:New York. 1997.

8. Fairley KF, Johnson R and Feehally J. Comprehensive Clinical Nephrology. Mosby: London. 2001.

9. Brenner B. Benner and Rector’s The Kidney 2 Vol Set (7th Edition).W.B. Saunders Company: Ontario. 2004.

10. CKD guideline Guidelines for Chronic Kidney Disease: Identifi cation, management and referral. http://www.renal.org/JSCRenalDisease/JSCRenalDisease.html

11. Higgins C. Understanding laboratory investigation. BlackwellScience: Oxford. 2000.

12. Brenner, B. Rector, F. The Kidney, Fourth Edition Volume1. W.B. Saunders Company: Ontario. 1991.

13. http://www.radiologyinfo.org/index

Further ReadingSociedad Española de Nefrología. Diagnóstico Sindrómico y Exploraciones Diagnósticas 1998. Harcourt Brace de España: S.A.

Pattison J.et al. A Colour handbook of Renal Medicine 2004. Manson Publishing Ltd: London.

Steddon S, Ashman N, Chesser A & Cunningham J. Oxford Handbook of Nephrology and Hypertension 2006. Oxford University Press: Oxford.

83


86


Learning Outcomes

• To gain insight into the prevalence of anaemia in Chronic Kidney Disease (CKD)

• To develop an understanding of the causes, signsand symptoms of anaemia in CKD patients

• To understand which CKD patients to screen for anaemia

• To review the current anaemia guidelines• To understand the current recommended

management strategies for anaemia managementin CKD patients

• To refl ect on the benefi ts of correcting anaemia in CKD patients

Defi nition of Anaemia in CKDThe World Health Organisation defi nes anaemia as haemoglobin (Hb) level of less than 11g/dl in pregnantwomen and children aged 6 months to 5yrs, less than 12g/dlfor non pregnant women and less than 13g/dl for men1.Management of anaemia should be considered in chronic kidney disease (CKD) when the Hb level is less than or equal to 11 g/dl. An estimated glomerular fi ltration rate (eGFR) ofless than 60ml/min/1.73m² should trigger investigation into whether anaemia is due to CKD. When the eGFR is greaterthan or equal to 60ml/min/1.73m2 the anaemia is more likelyto be related to other causes2.

87

Management of Anaemia in CKD

Anaemia of Chronic Kidney Disease (ACKD)Many conditions are associated with ACKD, mainly because many chronic, systemic conditions lead to abnormalities inhaemopoiesis (production of red blood cells)3. Anaemia inpatients with CKD may develop in response to a wide varietyof causes as systemic diseases have different effects on the kidney and the bone marrow.

Causes of ACKD1. Reduced Erythropoietin Production

Anaemia in CKD is normally normochromic and normocytic.Erythropoietin defi ciency is the primary cause of anaemia associated with CKD. Erythropoietin is predominantlyproduced by peri-tubular cells in the kidney and is thehormone responsible for maintaining the proliferation and differentiation of erythroid progenitor cells in the bone marrow. Loss of peri-tubular cells leads to an inappropriatelylow level of circulating erythropoietin. The production ofinfl ammatory cytokines (common in CKD) such as interleukin 1 and Tubular Necrosis Factor (TNF alpha) can inhibit the maturation of the progenitor cells4 and lead to the reductionin production of erythropoietin.

2. HaemolysisThe reason for impaired red blood cell survival (haemolysis)in CKD is not well understood although it is thought that uraemia plays a central role. In this situation a Coombs test is useful to look at the survival of the red cells. Normal redblood cell survival is 120 days in patients with CKD it maybe reduced to 90 days.

3. Iron Defi ciency2

Iron has an essential role in supporting erythropoiesis with 65% of the iron stored in the body used to form haemoglobin.Iron defi ciency should be considered in people with stage 3 and 4 CKD if the ferritin level is less than 100�g/l.

88


Measurements of Iron StatusSerum Ferritin: This refers to the amount of iron storedin the body. The body requires 150mg of iron to raise the haemoglobin by 1g/dl. As red cell production increases iron stores are depleted. Iron stores need to be adequate otherwise red blood cell survival is reduced.

Serum ferritin is commonly used as a standard marker for measuring iron defi ciency. However it can be falsely raised in cases of infection and infl ammatoryconditions. It is useful to measure the C reactive protein (CRP) at the same time as the ferritin. If the CRP is also raised then this will indicate that there is an infection orinfl ammatory condition and that the raised ferritin is not a true indication of the iron status at that time.

% Transferrin Saturation (%Tsats): This is the body’s transport system for iron. This needs to be >20% to be effective; however this is not a very reliable tool as %Tsats constantly alter. More than one measurement is required to ascertain an average reading.

% Hypochromic Red Cells: This is defi ned as anindividual cell with a haemoglobin concentration <10%. Normally 2.5% of red blood cells are hypochromic.If iron stores are insuffi cient and/or mobilisation ofiron is inadequate the amount of hypochromic red blood cells increase in number and when they are greater than 10%, iron supplementation is required5.

Defi nition of Iron Defi ciencyAbsolute Iron Defi ciency: Iron stores are inadequate to support the erythropoietic needs of the bone marrow, defi ned by a low serum ferritin level less than 100�g/L.

Functional Iron Defi ciency: Iron stores are adequatebut cannot supply bone marrow quickly enough with the

89


iron required to support demands of erythropoiesis when stimulated acutely. This is defi ned by normal or highserum ferritin, % transferrin saturation less than 20% or % hypochromic red cells greater than 10%.

4. Vitamin B12 and Folate Defi ciencyVitamin B12, also called cobalamin, is required to maintain healthy nerve cells, red blood cells and DNA. Vitamin B12 is bound to protein in food. Hydrochloric acid in the stomach releases B12 from the protein during digestion.Once released, B12 combines with a substance called intrinsic factor (IF) before it is absorbed into the bloodstream. Vitamin B12 defi ciency is defi ned when B12 levels are less than 160ng/l.

Pernicious anemia is a form of anaemia that occurswhen there is an absence of intrinsic factor. Absence ofintrinsic factor prevents normal absorption of B12 and results in pernicious anemia. Treatment for pernicious anaemia is by an initial treatment course of intramuscular hydroxycobalamin injections, 1mg three times a week, for two weeks followed by three monthly maintenance injection of 1mg which will continue indefi nitely6.

Folate and folic acid are forms of a water-soluble B vitamin.Folate is essential for the production and maintenance ofnew red blood cells. Folate is also needed to make DNA and RNA. Those with renal disease should have a serumfolate level > 20�g/l. Supplementation with folic acid 5mgonce a day should be given if the serum folate level is <20�g/l.

90


Causes of Anaemia Other than CKDNot all types of anaemia in patients with CKD will be ‘renalanaemia’ and causes of anaemia other than CKD should be actively investigated and excluded before a diagnosis ofanaemia associated with CKD is made2.

The above tests will exclude causes for anaemia other thanCKD, especially bone marrow suppression and haemolysis. It is important to screen for other causes of anaemia in order to reach the correct diagnosis. Haematological abnormalities needto be clearly recognised and appropriate treatment given.

Table 1: Other causes of anaemia

• Chronic blood loss• Hypothyroidism• Chronic infection or infl ammation• Hyperparathyroidism• Aluminium toxicity• Bone marrow infi ltration• Pure red cell aplasia• Malignancy

Table 2: Screening for anaemia of CKD

Investigations should be performed when Hb<12g/dl (men) or 11g/dl for women and should include the following tests:

• Haemoglobin• Red cell folate concentration• Serum B12• Serum ferritin• Serum % transferrin saturation• % Hypochromic red cells• Tests for haemolysis (Haptoglobin, lactate dehydrogenase,

Coomb’s test)• Reticulocyte count• C-Reactive protein (CRP)• Assessment of occult gastrointestinal blood loss• Nutritional status of the patient

91


Signs & Symptoms of Anaemia of CKDThe anaemia of chronic disease (ACD) may occur insidiouslyand is easy to overlook amid the general malaise related to the disease itself. Many of the signs and symptoms can be considered to be due to the effects of chronic disease but arein fact also signs and symptoms of anaemia7.

The prevalence of anaemia in patients with CKDThe importance of anaemia in CKD has been increasinglyrecognised since the introduction of erythropoietin(EPO) therapy in the late 1980s. However, until recentlyit has not been fully appreciated that anaemia beginsto develop early in the course of CKD. NHANES III study found lower levels of kidney function to be associated with lower haemoglobin levels and a higher prevalence and severity of anaemia8.

In the UK one study showed the population prevalenceof stage 3-5 CKD in this study was estimated to be 4.9%.

Table 3: Signs and Symptoms of ACKD

• Dizziness or light headedness• Fatigue and weakness• Headache• Irritability• Less endurance in exercise• Shortness of breath, especially with exercise• Pale skin and eyes• Rapid heartbeat• Reduced cognitive function

92


In those patients with stage 3-5 CKD the prevalence of anaemia, defi ned as a haemoglobin level <12g/dl in men and post-menopausal women and 11g/dl in premenopausal women, was 12.0%, with a haemoglobin level <11g/dl in 3.8%9.

Anaemia in Diabetes and CKDThose with CKD stage 3 and diabetes have a greater incidence of anaemia, 22% compared to 7.9% in non-diabetics10.Anaemia occurs early in the course of diabetic kidneydisease and is associated with inappropriately low erythropoietin concentrations11. A comparison of those with Type 2 diabetes and CKD and those with non-diabetic CKD,showed that those with Type 2 diabetes were signifi cantlymore anaemic12. Similar fi ndings have also been demonstrated in people with Type 1 diabetes and CKD compared with those without diabetes.

Cross-sectional surveys of patients with diabetes, have also demonstrated that at all levels of eGFR, anaemia was more prevalent in those with diabetes compared with the generalpopulation13,14. With increasing albuminuria, the prevalence ofanaemia was higher at each level of renal function, and that

Table 4: Stages of CKD and prevalence of anaemia

Stageof CKD

eGFR(ml/min/1.73m2)

Median Hbin men(g/dl) %

Median Hbin women(g/dl) %

Prevalence ofanaemia* %

2 60 14.9 13.5 1

3 30 13.8 12.2 9

4 15 12.0 10.3 33*Hb<12g/dl in men, Hb <11g/dl in women.

93


levels of erythropoietin were inappropriately low in those with anaemia15.

Cardiovascular Effects of Anaemia.Possible adverse effects of anaemia in patients with CKDinclude reduced oxygen utilization, increased cardiac output and left ventricular hypertrophy (cardiac dilatation) ± increased wall thickness. In a study of 318 non-dialysis patients a mean decrease in Hb of 0.5 g/dl from baseline of 12.8 ± 1.9 g/dl was found to be one of three factors that was associated with leftventricular hypertrophy (LVH)16.

Whether early anaemia treatment prevents development ofLVH, reduces cardiovascular mortality and morbidity, delaysprogression of CKD and reduces stroke and heart failure related hospitalisations, is clearly still open to question. However, there are currently three large studies seeking to answer these questions. The Correction of Haemoglobinand Outcomes in Renal Insuffi ciency (CHOIR)17 study, the CREATE18 trial (Cardiovascular Risk reduction by EarlyAnaemia Treatment with epoetin beta) and the TREAT19 (Trial to Reduce Cardiovascular Events with Aranesp Therapy)study should help to determine the optimal management ofpre-dialysis renal anaemia.

Guidelines for Management of AnaemiaWhen should Anaemia of CKD be treated?There are many anaemia guidelines and standards andeach country may use country specifi c. The Kidney Disease Outcomes Quality Initiative guidelines of the National KidneyFoundation (NKF K/DOQI)20 defi ne anaemia in CKD as a haemoglobin concentration of less than 11 g/dL in pre-menopausal females and pre-pubertal patients, and less than 12 g/dL in adult males and postmenopausal females.

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The Revised European Best Practice Guidelines (EBPG)5

defi ne anaemia as an Hb fall below the mean Hb level of thepopulation mean -2 Standard Deviation (SD) (i.e. <95%), as follows:

• <11.5 g/dl in adult female patients• <13.5 g/dl in adult male patients• <12.0 g/dl in adult male patients aged over 70

The UK NICE guidelines suggest a trigger for treatment when Hb �11g/dl.

Target or aspirational ranges of haemoglobin levels also varywith each guideline.Having so many sets of guidelines and haemoglobin rangescan be confusing. However, it is important to have an agreedset of evidence based guidelines to use in your unit when managing anaemia of CKD.

