dys glycemia in ckd 26 8-2015

Dysglycemia and CKD

BY

Alaa Wafa MD.Associate Professor of internal medicine

Diabetes & Endocrine unit.Mansoura university

2015

AGENDA

2

Background of Dysglycemia and CKD

Pathophysiology of Dysglycemia and CKD

Glycemic control and CKD

Insulin therapy and CKD

Conclusions

TEAMWORK- the power of a multidisciplinary approach

Patient and family

Nephrologist

Nurse Clinician

Diabetes Educator

Pharmacist

Registered Dietitian

Social Work

Diabetes:The Most Common Cause of ESRD

Primary Diagnosis for Patients Who Start Dialysis

Diabetes50.1%

Hypertension27%

Glomerulonephritis

13%Other

10%

United States Renal Data System. Annual data report. 2000.

No. of patientsProjection95% CI

1984 1988 1992 1996 2000 2004 20080

100

200

300

400

500

600

700

r2=99.8%243,524

281,355520,240

No.

of d

ialy

sis

patie

nts

(thou

sand

s)

©2006. American College of Physicians. All Rights Reserved.

Uremia alters the entire metabolism including that of carbohydrates, proteins and fats. It also causes electrolyte disturbances and upsets mineral and hormonal homeostasis. Directly or indirectly, glucose metabolism is disturbed by all these changes’.

Kumar, K.V. S. et al: Glycemic Control in Patients of Chronic Kidney Disease. \www.ijddc.com/article.asp?issn=0973-3939;year=2007; volume27; issue=4

International Journal of Diabetes in Developing Countries.

Diabetes and CKD

DysglycemiaThe Dysglycemia of diabetes includes two components: • (1) sustained chronic hyperglycemia that exerts its effects

through both excessive protein glycation and activation of oxidative stress

• (2) acute glucose fluctuations (glycemic variability).

Glycemic variability seems to have more deleterious effects than sustained hyperglycemia in the development of diabetic complications as both upward

(postprandial glucose increments) and downward (interprandial glucose decrements) changes activate the oxidative stress.

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Glucose variability

Multiple fluctuations of glycemia in the same individual within-day or day-to-day, or even over longer periods of time; that is, week to-week or visit-to-visit.

The concept of glucose variability was first introduced in the Diabetes Control and Complications Trial (DCCT), and defined as the standard deviation (SD) of daily blood glucose around the mean from each quarterly visit

Pathways within diabetes that lead to the development of vascular disease

Glomerular endothelial dysfunction (in particular, damage to the glycocalyx) is the likely step in initiating albuminuria1

This diagram shows the relationship between hyperglycaemia, insulin resistance, endothelial dysfunction, macrovascular disease and albuminuria in diabetes.1,2

8

Notes on this diagram1:Proposed major pathways are represented by pink arrows.

Pathways of less certain significance are represented by grey arrows.

In type 2 diabetes, other pathways not directly involving endothelial dysfunction, are likely in the pathogenesis of macrovascular disease and may also contribute to albuminuria (broken arrows).

Type 1 diabetes Type 2 diabetes

Cardiovasculardisease albuminuria

Insulin resistancesyndromeGlucose

Effector pathways

Endothelial (includingglycocalyx) dysfunction

Reference:1.Satchell SC and Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008;51:714-725. 2.Deckert T, et al. Diabetologia. 1989;32(4):219-26.

Am J Kidney Dis 2002; 39:S1

What is CKD?

• Presence of markers of kidney damage for three months, as defined by structural or functional abnormalities of the kidney with or without decreased GFR,

• Manifest by either pathological abnormalities or other markers of kidney damage, including abnormalities in the composition of blood or urine, or abnormalities in imaging tests.

• The presence of GFR <60 mL/min/1.73 m2 for three months, with or without other signs of kidney damage as described above.

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Diabetic kidney disease implies widespread vascular disease

• The epidemiology of albuminuria (abnormal levels of albumin in the urine) reveals a close association with vascular disease1

• Meta-analyses in general population and high risk cohorts demonstrated that albuminuria is associated with cardiovascular mortality independently of traditional cardiovascular risk factors2,3

• The presence of both generalised vascular dysfunction and albuminuria suggests a common cause of proteinuria4

Reference:1. Satchell SC and Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008;51:714-725. 2. Matsushita K, van der Velde M, Astor BC, et al. Lancet 2010;375(9731):2073–2081 3. Gansevoort RT, Matsushita K, van der Velde M, et al. Kidney Int. 2011;80(1):93–104. 4. Deckert T, et al. Diabetologia. 1989;32(4):219-26.

