Kidney Disease in Patients with HIV Infection and AIDS
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INVITED ARTICLE HIV/AIDS
Kenneth H. Mayer, Section Editor
Kidney Disease in Patients with HIV Infection and AIDS
Jonathan Winston,1 Gilbert Deray,5 Trevor Hawkins,2 Lynda Szczech,3 Christina Wyatt,1 and Benjamin Young4
1
Mount Sinai School of Medicine, New York, New York; 2University of New Mexico, Southwest CARE Center, Santa Fe; 3Duke University Medical Center, Durham,
North Carolina; 4Rose Medical Center, Division of General Internal Medicine, University of Colorado at Denver and Health Sciences Center, Denver; and 5Department
of Nephrology, Pitié–Salpêtrière Hospital, Paris, France
As patients infected with human immunodeficiency virus (HIV) live longer while receiving antiretroviral therapy, kidney
diseases have emerged as significant causes of morbidity and mortality. Black race, older age, hypertension, diabetes, low
CD4+ cell count, and high viral load remain important risk factors for kidney disease in this population. Chronic kidney
disease should be diagnosed in its early stages through routine screening and careful attention to changes in glomerular
filtration rate or creatinine clearance. Hypertension and diabetes must be aggressively treated. Antiretroviral regimens them-
selves have been implicated in acute or chronic kidney disease. The risk of kidney disease associated with the widely used
agent tenofovir continues to be studied, although its incidence in reported clinical trials and observational studies remains
quite low. Future studies about the relationship between black race and kidney disease, as well as strategies for early detection
and intervention of kidney disease, hold promise for meaningful reductions in morbidity and mortality associated with
kidney disease.
HISTORICAL PERSPECTIVE viable option [3–6]. Despite these improvements, risk factors
for kidney disease are highly prevalent among HIV-infected
The first reports of AIDS-related renal failure, published in the
patients, and kidney disease remains a significant cause of
mid-1980s, described cases of what we now recognize as HIV-
morbidity and mortality, even among those patients receiving
associated nephropathy (HIVAN) [1]. Before effective antiviral
HAART.
therapy became available, HIVAN was so frequent and its clin-
ical features were so dramatic—heavy proteinuria and rapid
EPIDEMIOLOGY AND RISK FACTORS FOR CKD
progression to end-stage renal disease (ESRD) in immunosup-
IN HIV-INFECTED PATIENTS
pressed black persons—that HIVAN became almost synony-
mous with HIV-associated chronic kidney disease (CKD). As CKD is defined as kidney damage or reduced kidney function
HIV spread through the black community, the ESRD incidence that persists for 13 months [7]. A useful indicator of kidney
increased substantially, and by the early 1990s, HIVAN became damage is elevated urinary protein excretion, measured qual-
the third leading cause of ESRD in black persons aged 20–64 itatively with use of a urine dipstick or measured quantitatively
years [2]. with use of a spot urine protein-to-creatinine ratio (or 24-h
Since that time, the incidence and spectrum of kidney dis- urine collection). Kidney function can be reliably estimated
eases in HIV-infected patients have been altered by the wide- from the serum creatinine by calculating the creatinine clear-
spread use of HAART. The clinical course of kidney disease is ance or glomerular filtration rate (GFR) through use of the
more indolent, the risk of ESRD has been reduced by 40%– Cockcroft-Gault or Modification of Diet in Renal Disease
60%, the 1-year survival rate while undergoing dialysis has (MDRD) equations, respectively. A GFR !60 mL/min meets
increased from 25% to 75%, and kidney transplantation is a criteria for CKD, a cutoff supported by epidemiologic data
linking lower GFR to an increased frequency of hospitalization,
Received 28 January 2008; accepted 13 August 2008; electronically published 23 October cardiovascular events, or death. Neither the Cockcroft-Gault
2008.
Reprints or correspondence: Dr. Jonathan Winston, Mount Sinai School of Medicine, One
nor the MDRD equations has been specifically validated in the
Gustave L. Levy Pl., Box 1243, New York, NY 10029 (jonathan.winston@mssm.edu). HIV-infected population. The MDRD equation was derived
Clinical Infectious Diseases 2008; 47:1449–57 from patients with low GFR and therefore can yield variable
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4711-0014$15.00
results in persons with normal renal function [8]. Nonetheless,
DOI: 10.1086/593099 these estimates remain the most highly validated formulas avail-
Kidney Disease and HIV/AIDS • 129Table 1. Antivirals and antibiotics with known nephrotoxicity.
Drug Reported nephrotoxicity Risk factor(s)
Acyclovir Crystal nephropathy Infusion, volume depletion
Adefovir Tubular toxicity CKD
Aminoglycoside ARF CKD, critical illness
Amphotericin ARF, tubular toxicity CKD, critical illness, prolonged illness
b-Lactams Interstitial nephritis b-Lactam allergy
Cidofovir ARF, tubular toxicity CKD
Foscarnet ARF, tubular toxicity CKD
Gancyclovir ARF (rare) …
Pentamidine Hyperkalemia, ARF CKD
Sulfonamide Interstitial nephritis, crystal nephropathy Sulfa allergy
Trimethoprim Hyperkalemia, increased creatinine level CKD, volume depletion
NOTE. Adapted from Berns and Kasbekar [27]. ARF, acute renal failure; CKD, chronic kidney disease.
