End Organ Damage-The Kidney

JogiRaju Tantravahi, M.D.Nephrology Fellowship Training Program Director

Division of Nephrology University of Florida College of Medicine

Staff nephrologist, Malcom Randall VA Medical Center

Disclosures of Financial Relationships

This speaker has no significant financial relationships with commercial entities to

disclose.

This speaker will not discuss any off-label use or investigational product during the program.

This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

Outline The spectrum of renal disease in HIV

infection The management of chronic kidney

disease Current methods for measuring renal function Preserving renal function Managing the complications of chronic kidney

disease Kidney transplantation in HIV infection

Tenofovir (Viread®) nephrotoxicity

The nephron…and there’s no need to complicate things.

Modified from brutal internet artwork

Blood goes in

Blood comes out

Filtrate of plasma made in the glomerulus

The filtrate of plasma is reabsorbed and modified throughout the nephron.

So how do you know that the patient has a kidney problem (and we’ll see this slide again)?

Elevated creatinine or a reduced calculated GFR

Electrolyte abnormalities, such as hyperkalemia, metabolic acidosis, or hyperphosphatemia

Abnormal urinalysis, with hematuria, pyuria, proteinuria, or casts

Decreased urine output or edema

Causes of chronic kidney disease in the HIV population

Elewa, U. et a. 2011 Nephon Clin Prac 118: 346-354

I cannot find significant fault with thespectrum of kidney diseases in patientswith HIV disease outlined by the authors.

However, in considering the causes of renal disease in the current HIV population,I suggest that more gain will be made ifwe focus on managing the routine causes ofchronic kidney that wee see in the general population *such as diabetes and hypertension), as I believe that the routine causes chronic kidney have or will become more prevalent than the exotic causes.

When I now see chronic kidney disease patient with HIV, I ask how well has the disease been controlled, what drugs does the patient take, and if the patient has diabetes or hypertension.

Normal glomerulus and collapsing glomerulopathy of HIV associated nephropathy

Normal glomerular structure, from H. Rennke, UpToDate

Obsolescent glomerulus

Thin, attenuatedtubules

Dilated tubules with microcystsand proteinaceouscasts

Global sclerosisseen in a glomerulusin a patient with thecollapsing glomerulopathyof HIV associated nephropathy. Note that the entire tuft is involuted withno open capillaries with likely mesangial cell proliferation.The capillaries in the

glomerular tuft are open,allowing for glomerularfiltration.

The cell numberis appropriate.

Wyatt, C.M, Meliambro, K., and Klotman P.E. 2012 Ann. Rev. Med. 63: 147-159

Kidney disease screening algorithm

Estrella, M.M., and Fine D. M. 2010 Adv Chronic Kid Dis 17: 26-35

Clinical concepts and entities you need to

understand and manage

So how do you know that the patient has a kidney problem (and here’s the slide again)?

Elevated creatinine or a reduced calculated GFR

Electrolyte abnormalities, such as hyperkalemia, metabolic acidosis, or hyperphosphatemia

Abnormal urinalysis, with hematuria, pyuria, proteinuria, or casts

Decreased urine output or edema

My chronic kidney disease management paradigm

FIGHT FOR EVERY NEPHRON! Measurements of renal function The stages of chronic kidney disease The consequences of chronic kidney disease

and their management Hypertension Anemia Bone and mineral metabolism Electrolyte abnormalities When things fail…replacement therapy with dialysis or

transplantation

Serum creatinine a surrogate marker for renal function normal range typically 0.6 mg/dl to 1.1 mg/dl higher values indicate worse renal function.

Problems equating elevated creatinine with renal dysfunction Muscular people

Large muscle mass Higher creatinine with normal renal function

Emaciated people Low/no muscle mass Falsely low creatinine in face of renal dysfunction

Ways to measure renal function, I

24 hour urine You need an adequate collection

Men should excrete between 15 mg/kg to 20 mg/kg of creatinine daily

Women should excrete between 10 mg/kg to 15 mg/kg creatinine daily

In near end stage renal disease, creatinine secretion is increased, so you need to measure the urea clearance as well and average the values

Ways to measure renal function, II

Cockroft-Gault formula CrCl (ml/min)= (140-age) x lean body weight (kg)

PCr (mg/dl) x 72

MDRD formula 170 x [Cr]-0.999 x [BUN]-0.170 x [Alb]0.318 x Age-0.176 x 0.762 (Female) x 1.180 (African

American)

CKD-EPI formula GFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 1.018 [if female] X 1.159

[if black] where Scr is serum creatinine (mg/dl), κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.