Table 5 - Target haemoglobin levels for treatment of ACKD using available guidelines

Target H i aemia Ma ageme t ideli es

D

D g dL

g dLer limit

ot de i ed

g dL

D g dL e ised

g dLer limit

i di id alised

e isedD

g dLca tio ith mai te a ce

g dL

M D

g dL

g dL D

g dL o D

a ada g dL

g dL D

g dL o D

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Treatment of Renal Anaemia Associated with CKDManaging Iron defi ciencyThe correction of iron defi ciency anaemia is essential before considering the use of any erythropoiesis stimulatingagents (ESA). In people with functional iron defi ciency, iron supplements should be given concurrently when initiatingESA therapy as adequate iron stores are necessary to allow an optimal response to ESA therapy2. ESA therapy should not be initiated in the presence of absolute iron defi ciency without also managing the iron defi ciency. Treatment with intravenous iron may, by itself, correct anaemia amongst some patients with CKD.

Oral ironOral Iron can be poorly absorbed and the absorption can be inhibited by other drugs such as calcium based phosphatebinders and aluminum and by taking it with food and tea. Vitamin C however assists absorption and taking iron supplements with a glass of orange juice may help. However with many renal patients having to cope with dietary changesand restrictions, this may not always be possible.

The side effects of oral iron such as constipation, diarrhoea and fl atulence can often prevent it being taken regularly.However, oral iron is used in practice mainly for non-dialysisand peritoneal dialysis patients where the practicalities ofadministering intravenous iron are limiting.

Intravenous IronIntravenous iron is currently available as two preparations inthe UK: Iron Dextran (Cosmofer®rr ) Iron Sucrose (Venofer®rr ).

Iron Dextran (Cosmofer®rr )6

A complex of ferric hydroxide with dextrans containing 5%(50mg/ml) of iron.

Dose: by intravenous slow infusion (up to 4hours) calculated according to bodyweight and iron defi cit (not recommended in a child under 14 years).

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Cautions: facilities for cardiopulmonary resuscitation must be at hand; increased risk of allergicreaction in immune or infl ammatory conditions; hepatic impairment; renal impairment; oral iron not to begiven until 5 days after last injection; pregnancy.

Contra-indications: history of allergic disorders includingasthma and eczema; infection; active rheumatoid arthritis.

Side-effects: nausea, dyspepsia, diarrhoea, chest pains,hypotension, dyspnoea, arthralgia, myalgia, pruritis,urticaria, rash, fever, shivering, fl ushing, headache; rarelyanaphylactic reactions; injection site reactions includingphlebitis reported.

There are concerns regarding risk of anaphylaxis with Iron Dextran. Dextran antibodies can exist but this is unknownuntil Iron Dextran is given to the patient and within secondsan anaphylactic reaction may occur. This means that this drug must be given in an environment where there are fullresuscitation facilities available.

The advantage of Iron Dextran is that it can be given as a singledose infusion which is advantageous if the patient has to travel long distances for treatment. It cannot be given undiluted as a bolus dose.

Iron Sucrose (Venofer®rr )6

A complex of ferric hydroxide with sucrose containing 2%(20mg/ml) of iron.

Dose: by slow intravenous injection (over 5-10 minutes) or by intravenous infusion, calculated according to body-weightand iron defi cit, consult product literature (not recommended in children).

Cautions: oral iron therapy should not be given until 5 daysafter last injection; facilities for cardiopulmonary resuscitation must be at hand; pregnancy.

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Contraindications: history of allergic disorders includingasthma, eczema and anaphylaxis; liver disease; infection.

Side-effects: nausea, vomiting, taste disturbances,headache, hypotension; less frequently paraesthesia, abdominal disorders, myalgia, fever, fl ushing, urticaria, peripheral oedema; rarely anaphylactoid reactions; injectionsite reactions including phlebitis have been reported.

Venofer®rr can be safely given to patients across all modalities ®

either as an infusion, or undiluted as a bolus dose via a butterfly needle. It is the most commonly used intravenous iron supplementation in renal medicine.

Haemodialysis patients are able to receive intravenous iron during dialysis without it being removed by dialysis. Thereforeall haemodialysis patients who require iron supplementationcan have intravenous iron rather than oral iron. The amountgiven will vary from unit to unit but a standard dose would be 100mg every fortnight as a maintenance dose. Or if the patient required a course of iron 1g it would be given over a 5-10 week period depending on the unit protocol.

Peritoneal and non-dialysis patients may receiveintravenous iron when their serum ferritin is <100g/dl,% Tsats<20% or %hypochromic Red Cells >10%. Patients who are intolerant of oral iron may be givenmaintenance intravenous iron every 6-8 weeks to maintain their serum ferritin >100�g/l.

In countries where the above preparations are not available Ferrous Gluconate may be used. Further information regarding this product should be soughtfrom the pharmaceutical provider.

Monitoring Iron StoresAll patients who are receiving erythropoiesis stimulatingagents (ESAs) require iron supplementation to support the demands made on the iron stores. Regular monitoring of iron

98


stores is essential during treatment. In CKD patients with a stable haemoglobin level not being treated with ESAs, iron stores should be measured every three to six months5. Patientswho are being treated with ESAs should have their iron status checked every 4 weeks during the correction phase (threemonths) and thereafter every three months5. Patients who arereceiving regular intravenous iron therapy should have their iron status checked every three months and the intravenous therapydiscontinued for at least a week prior to performing the tests5.

Iron toxicity needs to be avoided and if the serum ferritin is persistently above 500�g/l, and/or >40% Tsats greaterthan 40% iron supplementation should be withheld forup to three months as long as there are no signs of functionaliron defi ciency. Iron status should be measured monthly in these situations.

Erythropoiesis Stimulating Agents (ESAs)Treatment with ESAs should be offered to people with anaemia of CKD who are likely to benefi t in terms of qualityof life and physical function2. The choice of ESA should be discussed with the person with anaemia of CKD when initiating treatment and at subsequent review, taking into consideration the patient’s dialysis status, the route ofadministration and the local availability of ESAs. There is no evidence to distinguish between ESAs in terms of effi cacy2.

There are several commercial Erythropoiesis StimulatingAgents (ESAs) available. Those currently licensed for use in CKD are:

• Epoetin alfa• Epoetin beta• Darbepoetin alfa• Epoetin delta

They all work in a similar way by continually stimulating the bone marrow to produce red blood cells.

99


Route of AdministrationThe stage of CKD, treatment setting and patient choice should determine the route of ESA administration and type of ESA used. Convenience favours subcutaneous (SC) administration in non dialysis and peritoneal dialysis patients and intravenous (IV) administration in haemodialysis patients. However some preparations require higher doses when given intravenouslyand this needs to be considered.

Frequency of administrationThe CKD stage, treatment setting, effi cacy considerations, and type of ESA should determine the frequency of administration. Convenience favours less frequent administration, particularlyin non haemodialysis patients.

DosingThe initial ESA dose and ESA dose adjustments should be determined by the patient’s Hb level, the target Hb level, the observed rate of increase in Hb level, and clinical circumstances. ESA doses should be decreased, but not necessarily withheld, when a downward adjustment of Hb level is needed. Scheduled ESA doses that have been missed should be replaced at the earliest possible opportunity. ESA administration in ESA-dependent patients should continue during hospitalisation. Hypertension, vascular access occlusion, inadequate dialysis,history of seizures, or compromised nutritional status are not usually contraindications to ESA therapy.

Managing Non-Response to ESAsThe patient with anaemia and CKD should undergo evaluation for specifi c causes of non response whenever the Hb level is inappropriately low for the ESA dose administered.

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A process of elimination will determine the cause of non-response to treatment. However if none of the above are lacking and have all been fully investigated then a bone marrow aspiration may be necessary to rule out any other haematological cause of anaemia or non-response to treatment.

The Benefi ts of Treating ACKDUntreated anaemia has a number of adverse consequences both for the patient as well as for the healthcare system rangingfrom effects on quality of life, cognitive function and libido throughto increased mortality and morbidity with its associated costs.

Table 6 Screening for non-response

The following also need to be considered:• Chronic blood loss (e.g. from gastrointestinal or genitourinary

tracts)• Iron defi ciency• Folate / Vitamin B12 defi ciency• Reticulocyte count• Infection/inflammation• Tuberculosis, systemic lupus erythematosus (SLE)• Chronically rejecting transplants• Hyperparathyroidism / osteitis fi brosa• Aluminium/chloramine toxicity• Haemoglobinopathies (alpha, beta thalassaemia, sickle cell

anaemia)• Multiple myeloma, myelofi brosis, myelodysplasia• Malignancy• Malnutrition• Drugs interaction such as high dose ACE inhibitors• Inadequate dialysis• Antibodies to Epoetin - red cell aplasia

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The major risk is cardiovascular disease (CVD), with one of the earliest manifestations of left ventricular hypertrophy (LVH).Anaemia has both direct and indirect effects on left ventricularfunction and growth. Age, hypertension, and the level of Hb are independent predictors for the presence of LVH. A number of other studies have shown that anaemia predicts increased left ventricular mass, left ventricular dilatation, heart failureand death, and that anaemia is associated with increased hospitalisation rates and increased mortality21,22. Anaemia isalso a potent risk marker for poor outcome amongst patients with acute myocardial infarction.

The patients who are most likely to gain the greatest long-termbenefi t from correction of anaemia in CKD are those who are approaching dialysis. Early intervention to correct anaemia has the potential to impact on the progression of chronic kidney disease and effect patient morbidity, hospitalisation rates, quality of life and mortality.

Managing ACKDPeople offered ESA therapy and their primary care physiciansshould be given information about why ESA therapy is required, how it works and what benefi ts and side effects maybe experienced. When managing the treatment of people with anaemia of CKD, there should be agreed protocols defi ningroles and responsibilities of healthcare professionals.

People with anaemia of CKD should have access to a designated contact person or persons who haveprincipal responsibility for their anaemia management and who have skills in the following activities2:

• Monitoring and managing a caseload of patients in line with locally agreed protocols

• Providing information, education and support to empower patients and their families and carers to participate in their care

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• Co-ordinating an anaemia service for people with CKD, working between secondary and primary care andproviding a single point of contact, to ensure patients receive a seamless service of the highest standard

• Prescribing medicines related to anaemia managementand monitoring their effectiveness

In the UK ACKD is predominantly managed by nurses23, oftenwith the help of electronic algorithms. Nurses across Europe are now increasingly taking on this role.

References1. World Health Organization. Iron Defi ciency Anaemia, Assessment,

Prevention and Control: a guide for programme managers.2001.

2. National Collaborating Centre for Chronic Conditions. Anaemia management in chronic kidney disease: national clinical guidelinefor management in adults and children. Royal College of Physicians:London. 2006.

3. Spivak JL. The blood in systemic disorders. Lancet 2000; 355: 1707-12.

4. Peirera BJG, Sundaram S, Barrett TW, Butt NK, Porat R and King AJ. Cytokine production by human peripheral blood mononuclear cells stimulated by a Pseudomonas aeruginosa culture fi ltrate: Role ofplasma and polymyxin B. International Journal of Artifi cial Organs1996; 19;(5):276-283.

5. Revised European Best Practice Guidelines for Management ofanaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004; 19 ;(suppl 2) S1-S47.

6. British National Formulary. March 2007.7. Jenkins K. Anaemia in CKD Chapter 3 in Thomas N, editor.

Advanced Renal Nursing. Blackwell Publishing: London. 2005.8. Coresh J, Astor BC, Greene T et al. Prevalence of chronic

kidney disease and decreased kidney function in the adult USpopulation: Third National Health and Nutrition Examination Survey.Am J of Kidney Dis 2003; 41(1):112.

9. De Lusignan S, Stevens PE, O’Donoghue D et al. Identifying patients with chronic kidney disease from general practice computer records. Family Practice 2005;22(3):234–241.

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10. El Achkar TM, Ohmit SE, McCullough PA et al. Higher prevalence of anemia with diabetes mellitus in moderate kidney insuffi ciency:The Kidney Early Evaluation Program. Kidney Int 2005; 67(4):1483–1488.

11. Bosman DR, Winkler AS, Marsden JT et al. Anemia with erythropoietinefi ciency occurs early in diabetic nephropathy. Diabetes Care2001;24(3):495– 499.

12. Ishimura E, Nishizawa Y, Okuno S et al. Diabetes mellitus increases the severity of anemia in non-dialysed patients with renal failure.Journal of Nephrology1998; 11(2):83–86.

13. Thomas MC, MacIsaac RJ, Tsalamandris C et al. Unrecognizedanemia in patients with diabetes: a cross-sectional survey.Diabetes Care 2003;26(4):1164–1169.

14. Thomas MC, MacIsaac RJ, Tsalamandris C et al. The burden ofanaemia in Type 2 diabetes and the role of nephropathy: a cross-sectional audit. Neph Dialysis Transplant 2004;19(7):1792–1797.