able, and both equations are more sensitive than measurement in an analysis of 12 million patients who received care through
of serum creatinine alone. the Veterans Administration system, the multivariate hazard
Diabetes mellitus and hypertension are the 2 most frequent ratio for ESRD in HIV-infected persons was 4.56 (95% CI,
causes of CKD in the general population. They increase the 3.44–6.05) [19]. The natural history of CKD is also considerably
CKD risk 10-fold and account for 71% of all ESRD cases [3, more aggressive in HIV-infected blacks than in whites. Among
9]. Diabetes and hypertension are increasingly common among 4259 patients observed in the Johns Hopkins HIV Clinical Co-
persons with HIV infection. The prevalence of diabetes was hort from 1990 through 2004, the risk for incident CKD was
14% in the Multicenter AIDS Cohort Study, 4-fold higher than 2-fold higher among blacks (hazard ratio 1.9; 95% CI, 1.2–
in seronegative control persons [10], and was associated with 2.8). After CKD diagnosis, however, the decrease in GFR was
cumulative exposure to nucleoside reverse-transcriptase inhib- 6-fold more rapid among blacks, which dramatically increased
itors but not protease inhibitors (PIs) [11, 12]. Among those the likelihood of progression to ESRD (hazard ratio, 17.7; 95%
included in the Multicenter AIDS Cohort Study, the prevalence CI, 2.5–127) [20].
of hypertension is 3-fold higher than in age- and sex-matched The aging of an HIV-infected population is another impor-
control persons (34.2% vs. 11.9%; P ! .001), and hypertensive tant pathway by which the incidence of CKD can be expected
persons with HIV infection are more likely to have insulin to continue to increase. GFR normally decreases with age. The
resistance and metabolic syndrome (64.3% vs. 16.9%; P ! prevalence of CKD in the elderly population now approaches
.001) [13]. In a cross-sectional analysis of 129 HIV-infected 50% [21]. Other risk factors for CKD in HIV-infected patients
patients with CKD, the prevalence of documented hypertension are high viral load, low CD4+ lymphocyte count, and hepatitis
and the prevalence of diabetes mellitus were 55% and 20%, C virus coinfection [17]. The importance of recognizing CKD
respectively [14], which underscores the importance of opti- is underscored by the strong correlation between CKD and both
mizing blood pressure and achieving glycemic control as a morbidity and mortality. In the HIV Epidemiology Research
means of minimizing the impact of CKD concomitant with Study, proteinuria or an elevated serum creatinine level was
HIV infection. associated with an increased risk of hospitalization and mor-
Race is an important risk factor for CKD. Black persons tality [22, 23]. In the Women’s Interagency HIV Study, elevated
comprise 10% of the general population in the United States creatinine level and proteinuria were similarly predictive of an
but account for 130% of patients with ESRD [3]. Young, male increased risk of an AIDS-defining illness and mortality [24].
blacks have an 11-fold increased risk of CKD, compared with Acute renal failure (ARF) in HIV-infected persons. ARF is
their white counterparts [15]. Five new cases of ESRD develop highly prevalent among persons with HIV infection and, like
for every 100 cases of CKD in black persons, whereas only 1 CKD, is linked to morbidity and mortality. Major risk factors
new ESRD case develops for every 100 cases of CKD in whites are the same as in the general population, including older age,
[16]. The burden of kidney disease in black persons with HIV preexisting CKD, serious systemic illness or infection, and ex-
infection, compared with their HIV-infected white counter- posure to nephrotoxic agents [25, 26]. Liver disease and low
parts, is similarly disproportionate. Among persons with HIV CD4+ cell count also increase the risk of ARF among HIV-
infection who receive dialysis, 91% are black [3]. Black race infected persons. Table 1 lists antivirals and antibiotics with
increases the risk of microalbuminuria and proteinuria by at nephrotoxic potential that are commonly used in treatment of
least 2-fold [17, 18]. In a comparison between blacks and whites HIV-infected patients.
130 • Winston et al.Ten percent of patients in a large ambulatory clinic experi- Food and Drug Administration adverse event reporting system
enced at least 1 episode of ARF over a 2-year period [25]. More detected 12 additional confirmed cases [30–33]. Most cases
than one-half of these episodes were attributed to underlying required hospitalization for pain relief and stent insertion, per-
infections, 76% of which were AIDS-defining illnesses, and cutaneous nephrostomy, lithotripsy, or endoscopic surgical ex-
almost three-quarters of them necessitated hospitalization. traction. Predisposing factors are unknown, and the drug was
Drug-related complications accounted for nearly one-third of discontinued in most but not all cases.
cases—the conventional nephrotoxin amphotericin was most The association of tenofovir with kidney disease has been an
common—and liver disease accounted for 10% of cases. In an area of interest since the drug underwent preclinical testing,
analysis of administrative data from 12 million hospital dis- because of its structural similarity to adefovir and cidovir. These
charges in New York State, HIV infection was associated with acyclic nucleotide analogues are excreted by renal tubule cell
a 2.8-fold increase in documented ARF cases [26]. In-hospital uptake and secretion [34]. Cidofovir at therapeutic doses can
mortality was increased nearly 6-fold among HIV-infected pa- cause ARF, and a high incidence of ARF was noted when ad-
tients with documented ARF. efovir was tested for treatment of HIV-1 infection at dosages
of 120 mg per day, which is 10-fold higher than the dosage for
IMPACT OF ANTIRETROVIRAL THERAPY (ART) treating hepatitis B virus infection. Both agents induce proximal
ON RENAL FUNCTION renal tubule cell damage, clinically characterized by phospha-
Proper selection and dose-adjustment of antiretrovirals and turia, a modest amount of proteinuria (“tubule” proteinuria),
other commonly used drugs for patients with kidney disease and increases in serum creatinine [35, 36]. Consequently, con-
are important components of care for patients with HIV in- siderable attention has been paid to the incidence of ARF or
fection. Tables 2 and 3 summarize the nephrotoxic potential long-term reductions in GFR that are induced by tenofovir,
of antiretroviral agents and their recommended dose adjust- with use of data from phase II, III, and IV clinical trials; ex-
ments for those with kidney disease. Isolated case reports of panded access programs before drug approval; and observa-
nephrotoxicity have been reported with almost all agents, but tional cohort studies. Case reports of tenofovir-induced ARF
renal disease has been associated with indinavir and tenofovir do exist, sometimes associated with proteinuria, hypohospha-
more often than with other drugs [27, 28]. temia, euglycemic glycosuria, hypouricemia, hypokalemia, or
Indinavir causes nephrolithiasis and chronic interstitial ne- metabolic acidosis. This is known as Fanconi syndrome when
phritis in as many as 12% of patients who receive it. The most or all components are present.