Cystatin C, iothalmate clearance

MDRD formula: Levey , A.S.et al. 2006 Ann Int Med 145: 247-254CKD-EPI formula: Levey, A.S. et al. 2009 Ann Int Med 150: 604-612

Ways to measure proteinuria Urinary dipstick

Imprecise and not quantitative 24 hour urine collection

The collection has to be well done, or the result cannot be interpreted.

Spot urine for protein and creatinine The lab reports the value as mg protein/gram creatinine. Since

we generally excrete 1 gram creatinine daily, the spot urine ratio is generally reliable.

Albuminuria, tubular proteinuria vs. light chains Role of the urinary albumin to creatinine ratio, serum and urine

protein electrophoresis, serum free light chains

Communicating with your nephrologist:Stages of chronic kidney disease

Stage I: Normal GFR (greater than 90 ml/min) and persistent albuminuria

Stage II: GFR between 60 ml/min and 89 ml/min and persistent albuminuria

Stage III: GFR between 30 ml/min and 59 ml/min.

Stage IV: GFR between 15 ml/min and 29 ml/min.

Stage V: GFR less than 15 ml/min or end stage renal disease.

As formulated by the National Kidney Foundation

What does the kidney do? The major homeostatic organ

Electrolyte balance, acid-base balance, salt and water balance

Detoxification and drug metabolism Organic acids, renal excretion of drugs

An endocrine organ Terminal hydroxylation of vitamin D, erythropoietin

synthesis Glomerular filtration and reclamation

The incredible absorptive capacity of the kidney

Substance Filtered Excreted % net reabsorbed

Water 180 liters 0.5-3 liters 98-99%Sodium 26,000 mEq 100-250 mEq >99%Chloride 21,000 mEq 100-250 mEq >99%Bicarbonate 4,800 mEq 0 100%

Individuals with a normal GFR essentially can conserveall the sodium, water, and bicarbonate filtered at theglomerulus. However, fine hormonal control allow us toexcrete sodium, water, or even bicarbonate. Additionally, the kidneys are efficiently excrete potassium in a response to a potassium load.

The consequences of chronic kidney disease

Beyond the devastating effects of the loss of renal function in an of itself, chronic kidney disease is accompanied by a number of devastating complications. Cardiovascular disease Hypertension (including volume overload) Anemia Bone disease Protein malnutrition not related to cachexia Electrolyte abnormalities Metabolic acidosis

General principles regarding the management of chronic kidney disease

Hypertension control (target systolic blood pressure of 130 mm Hg or less) using renin-angiotensin system blockade (ACE inhibitor, angiotensin receptor blocker, mineralocorticoid receptor blocker, direct renin antagonist)

Diabetes control (target HbA1c of 7.0% or less)

Lipid control (target LDL of in the 70 range or a 20% reduction from baseline)

Summary of several trials, including UKPDS, IDNT, REIN I and II, RENAAL

Cardiovascular complications of chronic kidney disease

Accelerated atherosclerotic coronary disease

Left ventricular hypertrophy Increased prevalence of sudden death

(especially in the end stage renal disease population)

Medial coronary artery calcification

Renin-angiotensin system blockade: The mainstay of hypertension management in my practice

Clinical trials support the widespread use of renin-angiotensin system blockade for hypertension therapy and renal function preservation. Collaborative Study Group UKPDS RENAAL Trial IDNT Trial REIN Trials (both REIN I and REIN II) HOPE Trial

You have to be brave Renin-angiotensin system blockade abrogates

the loss of renal function and prevents cardiovascular mortality.

Expect a modest increase in the creatinine Tolerate up to a 25% increase in the creatinine as long

as the blood pressure comes under control.

Risk of hyperkalemia exists Manage with potassium lowering drugs rather than

stopping the drug

Risk of cough or angioedema

Hypertension and chronic kidney disease

Multi-modal therapy is required Polypharmacy is the rule, not the

exception ACE inhibitor Angiotensin receptor blockers Diuretics (loop and thiazide) Sympathetic blockade Calcium channel blockers (non-dihydropyridines in

patient with proteinuria) Aldosterone antagonists Other second line drugs (clonidine, hydralazine,

minoxidil, direct renin antagonists)

The ONTARGET studies ONTARGET: Telmisartan, ramipril, or both in

patients at high risk for vascular events. NEJM 2008 358: 1547-1559

“Renal” ONTARGET: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multi-center randomized, double blind controlled trial. Lancet 2008 372: 547-553

The bottom line Dual renin-angiotensin system blockade might

worsen renal disease, especially in patients without proteinuria.