Hazard ratios (HR) and 95% confidence intervals for cardiovascular mortality

according to ACR2

4

2

1

0.5

2.5 5 10 30 300 1000

HR

for C

VD

mor

talit

y (A

CR

stu

dies

)

ACR, mg/g

Adapted from Matsushita K, van der Velde M, Astor BC, et al. Lancet 2010;375:2073–2081.

These slides were sponsored by Janssen and developed in conjunction with the BRS CKD Strategy Group, following an advisory board that was organised by Janssen. Bedrock Healthcare Communications provided editorial support to members of the advisory board in developing the slides. Janssen reviewed the content for technical accuracy. The content is intended for a UK healthcare professional audience only.

JOB CODE PHGB/VOK/0914/0018bDate of preparation: January 2015

Pathophysiology of Dysglycemia & CKD

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Functions of the kidney

Filtration andreabsorption

Acid/basebalance

ElectrolyteBalance

Excretion oftoxic substances

Hormone production:• Calcitrol (healthy bones)

• Renin (BP regulation)• Erythropoieitin

(red blood cell production) Glucose reabsorptionand gluconeogenesis

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The kidneys’ contribution to glucose homeostasis

• Kidneys contribute to glucose homeostasis in many ways including: producing, filtering, reabsorbing and excreting glucose

• The kidneys produce approximately 20-25%1,2 of the total endogenousglucose production

• In a healthy individual* virtually all of the filtered glucose is actively reabsorbed into the blood by the sodium glucose co-transporters 2 and 1 (SGLT2 and SGLT1); virtually none is excreted in the urine2,3

*Normal physiological blood glucose range <6.5mmol/L before meals and <7.8mmol/L after mealsReferences:1. Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2:345-50.2. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010 Feb;27(2):136-42.3. Mitrakou A. Kidney: its impact on glucose homeostasis and hormonal regulation. Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S66-72

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The role of the kidney in glucose reabsorption

• There are two main sodium-glucose cotransporters: SGLT2 and SGLT11

• SGLT2 is mainly found in the proximal tubules of the kidneys1

• SGLT2 is responsible for reabsorbing approximately 90%of the glucose reabsorbed bythe kidney2

• The remaining glucose is reabsorbed by SGLT1 furtheralong the proximal tubule1

• The reabsorbed glucose is then returned to the blood2

Adapted from Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95:34-42.

Reference:1. Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95:34-42. 2. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14.

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The role of the kidney in glucose reabsorption

~180L filtered per day by the kidney1

References:1. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012 Jan;14(1):5-14.2. Clifford J. Bailey. Medscape Education Diabetes & Endocrinology. The Role of the Kidney in Glucose Control.. CME Released: 02/26/2013 ; Valid for credit through 02/26/2014.

A normal kidneyA kidney in a patientwith type 2 diabetes

Average blood glucose of ~100mg/dL2

Average blood glucose of ~150mg/dL2

~180g of glucose filtered per day2

No increase in SGLT2 cotransporters2

~250g of glucose filtered per day2

glucose reabsorption and elimination of glucose in the

urine2

Hyperglycaemia

Increase in SGLT2 cotransporters2

Selected actions of insulin

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The role of the kidney in insulin elimination

• The kidney plays a central role in the metabolism of insulin1

• Increased insulin levels suppress gluconeogenesis in the kidney and enhance glucose reuptake by the kidney2

• Six to eight units of insulin are degraded by a healthy kidney each day1

– This is approximately 25% of the daily production of insulin by the pancreas

References:1. Palmer BF and Henrich WL Carbohydrate and insulin metabolism in chronic kidney disease.. Available at: http://www.uptodate.com/contents/carbohydrate-and-insulin-metabolism-in-chronic-kidney-disease.2. Andrianesis V and Doupis J. The Role of Kidney in Glucose Homeostasis - SGLT2 Inhibitors, a New Approach in Diabetes Treatment. Expert Rev Clin Pharmacol. 2013;6(5):519-539.