15. Thomas MC, Cooper ME, Tsalamandris C et al. Anemia with impaired erythropoietin response in diabetic patients. Archives of Internal Medicine 2005;165(4):466–469.

16. Levin A, Thompson CR, Ethier J et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin.Am J of Kidney Dis 1999; 34(1):125–134.

17. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–98.

18. Macdougall IC. CREATE: New strategies for early anaemia management in renal insuffi ciency. Nephrol Dial Transplant2003;18: Suppl 2.

19. Mix TCH, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P, Levey AS et al. Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): Evolving the management of cardiovascular risk in patients with chronic kidney disease. American Heart Journal 2005;149 (3): 408-413.

20. NKF-KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006; 47:S1-S146.

21. Jones M, Schenkel B, Just J. Epoetin alfa’s effect on left ventricular hypertrophy and subsequent mortality. International Journal of Cardiology 2005;100 (2):253–265.

22. Weiner DE, Tighiouart H, Vlagopoulos PT et al. Effects of anemia and left ventricular hypertrophy on cardiovascular disease in patients with chronic kidney disease. Journal of The American Society of Nephrology 2005;16 (6):1803–1810.

23. Bennett L. The anaemia research nurse in effective multidisciplinarymanagement of patients on erythropoietin. EDTNA/ERCA Journal 1998; 24(3):38–39.

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Learning Outcomes

• To gain knowledge and understand the role of diet in the treatment of patients with Chronic KidneyDisease (CKD) stages 1-3

• To explain the role of diet in hypertensionmanagement

• To gain knowledge in the dietary management of hyperlipidaemia

• To understand the measures that should be taken to slow down the progression of CKD

IntroductionNutritional therapy is one of the cornerstones of treatment for patients with CKD stages 1-3. Early CKD is very common, but the majority of patients with early CKD do not progress to end stage renal disease (ESRD), but do have an increased risks of cardiovascular disease. Optimal management of the risk factors for cardiovascular disease also reduces the risk ofprogression from early CKD to ESRD.

The Aims of Nutritional Therapy

• To prevent progression from early CKD to ESRD• To reduce the risk factors for cardiovascular disease

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Nutrition and Chronic Kidney Disease (Stages 1-3)

Diet Therapy for CKD Stages 1 - 2 Recent research shows that 0.9% of the general population have CKD1. Those aged �75 years 50%, have CKD caused by the normal ageing of their kidneys. This can increase the chances of high blood pressure, heart disease or stroke. Although age is a non-modifi able risk factor, the time it takes to reach stage 4 and 5 CKD provides an opportunities to slow the progression of CKD, treat underlying co-morbidities, and to prevent the systemic complications that develop in the course of gradual loss of kidney function1, 2. A common factorassociated with this is hypertension, which contributes to the progression of CKD and is a major risk factor for cardiovascular disease3.

HypertensionHypertension management should focus on weight reduction and reducing sodium intake. Other variables include alcohol, potassium, calcium and a low fat diet that needs to includes fruit and vegetables (5-9 portions daily) and low fat dairy produce (2-4 servings daily) which will be rich in potassium, magnesium,calcium and will modestly reduce blood pressure4.

It is helpful to consider sodium and fl uid together as they are closely linked in the management of blood pressure. The body’s sodium and fl uid status is the main determinant ofblood pressure. Dietary restrictions should be implemented ifpatients are hypertensive to an intake of <100mmols sodium (6g salt) per day. A study by Law et al (1991)5 demonstratedthat in people aged 50-59 years, a reduction in daily sodium intake of 50mmol (about 3g of salt), attainable by moderate dietary salt reduction, after a few weeks, lowered systolicblood pressure by an average of 5mmHg, and by 7mmHg in those with high blood pressure (>170 mmHg); diastolic blood pressure would be lowered by about half as much5. The DASHstudy also demonstrated that a moderate sodium restriction

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showed a reduction in blood pressure of 5mmHg for systolicand 2mmHg for diastolic blood pressure in hypertensiveindividuals and the lower the sodium intake the greater thelowering of blood pressure6.

Most of the sodium people consume is from the salt added to processed foods such as breakfast cereals, bread and tinned foods. The majority of manufactured foods now provide nutritional labelling information with include data of the sodium content. Educational information needs to be provided to patients as 1.25g salt (0.5g sodium) or more per 100g is a lot of salt whereas, 0.25g salt (0.1g sodium) or less per 100g is a little salt. In order to reduce a person’s sodium intake youneed to provide advice on a reduction of salt added duringcooking and at the table before food is eaten, avoiding foodwhich is high in salt such as manufactured food, ready made meals, smoked or cured foods.

LipidsCKD patients are at a high risk for atherosclerotic cardiovascular disease. Hyperlipidaemia is common in patients with CKD, particularly those with nephrotic syndrome. In addition to accelerating the development of systemic atherosclerosis, experimental studies suggest that high lipid levels also maypromote progression of renal disease7. Furthermore, the benefi cial effect of lipid lowering is similar to that of loweringthe blood pressure in at least some models of chronic renal disease8. The amount and type of fat are prescribed on an individual basis and depend on factors such as serum lipid levels, protein intake and body weight9. In addition todietary changes, statins are prescribed for treating high LDLcholesterol (low-density lipoprotein) and reducing the levels to <100mg/dL (<2.59mmol/L)10. Dietary restrictions include a diet containing <10% of energy intake derived from saturated fatty acids (SFA). Some individuals (i.e. people with LDLcholesterol > 100mg/dl) may benefi t from lowering SFA intake

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to <7% of energy intake. Dietary cholesterol intake should be less than <300mg/day. Practically this means a reduction in saturated dietary fat such as butter, ghee, cakes, biscuits and instead using monounsaturated fats such as olive oil9. Theintake of trans-unsaturated fatty acids should be minimized. Recommendations also include two to three servings of fi sh per week to provide dietary n-3 polyunsaturated fatty acids (n-3 PUFA)11.

DiabetesIn people with diabetes, excessive consumption of protein may be harmful. Experts recommend that people with diabetic nephropathy consume the recommended dietary allowance for protein, but avoid high-protein diets. For those with greatlyreduced kidney function, a diet containing reduced amounts of protein may help delay the onset of kidney failure12. Anyonefollowing a reduced-protein diet should work with a dietitian to ensure adequate nutrition. Antihypertensive drugs and low-protein diets can slow kidney disease when signifi cant nephropathy is present. Intensive management of blood glucose is important for people with type 1 and type 2 diabetes, especially for those in early stages of diabetic nephropathy13.Intensive management is a treatment regimen that aims to keep blood glucose levels close to normal. The regimenincludes testing blood glucose frequently, administering insulin frequently throughout the day on the basis of food intake and physical activity, following a diet and activity plan, and consulting a health care team frequently.

Diet Therapy for CKD Stage 3As patients progress to CKD stage 3, dietary advice depends on many factors including existing co-morbidities, medications, blood biochemistry, nutritional status, weight and usual dietaryintake. Lifestyle advice as in stages 1-2 will form the main basis of diet therapy; however additional advice on protein,

110


phosphate, potassium, vitamins and minerals might also be provided dependent on the individual requirements of the patient.

Protein IntakeControl of protein intake may delay the progression of CKD and improve the effects of excessive accumulation of nitrogenouswaste14. A re-analysis of The Modifi cation of Diet in Renal Disease (MDRD) demonstrated that a 0.2g/kg a day reduction in protein intake correlated with a 1.15ml/min/year reduction in the rate of decline in glomerular fi ltration rate (GFR). This decline has been shown to correlate with a 41% prolongationof renal survival15.

A Cochrane systematic review further demonstrates the benefi ts of decreasing protein intake in the diet on delayingthe progression of CKD12. Unfortunately, the evidence is not conclusive and opinions are divided and furtherresearch is required in the future. Currently, there are variant recommendations of dietary protein intake for CKD patients (Table 1)

Although the benefi t of protein restriction may be suffi cient to delay renal replacement therapy for several years, there is a large cost in terms both of effort on the part of the healthcare team and patient, and of the relatively poor palatability of more severe protein restriction. Only highly compliant patients are

Table 1: Current recommendations of dietary protein intake for CKD patients

GlomerularFiltration Rate

(GFR)

Recommended proteinintake

(g/kg ideal body weight)

Professionalorganisation

> 30 ml / min 0.75 g / kg K/DOQI

< 30 ml / min 0.6 g / kg K/DOQI

20 - 30 ml / min 0.6 - 1.0 g / kg EDTNA / ERCA

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likely to comply with this regimen over a prolonged period16. Atpresent, optimal dietary treatment of non-diabetic patients with CKD is uncertain. A reasonable regimen consists of rigorousblood pressure control and the intake of approximately 0.8 to 1.0g/kg of high biologic value protein per day, with the lower value used in patients with progressive disease. It is possible, although not proven, that vegetable proteins and egg whites are a safer sources of protein, since they are less likely to increase glomerular fi ltration16.

Low-protein diets reduce the generation of nitrogenouswastes and inorganic ions, which cause many of the clinical and metabolic disturbances characteristic of uraemia such ashyperphosphataemia, metabolic acidosis, hyperkalaemia, and other electrolyte disorders16.

Nephrotic syndrome comprises of a group of symptomsincluding proteinuria (exceeding 3.5 grams per day), low blood protein levels, hypercholesterolemia, and oedema caused byvarious disorders that damage the kidneys, particularly the basement membrane of the glomerulus. It can both decreaseprotein excretion and diminish hepatic albumin synthesis;the net result is usually no change in the plasma albuminconcentration16.

Recommended nutritional managementg 9, 17:• Treatment of hypertension - low salt diet, (NKF K/DOQI:

1 - 2 g sodium/day)• Protein intake of 0.8 - 1.0 g protein / kg ideal body

weight• Adequate energy intake• Treat hyperlipidaemia: - manipulate fat intake - lipid-lowering drugs• Maintain fluid balance

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Renal Bone Disease and Nutritional InterventionsHyperphosphataemiaA tendency toward phosphate retention begins early in CKD, due to the reduction in the fi ltered phosphate load. Althoughthis problem is initially mild with hyperphosphataemia being a relatively late event, phosphate retention is intimately related to the common development of secondaryhyperparathyroidism. High circulating levels of parathyroidhormone play an important role in the developmentof renal osteodystrophy and possibly in other uraemic complications18.

PhosphateThe K/DOQI practice guidelines made the followingrecommendations for the goal serum phosphate at differentlevels of CKD19.

• At an estimated GFR between 15 and 59 ml/min/1.73m2 (stage 3 and 4 CKD), the serum phosphate should be between 2.7 and 4.6 mg/dl (0.87 and 1.49 mmol/L)

• The calcium phosphate product (corrected calcium x phosphate) should be maintained below <55 mg²/dl²,(<4.4 mmol²/L²) in patients with stage 3 to 5 CKD

PotassiumHyperkalaemia in CKD stages 1-3 is rare, however patients with CKD should be monitored on a regular basis to avoid hyper or hypokalaemia. In CKD stages 1-3 non-dietary reasons could be the cause of a hyperkalaemic episode and should be considered, this include blood transfusions, anaesthetics, insulin insuffi ciency, acidosis and medication20. Drugs that can cause hyperkalaemia include angiotensin-converting enzymeinhibitors (ACEI), angiotensin receptive blockers (ARB),beta-blockers, potassium-sparing diuretics (spironolactone),non-steroidal anti-infl ammatory drugs and ciclosporine.

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Vitamins and mineralsVitamin and mineral requirements are not well defi ned in CKD,but non-dialysed patients treated with a controlled-protein dietmay need some vitamin supplements. Vitamin preparationsshould contain the daily recommended intake of water-soluble vitamins, including folate2. The normal dietary intake of Vitamin C is 60mg/day and should not exceed 100mg/day because it plays a role in the formation of oxalosis2,18. Fat-solublevitamins and especially vitamin A, should be avoided as renalfunction decreases as this is raised in renal failure2, 20. Routinesupplementation of water-soluble vitamins will most likelyoutweigh the risk of defi ciency, especially in those patients who are unable to manage an adequate dietary intake18.

Mineral supplementation, including trace elements, is not recommended in this patient population. Iron supplementationshould be individualized and iron levels monitored closely2.It is important to avoid prescribing iron supplementation with phosphate binders to prevent drug interaction20. Zincsupplementation is only indicated once zinc defi ciency has been established20.

Summary ofrr Diet and Lifestyle AdvicefImproving diet and lifestyle is a critical component for reducingcardiovascular disease risk factors.

