Slide #1
Renal Disease and Toxicities: Issues for HIV Providers
Derek M. Fine, MD
Assistant Professor Johns Hopkins University School of Medicine
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Slide #3
HIV Kidney Disease: Why Do We Care?
Increasing prevalence of kidney disease 1 even though the incidence of AIDS nephropathy has remained constant since the mid-1990s2 Kidney function is abnormal in up to 30% of HIVinfected 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,
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
JAIDS. 2002 Apr 1;29(4):378-87. 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.
2 Schwartz
Kidney Disease is on the Rise in HIV Patients in the United States
Slide #4
Trends in diseases reported on U.S. death certificates that mentioned HIV infection
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Selik, JAIDS. 2002 Apr 1;29(4):378-87.
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
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Incidence and Causes of End-Stage Renal Disease (ESRD) in US
Slide #6
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
www.usrds.org/slides.htm.
Slide #7
Incidence of ESRD Among African Americans by Primary Disease (1999)
Diabetes Hypertension 20,748 3168 2186 24,535
HIV nephropathy Focal GN SLE nephritis Membranous nephropathy HUS
Amyloidosis Postinfectious GN 0
1703 315 96 90 34
10,000 20,000 30,000
African Americans Aged 20-65 years (n=66,063)
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
GN=glomerulonephritis; HUS=hemolytic anemia syndrome. Monahan M, et al. Semin Nephrol. 2001;21:394-402.
Disproportionate Affects of AIDS in Black and Hispanic Populations
1
Slide #8
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
1http://www.cdc.gov/hiv/graphics/images/l178/l178-12.ppt
2www.diabetes.org/uedocuments/NationalDiabetesFactSheetRev.pdf. DM Fine, MD. 3 Presented at RWCA Clinical Update, August 2006. www.americanheart.org/presenter.jhtml?identifier=3000927
Slide #9
Hypertension in HIV
4.5 4.0 3.5
Predictors of Mortality in Women with HIV following HAART Initiation
Szczech LA, et al. Clin Infect Dis. 2004;39:1199-1206.
Hazard Ratio (95% CI)
3.0 2.5 2.0 1.5 1.0
P < 0.0001 P = 0.003 P < 0.0001 P = 0.008 P = 0.04 P = 0.005
0.5 0.0
CD4 LymphocytePriorPrior History of Albumin Albumin History Proteinuria CreatinineHistory of (1/Cr) CD4 History of Creatinine (1/Cr) of Count AIDS-Defining Hypertension Lymphocyte AIDS-Defining Hypertension Illness Count Illness Proteinuria Albumin
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
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Slide #10
IDSA Guidelines - Screening Algorithm for HIV-Related Renal Diseases
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)
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Gupta SK, et al. Clin Infect Dis. 2005;40:1559-1585.
Slide #11
IDSA Guidelines - Screening Algorithm for HIV-Related Renal Diseases
(Continued)
Abnormal Values •Grade 1+ proteinuria by dipstick •Clcr or GFR <60 mL/min per 1.73 m2
No Abnormal Values
W/O Kidney Disease Risk Factors: With Kidney Disease •Follow clinically Risk Factors*: •Reassess based on •Rescreen annually signs/symptoms •Reassess per clinical events
•Evaluate proteinuria further with spot urine protein/cr ratio •Perform renal ultrasound •Consider referral to nephrologist for further evaluation & potential biopsy
*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
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Gupta SK, et al. Clin Infect Dis. 2005;40:1559-1585.
Slide #12
Creatinine is not sufficient as a measure of kidney function
GFR versus Serum Creatinine
9.0 8.0 Serum Creatinine (mg/dL)
7.0
6.0 5.0 4.0
3.0
2.0 1.0 0.0
Creatinine poor reflector of GFR
0
20 40
60 80 100 120 140 160 180
Inulin Clearance (mL/min/1.73 m2)
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Johnson R, et al. Comprehensive Clinical Nephrology. 2000. Mosby. St. Louis. 4.15.1–4.15.15.
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)
4 Variable Version
Cockcroft DW and Gault MH Nephron 1976; 16:31-41 Levey et al, JASN 2000; 11: 155A [Abstract]
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Slide #14
Cockcroft-Gault and MDRD Equations
C-G MDRD
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
6 variable: Cr, BUN, age, alb, race, sex 4 variable: Cr, age, race, sex
Slide #15
Assessment of Proteinuria
Using Protein/Creatinine Ratio
Random urine: Protein mg/dl
Creatinine mg/dl
24-hour urine - Gold Standard
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Ginsberg et. al. NEJM 309:25 p1543
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
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Slide #17
HIVAN must be diagnosed if present
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
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Very
Slide #18
HAART and HIVAN Incidence 12-Year Cohort Study
Risk of HIVAN low in
Cases per 1000 person-years
Presumed HIV-Associated Nephropathy Incidence Stratified by AIDS Status and Antiretroviral Use
patients without AIDS
45
40
35 30
No Antiretroviral Therapy Nucleoside Reverse Transcriptase Inhibitor Therapy
NO HIVAN when HAART used without AIDS
occurrence
25
20 15
Highly Active Antiretroviral Therapy
26.3
Lower HIVAN associated with NRTI and HAART
use compared with no ART in patients with AIDS
10
5 0
2.6
5.0
14.4
6.8
0.0
No AIDS
AIDS
(p < 0.001 for trend)
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.
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Lucas GM, et al. AIDS. 2004;20:18(3):541-546.
Slide #19
HIVAN Treatment
Dialysis-free Survival
No controlled randomized trials HAART Glucocorticoid therapy ACE-i/ARB Dialysis Transplant
1.00
Hopkins Nephrology HIV Cohort ARV Treatment of HIVAN: Dialysis Free Survival Estimates
Atta et al., Nephrol Dial Transpl, 2006
0.75
0.50
0.25
ARV Treatment
(n=26)
No ARV 0.00 0
(n=10)
P = (0.025)
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
1000 Time (days)
2000
3000
Slide #20
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
Adefovir
Blood TDF
Tenofovir
Lumen
Proximal Tubule
OAT1
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
MRP
Slide #21
Comparison of Renal Function Changes Johns Hopkins Cohort
TDF (n=344) 15 (4.4%) 46 (13.4%)
158 (45.9%) 125 (36.3%)
Decline in CrCl >50% decline 25-50% decline
1%-25% decline <0% decline
NRTI (n=314) 6 (1.9%) 34 (10.8%)
141 (44.9%) 133 (42.3%)
Adapted from Gallant J et al. CID 2005; 40:1194-1998
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
Slide #22
Tenofovir-associated Renal Dysfunction
Characteristic (N=27) Baseline creatinine; mg/dL 0.9 (0.5 – 2.1)
Peak creatinine; mg/dL
Post creatinine; mg/dL Fanconi Syndrome; n (%)
3.9 (0.89 – 20) P < .05
1.2 (0.67 – 2.6) P < .05 16 (59)
Return to baseline creatinine; n (%) Urine protein; n (%)
Hemodialysis; n (%)
Mean (range) unless otherwise specified
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.
22 (81) 6/17 (35)
2 (7)
Adapted from Zimmermann AE, et al. Clin Infect Dis. 2006;42(2):283-290.
Slide #23
Fanconi Syndrome
Proximal Tubule Cell
Glucose Phosphate Bicarbonate Sodium Amino Acids
X
X
X
Phosphate
Hypophosphatemia, acidosis, glycosuria, aminoaciduria, hypokalemia = FANCONI SYNDROME
DM Fine, MD. Presented at RWCA Clinical Update, August 2006.