Post on 15-Jul-2015
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
Incidence and Causes of End-Stage Renal Disease (ESRD) in US
www.usrds.org/slides.htm.
Slide #7
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
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.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
Cockcroft-Gault and MDRD Equations
6 variable: Cr, BUN, age, alb, race, sex4 variable: Cr, age, race, sex
C-G MDRD
Slide #15
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
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
DM Fine, MD.Presented at RWCA Clinical Update, August 2006.
Fanconi Syndrome
GlucosePhosphateBicarbonateSodiumAmino Acids
Hypophosphatemia, acidosis, glycosuria, aminoaciduria, hypokalemia = FANCONI SYNDROME
XX
X
Phosphate
Proximal Tubule Cell