The current recommendations are:• to balance calorie intake and physical activity to achieve

and maintain a healthy body weight (BMI 20-25)• to eat a diet rich in vegetables and fruit• choose wholegrain, high fi bre foods such as whole grain

cereals and wholemeal bread• to include oily fi sh in the diet two or three times a week

such as mackerel, sardines, salmon or fresh tuna• limit saturated fat to <7% of the total calorie intake and

cholesterol to <300mg/day by choosing lean meats

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and low fat dairy products and minimizing the intake ofhydrogenated fats (found in biscuits, crisps)

• to minimize the intake of food and drinks with addedsugars

• to prepare food with little or no salt• to consume alcohol in moderation• to ensure good blood glucose control if the person suffers

from diabetesAppendix I

Nutrition recommendation for CKD patient without dialysis

Recommendations20 American DieteticAssociation14

Protein0.6-1.0 g/kg IBW/day

(high biologicvalue >50%)*

0.75 g / kg / day

Energy 30-35 kcal/kg IBW/day Based on energyexpenditure

Carbohydrates 50%-60% of total calories 50-60 % of totalcalories

Total Lipids 30%-40% of total calories 25-35 % of totalcalories

SaturatedLipids 7%-10% of total calories <7 % of total calories

Poly-unsaturated

Lipids7%-10% of total calories Up to 10 % of total

calories

Mono-unsaturated

Lipids10%-20% of total calories Up to 20 % of total

calories

115


Sodium1800 - 2500 mg/day

(80 - 100 mmol sodium or 5 - 6 g salt per day)*

Varies 1 - 4 g / dayto no added salt,

depending onco-morbidities

Potassium 1.0 mmol/kg IBW with K+>5.5 mmol/l*

Usually no restrictionunless serum levels

are raised

Phosphorus 600 - 1000 mg/day(19 - 31 mmol/l)*

Monitor and restrict if > 4.6 mg/dl

(>1.49 mmol/L)

Calcium 1000 - 1500 mg/day1200 - 1500 mg /

day, maintain serumlevel at lower end

Fluids Urine volume 24-hours+ 750 ml No restriction

Magnesium DRI, no supplement No supplement

IronDRI, individualizedsupplementation if

indicated

Individualize fromstages 3 - 5

Zinc DRI, supplement if defi ciency confi rmed

Individualize fromstages 3 - 5

* EDTNA/ERCA 2001

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References1. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal

disease: a new paradigm. Am J Kidney Dis 2000; 35 (4 Suppl 1):S117-31.

2. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic ofcardiovascular disease in chronic renal disease: What do we know?What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32 (5): 853-906.

3. Bakris GL, Williams M, Dworkin L, et al. Preserving renal functionin adults with hypertension and diabetes: a consensus approach.National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000; 36 (3): 646-61.

4. Karppanen H, Karppanen P, Mervaala E. Why and how to implement sodium, potassium, calcium and magnesium changes in food items and diet? J Hum Hypertens 2005; 19 Suppl 3: S10-9.

Appendix 2Vitamins - diet may be supplemented with these quantities

Vitamins Quantity

Thiamine 1.5 mg / day21

Riboflavin 1.8 mg / day21

Pantothenic Acid 5 mg / day21

Niacin 20 mg / day21

Pyridoxine 5 mg / day21

Vitamin B12 3 �g / day20,21, Daily Recommended Intake (DRI)

Vitamin C 60 - 100mg/day3 (DRI)

Folic Acid 1 mg / day21

Vitamin A No supplement2,20, 21

Vitamin D Individualize from stages 3 - 52 ,20, 21

Vitamin E 15 IU / day21

Vitamin K No supplement2 ,20, 21

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5. Law MR, Frost CD, Wald NJ. By how much does dietary salt reduction lower blood pressure? III--Analysis of data from trials of salt reduction. BMJ 1991; 6;302(6780):819-24.

6. Sacks et al. DASH trial. N Engl J Med 2001; 344: 3-10.7. Fried L, Orchard T, Kasiske B. Effect of lipid reduction on the progression

of renal disease: A meta-analysis. Kidney Int 2001; 59: 260-269.8. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker

G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modifi cation of Diet in Renal Disease Study Group. N Engl J Med. 1994; Mar 31;330 (13): 877-84.

9. McCann L, editor. Pocket Guide to Nutrition Assessment of the Patient with Chronic Kidney Disease 3rd ed. National KidneyFoundation: New York. 2002.

10. NKF-K/DOQI Clinical Practice Guidelines for Management ofDyslipidemias in Patients with Kidney Disease. Am J Kidney Dis2003; 41 (4 Suppl 3): I-IV, S1-91.

11. Calder PC. N-3 fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clinical Science 2004; 107: 1-11.

12. Fouque D, Laville M, Boissel JP. Low protein diets for chronic kidney disease in non diabetic adults. The Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD001892. DOI: 10.1002/14651858.CD1892.pub2. 2006.

13. Diabetes Control and Complication Trail Research Group (DCTT).The effect of intensive therapy on the development and progression ofdiabetic nephropathy in the Diabetes and Complication Trial. KidneyInt 1995; 47 (6); 1703-20.

14. Byham-Gray L, Wiesen K, editors. A Clinical Guide to Nutrition Care in Kidney Disease.1st ed. Faulhaber Publisher: Chicago. 2004.

15. Levey AS, Adler S, Caggiuka AW et al. Effects of dietary protein restriction on the progression of advanced renal disease in the Modifi cation of diet in Renal Disease study. Am J Kidney Dis 1996;27:652 - 663.

16. Rose BD. Protein restriction and progression of chronic kidneydisease. Up-To-Date; 8/2006: 14.3.

17. NKF-K/DOQI Clinical practice guidelines for nutrition in CRF. Am JKidney Dis 2000; 35 (6), suppl 2: S9, S56-63.

18. Cronin RE, Treatment of hyperphosphatemia in chronic renal failure.Up-To-Date; 08/2006: 14.3.

19. NKF-K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003; (4) Suppl 3: S1-201.

20. Jacobs C. Costs and benefi ts of improving renal failure treatment – where do we go? Nephr Dial Transpl 2006; 21: 2049 – 2052.

21. Kopple JD, Massry SG. Nutritional Management of Renal Disease.1st ed. Williams and Wilkins: Baltimore. 1997.

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Learning Outcomes

• To gain knowledge and understanding about diabetes mellitus and the effect on kidney function

• To explain the effects of Chronic Kidney Disease (CKD) on diabetes control

• To gain an understanding of the treatment of diabetes

IntroductionDiabetes mellitus is the leading cause of end stage renal failure within the western world and the number of people developingdiabetes is increasing rapidly. The world wide number ofdiabetes cases reached 171 million in the year 2000 and this is predicted to rise to over 300 million by 2030, with a prevalence globally of 4.4% in all age groups1. Reasons for this rapid rise include an ageing population, unhealthy diets, sedentarylifestyles and the increase in obesity.

The World Health Organisation states that the number ofdeaths attributed annually to diabetes is around 3.2 million, with diabetes being the major causes of premature illness and death in most countries, mainly through the increased risk ofcardiovascular disease (CVD)2. Diabetes is among the leadingcauses of CKD, but its frequency varies between populations. According to the European Dialysis and Transplant Registry2004 the percentage of people with diabetes as the leadingcause of CKD ranges from 4.6% in Finland to 45.2% in Austria3.

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The Effect of Diabetes Mellitus on Progression CKD

What is Diabetes mellitus?Diabetes Mellitus is a condition that results in chronic highblood sugar levels (hyperglycaemia) due to insulin defi ciency,insulin resistance or a combination of these two factors.

Type 1 Diabetesyp - usually occurs in children or young adults, but can occur at any age and accounts for approximately 5-10% of all cases of diabetes2. It results from destruction ofthe cells that produce insulin, mainly by the autoimmunedestruction of the pancreatic beta cells. People with type 1 diabetes are dependent on insulin injections to survive as theydo not produce any of their own insulin.

Type 2 Diabetesyp - accounts for the majority of cases ofdiabetes (90-95%) and results from a combination of insulin defi ciency and insulin resistance. The level of hyperglycaemiais usually less severe and can be managed initially with a combination of lifestyle change and oral medication. As the disease progresses however the need for insulin injectionsto manage blood sugar levels becomes more likely. Lifestylefactors such as obesity and a sedentary lifestyle contribute to the increased risk of developing type 2 diabetes as do geneticfactors and ethnicity.

In the presence of typical symptoms of diabetes - weightloss, polyuria, polydipsia, blurred vision and glycosuria - a single fasting plasma glucose level of >7.0mmol1 or a randomplasma glucose of >11.1mmol1 is diagnostic. In the absence of symptoms two such values are needed. A formal glucose

Table 1: Diagnosis of Diabetes

Diabetes

Fasting plasma glucoseor2hr plasma glucose after a 75g oral glucose load

> 7.0mmmol/l (126mg/dl)or> 11.1mmol/l (200mg/dl)

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tolerance test can be ordered where a fasting glucose level is taken then the patient is given 75g of glucose and, 2 hours later, a further glucose level taken. Blood sugar monitoring(BM) tests can not be used for diagnosis2.

How does Diabetes Affect Renal Function? Although people with diabetes can develop any type of kidneydisease, the reason for the high risk of CKD in diabetes is related to the risk of developing diabetic nephropathy. This is a condition characterised by glomerular hyperfunction and hypertrophy, followed by microalbuminuria and then fi nallyprogressive decline in renal function to end stage disease. The exact cause of this is not completely understood but hyperglycaemia plays a role in damaging the microcirculation within the kidney. Hypertension which is highly prevalentparticularly in type 2 diabetes also plays a key part.

Can Diabetic Nephropathy be Prevented?p p y - Not all patients with diabetes will develop diabetic nephropathy. The prevalence is estimated to be 25-30% in type 2 diabetes, and amongwhite patients with type 1 diabetes of 15-30 years’ duration, in the United Kingdom, fewer than 20% will have establishednephropathy4. The prevalence ofnephropathy is higher amongpatients of Asian or African-Caribbean origin. Genetic factors,ethnicity, age and gender are all factors that can not be altered. However the risk of developing nephropathy can be reduced by controlling modifi able risk factors such as glycaemic control and blood pressure.

The Diabetes Control and Complications Study demonstrated the benefi ts of achieving good diabetes control in reducing the risk of developing diabetic nephropathy. Patients with type 1 diabetes assigned to intensive insulin treatment who achieved a mean HbA1c of 7.2% (compared with 9.1% in the control group) delayed the onset of microvascular complications

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such as diabetic nephropathy and also had a slower rate ofprogression of microvascular damage once established5.

The United Kingdom Prospective Diabetes (UKPDS) studyreported similar fi ndings in a large randomised control study ofpeople with type 2 diabetes. A 1% reduction in HbA1c result was associated with a 37% reduction in the risk of developingmicrovascular complications and a 21% reduction in risk ofany morbidity end point or death related to diabetes6.

There was no specifi c threshold found in either of these studies to indicate a level above which patients were at greater risk; any improvement in HbA1c is benefi cial in reducing the risk ofcomplications and the nearer normal the HbA1c concentration the better. The European Association for Study of Diabetes (EASD) recommend a target HbA1c of 6.5% or below7.

How does CKD affect diabetes control?Once CKD is established diabetes becomes diffi cult to control. Advancing CKD is associated with an increase in insulin resistance, this can result in more insulin being required or a conversion from tablets to insulin. However as the diseaseprogresses to end stage renal failure there is a reduction in insulin degradation resulting in a marked reduction in insulin requirements or even cessation of insulin / tablets in type 2 diabetes.

Potential problems in achieving good diabetic control in CKD:• Risk of severe hypoglycaemia with aggressive

control, particularly if dietary intake is unpredictable• Lack of symptoms of hypo- or hyper-glycaemia• Potential for inaccuracy of blood test results• Presence of other diabetes related complications e.g.

neuropathy or retinopathy• Effect of impaired renal function on treatments used to

control hyperglycemia

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Measuring Level of Diabetes ControlHbA1c - diabetes control can be assessed by serial measurement of HbA1c levels. This gives an assessment of glycaemic control for the previous 3months (assuming a normal red blood cell life).

High urea levels may interfere with some of the methods used to measure HbA1c, it is important check with the laboratorywhich assay they use and whether or not results will beaffected by urea levels.

Home Blood Glucose Monitoringg - patient self monitoring via home blood glucose meters is useful to determine the optimum insulin regime and monitor the effect on a daily basis of changesin treatment. Hydration levels, uric acid and the maltose used in some peritoneal dialysis fl uids, will affect some test strips. It is essential to check with the manufacturers any potential interference that may lead to inaccurate results before usinghome blood glucose results to change treatment.

