HIV-associated renal diseases in Africa—a desperate need for additional study
Division of Renal Diseases and Hypertension, George Washington University Medical Center
Keywords: creatinine clearance; epidemiology; glomerular filtration rate; HIV; HIV-associated nephropathy; HIV-associated glomerulonephritis; renal function
Since the emergence of Acquired Immune Deficiency Syndrome (AIDS) more than 25 years ago, renal disease has been recognized as a common and intimately associated complication of Human Immunodeficiency Virus (HIV) infection. It is now known that there are several renal syndromes and diseases associated with HIV infection. These diseases are more or less tightly linked with the viral infection, the expression of HIV genes in the kidney and the interaction of HIV proteins with renal cells. Approximately 50–60% of renal disease associated with HIV infection may be considered "classic HIV-associated nephropathy" (HIVAN) [1–6]. Many studies have suggested a dramatically heightened susceptibility to the development of renal disease in patients of African descent who become infected with HIV [7–11]. In the United States, the incidence of HIV-associated renal diseases, at least progressing to end-stage renal disease (ESRD), has stabilized or decreased [12]. This is undoubtedly due to major scientific advances in the production of highly active antiretroviral therapy (HAART), and the increased access to these medications in the United States and variably in developed countries throughout the world. However, HAART is expensive and is associated with a variety of complications including potential HAART-related nephropathies [13,14]. HAART also requires a life-long commitment and the ability to maintain appropriate specialized medical care [15].
In the United States, an unexpected concomitant of HAART therapy has been to impede our understanding of epidemiologic and pathogenic mechanisms underlying the development of renal diseases associated with the viral infection. The natural history of the renal diseases associated with HIV infection has been radically changed by therapy [14,16]. Most investigators believe HAART to be indicated in patients with renal disease in the presence of HIV infection, but specifically in the case of classic HIVAN, as well as HIV-associated thrombotic microangiopathies and immune complex renal diseases [6,17–21]. Therefore, the independent role of other therapies, such as glucocorticoids or angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), probably cannot be ethically assessed in any contemporary setting. Investigation of pathogenic mechanisms using sophisticated molecular biologic investigative techniques on renal tissue in patients who present with renal disease holds tremendous promise, but may be challenging in the setting of HAART.
Although the cumulative number of patients with AIDS approaches 1 million in the United States [22,23], these figures are dwarfed by the enormity of the epidemic in the rest of the world, and most importantly in Sub-Saharan Africa, where it is estimated that almost 25 million people are living with HIV/AIDS (a tragic prevalence of 5.9% of the population). 2.1 million deaths have occurred because of the epidemic in this part of the world [24]. Until recently, there have been few data regarding the epidemiology of renal disease associated with HIV infection in Africa. Recently, several reports have begun to appear, highlighting our lack of knowledge about renal diseases in this region and the importance of further study in this area.
Gernholtz et al. [25] performed a retrospective chart review of 104 renal biopsies, obtained between 2003 to 2004 in the Chris Hani Baragwanath Hospital near Johanesburg, South Africa. Classic HIVAN was found, but only in 
30% of the renal biopsies reviewed [25]. Perhaps more importantly, approximately 20% of the renal biopsies were classified as "HIV immune-complex kidney disease" [25]. This was a retrospective study, and therefore these data are limited by selection bias and small sample size. Nevertheless, the results are interesting and provide an opportunity for further research, if more rigorous prospective study designs can be implemented. The data also emphasize the key role of renal biopsy in diagnosing HIV-associated renal diseases, because only one-third of the biopsies from this hospital in South Africa met criteria for classic HIVAN. The relatively high prevalence rate of HIV immune-complex kidney disease runs counter to the notion that this type of renal disease occurs more often in Caucasian populations.
In another study from South Africa, Han et al. [26] evaluated 615 HIV-infected patients between 2002 and 2004. Approximately 6% of these patients had overt proteinuria [26]. However, microalbuminuria was screened for in only 90 of the 615 patients, and was present in 36% of the patients [26]. Thirty of these patients with microalbuminuria or overt proteinuria patients underwent renal biopsy [26]. HIVAN was found in 25 of the 30 patients who received renal biopsies [26]. These data suggest that HIVAN is possible in patients without overt nephrotic syndrome and even in patients who have only microalbuminuria.
Behar et al. [27] conducted a retrospective study of 176 HIV-infected patients in Israel. Approximately 70% of the patients in their study were of Ethiopian origin [27]. The patients of Ethiopian and non-Ethiopian origins did not fulfill any "clinical criteria" for HIVAN, leading the authors to conclude that genetic differences must account for the predisposition to HIVAN among African-Americans [27]. This study is severely limited by its retrospective design, small sample size, and the lack of confirmatory renal biopsies, making any conclusions difficult to interpret [27]. Nevertheless, it serves to emphasize the need for additional study of HIV-associated nephropathies in this part of the world, because the aetiologies for renal disease may be quite different from the spectrum of disease seen in the United States.
