HIV and Kidney

Slide #1

DM Fine, MD.Presented at RWCA Clinical Update, August 2006.

Renal Disease and Toxicities: Issues for HIV Providers

Derek M. Fine, MDAssistant Professor

Johns Hopkins UniversitySchool of Medicine

The International AIDS Society–USA

Slide #2


Objectives

Understand the growing problem of kidney disease in HIV patients

Review risk factors and screening for kidney disease

Discuss important causes of acute renal failure including drug toxicities

Slide #3


HIV Kidney Disease: Why Do We Care? Increasing prevalence of kidney disease1 even

though the incidence of AIDS nephropathy has remained constant since the mid-1990s2

Kidney function is abnormal in up to 30% of HIV-infected patients3

Kidney dysfunction is an independent predictor of mortality4

Is asymptomatic – if you don’t look you won’t know

Implications regarding drug dosing and toxicity

1`Selik, JAIDS. 2002 Apr 1;29(4):378-87.2 Schwartz EJ, et al. J Am Soc Nephrol. 2005; 16:2412-2420.3 Gupta SK, et al. Clin Infect Dis. 2005; 40:1559-1585.4 Szczech LA, et al. Clin Infect Dis. 2004;39:1199-1206.

Slide #4


Kidney Disease is on the Rise in HIV Patients in the United States

Selik, JAIDS. 2002 Apr 1;29(4):378-87.

Trends in diseases reported on U.S. death certificates that mentioned HIV infection

Slide #5


Risk Factors for Kidney Disease in HIV

Hypertension Diabetes mellitus Race and other genetic factors Family history Hepatitis C virus infection Decreased CD4 cell count Increased viral load

Slide #6


Incidence and Causes of End-Stage Renal Disease (ESRD) in US

www.usrds.org/slides.htm.

Slide #7


Incidence of ESRD Among African Americans by Primary Disease (1999)

Diabetes

Hypertension

HIV nephropathy

Focal GN

SLE nephritis

Membranousnephropathy

HUS

Amyloidosis

Postinfectious GN

African Americans Aged 20-65 years (n=66,063)

0 10,000 20,000 30,000

24,535

20,748

3168

2186

1703

315

96

90

34

GN=glomerulonephritis; HUS=hemolytic anemia syndrome.Monahan M, et al. Semin Nephrol. 2001;21:394-402.

Slide #8


Disproportionate Affects of AIDS in Black and Hispanic Populations

1http://www.cdc.gov/hiv/graphics/images/l178/l178-12.ppt2www.diabetes.org/uedocuments/NationalDiabetesFactSheetRev.pdf.3www.americanheart.org/presenter.jhtml?identifier=3000927

Black Americans are 1.8 times as likely to have diabetes mellitus than age-adjusted White Americans2

>30% of Black Americans over age 18 have hypertension3

1

Slide #9


0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

CD4Lymphocyte

Count

Prior History ofAIDS-Defining

Illness

Albumin Creatinine (1/Cr) Proteinuria History ofHypertension

Albumin

P < 0.0001 P = 0.003

Szczech LA, et al. Clin Infect Dis. 2004;39:1199-1206.

Hypertension in HIVH

aza

rd R

atio

(9

5%

CI)

P < 0.0001

Hypertension is an independent predictor of mortality Hypertension prevalence in HIV is 12-21 % Antiretrovirals may be associated with hypertension – Crane et al, AIDS, Apr 2006

Predictors of Mortality in Women with HIV following HAART Initiation

CD4 LymphocyteCount

Prior History ofAIDS-Defining

Illness

Albumin

P = 0.008

History ofHypertension

P = 0.005P = 0.04

Creatinine (1/Cr) Proteinuria

Slide #10


Kidney Disease Risk: Qualitative Assessment•Race•Family history of kidney disease•CD4+ lymphocyte count•HIV-1 RNA level•Nephrotoxic medication use (history)•Comorbidities

•Diabetes mellitus•Hypertension•Hepatitis C coinfection

Screening Studies at Initial HIV Documentation•Urine analysis (for proteinuria)•Serum creatinine (estimate Clcr or GFR using appropriate formula)

(Continued on next slide)

Gupta SK, et al. Clin Infect Dis. 2005;40:1559-1585.

IDSA Guidelines - Screening Algorithm for HIV-Related Renal Diseases

Slide #11


IDSA Guidelines - Screening Algorithm for HIV-Related Renal Diseases

Gupta SK, et al. Clin Infect Dis. 2005;40:1559-1585.

Abnormal Values•Grade ≥1+ proteinuria by dipstick•Clcr or GFR <60 mL/min per 1.73 m2

No Abnormal Values

(Continued)

•Evaluate proteinuria further with spot urine protein/cr ratio•Perform renal ultrasound•Consider referral to nephrologist for further evaluation & potential biopsy

W/O Kidney DiseaseRisk Factors:•Follow clinically•Reassess based on signs/symptoms•Reassess per clinical events

With Kidney DiseaseRisk Factors*:•Rescreen annually

*At-risk Groups Include:•African Americans•Patients with diabetes, hypertension, or hepatitis C coinfection•Patients with CD4+ cell counts <200 cells/mm3

•Patients with HIV RNA levels >4000 copies/mL

Slide #12


Johnson R, et al. Comprehensive Clinical Nephrology. 2000. Mosby. St. Louis. 4.15.1–4.15.15.