mainstay of prevention of this condition is adequate hydration, In fact, tenofovir-associated renal dysfunction is a rare event
with intake of at least 1.5 L of noncaffeinated fluid. One report in prospective clinical trials, particularly among ART-naive pa-
described 4 cases of renal colic and nephrolithiasis in patients tients. No significant change in GFR was demonstrated in a
who received lopinavir-ritonavir treatment, but a causal effect comparison of tenofovir versus stavudine in combination with
was not established [29]. Three cases of kidney stones con- lamivudine-efavirenz [37] or in a comparison of tenofovir-
taining atazanavir have been reported, and a review of the US emtricitabine versus fixed-dose zidovudine-lamivudine with
Table 2. Antiretrovirals shown to be potentially nephrotoxic.
Drug Reported nephrotoxicity Risk factor(s)
Abacavir Acute renal failure, interstitial nephritis (rare) …
Atazanavir Case reports of nephrolithiasis, interstitial Not established
nephritis, reversible renal failure
Didanosine Tubular dysfunction (rare) …
Efavirenz Single report of hypersensitivity reaction …
Enfuvirtide Single report of glomerulonephritis …
Indinavir Nephrolithiasis, crystalluria, dysuria, papil- Concomitant treatment with low-dose ritonavir; for nephrolithiasis, urine
lary necrosis, acute renal failure pH 16, low lean body mass, treatment with trimethoprim-sulfamethoxa-
zole or acyclovir, chronic infection with hepatitis B or hepatitis C virus,
warm environmental temperature, high indinavir concentration
Lamivudine Tubular dysfunction (rare) …
Ritonavir Reversible renal failure, but nephrotoxicity Concomitant treatment with nephrotoxic drugs, underlying renal pathology
not definitely established
Stavudine Tubular dysfunction (rare) …
Tenofovir Tubular toxicity, Fanconi syndrome (rare), Low body weight, impaired baseline renal function, concomitant treat-
decreased glomerular filtration rate ment with potentially nephrotoxic drugs
Kidney Disease and HIV/AIDS • 131Table 3. Nucleoside or nucleotide dosage adjustment for HIV-infected patients with reduced glomerular filtration rate.
Antiretrovirals Daily dosage Dosing in the case of renal insufficiency
Nucleoside reverse-transcriptase inhibitor
Abacavir 300 mg PO BID No need for dosage adjustment
Didanosine If 160 kg, 400 mg PO QD; if !60 kg, 250 mg QD For CrCl of 30–59 mL/min, 200 mg for weight 160 kg and 125 mg for weight !60 kg
For CrCl of 10–29 mL/min, 125 mg for weight 160 kg and 100 mg for weight !60 kg
For CrCl of !10 mL/min, 125 mg for weight 160 kg and 75 mg for weight !60 kg
For patients undergoing CAPD or HD, use same dose as for CrCl !10 mL/min
Emtricitabine 200 mg Oral capsule PO QD or 240 mg (24 mL) oral solution PO QD For CrCl of 30–49 mL/min, capsule of 200 mg every 48 h or solution of 120 mg every 24 h
For CrCl of 15–29 mL/min, capsule of 200 mg every 72 h or solution of 80 mg every 24 h
For CrCl of !15 mL/min, capsule of 200 mg every 96 h orsolution of 60 mg every 24 h or HD*
Lamivudine 300 mg PO QD or 150 mg PO BID For CrCl of 30–49 mL/min, 150 mg QD
For CrCl of 15–29 mL/min, 150 mg 1 time, then 100 mg QD
For CrCl of 5–14 mL/min, 150 mg 1 time, then 50 mg QD
For CrCl of !5 mL/min, 50 mg 1 time, then 25 mg QD or HD*
Stavudine If 160 kg, 40 mg PO BID; if !60 kg, 30 mg PO BID For CrCl of 26–50 mL/min, 20 mg every 12 h for weight 160 kg and 15 mg every 12 h for weight !60 kg
For CrCl of 10–25 mL/min, 20 mg every 24 h for weight 160 kg and 15 mg every 24 h or HD*
Tenofovir 300 mg PO QD For CrCl of 30–49 mL/min, 300 mg every 48 h
For CrCl of 10–29 kg, 300 mg twice weekly
for ESRD, 300 mg every 7 days or HD*
Tenofovir plus emtricitabine 1 Tablet PO QD For CrCl of 30–49 mL/min, tablet every 48 h
For CrCl !30 kg, not recommended
Zidovudine 300 mg PO BID For “severe” renal impairment or HD*, 100 mg TID or 300 mg QD
Nonnucleoside reverse-transcriptase inhibitor
Delavirdine 400 mg PO TID No dosage adjustment necessary
Efavirenz 600 mg PO QD, 1 tablet PO QD No dosage adjustment necessary; Atripla not recommended if CrCl !50 mL/min
Efavirenz-tenofovir-emtricitabine 600 mg PO QD, 1 tablet PO QD Atripla not recommended if CrCl !50 mL/min
Nevirapine 200 mg PO BID No dosage adjustment necessary
Protease inhibitor
Atazanavir 400 mg PO QD No dosage adjustment necessary for patients not requiring HD
Darunavir 600 mg Plus 100 mg ritonavir PO BID No dosage adjustment necessary
Fosamprenavir 1400 mg PO BID No dosage adjustment necessary
Indinavir 800 mg PO every 8 h No dosage adjustment necessary
