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NDT Advance Access originally published online on June 25, 2007
Nephrology Dialysis Transplantation 2007 22(10):2757-2762; doi:10.1093/ndt/gfm404
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Acute renal failure in HIV patients

Hassane Izzedine, Alain Baumelou and Gilbert Deray

Department of Nephrology, Pitie-Salpetriere Hospital, Paris, France

Correspondence and offprint requests to: Dr Hassane Izzedine, Department of Nephrology, La Pitié-Salpetrière Hospital, 47-80 Boulevard de I'Hopital, Assistance Publique-Hopitaux de Paris, Pierre et Marie Curie University, 75013 Paris-France; or Email: hassan.izzedine{at}psl.aphp.fr

Keywords: acute tubular necrosis; HAART; HIV



   Introduction
Top
 Introduction
Epidemiology
 Conclusion
 References
 
Acute Kidney Injury (AKI) is the generic term for an abrupt and sustained decrease in renal function, resulting in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products [1]. As renal failure is often asymptomatic, it must be detected by carefully tracking the serum creatinine level. Early recognition is critical. The earliest manifestations of AKI may be subtle. Losing the function of one half of the nephron mass will cause creatinine to rise from about 0.7 mg/dl only up to ~1.4 mg/dl. In general, the threshold used to identify AKI is a rise in the serum creatinine level ≥1.0 mg/dl, but smaller elevations should be taken as early signs of trouble [2]. The major cause of intrinsic renal azotaemia is acute tubular necrosis (ATN). Pre-renal azotaemia and ischaemic ATN occur on a continuum of the same pathophysiological process and together account for 75% of the cases of AKI [3]. Acute kidney injury incidence rates vary from 0.9% to 20% and mortality rates from 25% to 80% [1]. The mortality rate in AKI is dependent on the type of AKI and comorbidities of the patient. Indeed, in the Madrid study [4], patients with ATN had a mortality rate of 60%, while those with pre-renal or post-renal disease had a 35% mortality rate. Most deaths are not due to the AKI itself, but rather to underlying disease or complications.

Renal disease is an increasingly prevalent entity in human immunodeficiency virus (HIV)-infected patients. HIV-related renal impairment can present as acute or chronic kidney disease. In contrast to AKI due to pre-renal and post-renal causes, renal forms of AKI in HIV-infected patients are often related to HIV-mediated viral or immunological disease, or to treatment-related toxicity, both of which have changed since the introduction of highly active antiretroviral therapy (HAART) [5–7]. Because consensus on defining AKI does not exist, previous studies have relied on different criteria to identify AKI [8]. These findings should be interpreted with caution. Future studies should employ the RIFLE criteria for AKI in HIV-infected patients. We focused the discussion on HIV-infected patients who developed ATN (Table 1) [7,9–11].


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  		Table 1. Acute tubular necrosis in HIV-infected patients

 


   Epidemiology
Top
 Introduction
 Epidemiology
Conclusion
 References
 
Before the advent of HAART, acute kidney failure was associated with severe immunosuppression and opportunistic infections. Earlier data during the AIDS epidemic showed that ATN and thrombotic microangiopathies were the most common aetiologies of AKI in immunosupressed patients and suggested that the development of ATN is also predictive of mortality in HIV-infected patients [7,13]. However, these studies have only considered AKI identified through hospital records or biopsy databases [12–16], biasing these findings towards severe clinical conditions associated with ATN.

In the HAART era, rates and risk factors for AKI among HIV-positive individuals have not been extensively studied. Franceschini et al. [10] conducted an observational study of 754 HIV-infected patients recruited from a university-based infectious diseases clinic to assess the effect of low CD4 cell counts on the incidence of AKI, in ambulatory HIV-positive patients HAART treated. The authors reported an incidence of 5.9 cases of AKI per 100 patient-years (PY) [10]. AKI was defined as increases in serum creatinine level lasting at least 2 days: 0.5 mg/dl for patients with a baseline level < 2.0 mg/dl; 1.0 mg/dl for patients with a baseline level between 2.0 and 5.0 mg/dl; 1.5 mg/dl for patients with a baseline level of 5.0 mg/dl or higher. sixty-nine percent of study participants were men, 61% were African-American, and about one-quarter had a hepatitis C virus (HCV) coinfection. The median baseline CD4 cell count was over 350 cells/mm3; about one-third had a CD4 count < 200 cells/mm3. More than 90% of patients were on HAART. During follow-up, 69 patients developed AKI on 109 occasions (unadjusted incidence rate 6.4 cases per 100 PY). Renal failure was most common during the first year on HAART (19 cases per 100 PY). Given that, the authors recommended that kidney function should be carefully monitored during this period.