I will use dual renin-angiotensin blockade, but mainly in patients with proteinuria (greater than 1 g protein/gram creatinine) and only as a last resort in patients without proteinuria.

Common electrolyte abnormalities seen in the outpatient setting

Hyperkalemia (you’ll need to manage this)

Metabolic acidosis (you’ll need to manage this)

Hyperphosphatemia (not really your problem)

Hypocalcemia (only your problem if the patient has

symptoms like paresthesias)

Hyperkalemia, I Potassium value greater than 5.0

mEq/l. Patients who are in a steady state

with modestly elevated potassium are usually in no danger.

However, hyperkalemia can be a silent killer and should not be ignored.

Main symptom of hyperkalemia is profound weakness with arrhythmia as the mode of death

ECG findings in hyperkalemia

The ECG shows stereotypical findings including a first degree AV block, a widened QRS, and a ”sine wave” pattern in the terminal state.

http://www.merckmanuals.com/professional/endocrine_and_metabolic_disorders/electrolyte_disorders/disorders_of_potassium_concentration.html

Hyperkalemia, II Causes

Decreased GFR Drugs

ACE inhibitors, ARBs, beta-blockers Diet

Treatment Dietary restriction Diuretic therapy (mainly loop diuretic therapy) Daily low dose sodium polystyrene sulfonate

(Kayexelate®) Modification of drug regimen

Metabolic acidosis, I

Where a metabolic acidosis defined as a bicarbonate level less than 22 mEq/l.

Bicarbonate treatment of metabolic acidosis protects against deterioration of renal function

de Brito-Ashurst, I., et al. 2009 JASN 20: 2075-2084

Clinical concepts you need to understand but not necessarily manage

Anemia: The causes Decreased red blood cell half-life

(important) Malabsorption of iron and folate

(important) Chronic bleeding related to platelet dysfunction

from uremia (not important) Severe hyperparathyroidism (not important) Erythropoietin deficiency (very important)

As the GFR falls, anemia worsens

91 90–40 39–30 29–20 19–10 10

GFR (mL/min/1.73 m2)

Mea

n H

gb* (

g/dL

)

n = 18n = 59 n = 18 n = 34 n = 18n = 295

6

7

8

9

10

11

12

13

14

15

Adapted from Foley, R.N., 2002 Clin Nephrol 58 Supp 1: S58-S61.

Anemia management in chronic kidney disease

Rule out iron deficiency anemia, determine the cause if presents, and restore iron stores

Rule out folate or B12 deficiency Use an erythropoiesis stimulating agent

Erythropoietin-alpha (Procrit®) or darbepoietin (Aranesp®) in pre-ESRD

The results from several well done trials (CHOIR, CREATE, TREAT) in pre-ESRD patients have shown that the target hemoglobin should fall between 10 g/dl and 11 g/dl. Normalization of the hemoglobin should not be the goal.

CHOIR: Singh, A.K., et al. 2006 NEJM 355: 2085-2098. CREATE: Drueke, T.B. et al. 2006 NEJM 355: 2071-2084 TREAT: Pfeffer, M.A., et al. 2009 NEJM 361: 2019-2032.

Vitamin D synthesis and feedback loops (simplified)

Too much:Inhibits (parathyroid hormone)PTH gene transcriptionToo little: Induces PTH gene transcription

The fewer nephrons available, the less efficiently terminal hydroxylation of 25-hydroxycholecalciferol occurs.

Bone disease (or why we’re so obsessed with phosphate binders)

In Chronic Kidney Disease: Active vitamin D is not made because of

decreased 1-a-hydroxylase activity. Phosphorus levels rise because of the

decreased GFR Decreased vitamin D levels and

hyperphosphatemia increase PTH levels, and the increase in PTH activity starts several seemingly beneficial compensatory processes.

Pathophysiological networks in secondary hyperparathyroidism

Osteitis fibrosa

Hyperphosphatemia

Metabolic acidosis

Decreased GFR

SecondaryHyperparathyroidism

Decreased vitamin D synthesis

Hypocalcemia

Decreased calcium sensingreceptor occupancy

...with involution ofthe bone marrow space

FGF 23resistance

Bone disease, I Treatment begins with lowering the

phosphate level. Our options include: Non-calcium containing binders:

Sevelamercarbonte (Renvela®) 800 mg Lanthanum carbonate (Fosrenol®) 500 and 1000

mg Aluminum hydroxide (Amphojel®), which should

essentially never be used Some iron based phosphate binders are in

preparation Calcium containing binders

Calcium carbonate (TUMS®) Calcium acetate (PhosLo® and PhosLyra®) 667 mg

Bone disease, II The NKF, through K/DOQI, has

established the following PTH goals: Stage III chronic kidney disease: GFR

between 30 ml/min and 59 ml/min: Target PTH should be between 30-70.

