HIV Nephropathy: To Treat or Not to Treat?

HIV-associated nephropathy (HIVAN) represents a major complication of HIV infection. Its natural history has been well defined ? the development of nephrotic syndrome initially, then relentless progression to end-stage renal disease (ESRD) in most patients [Kidney Int 48:311-320,1995;Kidney Int (suppl 35) 40:S13-S18,1991]. As a result, the number of HIV-infected patients entering chronic dialysis programs is rising exponentially. Since renal transplantation is not an option, these ESRD patients will be dialysis-dependent for life.

Renal manifestations of HIV infection occur in 6-10% of HIV seropositive individuals [Kidney Int 44:1327-1340,1993;Am J Kidney Dis 26:446-453,1995]. Classic HIVAN is characterized histopathologically as a collapsing variant of focal segmental glomerulosclerosis with microcystic dilatation of tubules, tubulo-reticular inclusions and interstitial inflammation [Kidney Int 35:1358-1370,1989]. In our experience, as well as that of others [Kidney Int 44:1327-1340,1993], not all patients presenting with nephrotic syndrome and/or renal insufficiency have HIVAN. We have found proliferative glomerulonephritis (GN), membrano-proliferative GN, membranous nephropathy, fibrillary GN and amyloidosis in patients with a clinical presumptive diagnosis of HIVAN. We therefore feel that renal biopsy represents an important diagnostic procedure in patients being considered for drug treatment (discussed below) for HIVAN complicated by rapidly progressive and/or severe renal failure. Renal biopsy information also identifies patients not likely to benefit from treatment because of severe hypertensive nephrosclerosis, global sclerosis and diffuse interstitial fibrosis or other diseases (e.g. amyloidosis).

Until recently, therapeutic intervention in an attempt to alter the course of progression of HIVAN to ESRD has been considered futile. In 1994, Smith et al [Am J Med 97:145-151,1994] and Phinney et al [J Am Soc Nephrol 5:358,1994] reported a series of cases with impressive clinical responses to empirical treatment with prednisone with little morbidity and no mortality attributable to treatment. Following these reports, we decided to offer a trial of prednisone treatment to selected patients with severe renal disease and no contraindications to steroid treatment. Our experience has been similar to those reported, in that the majority of patients have responded well, sometimes dramatically, with substantial reductions in serum creatinine or nephrotic proteinuria and the cessation of the need for dialysis. Several patients, however, have developed bacterial or pneumocystis carinii pneumonia while on treatment, requiring temporary or permanent discontinuation of prednisone (with subsequent relapse of progressive renal failure). Each patient recovered from their pneumonia, and no other complications of steroid treatment occurred in other patients. In one of our patients we were able to obtain important insights into mechanisms by which prednisone exerts its beneficial effects in HIVAN. In a post-treatment renal biopsy after marked reductions in proteinuria and serum creatinine, there were remarkable reductions in the macrophage and other mononuclear cell infiltration and no evidence of the thrombotic microangiopathy found in the pre-treatment biopsy.

Although the benefits of steroid treatment for selected patients with HIVAN in the short term are beyond dispute, we remain concerned about the risks of serious and potentially life-threatening infections in these high risk patients. In addition, it remains to be determined whether steroid treatment will alter longer term outcomes by delaying or preventing the need for dialysis or by changing mortality. To address these important issues, a prospective, randomized, double-blind, multi-center study of the efficacy of prednisone in HIVAN has been developed by the AIDS Clinical Trials Group (ACTG 271), sponsored by the NIAID and chaired by Drs. Robert Kalayjian, Michael C. Smith and Michael Lederman. This is a very important study, the results of which should provide considerable guidance in deciding whether "to treat or not to treat."

Postscript: Unfortunately, ACTG 271 was withdrawn on May 13, 1996, due to low enrollment.