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The Spectrum of HIV-Associated Renal Disease

Many individuals with HIV disease develop at least transient alterations in renal function during the course of their infection. These can range from minor changes in fluid or electrolyte homeostasis to end-stage renal disease requiring dialysis. One clinically and histopathologically distinctive HIV-specific entity recognized since the epidemic's early years is HIV-associated nephropathy (HIVAN). The renal lesion of HIVAN, focal and segmental glomerular sclerosis, remains the pathology most often seen in HIV-infected patients with end-stage renal disease. However, there has been an increasing appreciation of the frequency of other histologic findings, suggesting a multiplicity of pathologic processes. This article explores the clinical, diagnostic, pathophysiologic, and therapeutic spectrum of intrinsic renal disease associated with HIV.

Definition and Epidemiology

Glomerulopathy has been reported in HIV-infected patients since 1984.¹ The predominant lesion, a specific variant of focal and segmental glomerulosclerosis, is a collapsing glomerulopathy with microcystic tubular dilatation, an interstitial inflammatory infiltrate, and tubuloreticular inclusion bodies on electron microscopy. Because the mechanism linking viral infection and the development of glomerulopathy has been unclear, the term HIV-associated nephropathy (HIVAN) is preferred.

Since HIVAN has not been included in the AIDS case definition, no nationwide data exist on incidence or prevalence of chronic renal failure in HIV/AIDS. However, in autopsy series, the prevalence of HIVAN has been reported to be from 3% to 7%,² and the U.S. Renal Data System has reported a steadily increasing incidence of HIVAN. According to this agency's most recent report, AIDS-related end-stage renal disease (ESRD) accounted for 0.5% of all cases of ESRD between 1989 and 1992; most of these were adult African Americans,^3,5 among whom HIVAN is the sixth leading cause of ESRD. CDC data collected from hemodialysis centers indicate that 1.5% of hemodialysis patients in 1994 were known to be HIV infected, but that HIV testing was routinely offered in only 28% of centers, allowing for the possibility of significant underreporting.⁴ A recent abstract by Winston and Klotman suggests that, based on rates in New York, 480 to 750 new cases of HIVAN can be expected annually in the U.S. in the near future, and that HIVAN will ultimately account for up to 20% of ESRD in young adult African Americans.⁵

HIVAN prevalence is probably not equally distributed among all groups infected with HIV; it has most often been described in young, black, male patients, often with a history of injection drug use. However, its expression is not limited to this paradigm; HIVAN has been described in both blacks and whites, males and females, patients with and without drug histories, and across an age spectrum that includes young children. No careful case-control studies have been performed to identify demographic or other factors definitely associated with development of HIVAN.

Natural History and Clinical Presentation

Kidney disease is typically described as having its origin in prerenal, renal, or postrenal abnormalities. Prerenal causes (e.g., dehydration, hypotension) decrease blood flow to the kidneys and thus the glomerular filtration rate; in one study these etiologies accounted for up to 40% of cases of acute renal failure in hospitalized AIDS patients. Post-renal etiologies, which are not common in HIV disease, obstruct the flow of urine through the ureters or urethra, leading to hydronephrosis.

Intrinsic renal diseases, described as acute or chronic, directly affect the function of kidneys and renal organelles, including glomeruli, renal mesangium, and collecting tubules. Despite the potentially reversible nature of acute renal failure, outcomes in one report were poor in all HIV-infected patients who had serum creatinine levels over 6 mg/dl and did not undergo dialysis.⁶ Drug-related nephrotoxicity is one of the most common causes of acute renal failure in patients with HIV.

In general, chronic renal disease is progressive and irreversible. Since the onset is frequently insidious, patients may be unaware of the presence of chronic renal disease until the process is far advanced and very little renal function remains. This is particularly true in HIVAN. Little information is available about the course of the disease prior to ESRD. Late stages of HIVAN are characterized by nephrotic range proteinuria (more than 3.5 g/24 hours) that may be accompanied by hypoalbuminemia and peripheral edema, although hyperlipidemia is less common than in other nephrotic syndromes. Complement levels are usually normal; erythrocytes and casts are seldom present in the urinary sediment; up to 25% of patients have some pyuria. Ultrasonography typically reveals normal-to-large-sized echogenic kidneys. Often, when HIVAN is diagnosed azotemia is already present and progression to ESRD is rapid.

Several observational studies have suggested that abnormality of protein excretion, without frank nephrotic syndrome, is common in HIV-infected populations, with elevated levels of urinary microalbumin detected in 20% to 30% of patients.⁷ It is not clear at this point whether these individuals are likely to develop more severe proteinuria and renal disease, but the observation does suggest that more subtle forms of glomerular injury might either precede HIVAN or represent a larger spectrum of renal disease, with focal and segmental glomerulosclerosis and HIVAN as the most extreme manifestations.