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Renal Metabolism of Insulin

30–80% of systemic insulin is metabolized particularly in the kidney .

The kidney is, therefore, the main organ responsible for metabolizing exogenous insulin administered to diabetic patients .

About 65% of insulin that reaches the kidney is filtered in the glomerulus and is, subsequently, metabolized in the proximal tubular cells.

About 35% of insulin diffuses from postglomerular peritubular vessels to the contraluminal cell membrane of the proximal tubular cell, where it is also degraded.

Less than 1% of filtered insulin appears in the urine

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Unlike insulin, C-peptide is not metabolized during its first pass through the liver and, approximately 70%of its plasma clearance is performed in the kidney For that reason, serum concentration of C-peptide reflects pancreatic liberation of endogenous insulin in subjects with normal renal function

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Hyperglycaemia drives diabetic kidney disease

1. Activation of protein kinase C1

2. Acceleration of the renin-angiotensin-aldosterone system (RAAS)1

3. Non-enzymatic glycation that generates advanced glycation end products1

– Circulating levels are raised in people with diabetes, particularly those with renal insufficiency, since they are normally excreted in the urine1

• Oxidative stress seems to be a theme common to all three pathways3

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Hypertension Overproduction of mesangial cell matrix

Tubulointerstitialinjury

Accelerationof RAAS

Advanced glycationend products (AGEs)

Protein kinase C andgrowth factors

Glomerulardamage

ProteinuriaNephron loss

Hyperglycaemia

Reference:1.Cade WT. Diabetes-Related Microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008;88(11):1322–1335. 2.Wolf G et al. (2005) From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54: 1626-1634. 3.Dronavalli S, Duka I and Bakris GL. Nat Clin Pract Endocrinol Metab. 2008;4(8):444-52.

Three mechanisms have been postulated that explain how hyperglycaemia causes tissue damage in the kidney:1-3

Dysglycemia drives diabetic kidney disease

• For instance, the urinary excretion rate of 8-iso-PGF2α, a reliable marker of oxidative stress, was found to be strongly, positively correlated (r = 0.86, p < .001) with glycemic variability assessed from the mean amplitude of glycemic excursions (MAGE) as estimated by continuous glucose monitoring systems (CGMS).

These observations therefore raise the question of whether we have the appropriate tools for assessing glycemic variability in

clinical practice ?

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• Patients with more variable HbA1c face a higher risk of microvascular complications, in terms of the frequency and amplitude of HbA1c fluctuation.

• The deleterious effect of glucose variability on the kidneys attributed to the metabolic memory induced by repeated exposure to glucose fluctuation.

• The precise mechanism has not been well determined; however, endothelial dysfunction and oxidative stress were found to be worsened by glucose variability compared with stable hyperglycemia, and could be reversed by Reduction of glucose fluctuations.

• Patients lagged in the ‘metabolic memory’ as a result of frequent HbA1c fluctuation with a large rang were much more prone to developing severe nephropathy than those with the same average HbA1c, but less variable HbA1c.

ConclusionsThe short-term glucose variability expressed by 2hPG-FPG is closely associated with decreased eGFR and an increased risk of CKD in patients with poor glycemic control (HbA1c≥7%).

Conclusions. Subjects with CKD and T2DM had poor glycemic control and significantly higher glycemic variability comparative to those without CKD, and especially to healthy volunteers. Assessment of glycemic variability indices through CGM is more accurate than HbA1c for the quantification of glycemic control in CKD diabetic patients

30



-50

-40

-30

-20

-10

0

Diabetes-related death

Myocardialinfarction

Microvascularcomplications

Peripheralvasculardisease

Lowering HbA1c by 1% significantly reduces:

Redu

ctio

n in

incid

ence

risk

pe

r 1%

redu

ctio

n in

HbA

1c

–21%*–14%*

–37%*–43%*

*p < 0.0001 Stratton IM et al. BMJ 2000;321:405–12

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Glycaemic Control in Diabetics with CKD

preserving renal function, avoiding the progression of CKD reducing cardiovascular complications and

those secondary to diabetes decreasing the mortality rate in CKD

patients, both in predialysis and dialysis

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Glycaemic Control in Diabetics with CKD

Diabetic Nephropathy

Diabetes, Obesity and Metabolism, 10,2008 , 811–823

Management of Hyperglycemia in Type 2 Diabetes, 2015:

