Current Concepts in HIV-Associated Nephropathy

In the early years of the HIV pandemic there was speculation that the kidney may be spared from major complications. By 1984, however, a broad spectrum of renal disease was reported in patients with AIDS, including a distinctive form of sclerosing glomerulopathy found predominantly among inner-city black injection drug users (IDU). HIV-associated nephropathy (HIVAN) is now a well-defined variant of focal segmental glomerulosclerosis which has characteristic clinical and histopathologic features and which now develops in 5-10% of patients infected with HIV [D'Agati VD, et al. J Am Soc Nephrol 1997;8:138]. Although it shows a remarkable predilection for black patients, HIVAN has been demonstrated in all subsets of HIV-infected patients regardless of age, sex, race, and mode of HIV acquisition. The nephropathy typically follows a fulminant course and progresses to end-stage renal disease (ESRD) in essentially all untreated cases. More importantly, despite remarkable advances in the treatment of HIV infection and its attendant complications, the incidence and prevalence of HIVAN have steadily increased. Urgent attention is needed to better define the pathogenesis of the disease and to evaluate potential treatment strategies.

Epidemiology

Perhaps more than any other condition, HIVAN now reflects the changing face of the HIV epidemic in the US. The incidence of HIVAN has risen by 30% per year since 1991 [Winston JA, et al. Semin Nephrol 1998;18:373]. Enhanced recognition of HIVAN and prolonged survival of HIV-infected patients with more intensive antiretroviral therapy may contribute to the increasing incidence. More importantly, while the incidence of HIV infection in many other groups is on the decline, there is a disproportionate increase in the rates of new infection among African-Americans. Given that the vast majority of patients with HIVAN are black and up to 10% of infected patients may develop HIVAN, the incidence will likely continue to rise in the coming years. Furthermore, many cases arise in injection drug users in urban centers with reduced access to care, resulting in more advanced illness on presentation. HIVAN is currently the third leading cause of ESRD in black adults under 65 years of age, accounting for 10% of cases [Winston JA, et al. Semin Nephrol 1998;18:373]. In some inner city dialysis units, the prevalence of HIV infection among patients with ESRD is as high as 38%.

Clinical Characteristics

Although HIVAN may be the first manifestation of HIV infection, it occurs predominantly as a late-stage complication. Nearly all patients have an AIDS-defining condition on diagnosis [Winston JA, et al. Kidney Int 1999;55:1036]. The clinical picture is that of progressive proteinuria and rapidly deteriorating renal function. Nephrotic range proteinuria develops in 90%, and progression to end-stage renal disease is inevitable in the absence of treatment, often within several months. It is not clear, however, whether markers of early nephropathy may be present prior to the onset of clinically significant proteinuria or renal insufficiency. Micro-albuminuria has been identified in 20% of HIV-infected patients and is inversely correlated with the CD4 count; however, no prospective information is available regarding progression to clinically significant renal disease in these patients [Luke D, et al. Clin Nephrol 1992;38:69-74].

Certain clinical findings may be more suggestive of HIVAN than of other common forms of nephropathy. Historically, hypertension, peripheral edema, and hypercholesterolemia have been uncommon despite nephrotic range proteinuria in many cases. Whether such findings represent distinctive characteristics of the nephropathy or are simply indicative of the poor overall health and nutritional status of patients with advanced HIV disease is debatable. The absence of edema may also reflect preservation of oncotic pressures by high serum globulin levels. The urine sediment is most often bland but may demonstrate microscopic hematuria or granular casts. Renal ultrasonography typically reveals echogenic kidneys that are normal or enlarged despite progression to ESRD.

Histopathology

The clinical picture presented above is suggestive of but not diagnostic for HIVAN. Patients presumed to have HIVAN may have other glomerular and/or interstitial lesions upon renal biopsy. Therefore, tissue diagnosis by biopsy remains the gold standard for HIVAN, particularly in clinical research protocols.

Although no single pathologic feature is pathognomonic of HIVAN, the constellation of histologic, immunologic, and ultrastructural features is highly distinctive. HIVAN is histologically defined by focal segmental glomerulo-sclerosis (FSGS), often with glomerular collapse, glomerular visceral epithelial cell hypertrophy, and a prominent tubulointersitial mononuclear infiltrate associated with fibrosis and microcystic tubular dilatation. Immunofluorescence microscopy frequently demonstrates deposition of IgM and C3 in the mesangium and areas of glomerulo-sclerosis. Electron microscopy typically shows tubuloreticular inclusions within glomerular and other vascular endothelial cells [D'Agati V et al. Semin Nephrol 1998;18:406].