Managing the Patient With DiabetesAll patients with diabetes should be seen at least annually by a family doctor or hospital consultant so that their condition can be monitored and any complications detected early. They maybe seen more often by diabetes nurses and diabetes educators to ensure that they have the right skills and knowledge to be able to self manage their diabetes where this is appropriate. Care of the person with diabetes should include8,9:

• Providing education to ensure self caring e.g. how to blood glucose monitor and how to adjust insulin if blood sugars are not controlled

• Assessing cardiovascular risk factors with the aim to reduce cardiovascular risk e.g. smoking cessation; consider aspirin and statins if appropriate; target BP (<130/80mmHg), total cholesterol (<4mmol/l) and HbA1c (<6.5%)

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• Annual screening for complications including eyes, feet and urine test for microalbuminuria/ proteinuria

• Support with lifestyle changes such as increasing physicalactivity and reducing weight and choosing a healthy diet

• Consider use of an angiotensin converting enzyme (ACE)inhibitor or angiotensin 2 antagonist if microproteinuria or overt proteinuria present

• Refer to a nephrologists when CKD stage 3-4, or sooner if there is a rapid deterioration in renal function which may suggest a non-diabetes related kidney disease

Treatments Used to Achieve Good Diabetes ControlLifestyle Changesy g

• A healthy balanced diet low in refi ned sugars is recommended in diabetes. When CKD is present particularly in advanced stages dietary restrictions are complex and advice from a dietician should be sort to enable the person to combine the various aspects of the dietary recommendations

• Exercise is an important aspect to maintain ideal weightand help control blood glucose levels

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PharmacologyTable 2: Oral Hypoglycaemic agents used in type 2 diabetes

Agents Side Effects Cautions in CKD

Sulphonylurea- acton the pancreas to increase insulinsecretion. Onlyeffective if patient stillproduces some oftheir own insuline.g. Glicalzide,Glipizide, Glyburide,Glimepiride

Usually mild and infrequentmay causegastrointestinalside effects -nausea, vomitingdiarrhoea orconstipationHypoglycaemia,weight gain

Risk of hypoglycaemiaAccumulation of drug ifrenal function impaired, reduce dose or avoidusing once patientreaches end stagerenal failure

Alpha- GlucosidaseInhibitors - delaysdigestion andabsorption of starch and sucrosee.g. Acarbose

Frequently causegastro-intestinalside effects

e.g fl atulenceand abdominalbloating, diarrhoea

Not recommended inCKD due to increasedlevels of the drugif kidney function impaired

Meglitinides- stimulateinsulin secretione.g Repaglinide,Nateglinide

Gastrointestinalside effects,rarelyhypoglycaemia

Caution advised due to the risk ofhypoglycaemia

Biguanides- suppresshepatic glucoseproduction andincrease insulinsensitivity in peripheral tissuee.g. Metformin

Gastrointestinalside effectssuch as nausea,vomiting,diarrhoea,fl atulence, metallic taste

Excreted mainlyunchanged in the urinethus if renal function isimpaired accumulationof the drug occurs.Should not be used if creatinine clearance isreduced due to risk oflactic acidosis. Cautionneeded once GFR is<50ml

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Thiazolidinediones- increase insulinsensitivitye.g. Rosiglitazone,Pioglitazone

Gastrointestinalside effects,weight gain,headacheanaemia,oedema, rarereports of liver toxicity

Metabolised by theliver thus not affectedby dialysis andaccumulation doesnot occur in CKD.However associatedwith heart failure andoedema and should beavoided in advancedCKD, especially if thereis pre-existing heartfailure

InsulinTable 3: Insulin used in type 1 diabetes and in some patients with type 2 diabetes

InsulinType Examples

Onsetof

action

Peakaction

Duration ofaction

Rapid ActingAspartLispro

Gluilisine

5-10 minsmust be

injected withfood

30-90mins

Up to4 hours

Short Acting

ActrapidHumulin S

HypurinNeutral

30 minsInject

20-30minsbefore food

1-2hours

Up to6-7

hours

IntermediateActing

InsulatardHumulin IInsuman

basal HypurinIsophane

60mins

3-6hours

18-24hours

Long actingAnalogues

DetemirGlargine

1.5-2hours

Minimalpeak

18- 24hours

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Insulin Regimes Examples

Subcutaneous insulin injections

Basal Bolus Regime

One or two injections per day of a basalinsulin (eg Glargine, Detemir, Isophaneinsulin ) with meal time injections of a short acting insulin (eg Aspart, Lispro,Glulisine,Soluble insulin)

Twice daily Mixed insulin

One injection of a mixture of basal andshort acting insulin given with breakfast andevening meal

Basal Insulin only

One or two injections per day of basalinsulin (eg Glargine, Detemir, Isophaneinsulin) given at breakfast, evening meal or pre bed. Usually given in combination withoral diabetes medication

Meal time only insulin

Injections of short acting insulin given witheach meal (eg Aspart, Lispro,Glulisine,Soluble insulin). Usually given in combination with oral diabetes medicationand not suitable for use in type 1 diabetes

Continuous Subcutaneous Insulin via a pump

Short acting insulin (eg Aspart, Lispro,Glulisine, Soluble insulin)administered subcutaneously via a small portable electronic pump device Pumps are an advantage in allowing fi ne adjustment to be made to insulin doses but they are expensive and there is potentiallyan increased risk of diabetic ketoacidosis developing

Inhaled Insulin

Relatively new to the market, inhaled insulin is short acting and is given at meal times via an inhalation device directly into the lungs.Must be used in conjunction with a subcutaneous basal insulin injection in type 1 diabetes. Contraindicated in smokers and those with respiratory diseases e.g. asthma

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KDOQI guidelines 2005 suggest that newer insulin regimesand insulin preparations should be used to maintain goodglycaemic control in CKD. Insulin analogues are associated with reduced risk of hypoglycaemia and increased predictabilityin their actions, thus helping to maintain better control8.

How to decide which insulin regime is bestThe choice of insulin regime often depends on a number offactors: the type of diabetes, the patients personal preference, the risk of hypoglycaemia, eating habits and persons lifestyle.If someone is active and has an erratic lifestyle a basal bolus regime is usually preferable to give more fl exibility. If someone is less active and needs help with their injections then a once daily or twice daily regime would be more suitable.

Cautions for Insulin Use in CKDThe kidneys play an important role in metabolising insulin, however there is little change in the metabolic clearance rate in CKD until there has been a substantial reduction in GFR.At this point there is a dramatic reduction in insulin clearanceincreasing the risk of severe hypoglycaemia occurring if insulin doses are not adjusted.

The effect on individual patients will vary depending on factorssuch as dietary intake, presence of other diabetes complications and the types of treatments they are prescribed. An integratedmultidisciplinary approach is required to minimise problemsand maintain adequate diabetes control.

Table 4: Recommendations for adjusting insulin with decline in renal function10

No dose adjustment required

GFR 10-50ml/min Reduce to 75% of baseline dose

GFR <10ml/min Reduce by as much as 50%

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Side Effects of InsulinInsulin has few side effects, occasionally people may develop sensitivity to insulin resulting in redness and infl ammation at the injection site but this is rare. The main concern whensomeone takes insulin is the risk of hypoglycaemia (bloodsugars <4mmol/s) resulting in symptoms of sweating, pallor, dizziness, shaking, confusion and possible collapse.

Action to take if hypoglycaemia occurs:• If conscious give patient a sugary drink, 3 glucose tablets

or Glucogel• Follow this with a carbohydrate based snack e.g. bread,

biscuits• If unconscious do not give anything by mouth use

intramuscular Glucagon or intravenous dextrose

Another side effect of insulin is possible problems with injectionsites with skin/ fat atrophy or hypertrophy occurring. This can be prevented by advising people to regularly change theirinjection sites.

What to do if patient is unwell

If the patient is unwell it is important to do the following:• Not to stop the insulin or tablets, they may even need

to be increased as hyperglycaemia is common in the presence of illness

• Increase blood glucose monitoring• Ensure hydration, maintaining fl uid balance• Refer to a medic if vomiting to prevent ketoacidosis

Other Complications of DiabetesThe person with diabetes who develops CKD is likely to have also developed a number of other complications related to

131


their diabetes. This is due to the fact that the vascular damagethat is occurring within the kidney also occurs in other areas. These complications include:

• Peripheral neuropathy and peripheral vascular disease resulting in high risk of foot ulceration and amputation

• Autonomic neuropathy resulting in postural hypotensionor gastric disturbances e.g. gastroparesis

• Cardiovascular Disease e.g. angina, stroke, myocardialinfarction or heart failure

• Retinopathy resulting in visual impairment and possible blindness

• Sexual dysfunction e.g. erectile dysfunction in men

The risk of these complications occurring can be reduced through tight control of blood pressure, cholesterol and blood sugar levels.

Key Points Summary• Diabetes is the leading cause of end stage renal disease

in the western world• The number of people developing diabetes is increasing

rapidly world wide• The risk of developing diabetic kidney disease can be

reduced through good diabetes control (HbA1c <6.5%)• Once CKD is established diabetes becomes diffi cult to

control and careful adjustment of treatment is needed to avoid problems

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Frequently asked Questions1 What is Diabetes Mellitus?

Diabetes is a condition that results in chronic high bloodsugar levels and is the result of insulin defi ciency, insulin resistance or a combination of these two factors.

2 What is the difference between type 1 and type 2 diabetes?

Type 1 diabetes is caused by an auto immune response in which the body destroys the cells that make insulin.The person with type 1 diabetes is dependent on insulin injections to survive as they do not make any of their own. In type 2 diabetes the person still produces some insulin but not enough or may be insulin resistant and can be treated with diet, tablets but some patients will need insulin.

3 Why do a lot of patients with diabetes have CKD?Diabetic nephropathy which results in microalbuminuria then progressive decline in renal function is caused byhigh blood sugar levels. People with diabetes are also more likely to have high blood pressure which contributes to CKD.

4 Can diabetic nephropathy be prevented?Yes, good diabetes control and tight control of blood pressure reduces the risk of diabetic nephropathy

5 How does CKD affect diabetes control?A person with CKD is likely to have diffi culty in managingblood sugar levels and may be at risk of severe hypoglycaemia due to poor clearance of medication

6 Are diabetes treatments safe to use in CKD?Many of the oral medications used to treat diabetes become contra-indicated in advanced CKD or should be used with caution. Insulin can be used safely in all stages of CKD and is not affected by dialysis. However signifi cant reductions in dose may be needed once GFR falls below 20.

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References1. Wild S, Roglic G, Green A et al. Global Prevalence of Diabetes.

Diabetes Care 2004; 27, (5): 1047-1053.2. World Health Organisation, Facts and Figures, 2007.

http://www.who.int/diabetes/facts/world_fi gures/en3. ERA-EDTA. European Dialysis and Transplantation Registry,

2004. http://www.era-edta-reg.org/index.jsp4. Harvey JN, Rizvi K, Craney L, Messenger J, Shah R, Meadows PA.

Population-based survey and analysis of trends in the prevalence ofdiabetic nephropathy in Type 1 diabetes. Diabetes Medicine 2001;18: 998-1002.

5. DCCT. Diabetes Control and Complications Trial Research Group – The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependant diabetes mellitus. N Engl Med 1993; 329:304.

6. Stratton I, Adler A, Neil A et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405-412.

7. EASD. Guidelines on Diabetes, pre diabetes and cardiovascular disease. EASD 2007. http://www.easd.org/

8. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients. NKF 2005.http://www.kidney.org/professionals/KDOQI/guidelines_cvd/guide11.htm

9. British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The StrokeAssociation – JBS2: Joint British Society Guidelines on Prevention of Cardiovascular Disease in Clinical Practice. BMJ 2005; 91, (suppl v).

10. Snyder RW and Berns JS. Use of insulin and oral hypoglycaemic medications in patients with diabetes mellitus and advanced kidneydisease. Semin Dial 2004;17: 365.

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Learning Outcomes

• To gain knowledge and understanding of the Cardiovascular (CV) risk associated with Chronic Kidney Disease (CKD)

• To evaluate and understand how CV risk can be reduced in patients with CKD

IntroductionCardiovascular disease (CVD) occurs as a result of disease processes affecting the heart and blood vessels with the underlying cause being atherosclerosis. This results in cardiovascular (CV) events such as myocardial infarction,stroke, and heart failure. CVD is the leading cause ofdeath in end stage kidney disease1. The risk of developingcardiovascular disease is multifactorial and the increased riskstarts early in the course of chronic kidney disease (CKD).When cardiovascular events occur morbidity and mortalityis higher amongst patients with CKD and the implications of CV disease are for many far greater than the risk of the progression to end stage renal failure. If the burden of CV risk in CKD is to be reduced, all patients with CKD need to be offered preventative advice and treatments to reduce this risk.