Lopinavir-ritonavir 400–100 mg PO BID or 800–200 mg PO QD (QD for treatment-naive patients only) No dosage adjustment necessary
Nelfinavir 1250 mg PO BID No dosage adjustment necessary
Ritonavir 600 mg PO BID No dosage adjustment necessary
Saquinavir soft gel cap 1200 mg TID No dosage adjustment necessary
Tipranavir 500 mg PO BID; with ritonavir, 200 mg PO BID No dosage adjustment necessary
Entry inhibitor
Enfuvirtide 90 mg Subcutaneously every 12 h No dosage adjustment necessary
Maraviroc The recommended dose differs on the basis of concomitant medications No dosage recommendation; use with caution; patients with CrCL !50 mL/min should receive
because of drug interactions: 150 mg, 300 mg, or 600 mg BID maraviroc and CYP3A inhibitor only if potential benefit outweighs the risk
Integrase inhibitor
Raltegravir 400 mg BID QD No dosage adjustment
NOTE. Adapted from US Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1–infected adults and adolescents [61]. Atripla, efavirenz-emtricitabine-tenofovir;
BID, twice per day; CAPD, continuous ambulatory peritoneal dialysis; CrCL, creatinine clearance level; ESRD, end-stage renal disease; HD, hemodialysis; HD*, dose after HD; PO, orally; QD, every day; TID, 3
times per day.efavirenz in ART-naive patients during 144 weeks of treatment discontinuation (1%–2%) was observed when lopinavir (800
[38]. Adverse renal events did not develop in a subgroup anal- mg) plus ritonavir (200 mg) once per day was compared with
ysis of blacks in these 2 trials [39]. In the Development of 400 mg/100 mg twice per day and when fosamprenavir-rito-
Antiviral Therapy trial, which exclusively comprised patients navir was compared with atazanavir-ritonavir, all in combi-
from Uganda and Zimbabwe, 2469 (74%) of the 3316 enrolled nation with tenofovir-emtricitabine [48, 49]. In the CASTLE
patients received first-line ART with tenofovir and zidovudine- Study—which compared atazanavir-ritonavir at 300 mg/100
lamivudine. The overall incidence of severe reduction in GFR mg once per day with lopinavir-ritonavir at 400 mg/100 mg
was low (1.6%), and no difference in renal safety endpoints twice per day, both with fixed-dose tenofovir-emtricitabine—
was detected between the regimens [40]. the rate of adverse event–related drug discontinuations was low
Decreases in GFR in tenofovir-treated patients have been (2% and 3%, respectively) [50]. The impact of a potential in-
reported. In the Johns Hopkins Cohort, GFR decreased to a teraction between boosted PIs and tenofovir was specifically
greater extent in tenofovir-treated patients than in non–ten- analyzed in the HIV Outpatient Study cohort by comparing
fovir-treated patients (19 vs. 11 mL/min), an effect restricted renal function in 300 tenofovir-treated patients who received
to treatment-experienced patients [41]. Treatment-experienced either nonnucleoside reverse-transcriptase inhibitors or boosted
patients could be more sensitive to adverse effects of tenofovir, PIs (atazanavir or lopinavir). The 12-month intrapatient change
more likely to experience adverse drug interactions, or more in rate of creatinine clearance was not different between groups
likely to develop kidney disease because of advanced HIV dis- [51].
ease and its attendant comorbidities. The HIV Outpatient Study Data on the safety of tenofovir among patients with CKD
compared the renal outcomes of 593 tenofovir-treated subjects is very limited. A small historical case series of 13 persons
and 521 HAART-treated subjects who did not receive tenofovir. with CKD (median creatinine level, 1.7 mg/dL; median cre-
Tenofovir was associated with a small but statistically significant atinine clearance, 56 mL/min; median GFR, 49 mL/min/1.73
decrease in GFR, but only 1.1% of tenofovir-treated patients m2) who received tenofovir for a median of 13 months showed
discontinued the drug because of adverse renal events [42]. a confirmed increase in National Kidney Foundation stage in
Area under the curve for tenofovir is increased when it is 2 persons [52]. Eleven of 13 patients received an inappropriately
combined with ritonavir-boosted PIs. One explanation has been high daily dosage of tenofovir, but limited median 12-month
that boosted PIs increase tenofovir’s nephrotoxic potential by changes in creatinine clearance level or GFR were observed
competing for the same renal transporters, thus impairing its (+2.9 mL/min and +3.7 mL/min/1.73m2, respectively). Several
tubule secretion, but recent studies do not support such a patients had significant improvement in measured renal
mechanism [43]. In 1 study involving ∼140 subjects, a teno- function.