Caution should be exercised when interpreting studies of HIV-associated renal diseases from a single country in Sub-Saharan Africa since access to health care, including to HAART, can vary widely from one country to another and within a particular country. In addition, socio-economic conditions can vary dramatically across Sub-Saharan Africa [28] which poses a significant confounding variable when trying to interpret such studies regarding the larger epidemic of HIV infection across the region.
In this issue of Nephrology Dialysis Transplantation, Wools-Kaloustian and colleagues performed a cross-sectional study of 373 ‘medically stable, HIV-infected, antiretroviral naïve adults presenting to an HIV clinic in western Kenya’ [29]. The purpose of their study was to evaluate the risk factors for renal disease in this patient population, and to determine if screening for renal failure is needed prior to the institution of HAART [29].
The results of this study are truly inconclusive. In a set of potentially highly susceptible patients, there was little evidence of proteinuria (6.2%), but a 16.3% prevalence of possible abnormal renal function [29]. This led the authors to conclude that screening for renal failure prior to the institution of HAART is necessary in Sub-Saharan Africa [29]. The prevalence of HIV-associated nephropathy in the literature has been reported to range between 1–15%, depending on the setting [17,18,20,30–34]. Most nephropathies associated with HIV are characterized by proteinuria. Therefore, the results from this study with a higher prevalence of renal dysfunction than proteinuria, are unexpected.
Nevertheless, the study is important because it highlights the fact that the tragedy in Africa represents a true opportunity for refining our understanding of the epidemiology of HIV-associated renal diseases. This study points out how important it will be to develop valid methods for estimating renal function in HIV-infected patients of different ethnicities, at different stages of disease. It also shows how critical the proper quantification of glomerular permeability defects, through use of urinary protein to creatinine ratios, or preferably albumin to creatinine ratios are in HIV-infected patients [21]. Because of a "lack of resources," this study used dipstick methods to screen for proteinuria, which has limited sensitivity and specificity, serving to potentially bias the reported prevalence of proteinuria in this study sample.
The study used estimating equations including the MDRD, abbreviated MDRD equation, and the Cockcraft-Gault equations, to estimate GFR or creatinine clearance. These equations have not been validated in this patient population or in HIV-infected patients in general. We performed a literature search and were unable to find any studies that specifically addressed the validity of GFR or creatinine clearance estimating equations in the HIV population. Moreover, the MDRD equation has not been validated in patients without chronic kidney disease, and is believed to underestimate GFR in patients with GFR estimated to be above 60 ml/min [35]. This may potentially explain why there is a discrepancy between the prevalence of chronic kidney disease and the much lower prevalence of proteinuria in this relatively "healthy cohort" of patients without significant risk factors for non-viral renal disease.
The glomerular filtration rate can also be affected by diet, and the creatinine clearance can be modified by intake of meat and protein, muscle mass, medications, and intercurrent catabolic illness. These modifying factors for GFR and creatinine clearance are especially pertinent in HIV-infected patients living in Sub-Saharan Africa. In an optimal setting, 24 h urines to estimate creatinine clearance or iothalamate clearance studies could be done. In addition, proteinuria could be estimated with urinary protein to creatinine ratios or 24 h quantification of proteinuria.
As Wools-Kaloustian et al. [29] point out, this part of the world lacks the necessary resources for such "optimal" studies to be done. It is this lack of access to healthcare and resources that has also contributed in many ways to the unfortunate HIV epidemic in Sub-Saharan Africa. Additional studies are urgently needed to address the unique epidemiology and treatment concerns of HIV-associated renal diseases in this medically under-served region of the world.
Conflict of interest statement. P.L.K.is a stock holder in Johnson and Johnson—215 shares <$15 000. This is his only potential conflict—they make at least one antiretroviral drug. He has had no commercial relationships with pharmaceutical companies or medical education companies for more than 1 year and is currently a Professor of Medicine at George Washington University, on leave of absence, employed by the American Society of Nephrology.
S.D.C. is a shareholder in US healthcare company Johnson and Johnson which is currently testing two antiretroviral agents. This is his only potential conflict. He has no commercial relationships with pharmaceutical companies or medical education companies.
(See related article by Kaloustian et al. Renal disease in an antiretroviral-naïve HIV-infected outpatient population in Western Kenya. Nephrol Dial Transplant 2007; 22: 2208–2212.)
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Accepted in revised form: 5. 4.07
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Related articles in NDT:
- Renal disease in an antiretroviral-naïve HIV-infected outpatient population in Western Kenya
- Kara Wools-Kaloustian, Samir K. Gupta, Eva Muloma, Willis Owino-Ong’or, John Sidle, Ryan W. Aubrey, Jianzhao Shen, Kirwa Kipruto, Beth E. Zwickl, and Mitchell Goldman
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