Stage IV chronic kidney disease : GFR between 15 ml/min and 29 ml/min. Target PTH should be between 70-110.

Stage V chronic kidney disease: GFR less than 15 ml/min or end stage renal disease or end stage renal disease. Target PTH should be between 150-300.

Bone disease, III Vitamin D and vitamin D analogues directly inhibit

expression of the PTH mRNA. The options include: 1,25-dihydroxy-vitamin D (Calcitriol®, or Rocaltrol®) 19-nor-1,25-dihydroxy-vitamin D2 (Paricalcitol®, or

Zemplar® ) 1-a-hydroxy-vitamin D2 (Doxercalciferol®, or Hectorol®)

Only one non-vitamin D PTH suppressor, cinacalcet, or Sensipar®, exists. Cincalcet binds to the calcium sensing receptor on the parathyroid gland and prevents release of PTH from storage granules.

I find little use for the calcium/vitamin D preparation or for 25-OH-cholecalciferol in advanced stage III or stage IV chronic kidney disease.

My office guidelines for chronic kidney disease management, I

Blood pressure control Target systolic blood pressure of 130 mm Hg or less

on an ACE inhibitor or ARB based regimen (which will also reduce proteinuria)

Diabetes control Target HbA1c less than 7.0%

Lipid control Target LDL in the 70 range or a 20% reduction from

baseline (SHARP study) using statin therapy

My office guidelines for chronic kidney disease management, II

Anemia Target hemoglobin 10 g/dl and 11 g/dl after iron stores

have been repleted

Bone Target phosphorus level below 4.5 mg/dl using

phosphate binders and achieve appropriate PTH control.

Electrolytes and metabolic acidosis Limit potassium, replace bicarbonate

When things get worse…and they will

Re-double your efforts to make sure that conservative management has been optimized and that the underlying disease states are stable.

Has a new drug been started (drug induced allergic interstitial nephritis)?

Could the patient have ureteral obstruction? Is there a concurrent severe illness? Discuss dialysis and transplantation.

Kidney transplantation: an option in very selected patients, I

40 kidney transplants at a single center CD4 count greater than 200 cells/mm3, viral load < 400

copies/ml. Induction with basiliximab and intravenous

methylprednisone and maintenance with prednisone, tacrolimus, and sirolimus (a regimen now proven to be sub-optimal).

Two year overall survival was 82%, graft survival was 71%, and acute rejection occurred in 22% of patients.

None of the patients had a reduction in the CD4 count, and no opportunistic infections were noted. By and large the HIV viral load was undectatable.

Kumar, M.S. et al. 2005 Kidney Int 67: 1622-1629

Kidney transplantation: an option in very selected patients, II

150 HIV infected patients followed at 19 transplant centers transplanted between 2003 and 2009

Patients had a CD4 count greater than 200 cells/mm3, viral load < 50 copies/ml.

Immunosuppressive regimen was modern. 1 year patient survival was 94.6% and 3 year patient

survival was 88.2% 1 year graft survival was 90.4% (acceptable) and 3 year

graft survival was 73.7% (not great). CD4 counts did not fall, but viremia worsened in patients

who received anti-thymocyte globulin induction. But acute rejection rates were unacceptably high.

Stock, P.G., et al. 2010 NEJM 363: 2004-2014

So when should you enlist the aid of a nephrologist?

Anytime you want… Patients with stage III CKD When the velocity of the increase in the

creatinine rises above what you would expect Blood pressure becomes more difficult to

control. Urinary protein excretion rate rises into the

nephrotic or high non-nephrotic range. Electrolyte abnormalities present or more

difficult to manage.

Two slides regarding tenofovir

Izzedine, H., Harris, M., and Perazella, M. 2009 Nat Rev Neph 9: 563-573

Tenofovir use in chronic kidney disease

Undoubtedly, a measurable incidence of Fanconi syndrome and chronic kidney disease exists in patients receiving tenofovir.

However, a recent systematic review (Cooper, R.D. et al 2010 Clin Inf Dis 51: 496-505) noted that the risk was small and perhaps limited to underweight patients or those with a high viral load and low CD4 count.

They did not see the need to withhold tenofovir if the drug was needed and if the renal function and electrolytes were monitored carefully.