Wyatt et al. [11] examined the incidence and predictors of AKI in acute care hospitals in New York State in 1995 (pre-HAART) or 2003 (post-HAART) and the impact of AKI on in-hospital mortality in the post-HAART era from the state Planning and Research Cooperative System database. The presence of AKI was determined by a diagnosis code 584, which identified a diagnosis of AKI based on the clinical judgment of the treating physician. There were 52 580 adult HIV-infected patients discharged from hospital in 1995, and 25 114 in 2003. Compared with uninfected patients, HIV-infected patients had an increased incidence of AKI in both the pre-HAART [2.9 vs 1.0%, adjusted odds ratio (OR), 4.62; 95% confidence interval (CI), 4.30–4.95] and post-HAART eras (6.0 vs 2.7%, adjusted OR, 2.82; 95% CI, 2.66–2.99). AKI was associated with mortality among HIV-infected patients in the post-HAART era (OR, 5.83; 95% CI, 5.11–6.65). Renal replacement therapy was prescribed in only 1% of discharges among patients with HIV in 2003, and in <1% in 1995. Hospitalizations of HIV-infected patients that were complicated by AKI were also complicated by much higher in-hospital mortality (27%) than that seen in admissions of HIV-infected patients without AKI (4.5%). After adjusting for confounding factors, AKI was associated with a nearly 6-fold increase in in-hospital mortality among HIV-infected patients in 2003 (OR, 5.83; 95% CI, 5.11–6.65) [11].

Several acute kidney injury and/or mortality risk factors have been identified. In Franceschini's study, incidence rates of AKI were higher among patients with lower CD4 cell counts (15 cases per 100 PY for CD4 counts <100 cells/mm3 vs 1 case per 100 PY for CD4 count of 500 cells/mm3 or higher). The incidence rate was also higher among patients with HCV co-infection. In an analysis adjusting for potentially confounding factors, the following remained significantly associated with increased risk of renal failure: low CD4 cell count (P < 0.001); number of years of previous antiretroviral therapy (P < 0.001), and HCV co-infection (P = 0.02). The highest incidence was observed in HIV/HCV co-infected patients who also had low CD4 cell counts (25 cases per 100 PY for those with CD4 counts <100 cells/mm3) [10]. Furthermore, Wyatt et al. reported that AKI was significantly associated with age, diabetes mellitus and chronic kidney disease, as well as acute or chronic liver failure or hepatitis co-infection in the post-HAART cohort [12]. Finally, most AKI episodes (52%) in Franceschini study were due to infections or antibiotic and antifungal drug toxicity, with <10% of events directly related to antiretroviral reversible nephrotoxicity (including indinavir, tenofovir and nevirapine) [10].

A CD4 count <200 cells/kl, remained an independent predictor of experiencing AKI [10] and the most important predictor of HIV-1-related morbidity and mortality.

Hepatitis C virus co-infection is common among HIV-1-infected patients and may be associated with increased morbidity and mortality [17,18]. HCV co-infection occurs in 15–30% of all HIV-infected patients in the United States [19]. Among HIV/HCV co-infected patients, an estimated 30% of AKI events are caused by underlying liver disease [10]. Furthermore, liver failure has been associated with a higher risk of renal toxicity for a number of drugs, e.g. antiviral [20] and increased in-hospital death in patients with AKI in the intensive care unit (odds ratio 3.1; 95% CI, 1.9–4.9) [21].