Pathogenesis

Evidence is accumulating to support the hypothesis that HIVAN is a direct result of infection of the kidney with HIV-1 and the resultant expression of viral gene products. Transgenic mice that express HIV envelope and regulatory proteins (gag/pol genes disrupted) develop a progressive nephropathy that mimics HIVAN to the histologic level with 100% penetrance [Klotman PE, et al. Curr Top Microbiol Immunol 1996;206:197]. The develop-ment of renal disease appears dependent upon HIV-1 expression within the kidney itself: normal kidneys transplanted into transgenic mice do not develop renal disease, whereas transgenic kidneys transplanted in normal mice will develop the features of HIVAN [Bruggeman LA, et al. J Clin Invest 1997;100:84]. The site of productive kidney infection in humans has not been established and may involve infection of renal parenchymal cells or of infiltrating macrophages or lymphocytes.

The pathogenic model will have to explain the racial predilection in HIVAN. The sporadic occurrence of an idiopathic collapsing glomerulosclerosis predomin-antly in black, non-HIV-infected patients suggests that HIVAN may represent a genetically determined response to glomerular injury which is induced by direct viral infection, the effects of viral products, and/or the effects of inflammatory or proliferative cytokines. Some authors have suggested that the racial predilection may reflect differences in host susceptibility to renal infection, perhaps via differences in viral co-receptors.

Transforming growth factor (TGF-ß) has received the most attention as a potential mediator of HIVAN. TGF-ß increases deposition of extracellular matrix in the kidney and is fibrogenic by stimulating production of collagen [Schwartz EJ, et al. Semin Nephrol 1998;18:436]. TGF-ß production by macrophages may be stimulated by the viral protein Tat and may reciprocally increase expression of the HIV-1 LTR promoter. Thus, a vicious cycle of accelerating viral replication, TGF-ß expression, and matrix accumulation with fibrosis may ensue [Yamamoto T, et al. Kidney Int 1999;55:579]. Angiotensin II increases synthesis of TGF-ß and blockade of the renin-angiotensin system may be a therapeutic mechanism of action for angiotensin converting enzyme (ACE) inhibitors.

Management

Until recently, a sense of therapeutic nihilism has prevailed over the manage-ment of HIVAN. Even now, despite potent antiretroviral therapy, evidence for improved renal survival with corticosteroids and ACE inhibitors, and better survival on dialysis, no formal guidelines or recommendations exist for the management of HIVAN.

The treatment of patients with HIVAN is likely incomplete without HAART, as nearly all patients have an AIDS-defining condition or a CD4 count below 200 at the time of diagnosis. Since viral replication and gene expression appear to have pathogenic significance in HIVAN, antiretroviral therapy may be expected to alter the course of the disease. Uncontrolled studies suggest that AZT reduces proteinuria and preserves renal survival but is beneficial only for those patients with absent or minimal renal insufficiency who are able to remain on AZT [Ifudu O, et al. Am J Nephrol 1995;15:217]. While data on the effects of HAART on HIVAN are lacking, there is hope that such therapy used early in the course may ameliorate or reverse the disease. In one report, treatment with d4T, 3TC, and nelfinavir was associated with reversal of ESRD and significant recovery of early histopathologic changes in a patient with HIVAN [Wali R., et al. Lancet 1998;352:783]. As will be seen with other forms of therapy, the diagnosis must be made as early as possible to assure that permanent glomerular damage has not become widespread, making response to therapy less likely. In all patients with renal insufficiency, serum creatinine should be monitored closely when initiating indinavir and ritonavir, as both have been reported to cause reversible renal failure.

In an uncontrolled trial, prednisone (60 mg QD for a mean of 4 weeks and then tapered) was demonstrated to reduce serum creatinine in 17/19 patients and to reduce urinary protein excretion in 12/13 patients with HIVAN [Smith M., et al. Am J Med 1996;101:41]. The median time to creatinine nadir was five weeks. Four of the 17 responders had renal survival beyond 45 weeks, and two went more than 80 weeks off steroids without developing ESRD. Three of five patients re-treated for relapse after their initial course of prednisone responded similarly to a second course. Opportunistic infections occurred in six patients, and two patients developed reactivation of herpesvirus infection and acute psychosis.

To better assess the risks of steroid treatment in this population, we recently performed a retrospective cohort study in the Johns Hopkins AIDS clinic of 21 patients with biopsy-proven HIVAN [Eustace J, et al. submitted for publication]. All had a serum creatinine >2 mg/dl (mean = 6.5 mg/dl). Patients treated with prednisone (1mg/kg/d for 1 month, then tapered over 2-4 mos.) had preserved renal survival compared to untreated controls. Eight of 11 and 3 of 11 treated patients had independent renal function at 6 and 12 months post-biopsy, respectively, whereas only 1 of 8 untreated controls had renal survival at 6 months before developing ESRD by 12 months. No increase in serious infections or hospitalizations was found among those treated with steroids. The mechanism of action of corticosteroids is unclear. Repeat renal biopsy after steroid treatment in one patient revealed a marked decrease in the interstitial mononuclear infiltrate, suggesting modulation of inflammatory activity or cytokine production [Briggs WA, et al. Am J Kidney Dis 1996;28:618].

