Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is a syndrome caused by focal sclerosing glomerulopathy and typically presents with severe proteinuria, renal failure, and rapid progression to end-stage renal disease (ESRD). It is the most common cause of ESRD in HIV-1-seropositive patients.1 Human immunodeficiency virus-associated nephropathy is much more likely in patients of African descent,2-5 which suggests an interaction between underlying genetic factors and HIV. The prevalence of HIVAN in HIV-positive patients has been estimated from 3.5% in clinical studies to 12% in autopsy studies.1 The risk factors include a CD4 cell count of less than 200 cells/mm3 and a high viral burden. It has also been documented in patients with acute HIV infection.6,7 A prior study reported biopsy-proven HIVAN in patients with undetectable viral loads.8 The treatment of this condition has been focused on the use of highly active antiretroviral therapy (HAART), angiotensin-converting enzyme (ACE) inhibitors, and corticosteroids. The prognosis of HIVAN without adequate treatment is poor. Cases have been documented in which initiation of antiretroviral treatment led to remission within a few weeks.9,10 Although there is strong observational data supporting the importance of HAART in the treatment of HIVAN, there are no prospective randomized and controlled trials that support the use of HAART in these patients. We report a patient with dialysis-dependent chronic kidney disease secondary to HIVAN who was able to stop dialysis 2 months after initiation of HAART therapy combined with corticosteroids.
A 28-year-old African American man with no significant medical history was admitted to the hospital with a 4-week history of generalized weakness, 2 weeks of progressive difficulty walking and lower extremity weakness, and a 2-day sensation of numbness in the fingers. He also reported weight loss, mild dyspnea on exertion, and decreased sensation in the lower extremities. The remaining medical history was noncontributory. His social history was notable only for occasional ethanol use. He stated that he was in a mutually monogamous heterosexual relationship for the past 1 year in which he reported unprotected sexual intercourse. On admission, he was afebrile, had a blood pressure measuring 150/95 mm Hg, a heart rate of 89 beats per minute, and respiratory rate of 19 breaths per minute. Oxygen saturation by pulse oximetry was 97% on room air. He was alert and oriented times three, not in acute distress, and pale. No oropharyngeal thrush was visible. The neurological examination demonstrated mildly decreased motor strength of 4/5 in the lower extremities, intact and symmetric sensation, hyperreflexia of 3/4, and a wide-based gait.
Laboratory workup revealed a creatinine level of 8.4 mg/dL, hemoglobin of 8.9 g/dL, lymphopenia (0.5 K/μL), mild thrombocytopenia (146 K/μL), and a serum albumin of 2.3 g/dL. Urinalysis revealed greater than 300 mg/dL of proteinuria, without casts or eosinophils. A 24-hour urine collection showed 8.9 g of total protein excretion. Renal ultrasound revealed enlarged (14-15 cm) echogenic kidneys bilaterally, without evidence of hydronephrosis. He became anuric within a few days of admission and remained so for the remainder of his 3-week admission. Magnetic resonance imaging of the spine was conducted and showed no significant canal stenosis or neural foramina narrowing at any level. The spinal cord in signal and caliber was normal, and no enhancing lesions were identified. Nerve conduction study and electromyography were consistent with a chronic left C7-T1 polyradiculopathy and mild peripheral neuropathy. An HIV test was performed because of the patient's heavy proteinuria and large kidneys. Results of HIV enzyme-linked immunosorbent assay and Western blot were positive. He was found to have a CD4 count of 15 cells/μL and a viral load of 560,126 copies/mL. Antinuclear antibody and rheumatoid factor were negative. Complement levels were normal. Hepatitis B and C serologies and glomerular basement membrane antibodies were negative. The patient underwent percutaneous core renal biopsy which revealed glomerular sclerosis (Fig. 1), microcystic dilatation of tubules, tubular atrophy, interstitial chronic inflammation and fibrosis, and endothelial tubuloreticular inclusions consistent with HIVAN (Figs. 2, 3).
He was started on HAART (abacavir, lamivudine, atazanavir, and ritonovir) as an inpatient, along with corticosteroids (prednisone, 60 mg daily) and an ACE inhibitor (lisinopril, 10 mg daily). Hemodialysis commenced shortly after admission and was continued upon discharge from the hospital. Two months later, he presented at dialysis with fever and chills. Multiple blood cultures drawn at the time of admission and afterward grew Enterobacter cloacae and Stenotrophomonas (Xanthomonas) maltophilia. His central vein hemodialysis catheter was removed for presumed catheter-related bacteremia. It was also noted that the patient's creatinine level at the time of admission was 2.3 mg/dL; upon questioning, he revealed that his urine output has increased significantly over the past several weeks. A 24-hour creatinine clearance at that time was 41 mL/min per 1.73 m2, and total protein excretion was 3.1 g/d. Hemodialysis was discontinued; CD4 count obtained at that time was 94 cells/μL, and HIV viral load was 3472 copies/mL. At last follow-up of 16 months after stopping dialysis, his serum creatinine level was 2.3 mg/dL, and estimated (Modification of Diet in Renal Disease) glomerular filtration rate was 40/mL per 1.73 m2. The HIV-1 RNA quantitative polymerase chain reaction was 242 copies/mL, and absolute CD4 count was 417/μL.