Ser

um

Cre

ati

nin

e (m

g/d

L)

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0

0 20 40 60 80 100 120 140 160 180

Inulin Clearance (mL/min/1.73 m2)

Creatinine poorreflector of GFR

GFR versus Serum Creatinine

Creatinine is not sufficient as a measure of kidney function

Slide #13


Estimates of GFR: Cockcroft-Gault and MDRD (modified diet in renal disease) Formula

CG = (140-age) x weight x (0.85 if F) (Pcr) x 72

MDRD = 186 x Pcr(mg/dl)-1.154 x age (yr) – 0.203

x (1.212 if black) x (0.742 if female)

Cockcroft DW and Gault MH Nephron 1976; 16:31-41Levey et al, JASN 2000; 11: 155A [Abstract]

4 Variable Version

Slide #14


Cockcroft-Gault and MDRD Equations

6 variable: Cr, BUN, age, alb, race, sex4 variable: Cr, age, race, sex

C-G MDRD

Slide #15


Assessment of ProteinuriaUsing Protein/Creatinine Ratio

Ginsberg et. al. NEJM 309:25 p1543

Random urine:Protein mg/dl Creatinine mg/dl

24-hour urine - Gold Standard

Slide #16


Differential Diagnosis of ARF in HIV HIV Related

HIVAN Thrombotic Microangiopathy Membranoproliferative GN Immune Complex GN (MPGN or Lupus Like) Medication

Indinavir, Tenofovir, Sulfadiazine, Pentamidine, Sulfamethoxazole and trimethoprim

Other Usual causes in general population – pre-renal, etc AIN – multiple medication exposures Hepatitis B and C related disease Rhabdomyolysis – statins and PI’s

Slide #17


HIVAN must be diagnosed if present

Very rapid renal failure to ESRD over weeks to months makes diagnosis essential

Usually nephrotic range proteinuria (> 3 grams)

Detectable viral load Diagnosis only definitive by BIOPSY HAART can treat and prevent disease

Slide #18


HAART and HIVAN Incidence 12-Year Cohort Study

No AIDS AIDS

Cas

es p

er 1

000

per

son

-yea

rs

0

5

10

15

20

25

30

35

40

45

Lucas GM, et al. AIDS. 2004;20:18(3):541-546.

Numbers in bars represent point estimates for HIV-associated nephropathy incidence in cases per 1000 person-years. Brackets above bars represent upper limits of 95% confidence intervals.

No Antiretroviral Therapy

Nucleoside Reverse Transcriptase Inhibitor Therapy

Highly Active Antiretroviral Therapy

Presumed HIV-Associated Nephropathy Incidence Stratified by AIDS Status and

Antiretroviral Use

2.65.0

26.3

14.4

6.80.0

Risk of HIVAN low in

patients without AIDS

NO HIVAN when

HAART used without

AIDS occurrence

Lower HIVAN associated

with NRTI and HAART

use compared with no

ART in patients with AIDS

(p < 0.001 for trend)

Slide #19


HIVAN Treatment

No controlled randomized trials

HAART Glucocorticoid

therapy ACE-i/ARB Dialysis Transplant

Dia

lysi

s-fr

ee S

urv

ival

(n=26)

No ARV P = (0.025)

ARV Treatment

(n=10)

10000 2000 3000

0.00

0.25

0.50

0.75

1.00

Time (days)

Hopkins Nephrology HIV CohortARV Treatment of HIVAN: Dialysis Free Survival EstimatesAtta et al., Nephrol Dial Transpl, 2006

Slide #20


TENOFOVIR

Adefovir Tenofovir

Tenofovir closely related to adefovir

Adefovir is a well described nephrotoxin

Tenofovir freely filtered; also secreted by proximal tubule

Nephrotoxicity vigilance in clinical trials – no nephrotoxicity reported

TDFBlood Lumen

OAT1

MRP

ProximalTubule

Slide #21


Comparison of Renal Function ChangesJohns Hopkins Cohort

141 (44.9%)158 (45.9%)1%-25% decline

133 (42.3%)125 (36.3%)<0% decline

34 (10.8%)46 (13.4%)25-50% decline

6 (1.9%)15 (4.4%)>50% decline

NRTI

(n=314)

TDF

(n=344)Decline in CrCl

Adapted from Gallant J et al. CID 2005; 40:1194-1998

Slide #22


2 (7)Hemodialysis; n (%)

1.2 (0.67 – 2.6) P < .05Post creatinine; mg/dL

22 (81)Return to baseline creatinine; n (%)

6/17 (35)Urine protein; n (%)

16 (59)Fanconi Syndrome; n (%)

3.9 (0.89 – 20) P < .05Peak creatinine; mg/dL

0.9 (0.5 – 2.1)Baseline creatinine; mg/dL

Characteristic (N=27)

Mean (range) unless otherwise specified

Tenofovir-associated Renal Dysfunction

Adapted from Zimmermann AE, et al. Clin Infect Dis. 2006;42(2):283-290.

Slide #23


Fanconi Syndrome

GlucosePhosphateBicarbonateSodiumAmino Acids

Hypophosphatemia, acidosis, glycosuria, aminoaciduria, hypokalemia = FANCONI SYNDROME

XX

X

Phosphate

Proximal Tubule Cell

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HIV and Kidney