fovir-boosted PI regimen was associated with a 7–10 mL/min All of these data show low absolute rates of drug discontin-
greater decrease in GFR over 48 weeks, compared with a te- uation caused by renal dysfunction (0%–2%) or no differences
nofovir–nonnucleoside reverse-transcriptase inhibitor or non– in severe renal adverse events when tenofovir-containing reg-
tenofovir-containing regimen [44]. A higher proportion of te- imens are compared with regimens not containing tenofovir
nofovir-treated patients in that report were treatment experi- [53–55]. GFR can decrease 7–10 mL/min over the course of 1
enced, which perhaps contributed to those observations. In year in tenofovir-treated patients, but in most studies, the in-
another study, 53 patients treated with tenofovir and boosted crease in serum creatinine level was too small to be identified
atazanavir after multiple prior treatment failures experienced as clinically significant (∼0.05 mg/dL), GFR remained in the
a 7.8 mL/min decrease in GFR over 48 weeks [45], but control normal range, and the rate of drug discontinuation was not
individuals were not studied. In an observational study of 445 greater for patients who received tenofovir. If the decrease in
tenofovir-treated patients observed for a mean of 13 months, GFR were to continue for many years, it would have serious
GFR decreased a mean of 7 mL/min, and 2% of patients ex- clinical implications, but no such trend has been reported.
perienced a decrease in GFR to !60 mL/min. Concurrent use These data underscore the importance of carefully screening
of didanosine or amprenavir increased the risk of a decrease patients for preexisting renal disease, of following recommen-
in GFR [46]. Again, the change in GFR in non–tenofovir-con- dations for appropriate dosage adjustments in patients with
taining regimens was not reported. renal impairment, and of closely monitoring patients for
Several reports support the renal safety of tenofovir-boosted changes in renal function. From the renal safety perspective, it
PI regimens. When tenofovir was coadministered with either would be prudent to seek an alternative and equally effective
atazanavir-ritonavir or lopinavir-ritonavir in heavily treatment- agent for patients who initiate ART with impaired kidney func-
experienced patients, the rate of drug discontinuation attrib- tion (GFR, !60 mL/min), although other safety issues must
utable to renal disease was 1.3% [47]. A similar rate of drug also be considered.
Kidney Disease and HIV/AIDS • 133TREATING HIV-INFECTED PATIENTS WITH CKD considered for patients with unexplained kidney disease, es-
pecially those with heavy proteinuria or reduced GFR, because
Kidney function should be assessed according to existing In-
they are at the greatest risk of ESRD. It is difficult to predict
fectious Diseases Society of America guidelines [28]. All patients
which disease may be affecting the kidneys on clinical grounds
should have a screening urinalysis and a calculated estimate of
alone, although in 1 center, HIVAN was considerably more
GFR. Those at high risk for kidney disease (i.e., those with
common when viral load was 1400 copies/mL, whereas diseases
black race, CD4+ count !200 cells/mm3, HIV RNA levels 14000
such as hypertension, diabetes, or classic focal segmental glom-
copies/mL, diabetes, hypertension, or coinfection) should be
erulosclerosis were more common when viral load was !400
screened annually to detect subtle changes over time. The stan-
copies/mL [60]. A special circumstance for a kidney biopsy
dard urinary dipstick is a sufficient screen for proteinuria, but
exists when seeking the diagnosis of HIVAN in a HAART-naive
diabetic patients must be tested for microalbuminuria, defined
patient with kidney disease, particularly when ART would not
as urinary albumin excretion of 30–300 mg/mg creatinine, a
otherwise be warranted because of a CD4+ T cell count 1350
range not detected using conventional dipsticks [56]. Microal-
buminuria in diabetic patients predicts subsequent decreases cells/mm3. Ongoing viral replication is directly responsible for
in GFR, and treatment with angiotensin-converting enzyme the renal disease in HIVAN, and ART is recommended, irre-
inhibitors or angiotensin-receptor blockers is indicated [57]. spective of CD4+ T cell count, because it preserves kidney func-
Microalbuminuria in nondiabetic patients has been linked to tion and improves survival [5, 61, 62].
future cardiovascular events [58], a risk that may be modified For most patients, the most effective approach to CKD treat-
by angiotensin-converting enzyme inhibitors or angiotensin- ment is effective medical management of diabetes and hyper-
receptor blockers [59]. Several issues warrant further study tension. Blood pressure should be monitored at each office visit,
when considering routine testing for microalbuminuria in non- and antihypertensive treatment should be targeted to a blood
diabetic patients with HIV infection: the reproducibility of the pressure !130/80 mm Hg [63]. Angiotensin-converting enzyme
measurements, their proper timing (before or after initiation inhibitors or angiotensin-receptor blockers are the drugs of first
of ART), and proven benefits of long-term treatment with an- choice, because they reduce urinary protein excretion [57] and
giotensin-converting enzyme inhibitors or receptor blockers. slow the progression to ESRD (figure 2). Beta-blockers or non-
The general approach to diagnosing the cause of kidney dis- dihydropyridine calcium channel blockers are alternatives, but
ease is to seek reversible causes. Information obtained through their metabolism can be blocked by PIs. Most patients with
the patient history and physical examination should be sup- hypertension and diabetes will require at least 2 antihyperten-
plemented by a urinalysis to quantify protein excretion and to sive medications to achieve optimal control of blood pressure
test for urinary cells and casts, as well as a renal sonogram to [64].
assess kidney size and structure. Additional testing should be Glycemic control is critically important in delaying the pro-
individualized (figure 1). A kidney biopsy should be strongly gression of diabetic nephropathy. The American Diabetes As-
Figure 1. A simplified algorithm for diagnosing and treating chronic kidney disease (CKD)
134 • Winston et al.fees from Nabi Biopharmaceuticals, Fresenius Medical Care, Glaxo-
SmithKline, Gilead, Genzyme, Abbott, Amgen, and Ortho Biotech; and
grant support from Ortho Biotech Clinical Affairs, GlaxoSmithKline, Pfizer,
and Genzyme. C.W. has received grant support from the Gilead Foundation
and lecture fees from Gilead Sciences and Roche. B.Y. has been a consultant
to Bristol-Myers Squibb, Cerner Corporation, Gilead Sciences, Glaxo-
SmithKline, Hoffman-LaRoche, Merck, Monogram Bioscience, Pfizer, and
Vertex Pharmaceuticals; has served on the speakers’ bureau for Glaxo-
SmithKline, Merck, and Monogram Bioscience; and has received grant and/
or research funding from Bristol-Myers Squibb, Cerner, Gilead Sciences,
GlaxoSmithKline, Hoffman-LaRoche, and Merck. G.D.; no conflicts.