A Patient-Centered ApproachUpdate to a Position Statement of the American Diabetes Association (ADA)

and the European Association for the Study of Diabetes (EASD)

Diabetes Care 2015;38:140–149Diabetologia 2015;58:429–442

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

HbA1c ≥9%

Metformin intolerance or

contraindication

Uncontrolled hyperglycemia

(catabolic features, BG ≥300-350 mg/dl,

HbA1c ≥10-12%)

Antihyperglycemic agents and CKD

Diabetes mellitus (DM) is the leading cause of chronicrenal failure (CRF) and dialysis therapy . Numerousdrugs with different action mechanisms may serve to

reduce both acute and chronic diabetic complications aswell as to improve the quality of life in diabetic patients

In patients with CKD, therapeuticpossibilities are limited because of reduction in glomerularfiltration rate (GFR) that is accompanied by accumulation

of some oral agents and/or their metabolites

38

39

Antihyperglycemic Agents and CKD

Figure 3. Approach to starting & adjusting insulin in T2DM

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

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Insulin Therapy in Patients with CKD

Diabetic Nephropathy TIDM: Intensive insulin therapy was more effective as regards glycaemic control (HbA1c 7.2 vs. 9.1%) than conventional insulin therapy in 1441 type 1 diabetics treated for an average treatment period of 6.5 years.

39% reduction in microalbuminuria risk (>40 mg/day) (primary prevention)

54% reduction in progression to macroalbuminuria (>300 mg/ day) (secondary intervention)

The effect of intensive treatment of diabetes on thedevelopment and progression of long-term complications

n insulin-dependent diabetes mellitus: The DiabetesControl and Complications Trial ResearchGroup. N Engl J Med 1993; 329: 977–986.

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Diabetic Nephropathy• T2DMalso benefit from intensive insulin therapy. In a 6-year study, performed on 110 non-obese Japanese patients with type 2 diabetes, intensive insulin therapy was associated with

• primary prevention (7.7 vs. 28%) • secondary intervention (11.5 vs.32%) .

Ohkubo Y, Kishikawa H, Araki E et al. Intensiveinsulin therapy prevents the progression of diabetic microvascular complications in Japanese patients withnon-insulin-dependent diabetes mellitus: a randomizedprospective 6-year study. Diabetes Res Clin Pract1995; 28: 103–117.

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Diabetic NephropathyAmong the main limitations of intensive insulin therapy Hypoglycaemia

Weight gain.

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Insulin Therapy in HD

Diabetic Nephropathy• InHD patients, insulin requirements are reduced in probable relationship with an improvement in IR associated to dialysis procedure

• Hypoglycemic events tended to be higher than in the predialysis period. Moreover, the residual diuresis decrement during the first year on HD is associated with a significant reduction of insulin requirements

• patients with residual diuresis <500 ml/day showed a reduction in insulin needs by about 29%, whereas no changes were reported in patients with higher residualDiuresis

47

Insulin Therapy in HD

Diabetic Nephropathy• Adequate glycaemic control in HD diabetic patients : two

doses of intermediate-acting insulin and or one basal insulin + preprandial dose of rapid-acting insulin as needed .

• HD solutions with high glucose concentration have shown to be useful in preventing hypoglycemic events during the HD session, without significant effects on HbA1c

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Insulin Therapy in PD


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Insulin Analogues in Renal Insufficiency


TEAMWORK- the power of a multidisciplinary approach

Patient and family

Nephrologist

Nurse Clinician

Diabetes Educator

Pharmacist

Registered Dietitian

Social Work

51

Conclusions

Diabetic NephropathyGlycaemic control in CKD diabetic patients can be difficultt to be obtained because of multiple factors intrinsic to diabetes, renal insufficiency and concomitant therapy(pharmacological, dialytic and immunosuppressive therapy).

IR and hyperinsulinaemia can impair the capacity to reach satisfactory target blood glucose levels.

Intensive insulin therapy is an adequate option for improving glycemic control in CKD although it might increase the risk of hypoglycaemic events.

insulin analogues in CKD patients has been associated with potential advantages and benefits with regard to glycaemic control.

[email protected]@mans.edu.eg

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dys glycemia in ckd 26 8-2015

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