What is the risk of CV disease in CKD?It is well recognised that patients with end stage renal failure have much higher CV mortality and morbidity rates than patients without renal failure. The death rate is 5-90 times

137

Cardiovascular Risk in CKD

greater in dialysis patients than the general population, the difference being greatest in the younger age group1. Howeverwhat may not be well recognised is the fact that this increased CV risk starts early in the course of CKD.

A study of more than 1.1 million adults from the Kaiser Permanente Renal Registry in San Francisco, found that when kidney function measured as estimated glomerular function(eGFR) dropped, the risk of death and cardiovascular events such as heart disease and stroke, increased. Compared with patients whose eGFR was at least 60ml/min/1.73m2:

• The increased risk of death ranged from 17% in those with eGFR 45-59ml/min/1.73m2 to 600% in those with eGFR <15ml/min/1.73m2

• The increased risk of cardiovascular disease (CVD)events ranged from 43% in those whith eGFR 45-59ml/min/1.73m2 to 343% in those whith eGFR <15ml/min/1.73m2

The KDOQI3 Guidelines state that: patients with chronic kidneydisease, irrespective of diagnosis, are at increased risk of CVD,including coronary heart disease, cerebrovascular disease,peripheral vascular disease, and heart failure. Both “traditional” and “chronic kidney disease related (non-traditional)” CVD risk factors may contribute to this increased risk.

• All patients with chronic kidney disease should be considered in the “highest risk” group for cardiovascular disease, irrespective of levels of traditional CVD risk factors3

Traditional Risk Factors for CV DiseaseNon Modifi able CVD Risk Factors

• Age > 55yrs for men, age >65yrs women• Family history of early CV death• Ethnicity

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Modifi able CVD risk factorsThe Interheart study identifi ed that there were nine potentiallymodifi able risk factors for developing cardiovascular disease, which are as follows4:

• Smoking• Dyslipidaemia• Hypertension• Diabetes• Abdominal obesity• Psychosocial factors• Lack of daily consumption of fruit and vegetables• Regular excessive alcohol intake• Lack of regular physical activity

Smoking.- Smoking is a major contributory factor to CV risk, cardiac events fall 50% in people who stop smoking and the risk of CVD, including acute myocardial infarction, stroke and peripheral vascular disease, also decreases signifi cantlyover the fi rst two years after stopping smoking5. The CV risks relating to smoking are no different in patients with CKD to that of the general population however the consequences may be far greater including a more rapid progression of CKD.

Dyslipidaemia.- In worldwide studies, 46% of coronary heart disease deaths are attributable to raised cholesterol levelsand cardiovascular risk increases directly in relation to theconcentration of total cholesterol6. In the presence of CKD, triglyceride clearance may be impaired leading to raised serum triglycerides and HDL cholesterol, which is cardio protective, is decreased.

Hypertension.- Hypertension leads to left ventricular hypertrophy and is a major risk factor for CV disease. The risk for both coronary heart disease and stroke increases progressively with every increment in blood pressure above 110/75mmHg7. High blood pressure can be both a cause ofCKD and a consequence of it. The prevalence of hypertension

139


among patients with CKD reported in previous studies has ranged from 60 to 100%, depending on the study population, the cause and the level of renal dysfunction8.

Diabetes.- Diabetes is now well recognised as a major CVrisk factor with up to 75% of people with diabetes dying fromCV disease. The relationship between blood sugar levels and CV risk is continuous with every 1% rise in HbA1c level associated with 14% more deaths9. If diabetes and CKD are present together the patient is considered to be very high riskof a CV event. In 5 years 32% of patients with type 2 diabetes who develop microalbuminuria are dead with cardiovascular disease accounting for 53% of these deaths10.

Weight control.- Excess body weight is associated withhigh blood pressure, raised cholesterol and type 2 diabetes, contributing to morbidity and mortality from heart disease and stroke11. Obesity also plays an important role in progression ofkidney disease.

CKD Related CV Risk FactorsIntensive treatment of conventional CV risk factors hasnot resulted in improved outcomes in CKD patients12. Thisimplies that other CV risks factors exist that are specifi c to CKD patients, these are discussed below:

Vascular Calcifi cation.- CKD patients have excessive vascular calcifi cation. Signifi cant coronary calcifi cation has been observed in end stage renal failure patients as early as in their 30’s and this has been noted to progressively increase overtime13. Vascular calcification leads to increased stiffnessin arterial walls, reduced vascular compliance and increased systolic blood pressure, this puts stress on the heart andeventually leads to CV morbidity and mortality.

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Calcium and Phosphorus Metabolism.- CKD is associated with changes in mineral metabolism. Abnormal calcium and phosphorous metabolism are independent predictors of death in ESRD due to vascular calcification13.

Infl ammation.- Inflammation which is common in the uraemicstate is linked to high CV mortality. Also atherosclerosis which is common in CKD patients represents an infl ammatory state which leads to worsening anaemia14.

Anaemia.- The available evidence, consisting of largedatabase analysis and population studies, clearly show that low haemoglobin (Hb) levels are associated with higher rates ofhospitalisations, cardiovascular disease, cognitive impairment, and other adverse patient outcomes, including mortality15.When anaemia is present the workload on the heart increases which can lead to left ventricular hypertrophy, increasing the risk of death from heart failure or ischaemic heart disease.

How can CV risk be reduced?CV risk reduction can be achieved through lifestyle and risk factor intervention, appropriate drug therapies to lower blood pressure, modify lipids and reduce glycaemia, as well as the use of anti-thrombotic medication. As most patients with CKD have multiple risk factors for CVD a multi-disciplinary,coordinated approach will be necessary. The data available to support CV risk reduction is not specifi c to reducing risk in CKD however evidence from general population studies supports the following key interventions:

The key lifestyle interventions to reduce CV risk are:• To stop smoking.- cardiac events fall 50% in people

who stop smoking and the risk of CVD also decreases signifi cantly over the fi rst two years after stoppingsmoking5

• Make healthier food choices.- nutritional intake is animportant part of reducing CV risk through reductions in

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for example salt, fat and alcohol intake. However due to the complexity of dietary restrictions in CKD a full nutritional assessment with a dietitian will be necessaryto help people to make healthier choices that not onlyreduce traditional CV risk but also take into account CKDspecifi c risk factors such as anaemia and bone disease rather than bone metabolism

• Increase aerobic activity.- regular moderate physicalactivity can reduce overall CV risk. For example, brisk walking for half an hour per day reduces relative CHDrisk by 20%16. The goal for all people with CKD should be 30 mins of exercise most days of the week, however for those not currently active low levels are recommendedinitially with a gradual increase

• Optimise weight and weight distribution (e.g. reducingcentral obesity) Reducing weight to a body mass index (BMI) of 25 is preferable, however, a reduction of 5-10%of initial body weight is still associated with signifi cant health benefi ts including improved blood pressure, lipid and glucose metabolism17

Table 1: Key Treatment Targets3, 18

WaistCircumference

Men < 102cm (Asian men < 90cm)Women < 88cm (Asian women < 80cm)

Body Mass Index < 25

Blood Pressure < 130mmHg and < 80mmHg(though this target may vary depending on other clinical factors)

Lipids LDL-C < 100mg/dl (< 2.6mmol/l)Triglycerides < 200mg/dl (2.26mmol/l)

Glucose Fasting � 6.0mmol/lHbA1c < 6.5%

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Blood Pressure.- meta-analysis and systematic reviews ofblood pressure lowering have consistently demonstrated the benefi t of blood pressure reduction in reducing CV risk, the benefi t of treatment driven by the quality of blood pressure control19. KDOQI guidelines place all those with CKD in the “highest risk” group for CV development and as such will require pharmacological as well as lifestyle intervention to lower blood pressure to <130/80mmHg3. A multi-disciplinaryapproach used to deliver multiple interventions for blood pressure and other CV risk factors has been shown to be benefi cial to help reduce CV risk20.

Lipid Lowering.- The benefi t of lipid lowering in reducingcardiovascular risk has been demonstrated in numerousrandomised control trails and is considered to be even morebenefi cial in people at high CV risk. The ASCOTT-LLA and the Heart Protection Study demonstrated that loweringLDL-C levels by 1mmol/l in high risk patients with onlymoderately raised levels reduced risk of coronary heart disease by 25% and 36% respectively21.

NKF KDOQI guidelines recommend aggressive treatment ofraised cholesterol levels in CKD22. Lifestyle advice to reduce total and LDL cholesterol, lower triglycerides and increaseHDL and drug therapy with statins is indicated in most highrisk people and can be used safely and effectively in CKD.

Antithrombotic Treatments.- anti-thrombotic treatmentshave been shown to have signifi cant positive benefi ts in patients at high risk of CVD23. Low dose Aspirin is indicatedif 10 yr CV risk is >20% and blood pressure is controlled to <150/90 mmHg24.

Targets for CKD specifi c CV risk factors3

• Correction of anaemia.- target Hb levels 11-12 g/dl.(Hb<12.0 g/dl in men, Hb<11.0 g/dl in women). (Seeanaemia chapter for further information). More evidence

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is needed as to the most appropriate Hb values to reduceCVD risk

• Correction of serum phosphate/calcium.- targetphosphorus levels (3.5-5.5 mg/dl / 1.13-1.78 mmol/l)

• Parathyroid Hormone level should also be controlled to reduce CV risk with a targetPTH-150/300 pg/ml (16.5-33.0 pmol/l)

• Non-calcium based binders should be used if there issevere vascular calcification

Key Points• The risk of CV disease is very high in CKD• The majority of people from CKD will die from CVD and

for many it is more important than the implications ofreaching end stage renal failure

• People with CKD will have traditional risk factors for CKD the same as the general population but also have CKD specifi c risk factors increasing the risk further

• CV risk can be reduced in CKD by addressing individual CV risk factors

• As CV risk factors will be numerous; a coordinated multi-disciplinary approach to treatment will be essential

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Frequently Asked QuestionsWhat is Cardiovascular Disease?Cardiovascular disease (CVD) occurs as a result of disease processes affecting the heart and blood vessels with the underlying cause being atherosclerosis. This results in CVevents such as myocardial infarction, stroke, and heart failure.

What is the risk of CVD in CKD? The risk of CVD starts early in the course of CKD. When microalbuminuria is present even before eGFR starts to fall CV risk is already increasing and the risk progresses substantiallyas the person approaches end stage renal failure.

What traditional CVD risk factors affect people with CKD?Smoking, dyslipidaemia, hypertension, diabetes, abdominal obesity, psychosocial factors, lack of daily consumption offruit and vegetables, regular excessive alcohol intake, lack ofregular physical activity.

What specifi c CKD related CVD risk factors are there? Anaemia, vascular calcifi cation, abnormal calcium and phosphorous metabolism, infl ammation.

How can CV risk be reduced?A multi-disciplinary, multi-intervention approach is necessaryto help people deal with the numerous CV risk factors they are likely to need. This will include lifestyle modifi cation e.g. stop smoking, reduce weight, exercise more and make healthier food choices. Pharmacological treatment will also usuallybe needed to achieve strict targets for blood pressure, lipid and glycaemic control as well as to control anaemia and bone metabolism problems.

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References1. US Renal Data System USRDS Annual Data Report. National

Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda MD. 2002.

2. Go A, Chetow G, Fan D, McCulloch C, and Hsu C. Chronic Kidney Disease and the risks of death, cardiovascular events and hospitalisation. N Engl J of Med 2004; 35: 1296-1305.

3. NKF KDOQI Guideline 15. Association of Chronic Kidney Disease with Cardiovascular disease. NKF 2002. http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p7_risk_g15.htm

4. Yusuf S, Hawken S and Ounpuu S et al. Effect of potentially modifi able risk factors associated with myocardial infarction in 52 countries. The interheart study. Lancet 2004; 364, (9438): 937-52.

5. World Health Organisation. CVD prevention and control: missed opportunities. 2007. http://www.who.int/cardiovascular_diseases/prevention_control/en/

6. Magnus P & Beaglehole R. The real contribution of the major risk factors to the coronary epidemic. Arch Intern Med 2001; 161, (22):2657.

7. Lloyd-Jones D, Evans & J Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community JAMA2005; 294:466.

8. Whelton PK, Perneger TV, Brancati FL & Klag MJ. Epidemiologyand prevention of blood pressure-related renal disease. J HypertensSuppl 1992; 10: S77–S84.