The role of immunosuppression in the development of HIVAN is not entirely clear. Early reports emphasized the disease in patients with frank AIDS, most of whom were severely immunosuppressed. Now that HIV infection is commonly identified in earlier stages it is recognized that HIVAN can occur in the presence of higher CD4 cell counts. A review from New Haven of all known cases of HIVAN that were treated with peritoneal dialysis between 1987 and 1992 identified 12 patients with asymptomatic HIV disease who had a median CD4 cell count of 660 cells/mm³, and 27 patients with advanced HIV disease who had a median CD4 cell count of 31 cells.⁸ Other series have reported that up to 50% of patients with HIVAN develop renal failure before progressing to AIDS.

Histopathology

Earlier reports characterized the predominant glomerulopathy associated with HIV as a specific variant of focal and segmental glomerular sclerosis (FSGS) as previously described. Further examination of biopsy and autopsy specimens from diverse patient populations has expanded the histologic spectrum to include, among others, minimal-change disease, crescentic and noncrescentic IgA nephropathy, and diffuse proliferative glomerulonephritis. In fact, some centers have reported finding the conventionally described FSGS lesion in only a minority of HIV-positive patients. Potential explanations for the variety of histologic changes include differences in patient characteristics (race, HIV exposure, age), in threshold for and timing of obtaining biopsy, and, possibly, different etiologic processes. Autopsy specimens typically reveal a greater variety of lesions than do biopsies. Mesangial hyperplasia is particularly common in kidneys of AIDS patients at autopsy but this condition⁸ is only rarely associated with significant antemortem proteinuria or azotemia. Some writers have speculated that mesangial hyperplasia may be the earliest manifestation of a process that eventually progresses to glomerulosclerosis.⁹

The etiology of HIVAN is unknown. In some studies, HIV antigens or HIV genetic sequences have been identified in the kidneys of affected individuals, but these observations have not been consistently reproduced. Other investigators have hypothesized that the formation of HIV antigen-antibody complexes is involved in pathogenesis, or that macrophages activated by HIV infection produce cytokines that lead to renal injury. A recent report suggested that apoptosis of renal tubular cells may be important.¹⁰ Given the unequal distribution of HIVAN in various populations, it seems likely that pathogenesis depends at least in part on genetic or environmental factors that have not yet been identified.

Role of Biopsies

The role of renal biopsy remains somewhat controversial at this time. In some centers, biopsies are not routine for patients presenting with typical proteinuria, azotemia, and large echogenic kidneys. There is probably a general reluctance to recommend invasive diagnostic procedures for HIVAN, since there is no effective treatment for it.

One reason to consider a more aggressive diagnostic approach is the growing number of histologic types of renal lesions seen in HIV disease and the possibility that some of these may be more responsive to therapy. For instance, Jindal et al. reported a case of crescentic IgA nephropathy in an HIV-infected patient that was successfully treated with pulse methylprednisolone.¹¹ Similarly, an anecdotal report has been made of IgM glomerulopathy treated successfully with steroid therapy.¹² Increasingly, anecdotal reports of improved renal function after treatment with antiretroviral drugs or steroids raise the possibility that some subset of patients may benefit from such treatment. Renal histopathology may turn out to be an important means of identifying these groups.

For purposes of investigation, renal biopsies are invaluable. Examining biopsy specimens with immunohistochemistry, in situ hybridization, PCR of microdissected tissue, and immunodiffusion of acid eluates has begun to illuminate processes by which HIV manifests itself in the kidney. Additional work should continue to shed light on this process, which argues in favor of biopsies, particularly in academic centers.

Treatment

To date, no treatment has been shown to substantially alter or reverse the course of HIVAN. A number of anecdotal reports as well as several retrospective studies have suggested that antiretroviral treatment may slow HIVAN progression. Most of the patients who responded to treatment did so despite having nephrotic proteinuria, advanced renal insufficiency, or both. In one retrospective review of patients infected with HIV perinatally a (nonsignificant) trend toward delay in renal failure and increase in life expectancy was seen in patients who were treated with AZT, ddI, or intravenous immunoglobulins before the onset of clinical HIVAN.¹³

Immunomodulators such as corticosteroids and cyclosporine have also been reported to slow the progression of HIVAN and possibly to reverse some of the associated proteinuria and azotemia.¹⁴ However, it seems that when steroids are withdrawn most patients relapse. The safety of long-term corticosteroid use in this population has not been established. Recently, there has been interest in the potential benefit of angiotensin-converting enzyme (ACE) inhibitors in proteinuric patients without ESRD. Although very few patients have received this treatment, one report suggests a possible slowing of disease progression.¹⁵

Given the lack of effective therapy and the progressive nature of HIVAN, most patients eventually need dialysis or transplantation. Kidneys have seldom been transplanted into patients with known HIVAN, but many centers routinely offer dialysis. Early reports suggested that survival of AIDS patients on dialysis was uniformly short and that dialysis should only be offered to patients with earlier stages of HIV disease. More recent studies have suggested that patients with ESRD who are dialyzed live about as long as patients with normal renal function but similarly advanced HIV disease. Well-controlled studies, however, have not been done.