References
1. Rao TK, Filippone EJ, Nicastri AD, et al. Associated focal and segmental
glomerulosclerosis in the acquired immunodeficiency syndrome. N
Engl J Med 1984; 310:669–73.
2. Winston JA, Klotman PE. Are we missing an epidemic of HIV-asso-
ciated nephropathy? J Am Soc Nephrol 1996; 7:1–7.
Figure 2. Relationship between achieved blood pressure controls and 3. US Renal Data System. USRDS 2007 annual data report: atlas of chronic
decreases in glomerular filtration rate (GFR) in clinical trials of diabetic kidney disease and end-stage renal disease in the United States. Be-
and nondiabetic renal disease. HTN, hypertension; MAP, mean arterial thesda, MD: National Institutes of Health, National Institute of Dia-
blood pressure. Reprinted from Bakris et al. [64] with permission. betes and Digestive and Kidney Diseases, 2007.
4. Ahuja TS, Grady J, Khan S. Changing trends in the survival of dialysis
patients with human immunodeficiency virus in the United States. J
sociation recommends that adults with diabetes strive to main- Am Soc Nephrol 2002; 13:1889–93.
5. Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman
tain a glycated hemoglobin A1C level of !7.0%, preprandial PE. Highly active antiretroviral therapy and the epidemic of HIV+
plasma glucose level of 90–130 mg/dL (5.0–7.2 mmol/L), and end-stage renal disease. J Am Soc Nephrol 2005; 16:2412–20.
peak postprandial plasma glucose level of !180 mg/dL (!10.0 6. Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD.
Highly active antiretroviral therapy and the incidence of HIV-1–as-
mmol/L). Components of a successful glycemic control plan
sociated nephropathy: a 12-year cohort study. AIDS 2004; 18:541–6.
include blood glucose self-monitoring, hemoglobin A1C testing 7. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of
at least 2 times each year for patients who meet treatment goals chronic kidney disease and decreased kidney function in the adult US
and quarterly for patients who have not met their goals, and population: Third National Health and Nutrition Examination Survey.
Am J Kidney Dis 2003; 41:1–12.
individualized medical nutrition therapy. 8. Stevens LA, Coresh J, Feldman HI, et al. Evaluation of the modification
Kidney disease tends to be asymptomatic and is usually not of diet in renal disease study equation in a large diverse population.
the primary focus of a visit to an HIV clinic [28]. The presence J Am Soc Nephrol 2007; 18:2749–57.
9. Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease aware-
of kidney disease should be anticipated, and screening and ness, prevalence, and trends among U.S. adults, 1999 to 2000. J Am
proper interpretation of the relationship between serum cre- Soc Nephrol 2005; 16:180–8.
atinine level and GFR are recommended. Just as optimal control 10. Brown TT, Cole SR, Li X, et al. Antiretroviral therapy and the prev-
alence and incidence of diabetes mellitus in the multicenter AIDS
of HIV replication is achievable for most patients, so too is
cohort study. Arch Intern Med 2005; 165:1179–84.
control of hypertension and diabetes. The future holds enor- 11. Brown TT, Li X, Cole SR, et al. Cumulative exposure to nucleoside
mous opportunities for research in new markers for early de- analogue reverse transcriptase inhibitors is associated with insulin re-
tection of kidney disease, prevention strategies, novel thera- sistance markers in the Multicenter AIDS Cohort Study. AIDS 2005;
19:1375–83.
peutics, and a better understanding of the interaction between 12. Tien PC, Schneider MF, Cole SR, et al. Antiretroviral therapy exposure
black race and kidney disease. and incidence of diabetes mellitus in the Women’s Interagency HIV
Study. AIDS 2007; 21:1739–45.
Acknowledgments 13. Gazzaruso C, Bruno R, Garzaniti A, et al. Hypertension among HIV
patients: prevalence and relationships to insulin resistance and meta-
We acknowledge Healthmatters Communications for receiving payments bolic syndrome. J Hypertens 2003; 21:1377–82.
from the commercial supporter for research and editorial assistance. 14. Wyatt CM, Winston JA, Malvestutto CD, et al. Chronic kidney disease
Financial support. This article is derived from a content-development in HIV infection: an urban epidemic. AIDS 2007; 21:2101–3.
meeting, Renal Considerations in HIV Management (2007). An indepen- 15. Stehman-Breen CO, Gillen D, Steffes M, et al. Racial differences in
dent educational grant for this program, including a Continuing Medical early-onset renal disease among young adults: the coronary artery risk
Education–certified Web cast, was provided by Gilead Sciences Medical development in young adults (CARDIA) study. J Am Soc Nephrol
Affairs. 2003; 14:2352–7.