9. Stratton I, Adler A, Neil H, Mathews D et al -on behalf of the UKPDS study group Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35):prospective observational study. BMJ 2000; 321 (7258): 405-12.

10. Royal College of General Practitioners UK. Type 2 diabetes :Diabetic renal disease :prevention and early management. RCGP: Universityof Sheffi eld UK. 2002.

11. Field A, Coakley E, Must A et al. Impact of overweight on the risk ofdeveloping common chronic diseases during a 10-year period. Arch Intern Med 2001; 61(13):1581-6.

12. Rakhit D, Marwick T, Armstrong K et al. Effect of aggressive risk factormodifi cation on cardiac events and myocardial ischemia in patients with CKD. Heart 2006; 92:1402-1408.

13. Goodman W, Goldein J, Kuizon B et al. Coronary artery calcifi cation in young adults with end stage renal failure undergoing dialysis.N Engl J of Med 2000; 342:1478-1483

14. Ross R. Atherosclerosis - an infl ammatory disease. N Engl J Med1999; 340:115-126.

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15. Levin A and Foley RN. Cardiovascular disease in chronic renal insuffi ciency. Am J Kidney Dis 2000; 36:S24-S30.

16. Tanasescu M, Leitzmann M, Rimm EB et al. Exercise type and intensityin relation to CHD in men. JAMA 2002; 288(16): 1994–2000.

17. Department of Health. National Service Framework for CoronaryHeart Disease. Department of Health 2000.

18. British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association. JBS2: Joint British Society Guidelines on Prevention ofCardiovascular Disease in Clinical Practice. BMJ 2005; 91, S5.

19. Williams B, Poulter N, Brown M, Davis M, Mcinnes G, Potter J et al. British Hypertension Society Guidelines: Guidelines for the management of hypertension: report of the 4th working party ofthe British Hypertension Society. BHS IV. Journal of Human Hypertension 2004; 18, 139-185.

20. Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med2003; 348:383-393.

21. Sever P, Dahlof B, Poulter N et al. Prevention of coronary and stroke events with Atorvastatin in hypertensive patients who have averageor lower than average cholesterol concentrations, ASCOTT-LLA: a multicentre randomised control trial. Lancet 2003; 361(9364):1149-58.

22. NKF KDOQI. Managing Dyslipidemias in Chronic Kidney Disease Am J of Kidney Dis 2003; April.

23. Anti-thrombotic Trialist Collaborative. Collaboration and meta analysisof randomised trials of ant-platelet therapy for the prevention of death, myocardial infarction and stroke in high risk people. BMJ 2002; 324:71-86.

24. Chronic Kidney Disease in Adults: UK CKD Guidelines forIdentifi cation, Management and Referral of Adults 2005. Available from: http//.www.renal.org/CKDguide/ckd.html.

25. Heart Protection Study Collaborative. Heart protection study ofcholesterol lowering with Simvastatin in 20,536 high risk individuals: a randomised placebo controlled trial. Lancet 2002; 360:7-22.

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Learning Outcomes

• To gain knowledge of the management of hypertension in patients with Chronic KidneyDisease (CKD)

• To understand the specifi c indications and contra-indications of antihypertensive medications

• To highlight specifi c precautions when usingantihypertensive drugs in patients with CKD

IntroductionThe aim of this chapter is to provide an overview of the pharmacological management of hypertension. The term CKD encompasses chronic renal failure of manydifferent origins1. Trials investigating the effect ofdifferent therapies on the evolution of renal function have usually included patients with primary renal diseasesand/or early or established diabetic nephropathy2.Current international hypertension guidelines3,4 recognisemicroalbuminuria, elevation serum creatinine and a reduction in estimated GFR (eGFR) as major cardiovascular (CV) risk factors and further increase the risk if pre-existing CV risk factors already exist. In fact, patients progressing to end-stagerenal disease (ESRD) are a minority in individuals developingthe different forms of CKD, and could be considered as survivors because CV disease accounts for the death of the great majority of patients with CKD before the development of ESRD5,6.

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Management of Hypertension in CKD

The fact that CKD and CV disease are so closelyassociated has raised interest in investigatingthe evolution of renal function in trials involvinghypertensive, as well as heart failure and post-myocardialinfarction patients. This interest is fully justifi ed by the demonstration, in all these situations, of the predictive capacity of renal function alterations for the development ofCV events or death. From its earliest stages, the presence of CKD must be considered as presenting an increased CV risk in any hypertensive patient and in any patient presenting with established forms of cardiovascular disease7.

Reduction of CV events in CKD population requires the implementation of effective integral therapeutic interventions that simultaneously protect both the kidneyand the cardiovascular system. These interventionshave to be implemented at the earliest stage possible in CKD, the attainment of strict blood pressure (BP) control is essential and hypertension should be treated fi rst in anypatient with an elevated global CV risk.

Hypertensive nephropathy was very common in untreatedprimary hypertension. In one study proteinuria was present in 42% and CKD present in 18% of a series of 500 patients followed until death8. With the adventof antihypertensive therapy the cardiovascular and renal prognosis of hypertensive patients improved dramatically, and the general belief is that only a very small percentage of patients (<2%) develop CKD. However, some studies have indicated that the prognosis of renal function is not so good in hypertensive patients, and that renal insuffi ciency is still prevalent in essential hypertension7.

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Mechanisms of Action and Renal Effects of Antihypertensive TherapyDiureticsThere are three main types of diuretics as follows:

• Loop diuretics• Thiazides• Distal potassium-sparing agents

Loop DiureticsThe prime action of loop diuretics occurs in the thick ascendinglimb of the loop of Henle. The addition of loop diuretic decreases the absorption of sodium. Loop diuretics can cause hyponatraemia, hyperkalaemia, hypomagnesaemia andmetabolic alkalosis. They raise the plasma concentrations ofurate and cholesterol, and can impair carbohydrate tolerance. Acute renal failure can develop if the diuresis or fall in blood pressure is excessive.

ThiazidesThe major site of action of thiazide diuretics is the proximal distal convoluted tubule, where they block the coupled reabsorption of sodium and chloride. Unlike loop diuretics, they do not block reabsorption in the loop of Henle; thereforethiazides do not impair the urine concentrating mechanism. Thiazide therapy raises the serum urate concentration, andthey are contraindicated in patients with gout. Thiazidescan impair carbohydrate tolerance and increase plasma cholesterol concentration.

Distal Potassium-Sparing AgentsThese agents act on the principal cells in the distal convoluted tubule and initial connecting tubule and the cortical collectingduct, where they inhibit entry of sodium. Their main action is to reduce the excretion of potassium; however, hyperkalaemiais a potentially lethal complication of using these drugs.The risk is dose-dependent and increases considerablyin patients with CKD or in those receiving potassium

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supplements. Hyperkalaemia is potentiated by other drugsthat impair potassium excretion or raise the plasma potassium, such as angiotensin-converting enzyme (ACE) inhibitors, non-steroidal anti-infl ammatory drugs (NSAID), beta-blockers or heparin which limits aldosterone synthesis.

�-Adrenergic Antagonists�-Adrenergic antagonists (“beta blockers”) attenuate sympathetic stimulation through competitive antagonismof catecholamines at �-adrenergic receptors. The initialsystemic haemodynamic effects are decreases in heart rate (HR) and cardiac output (CO) and an increase in total peripheral vascular resistance (TPVR) proportional to the degree of cardiac depression. In general,�-adrenergic antagonists have little or no clinicallyimportant effect on glomerular fi ltration rate (GFR),effective renal plasma fl ow (ERPF), or renal vascular resistance (RVR). The long-term oral administration of�-adrenergic antagonists usually has no effect on sodium, potassium or free water excretion. This means bodyfl uid composition and weight are unchanged.

Central � - Adrenergic AgonistsCentral �2-adrenergic agonists have a direct effect on specifi c pre-synaptic and post-synaptic �2-adrenergicreceptors located at midbrain and medullary sites. The net pharmacologic effect is a reduction in catecholamine release and turnover. In general,central �2-adrenergic agonists have little or no clinicallyimportant effect on GFR or ERPF. Fractional excretion of sodium and potassium is unchanged, and body fl uid composition and weight are not modifi ed.

Peripheral � -Adrenergic Antagonists�1-adrenergic antagonists induce dilation of both resistance and capacitance vessels by selectively inhibitingpost-junctional �1-adrenergic receptors. The net physiologiceffect is a decrease in TPVR. �1-adrenergic antagonists have

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little or no clinically important effect on GFR or ERPF. However, fractional sodium excretion is reduced and the extracellularfl uid compartment is expanded.

Direct-Acting VasodilatorsDirect-acting vasodilators may have an effect on both arterial resistance and venous capacitance. The net physiologic effect is a decrease in TPVR associated with increases in HR and CO. Monotherapy with Hydrallazine and minoxidil is associated with salt andwater retention and expansion of plasma and extracellular fluid volumes. Retention of salt and water is notrelated to a reduction in GFR; it may be due to a direct drugeffect on the proximal convoluted tubule.

Calcium AntagonistsThe calcium antagonists are a chemicallyheterogeneous group of drugs sharing a common antihypertensive mechanism of action: interferencewith entry of calcium into smooth muscle cells ofresistance arterioles through L-type voltage-operatedchannels. The net physiologic effect of calcium antagonistsis a decrease in TPVR. All of the calcium antagonists induce an acute natriuresis and diuresis. This effect appears to be independent to a direct drug effect on either the proximal tubule or segments located more distally than the loop of Henle.

Angiotensin-Converting Enzyme Inhibitors (ACEI)Angiotensin-converting enzyme (ACE) inhibitors lower blood pressure by decreasing TPVR. In general, ACE inhibitors maintain GFR, increase ERPF, and decrease RVR in patients who have essential hypertension with normal renal function. Urinary protein excretion is decreased. In patients with impaired GFR, a marked improvement in renal function mayoccur. The decrease in proteinuria is unrelated to changesin systemic blood pressure, GFR, ERPF, or fi ltration fraction. ACE inhibitors may produce functional renal insuffi ciency in patients who have essential hypertension with severe bilateral

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hypertensive nephrosclerosis, in patients with severe bilateral renal artery stenosis, or in patients with stenosis of the renal artery of a solitary kidney. Finally, ACE inhibitors have been demonstrated to reset sodium and water homeostasis, by an initial natriuresis and water diuresis, and to spare potassium loss. Clinically signifi cant potassium retention may occur, especially in the presence of renal disease, therefore concurrent administration of potassium supplements, potassium sparingdiuretics, or drugs impairing potassium excretion should beavoided.

Angiotensin II Receptor Blockers (ARBs)Angiotensin II receptor blockers reduce TVPR and systemicarterial pressure in hypertensive patients. In patients with essential hypertension, ARBs generally have no discernible effecton GFR as assessed by creatinine clearance. In patients with renalimpairment and renovascular occlusivedisease, reversibleincreases in serum creatinine have been reported following commencement on ARB. Angiotensin II receptor antagonists produce a modest natriuretic action through blockade.

Table 1. Showing most indications and contraindications of the major classes ofantihypertensive medications4.

Contraindications

Class Conditionsfor use Compelling Possible

Diuretics(Thaizdies)

• Congestive heart failure

• Elderlyhypertensives

• Isolated systolichypertension

• Hypertensives ofAfrican origin

• Gout • Pregnancy

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Class Conditionsfor use Compelling Possible

Diuretics(Loop)

• Renal insuffi ciency• Congestive heart failure

Diuretics(Anti-

aldosterone)


• Post myocardialinfarction

• Renal failure• Hyperkalaemia

Beta-blockers

• Angina pectoris• Post myocardialinfarction

• Congestive heart failure (up-titration)

• Pregnancy• Tachyarrhythmia’s

• Asthma• Chronicobstructivepulmonarydisease(COPD)

• A-V block(Grade 2 or 3)

• Peripheralvascular disease

• Glucoseintolerance

• Athletes andphysically activepatients

Calciumantagonists(Dihydro-pyridines)

• Elderly patients• Isolated systolichypertension

• Angina pectoris• Peripheral vascular disease

• Carotidatherosclerosis

• Pregnancy

• Tachyar-rhythmia’s

• Congestive heartfailure

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Calciumantagonists(Verapamil, diltiazem)

• Angina pectoris• Carotidatherosclerosis

• Supraventriculartachycardia

• AV block (grade2 or 3)

• Congestiveheart failure

Angiotensin-converting

enzyme(ACE)

inhibitors


• LV dysfunction• Post myocardialinfarction

• Non-diabeticnephropathy

• Type I diabetic nephropathy

• Proteinuria

• Pregnancy• Hyperkalaemia• Bilateral renalartery stenosis

AngiotensinII receptor

antagonists(AT1

blockers)

• Type 2 diabeticnephropathy

• Diabeticmicroalbuminuria

• Proteinuria• Left ventricularhypertrophy

• ACE-inhibitor cough

• Pregnancy• Hyperkalaemia• Bilateral renalartery stenosis

Alfa-blockers•Prostatichyperplasia (BHP)

• Hyperlipidaemia

•Orthostatichypotension

•Congestiveheart failure

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Table 2. Describes the most common and specifi c side effects of antihypertensivemedications and relevant precautions that should be considered for theiradministration9.