An increase in the serum creatinine level has been observed with indinavir treatment in 14–33% of patients [22]. Most elevations in serum creatinine levels normalize within weeks after the discontinuation of indinavir. Case reports have linked ritonavir use to reversible renal failure [23]. All reported patients who showed an increase in the serum creatinine level received ritonavir at a dose of 800–1200 mg per day. There were no reports of ritonavir or indinavir nephrotoxicity when used at the dose of 100 mg twice a day or 400 mg twice a day, respectively. Anectodal AKI cases have been reported related to didanosine, atazanavir, abacavir and lamivudine-stavudine treatment [22].

Pivotal controlled studies in humans found Tenofovir DF (TDF) to be safe, with an incidence of TDF-associated renal impairment (elevated serum creatinine or hypophosphataemia) being 1–3% and with minimal differences from non-TDF treated controls [23,24]. However, during post-marketing surveillance, several cases of Fanconi syndrome and/or AKI have been observed in patients receiving TDF in combination with other antiretroviral agents.

Recent reports have linked HAART regimens that contain TDF to a mild, time-dependent elevation in the serum creatinine level and a decrease in the glomerular filtration rate. One study of 174 patients found a lower mean glomerular filtration rate, as calculated by creatinine clearance (97 ml/min/1.73 m2 vs 107 ml/min/1.73 m2), with 38% of patients showing an impaired glomerular filtration rate in the TDF arm compared with 29% in the control group [25]. The patients with decrease in glomerular filtration rate on a TDF-containing regimen remained well within an accepted range and did not stop taking TDF. However, in the prospective HIV out-patient Study (HOPS) Cohort, despite more advanced HIV disease at baseline that could predispose to incident renal insufficiency, patients on TDF-containing HAART with either ritonavir/lopinavir or ritonavir/atazanavir did not experience greater decrements in renal function during the first year of observation than patients on TDF-containing HAART regimens without these agents or other protease inhibitors [26]. Table 2 summarizes risk factors for renal anomalies with the use of tenofovir [25, 26–35].


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  		Table 2. Risk factors for renal anomalies with the use of Tenofovir

 
Underlying mechanisms
Over the past few years, considerable progress has been made in the molecular identification and characterization of organic anion and cation transporters in the kidney. The process of secreting organic anions (OA) and cations (OC) through the proximal tubular cells is achieved via unidirectional transcellular transport, involving the uptake of OA and OC into the cells from the blood across the basolateral membrane, followed by extrusion across the brush-border membrane into urine. Drug accumulation in renal proximal tubule cells is classically a function of both uptake at the basolateral membrane and efflux at the luminal membrane. Alterations of this equilibrium between blood-into-cell and cell-into-lumen transports may result in intracellular accumulation of the drug that may result in local toxicity. Treatments that block efflux, like those that enhance uptake, may thus increase both accumulation and toxicity [36]. We hypothesized that polymorphisms in the renal tubular drug transporter genes MRP2 or MRP4 would influence the disposition of TDF and could, therefore, affect the risk of renal toxicity [36]. We showed that renal tubular dysfunction related to TDF therapy outcome was significantly associated with a single non-synonymous G-A substitution at position 1249 of ABCC2 [also called ‘MRP2’, which encodes multidrug resistance protein (MRP) 2] and with an ABCC2 haplotype comprising four polymorphisms, including 1249 G-A (unadjusted odds ratio, 4.25; lower bound of 95% CI, 1.25–14.5). Additionally, a T-A substitution at position 3563 and a haplotype including this polymorphism were significantly associated with the absence of renal toxicity (none of the case patients had these variants). A synonymous polymorphism in ABCC4 (also called ‘MRP4’, which encodes MRP4) was also associated with the outcome (P = 0.04) but does not alter the amino acid sequence of the encoded protein. We then provide the first report of a possible association between a human genetic variant and TDF-associated renal dysfunction [36].



   Conclusion
Top
 Introduction
 Epidemiology
 Conclusion
References
 
HAART changed all the facts concerning HIV care, to the extent that incidence of AKI and AKI as a mortality predictor in HIV-infected patients in HAART era must be re-established in future prospective clinical studies. Those studies should employ the RIFLE criteria for AKI. Future pharmacogenetic studies are awaited to determine patients susceptible to developing renal side effects and to personalize our approach to each.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Epidemiology
 Conclusion
 References
 

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Received for publication: 18. 1.07
Accepted in revised form: 30. 5.07


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