The protective properties of ACE inhibitors have been demonstrated in animals and humans with diabetic and nondiabetic proteinuric renal diseases. Captopril prevents nephropathy in the transgenic mouse model of HIVAN [Bird JE, et al. J Am Soc Nephrol 1998;9:1441]. Two studies have evaluated ACE inhibitors as a means of preserving renal function in patients with biopsy-proven HIVAN. Kimmel and colleagues found that captopril (up to 25 mg TID) prolonged renal survival in treated patients (156 days) versus untreated controls (37 days) [Am J Kidney Dis 1996;28:202]. In two patients for whom the ACE inhibitor was initiated with a creatinine <2.3, the serum creatinine and urine protein levels were stable for 2 and 3.5 years respectively in follow-up. Burns and colleagues treated 12 patients with a creatinine <2.0 (5 with nephrotic range proteinuria) with fosinopril (10 mg QD), stabilizing creatinine and reducing proteinuria versus controls over a 24 week period [J Am Soc Nephrol 1197;8:1140]. All controls and no cases progressed to ESRD over the study period, again suggesting treatment with an ACE inhibitor may be most beneficial when initiated at the earliest possible time after diagnosis. The authors have subsequently recommended that at-risk patients with new renal failure (creatinine >1.6) or proteinuria in excess of 500 mg/day be considered for renal biopsy and ACE inhibitor therapy if HIVAN is demonstrated [Burns GC, et al. Am J Kidney Dis 1998;4:720]. Patients starting treatment with ACE inhibitors should be monitored for hyperkalemia, progressive azotemia, or volume depletion. The mechanism of ACE inhibitors' effect may include changes in renal hemodynamics, reduction of TGF-B synthesis, or interference with ACE-mediated pathways involved in antigen processing and presentation between macrophages and T-lymphocytes.

When other medical treatments fail, dialysis is lifesaving. Early in the epidemic, survival of HIV-infected patients on dialysis was poor, reflecting the late stage of HIV infection at the time of diagnosis and limited antiretroviral options. While survival on dialysis has improved, outcomes remain correlated with the stage of infection. In a recent 10-year review, median survival was 11.3 vs 5.3 months for those patients with CD4 counts >50 and <50 respectively. Infections and the wasting syndrome accounted for 68% of deaths [Dave MB, et al. Clin Nephrol 1998;50:367]. Recent figures suggest one- and three-year mortality rates for HIVAN-induced ESRD of 50% and 68% respectively, equivalent to patients who develop other AIDS-defining conditions [Laradi A, et al. J Am Soc Nephrol 1997;8:141]. The impact of HAART has not been assessed in the dialysis-dependent population, but one would expect survival to improve commensurate with appropriate treatment.

Survival rates are similar between patients on hemodialysis (HD) and peritoneal dialysis (PD). The mode of dialysis should be determined by patient preference and resources. It is unclear whether HIV-infected patients have higher overall rates of peritonitis, although peritonitis due to fungi and pseudomonas are more common [Dressler R, et al. Am J Med 1989;86:787], and rates of peritonitis are increased with concomitant IDU [Tebben JA, et al. Kidney Int 1993;44:191].

The costs attributable to treating HIV-infected patients with dialysis have not been assessed. HIV-infected patients have more frequent complications with vascular access for HD, particularly in the setting of concomitant IDU. IDU may preclude placement of a native arteriovenous fistula, the preferred form of access, due to lack of suitable veins. The placement of prosthetic arteriovenous grafts is associated with higher rates of infection and thrombosis in HIV-infected patients [Brock JS, et al. J Vascular Surg 1992;16:904]. Indwelling central venous catheters may be the most feasible option, but are fraught with risk of line sepsis. PD-associated fungal or pseudomonal peritonitis requires surgical removal of the catheter. Anemia in HIV-infected patients with chronic renal failure tends to be more severe and less responsive to recombinant erythropoeitin. Finally, active injection drug use is frequently accompanied by nonadherence which may result in more frequent hospital admissions. Because of these excess complications, the cost required to dialyze an HIV-infected patient is probably substantially greater than the $57,660/year required for the average patient on hemodialysis [US Renal Data System, USRDS 1997 Annual Data Report].

Future Directions

Progress in the care of patients with HIVAN will come from further understanding of its pathogenesis and critical appraisal of diagnostic and therapeutic strategies. The impact of HAART on the incidence, severity and progression of HIVAN must be addressed. The utility of routine screening for subclinical proteinuria or elevated creatinine is unknown. Perhaps screening for microalbuminuria could identify patients at risk for HIVAN at an earlier stage of disease when a better response to ACE inhibitors or HAART may be seen. For patients with established disease, regimens employing steroids and ACE inhibitors or HAART to induce and maintain remission need to be examined. Ultimately, randomized, controlled clinical trials are needed to evaluate the available treatment strategies. Such trials must control for a range of confounders including creatinine clearance, proteinuria, concurrent medications and antiretrovirals, histologic features, stage of viral illness, and viral load, as well as host and demographic features. The goal of early diagnosis and treatment is the preservation of renal function and avoidance of dialysis, a morbid and costly outcome.

Eric Nuermberger, M.D. is a fellow in the Division of Infectious Diseases, Johns Hopkins University, School of Medicine