Potential conflicts of interest. J.W. has received consulting and lecture 16. Hsu CY, Lin F, Vittinghoff E, Shlipak MG. Racial differences in the
fees from Gilead Sciences. T.H. has received consulting and/or speaker fees progression from chronic renal insufficiency to end-stage renal disease
from Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, in the United States. J Am Soc Nephrol 2003; 14:2902–7.
Merck, Monogram Bioscience, Pfizer, and Tibotech. L.S. has received con- 17. Szczech LA, Gange SJ, van der Horst C, et al. Predictors of proteinuria
sulting fees from Ortho Biotech Clinical Affairs, Nabi Pharmaceuticals, and renal failure among women with HIV infection. Kidney Int
Gilead, Fresenius Medical Care, Kureha, Affymax, and Acologix; lecture 2002; 61:195–202.
Kidney Disease and HIV/AIDS • 13518. Szczech LA, Grunfeld C, Scherzer R, et al. Microalbuminuria in HIV black antiretroviral-naive patients [poster 505]. In: Program and ab-
infection. AIDS 2007; 21:1003–9. stracts of the 14th Conference Retroviruses and Opportunistic Infec-
19. Choi AI, Rodriguez RA, Bacchetti P, Bertenthal D, Volberding PA, tions (Los Angeles, CA). Alexandria, VA: Foundation for Retrovirology
O’Hare AM. Racial differences in end-stage renal disease rates in HIV and Human Health, 2007.
infection versus diabetes. J Am Soc Nephrol 2007; 18:2968–74. 40. Reid A, Stöhr W, Walker AS, et al; for the Development of Antiretroviral
20. Lucas GM, Lau B, Atta MG, Fine DM, Keruly J, Moore RD. Chronic Therapy Trial. Severe renal dysfunction and risk factors associated with
kidney disease incidence, and progression to end-stage renal disease, renal impairment in HIV-infected adults in Africa initiating antiret-
in HIV-infected individuals: a tale of two races. J Infect Dis 2008; 197: roviral therapy. Clin Infect Dis 2008; 46:1271–81.
1548–57. 41. Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function
21. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney associated with tenofovir disoproxil fumarate treatment, compared
disease in the United States. JAMA 2007; 298:2038–47. with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect
22. Gardner LI, Holmberg SD, Williamson JM, et al. Development of Dis 2005; 40:1194–8.
proteinuria or elevated serum creatinine and mortality in HIV-infected 42. Young B, Buchacz K, Baker RK, et al. Renal function in tenofovir-
women. J Acquir Immune Defic Syndr 2003; 32:203–9. exposed and tenofovir-unexposed patients receiving highly active an-
23. Gardner LI, Klein RS, Szczech LA, et al. Rates and risk factors for tiretroviral therapy in the HIV Outpatient Study. J Int Assoc Physicians
condition-specific hospitalizations in HIV-infected and uninfected AIDS Care (Chic Ill) 2007; 6:178–87.
women. J Acquir Immune Defic Syndr 2003; 34:320–30. 43. Cihlar T, Ray AS, Laflamme G, et al. Molecular assessment of the
24. Szczech LA, Hoover DR, Feldman JG, et al. Association between renal potential for renal drug interactions between tenofovir and HIV pro-
disease and outcomes among HIV-infected women receiving or not tease inhibitors. Antivir Ther 2007; 12:267–72.
receiving antiretroviral therapy. Clin Infect Dis 2004; 39:1199–206. 44. Goicoechea M, Liu S, Best B, et al. Greater tenofovir-associated renal
25. Franceschini N, Napravnik S, Eron JJ Jr, Szczech LA, Finn WF. Inci- function decline with protease inhibitor–based versus nonnucleoside
dence and etiology of acute renal failure among ambulatory HIV- reverse-transcriptase inhibitor–based therapy. J Infect Dis 2008; 197:
infected patients. Kidney Int 2005; 67:1526–31. 102–8.
26. Wyatt CM, Arons RR, Klotman PE, Klotman ME. Acute renal failure 45. Gerard L, Chazallon C, Taburet AM, Girard PM, Aboulker JP, Piketty
in hospitalized patients with HIV: risk factors and impact on in-hospital C. Renal function in antiretroviral-experienced patients treated with
mortality. AIDS 2006; 20:561–5. tenofovir disoproxil fumarate associated with atazanavir/ritonavir. An-
27. Berns JS, Kasbekar N. Highly active antiretroviral therapy and the tivir Ther 2007; 12:31–9.
kidney: an update on antiretroviral medications for nephrologists. Clin 46. Crane HM, Kestenbaum B, Harrington RD, Kitahata MM. Amprenavir
J Am Soc Nephrol 2006; 1:117–29. and didanosine are associated with declining kidney function among
28. Gupta SK, Eustace JA, Winston JA, et al. Guidelines for the manage- patients receiving tenofovir. AIDS 2007; 21:1431–9.
ment of chronic kidney disease in HIV-infected patients: recommen- 47. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-Week comparison of
dations of the HIV Medicine Association of the Infectious Diseases once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in
Society of America. Clin Infect Dis 2005; 40:1559–85. patients with multiple virologic failures. AIDS 2006; 20:711–8.
29. Doco-Lecompte T, Garrec A, Thomas L, Trechot P, May T, Rabaud C. 48. Johnson MA, Gathe JC Jr, Podzamczer D, et al. A once-daily lopinavir/
Lopinavir-ritonavir (Kaletra) and lithiasis: seven cases. AIDS 2004; 18: ritonavir–based regimen provides noninferior antiviral activity com-
705–6. pared with a twice-daily regimen. J Acquir Immune Defic Syndr
30. Chang HR, Pella PM. Atazanavir urolithiasis. N Engl J Med 2006; 355: 2006; 43:153–60.
2158–9. 49. Smith KY, Weinberg WG, DeJesus E, et al. Fosamprenavir or atazanavir
31. Pacanowski J, Poirier JM, Petit I, Meynard JL, Girard PM. Atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine,
urinary stones in an HIV-infected patient. AIDS 2006; 20:2131. for the initial treatment of HIV infection: 48-week results of ALERT.