Renal disease is a common finding in patients infected with HIV. Three major groups of nephropathy have been identified: classic HIVAN, HIV-associated thrombotic microangiopathy, and HIV-associated immune-mediated glomerulonephritides.11 In general, HIVAN seems to be mainly limited to patients of African descent, whereas most cases of renal disease in the white population seem to be immune complex-mediated glomerulonephritis.12 Human immunodeficiency virus-associated nephropathy clinical features include advanced renal failure and proteinuria, a lack of peripheral edema despite the severe loss of protein, and frequently, enlarged kidneys visible on renal ultrasound.1 The mechanisms by which these changes occur are not well understood. In vitro studies suggest that HIV can infect glomerular endothelial, mesangial, and tubular cells.13,14 The mechanism of cellular entry is unclear because the HIV coreceptors do not seem to be expressed in renal cells.15 Human immunodeficiency virus can persist as a reservoir after effective therapy in glomerular epithelial and tubular cells.16
This patient presented with typical epidemiological and clinical findings of HIVAN. There was no evidence of coexisting renal disease in the patient. Prerenal and postrenal causes were excluded. Also, other renal causes were investigated and excluded, including interstitial nephritis (no urinary eosinophils and by pathology), HIV-associated thrombotic microangiopathy (by peripheral smear, biopsy, and biochemical studies), and immune-mediated glomerulonephritides (by negative serology and absence on pathological examination). No serological markers for hepatitis A, B, or C viruses were detected. The patient was found to have a CD4 count of 15 cells/μL and a viral load of 506,126 copies/mL. Although HIVAN typically occurs late in the course of HIV infection,17 there is a case report of a biopsy-proven HIVAN during primary infection.18 Another report describes that HIV infection of the kidney can occur during acute seroconversion.16
Our patient was started immediately on HAART according to the Infectious Diseases Society of America guidelines for management of chronic kidney disease in HIV-infected patients,19 which state that patients with HIVAN should be treated with HAART at diagnosis, and HAART should not be withheld simply because of the severity of the renal disease. The pathogenesis of HIVAN is still not perfectly understood, but presumably this is a direct result of transgene expression in the kidney.20 Under this perspective, HAART would improve kidney function and histological changes in the kidney by decreasing the HIV gene expression.16 This is consistent with our clinical findings and other reports9,10,21 that also describe the resolution of renal failure after the initiation of HAART. However, there is 1 case report that demonstrated spontaneous resolution of acute renal failure in a patient with biopsy-proven HIVAN.22 More studies need to be done to clarify this point.
The guidelines also recommend that addition of ACE inhibitors, angiotensin II receptor blockers, and prednisone should be considered in patients with HIVAN if HAART alone does not result in improvement of renal function. Highly active antiretroviral therapy also seems to have a protective renal effect. Lucas et al23 reported a 60% reduction in the risk of development of HIVAN. Dietary protein restriction is not proven and should only be attempted under close dietetic supervision.19
The progression of HIVAN to ESRD can be rapid, and many patients need to be started on dialysis. Survival of HIV-infected dialysis patients has remarkably improved in the United States,24 and the survival of HIV-infected hemodialysis patients on HAART is better than that of patients on suboptimal antiretroviral therapy.25 Those patients are achieving survival rates comparable to those of dialysis patients without HIV infection.19 The patient we present was started on hemodialysis and, after 2 months, was admitted because of an infected central vein hemodialysis catheter. The catheter was removed, and it was noted that the creatinine level remained stable several days after stopping dialysis. Wali et al21 reported a patient who received 3 months of dialysis before it was discontinued after his renal function improved. Some patients do not respond to the treatment as our patient did. This could be explained in part by the timing of HAART initiation (before fibrosis has established) and by the fact that the kidney is a reservoir for HIV; HIVAN may continue in some patients despite undetectable viral load.16
Because ESRD secondary to HIVAN is potentially reversible with HAART, patients presenting with nephropathy characterized by proteinuria and progressive renal failure should be tested for HIV infection. Infectious Diseases Society of America guidelines recommend that all HIV patients, at the time of diagnosis, should be assessed for existing kidney disease with a screening urinalysis for proteinuria and a calculated estimate of renal function. Additional evaluations and referral to a nephrologist are recommended for patients with proteinuria of scale 1+ or more by dipstick analysis or glomerular filtration rate of less than 60 mL/min per 1.73 m2. Indications for renal biopsy in patients with HIV infection should be the same as in patients without HIV. When indicated, renal biopsy is recommended whenever feasible because treatment options and prognosis may be influenced by the histological diagnosis.19
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