Side effects Precautions

Diuretics*

• Hypokalaemia• Hyperuricaemia• Metabolic alkalosis•Hyponatremia•Hypernatremia• Dyslipidaemia• Dehydration•Glucose intolerance• Erectile dysfunction•Hyperkalaemia(potassium sparingdiuretics)

• Avoid high doses use*• Avoid potassium sparingdiuretics with renalinsuffi ciency

Beta-blockers

• Bradycardia• Fatigue•Cold extremities•Bronchoconstriction•Dyslipidaemia•Glucose intolerance

• In patients with cardiacfailure start with a minimaldose and they require close clinical monitoringbefore increasing the dose

• Never stop abruptly

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Calciumantagonists

•Low extremitiesoedema

• Headache• Palpitations•Tachycardia•Sweating• Face redness• Nocturia•Constipation andbradycardia with Verapamil

• Due to the bradycardiceffect, Verapamil andDiltiazem shouldn’t beuse together with beta-blockers

ACEI

•Cough in 5-20% ofpatients

•Hyperkalaemia• Acute decrease in renal function

• First dosehypotension in patients withvolume depletion

• Rash• Angioedema

• Care in patients with intermittent claudicationas there may be possible renal artery stenosispresent

• Monitor kidney functionprior to and postcommencement

• For volume depletion patients the depletion must be corrected beforetreatment

ARB•Similar to ACEIexcept without thecough

•Similar to ACEI

Alfa-blockers

•First dosehypotension

•Orthostatichypotension

•Give fi rst dose at bedtime•Check for orthostatic hypotension prior to commencement in elderlypatients and diabetics patients

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Renal Protection The renoprotection provided by antihypertensive agentsdepends on their capacity to lower systemic blood pressure and also on their specifi c effects on renal haemodynamics;these effects can positively or negatively infl uence intra-glomerular pressure. In hypertensive patients with CKD,antihypertensive therapy should aim for a target of�130/80mmHg initially using an ACE inhibitors or ARB to inhibit the renin-angiotensin system and thenadding diuretics and other agents as needed4. ACEinhibitors, ARBs and possibly aldosterone antagonistsare indicated because they reduce proteinuria in both diabetic and non-diabetic nephropathy. In the presence of proteinuria higher than 1 g/day, the recommended targetfor blood pressure control is �125/75 mmHg3, 4

A reduction in proteinuria to 0.5 g/day is associated with a slower progression of both renal and cardiovascular disease. Similarly, both ACE inhibitors and ARBs are associated with a slower GFR decline although without a return to normal values. There may also be an argument for using a non-dihydropyridine (DHP) calcium channel blocker (CCB)although DHP CCBs may increase proteinuria and even accelerate the decline in GFR.

The possible specifi c adverse effects of DHP CCBs may result in countering the benefi ts of better blood pressure control.

Precautions should be taken into consideration for the useof concomitant treatments that can cause drug induced hyperkalaemia in CKD patients10, especially combinations ofthe following:

• ACEI and ARB• Potassium sparing diuretics• Potassium supplements• Non-steroids antiinfl ammatory (NSAIDs) drugs• COX-2 inhibitors

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• Heparin and low molecular weight heparins• Digoxin toxicity (but not at therapeutic levels)• Ciclosporin and Tacrolimus• Beta-blockers, Trimethoprim, Ketoconazole and Pentamidine

Treatment of Hyperkalaemia• If eGFR 60 ml/min, commence on a loop diuretics and

continue to treat with ACEI or ARB with serum potassium �5.5mmol/L

• If the potassium >5.5mmol/L correct the hyperkalaemiawith a loop diuretics and correct the metabolic acidosis, ifpresent, with bicarbonate

• Do not use spironolactone dosage >25mg per day if usingACEI

• Advice on dietary restriction of potassium• Stop NSAIDs• Discontinue ACEI/ARB or spironolactone if potassium

continually >5.5.mmol/l

Lifestyle ChangesAlong with the use of antihypertensive medication, education on health promotion should be addressed in this group ofpatients. It is important to ensure that all advice is providedin a culturally sensitive way and various types of educational tools are provided e.g. DVD, written information leafl ets etc. The following health advice should be given along with the advice given for the reduction in cardiovascular risk factors10:

• Weight loss - obesity (BMI>30kg/m2)• Healthy eating and reduction in salt intake• Exercise• Education in alcohol intake• Reduction in caffeine intake• Reduce stress• Smoking cessation

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ConclusionsIndividuals with CKD usually present with hypertensionand multiple other risk factors for CV disease. The risk attributable to CKD or to the presence of the other factors may be totally independent. An integralCV protection programme is required in patients presenting with CKD. Antihypertensive and other cardiovascular drugs, like statins or aspirin, can alsoprevent further decline in renal function. It is importantto ensure a good understanding of the indications for use, contraindications and side effects ofantihypertensive medications, along with the benefi ts that can be achieved by effective and early treatment of hypertension.

References1. K/DOQI clinical practice guidelines on hypertension and

antihypertensive agents in chronic kidney disease. Am J Kidney Dis2004; 43: S1-S290.

2. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renaloutcomes: systematic review and meta-analysis. Lancet 2005; 366: 2026-2033.

3. Chobanian A, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7 Report. JAMA 2003;289: 2560-2572.

4. Guidelines Committee: 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management ofarterial hypertension. J Hypertens 2003; 21: 1011-1053.

5. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalisation. N Engl J Med 2004; 351: 1296-1305.

6. Weiner DE, Tabatabai S, Tighiouart H, et al. Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis 2006; 48: 392-401.

7. Segura J, García-Donaire JA, Praga M, Ruilope LM. Chronic kidneydisease as a situation of high added risk in hypertensive patients. J Am Soc Nephrol 2006; 17 Suppl 2: S136-140.

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8. Perera GA. Hypertensive vascular disease: description and natural history. J Chronic Dis 1995; 1: 33-42.

9. Manual de intervención de enfermería en Hipertensión y RiesgoCardiovascular. Group EHRICA.

10. Steddon S, Ashman N, Chesser A and Cunningham J. OxfordHandbook of Nephrology and Hypertension. Oxford UniversityPress: Oxford 2006.

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Patient InformationPeople who are diagnosed with chronic kidney disease (CKD)should be provided with adequate and appropriate information. Informing and educating people to enable them to live with and manage their chronic disease empowers them to take control of their own health. The following are some suggestions ofthe information that people with CKD stage 1-3 should receive and also a list of useful websites.

Where are the kidneys?Most people are born with two kidneys, however you can live a normal life with one kidney. The kidneys are located at the back of your body just below your rib cage and they are about the size of your fi st.

Abdominal aorta

Left kidney

Left ureter

Interior vena cava

Right kidney

Right ureter

Urinary bladder

Urethra

NORMAL ANATOMY OF THE KIDNEYSAND URINARY TRACT

(www.kidney.org)

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Patient Information

What do the kidneys do?They fi lter the blood and remove excess fl uid, toxins and waste products. They regulate susbtances in your body suchas calcium and phosphate (from cheese and milk products) for healthly bones, potassium which regulates your heart rhythm(from tomatoes, bananas etc) and many other substances that you get from your food which your body needs to stayhealthy. They remove excess fl uid and also help control yourblood pressure, produces a hormone called erythropoietin,(EPO) which stimulates the bone marrow to produce healthyred blood cells so you do not become anaemic. The waste products from the body are removed by the kidney and leave your body as urine.

What does the term chronic kidney disease (CKD) mean?This term means that the kidneys have been damaged and are not working as well as they should normally.

How common is CKD?Around 1 in 10 people have CKD; however it is less common in young adults. In the older person it is more common dueto the natural ageing of the kidneys. A number of diseases can damage the kidneys such as diabetes, hypertension (highblood pressure) and some inherited conditions. Almost all ofthese will damage both your kidneys at the same time.

How do you know if you have CKD?In most cases CKD does not cause any symptoms, and is detected because they have a test that shows an abnormality. These may be urine tests for blood or protein; an X-ray or scan of the kidneys; or a blood test to measure kidney function. Most cases are discovered by your GP/family doctor as part of normal care.

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What are the causes CKD?The most common causes of CKD is, diabetes, high blood pressure and the natural agening process of the kidney. There are other causes such as infl ammation of the kidneys (e.g.glomerulonephritis), inherited diseases (e.g. polycystic kidneydisease) and autoimmune diseases (e.g. systemic lupus erythematosus). Only a small number of causes of CKD can be completely cured.

Measurement of kidney functionA blood test called eGFR (estimated glomerular fi ltration rate)is used to measure kidney function and is calculated from a substance in the blood called creatinine. Creatinine is a waste product excreted by the kidneys.

What is normal kidney function?Normal kidney function is when the eGFR is � 90 ml/min/1.73m2 in young adults. Some people have an eGFR between 60-90 ml/min and this is considered normal kidney function if there is no blood or protein in the urine or any disease or identifi ed problem with the kidney.

Over the age of 40 years the eGFR falls by 1ml/min per yearand so in the older person (over 75 years) the eGFR may be lower (i.e. 50-60 ml/min).

What does it mean to have CKD Stage 1, 2 or 3?Stage 1:g It means there is mild damage to the kidney and is not something that you should be overly concerned about. The eGFR is >90 ml/min/1.73m2, with blood or protein in your urine and/or some sign of kidney damage has shown up on a test.

Stage 2:g It means there is mild damage to the kidney and isnot something that you should be overly concerned about. The

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Patient Information

eGFR is between 60-90 ml/min/1.73m2, with blood or protein in your urine and/or some sign of kidney damage has shown up on a test.

Stage 3:g It means that there is some moderate damage to thekidney. The eGFR is between 30-59 ml/min.

What is the treatment for CKD?It is important to treat high blood pressure. If it is above 140/85 mmHg on three consecutive occasions, you will need some blood pressure medication. The aim is to get your blood pressure to 130/80 mmHg or lower. It is also important to have your cholesterol level checked and you may be advised to take an aspirin a day. Those people with diabetes need to have good control of their blood sugar to prevent further damage to the kidneys.

How often will I need to have my kidney function checked?You may be asked to either have your kidney function checked every six months or annually.

This will involve a blood and urine test. Your GP/family doctor will refer you to a kidney specialist if your kidney functiondeclines.

What can I do to help?Try to live a “healthy” lifestyle as you are more at risk ofgetting heart disease and developing further damage to yourkidneys.

Try to do the following:• If you are overweight, you should lose weight• Try to exercise regularly• Stop smoking

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• If you have diabetes, make sure you speak with yourdiabetes team and you have good control of yourdiabetes

• It is important to take your blood pressure medications ifyou have been given them to keep your blood pressure down and prevent further damage to your kidneys

• Reduce the amount of salt in the diet in order to helpcontrol your blood pressure

• Eat a healthy balanced diet, lower the amount ofcholesterol in your diet

• Drink about 2 litres of fl uid a day (2 litres is about 10 cups or 6 mugs). There is no benefi t in drinking largeamounts of fl uid, except in people who get lots of urine infections, or in a few other special cases

• Avoid anti-infl ammatory drugs (includes some that youcan buy over the counter without a prescription unless your GP/family doctor has approves them e.g. Ibuprofen

• Consider buying an automatic blood pressure monitor to check your blood pressure at home

• Have an annual fl u vaccination, and have the pneumonia (pneumococcal) vaccine once (talk to your GP/familydoctor about this)

• Attend for your kidney function checks when asked to byyour GP/family doctor or nurse

• If you do have a kidney disease, tell your family as they may need to check with their GP/family doctor that it not a disease that runs in the family

• You need to let other doctors and nurses know thatyou have a problem with your kidneys e.g. if you go to accident and emergency or have an operation or procedure

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Patient Information

Add your national kidney patient association details to the leafl et so your patients can make contact with them.

Useful Patient Information WebsitesRenal patient information:

www.renalpatient.org

Kidney patient guide:www.kidneypatientguide.org.uk

National Kidney Federation:www.kidney.org.uk

Kidney Research UK:www.nkrf.org.uk

The National Kidney Foundation:www.kidney.org

chronic kidney disease 1-3 stages

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