32. Anderson PL, Lichtenstein KA, Gerig NE, Kiser JJ, Bushman L. Ata- ALERT (COL103952) Study Team. AIDS Res Ther 2008; 5:5.
zanavir-containing renal calculi in an HIV-infected patient. AIDS 50. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily ata-
2007; 21:1060–2. zanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in com-
33. Chan-Tack KM, Truffa MM, Struble KA, Birnkrant DB. Atazanavir- bination with tenofovir and emtricitabine, for management of anti-
associated nephrolithiasis: cases from the US Food and Drug Admin- retroviral-naive HIV-1–infected patients: 48 week efficacy and safety
istration’s Adverse Event Reporting System. AIDS 2007; 21:1215–8. results of the CASTLE study. 2008; 372:646–55.
34. Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion 51. Buchacz K, Young B, Baker RK, et al. Renal function in patients re-
transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral ceiving tenofovir with ritonavir/lopinavir or ritonavir/atazanavir in the
nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 2001; 20: HIV Outpatient Study (HOPS) cohort. J Acquir Immune Defic Syndr
641–8. 2006; 43:626–8.
35. Kahn J, Lagakos S, Wulfsohn M, et al. Efficacy and safety of adefovir 52. Young B, Buchacz K, Moorman A, Wood KC, Brooks JT. Renal function
dipivoxil with antiretroviral therapy: a randomized controlled trial. in patients with pre-existing renal disease receiving tenofovir-contain-
JAMA 1999; 282:2305–12. ing HAART in the HIV Outpatient Study (HOPS) cohort. In: Program
36. Lalezari JP, Stagg RJ, Kuppermann BD, et al. Intravenous cidofovir for and abstracts of the 47th Annual Interscience Conference on Anti-
peripheral cytomegalovirus retinitis in patients with AIDS: a random- microbial Agents and Chemotherapy, (Chicago, IL). Washington, DC:
ized, controlled trial. Ann Intern Med 1997; 126:257–63. American Society for Microbiology, 2007.
37. Izzedine H, Hulot JS, Vittecoq D, et al. Long-term renal safety of 53. Moreno S, Domingo P, Palacios R, et al. Renal safety of tenofovir
tenofovir disoproxil fumarate in antiretroviral-naive HIV-1–infected disoproxil fumarate in HIV-1 treatment-experienced patients with ad-
patients: data from a double-blind randomized active-controlled mul- verse events related to prior NRTI use: data from a prospective, ob-
ticentre study. Nephrol Dial Transplant 2005; 20:743–6. servational, multicenter study. J Acquir Immune Defic Syndr 2006; 42:
38. Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, 385–7.
emtricitabine, and efavirenz compared with zidovudine/lamivudine 54. Jones R, Stebbing J, Nelson M, et al. Renal dysfunction with tenofovir
and efavirenz in treatment-naive patients: 144-week analysis. J Acquir disoproxil fumarate–containing highly active antiretroviral therapy reg-
Immune Defic Syndr 2008; 47:74–8. imens is not observed more frequently: a cohort and case-control study.
39. Gallant JE, Pozniak AL, Staszewski S, et al. Efficacy and safety of te- J Acquir Immune Defic Syndr 2004; 37:1489–95.
nofovir DF (TDF)–containing vs non-TDF–containing regimens in 55. Winston A, Amin J, Mallon P, et al. Minor changes in calculated
136 • Winston et al.creatinine clearance and anion-gap are associated with tenofovir di- 61. Panel on Antiretroviral Guidelines for Adult and Adolescents. Guide-
soproxil fumarate–containing highly active antiretroviral therapy. HIV lines for the use of antiretroviral agents in HIV-1–infected adults and
Med 2006; 7:105–11. adolescents. Department of Health and Human Services. 29 January
56. National Kidney Disease and Education Program. Quick reference on 2008;1–128. Available at http://www.aidsinfo.nih.gov/ContentFiles/
UACR and GFR. Available at: http://nkdep.nih.gov/resources/uacr AdultandAdolescentGL.pdf. Accessed 12 October 2008.
_gfr_quickreference.htm. Accessed 3 December 2007. 62. Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the
57. Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. treatment of HIV-associated nephropathy. Nephrol Dial Transplant
Diabetes Care 2004; 27(Suppl 1):S79–83.
2006; 21:2809–13.
58. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardio-
63. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the
vascular events, death, and heart failure in diabetic and nondiabetic
Joint National Committee on prevention, detection, evaluation, and
individuals. JAMA 2001; 286:421–6.
treatment of high blood pressure: the JNC 7 report. JAMA 2003; 289:
59. Arnold JM, Yusuf S, Young J, et al. Prevention of heart failure in patients
in the Heart Outcomes Prevention Evaluation (HOPE) Study. Cir- 2560–72.
culation 2003; 107:1284–90. 64. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in
60. Estrella M, Fine DM, Gallant JE, et al. HIV type 1 RNA level as a adults with hypertension and diabetes: a consensus approach. National
clinical indicator of renal pathology in HIV-infected patients. Clin Kidney Foundation Hypertension and Diabetes Executive Committees
Infect Dis 2006; 43:377–80. Working Group. Am J Kidney Dis 2000; 36:646–61.
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