Hemodialysis and peritoneal dialysis are both reasonable options for HIV- infected patients. Some investigators have reported no increased risk for peritonitis among HIV-infected patients on peritoneal dialysis; others report an increased risk, with fungi and pseudomonas more commonly the causative organism. Unusual organisms such as cryptococcus and MAC have been cultured from peritoneal dialysis fluid of AIDS patients. As for complications of hemodialysis in HIV-infected patients, there are little data.

Clinical Issues

Despite the lack of effective therapy, it's important to recognize HIVAN early. A yearly urinalysis to check for proteinuria is easy to do and may identify patients before the onset of renal failure. Dialysis requires an enormous commitment from the patient and the caregivers. It is prudent to begin talking about dialysis well before it becomes necessary, which provides the opportunity to educate, to decide together on the best modality, and to arrange services.

Sometimes the dialysis center takes over large parts of primary care for HIV-infected patients. It's important for nephrologists to understand the basics of treatment for HIV, just as for diabetes of hypertension. All aspects of medical management become more difficult when a patient with HIV develops renal failure. The optimal doses of the newer antiretroviral drugs for patients on dialysis are, for example, not known. In the absence of more specific information we use the minimal effective dose and watch for any signs of excess toxicity.

Conclusion

After more than a decade of clinical experience, our understanding of HIV-associated renal disease remains incomplete. Among the important questions to be addressed are the nature of the pathologic processes leading to HIVAN, its natural history, the relation between FSGS and other renal lesions seen with HIV, and the potential benefits of various therapeutic interventions. Despite uncertainties, however, dialysis can potentially provide a reasonable quality of life to HIV patients with ESRD.

— Michael Rigsby, MD, and Susan Crowley, MD

Both Dr. Rigsby and Dr. Crowley are Assistant Professors of Medicine at Yale University School of Medicine; Dr. Crowley directs the dialysis unit and Dr. Rigsby directs HIV/AIDS care at the West Haven campus of VA Connecticut Healthcare System.

Published in AIDS Clinical Care July 1, 1996

Citation(s):

1. Rao TK et al. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 1984 310 669-673.

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2. Seney FD et al. Acquired immunodeficiency syndrome and the kidney. Am J Kidney Dis 1990 16 1-13.

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3. U.S. Renal Data System, USRDS 1995 Annual Data Report. National Institutes of Health, NIDDK. Bethesda, MD, April 1995. 1995 The data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government. .

4. Tokars JI et al. National surveillance of dialysis associated diseases in the United States, 1992. ASAIO J 1994 40 1020-1031.

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5. Winston JA and Klotman PE. Are we missing an epidemic of HIV-associated nephropathy (HIVAN)? J Am Soc Nephrol 1995 6 abstract 408-408.

6. Rao TKS. The types of renal disease in the acquired immunodeficiency syndrome. N Engl J Med 1987 316 1062-1068.

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7. Kimmel PL et al. Abnormal urinary protein excretion in HIV-infected patients. Clin Nephrol 1993 39 17-21.

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8. Tebben JA et al. Outcome of HIV-infected patients on continuous ambulatory peritoneal dialysis. Kidney Int 1993 44 191-198.

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9. Bourgoignie JJ. Renal complications of human immunodeficiency virus type 1. Kidney Int 1990 37 1571-1584.

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10. Bodi I et al. Apoptosis in human immunodeficiency virus-associated nephropathy. Am J Kidney Dis 1995 26 286-291.

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11. Jindel KK et al. Crescentic IgA nephropathy as a manifestation of human immune deficiency virus infection. Am J Nephrol 1991 11 147-150.

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12. Appel RG and Neill J. A steroid-responsive nephrotic syndrome in a patient with human immunodeficiency virus infection. Ann Intern Med 1990 113 892-893.

13. Strauss J et al. Anti-HIV therapy does affect progression of HIV-associated nephropathy. J Am Soc Nephrol 1995 6 abstract 430-430.

14. Rahman M et al. Prednisone ameliorates the progression of HIV-associated nephropathy (HIV-AN). J Am Soc Nephrol 1995 6 abstract 430-430.

15. Burns GC et al. Response to early and prolonged inhibition of angiotensin-converting enzyme in human immunodeficiency virus-associated nephropathy. J Am Soc Nephrol 1995 6 abstract 403-403.