You are in: eMedicine Specialties > Nephrology > The Kidney in Systemic Diseases HIV NephropathyArticle Last Updated: Jan 30, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Moro O Salifu, MD, MPH, Director, Nephrology Fellowship Program, Associate Professor, Department of Internal Medicine, Division of Nephrology, SUNY Downstate Medical Center Moro O Salifu is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Artificial Internal Organs, American Society of Nephrology, and National Kidney Foundation Coauthor(s): Sidhartha Pani, MD, Nephrology Attending, Department of Internal Medicine, Division of Nephrology, Melrose-Wakefield Hospital, Sommerville Hospital, Carney Hospital; Nilanjana Misra, MD, Research Associate, Department of Internal Medicine, Division of Infectious Diseases, Brookdale University Hospital and Medical Center Editors: Laura L Mulloy, DO, FACP, Professor of Medicine, Chief, Section of Nephrology, Hypertension and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine, Director of Nephrology Training Program, Kidney Disease Program, University of Louisville School of Medicine; Director, Metabolic Stone Clinic; Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine; Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System Author and Editor Disclosure Synonyms and related keywords: HIV associated nephropathy, HIV-associated nephropathy, HIVAN, HIV-related nephropathy, HIV infection, HIV disease, AIDS-related nephropathy, AIDS associated nephropathy, AIDS-associated nephropathy, renal disease, kidney disease, end-stage renal disease, ESRD, end-stage kidney disease, end stage renal disease, end stage kidney disease, kidney infection, pre-renal azotemia, prerenal azotemia, focal segmental glomerulosclerosis, FSGS, renal failure, kidney failure, anti-retroviral therapy, antiretroviral therapy, proteinuria, virus-induced renal injury, viral-induced renal injury, virus-induced kidney injury, viral-induced kidney injury INTRODUCTIONSection 2 of 11
  Human immunodeficiency virus (HIV) infection can cause a broad spectrum of clinical manifestations, ranging from an asymptomatic carrier state to severe immunodeficiency. Renal disease is a relatively common complication in patients with HIV disease. Renal disease can result from direct kidney infection with HIV or from the medications used to treat HIV and their resulting adverse effects. Further, patients with HIV disease are at risk for developing prerenal azotemia due to volume depletion resulting from salt wasting, poor nutrition, nausea, or vomiting. The phrase HIV-associated nephropathy (HIVAN), formerly known as AIDS-associated nephropathy, consists of a pentad of findings, including (1) proteinuria, (2) azotemia, (3) normal-to-large kidneys on ultrasonography images, (4) normal pressure, and (5) focal segmental glomerulosclerosis (FSGS) on renal biopsy findings. Once diagnosed, rapid progression to renal failure and end-stage renal disease (ESRD), leading to the need for dialysis, was the norm in the preantiretroviral therapy era. Antiretroviral therapy has changed the natural course of this disease. Although FSGS is the predominant glomerular lesion in HIVAN, other reported glomerular lesions in patients with HIV include IgA nephropathy, cryoglobulinemia, amyloidosis, and a lupuslike immune complex glomerulopathy. Physicians must consider HIVAN in patients who are seropositive for HIV and have proteinuria. For excellent patient education resources, visit eMedicine's Immune System Center and Sexually Transmitted Diseases Center. Also, see eMedicine's patient education articles HIV/AIDS and Rapid Oral HIV Test. EPIDEMIOLOGYSection 3 of 11
According to the US Renal Data System (USRDS), HIVAN accounts for approximately 1% of new ESRD cases in the United States. HIVAN is observed in patients regardless of the route by which HIV was contracted, but it may be less prevalent in men. For instance, HIVAN is uncommon in San Francisco, a city in which the HIV population consists mainly of white men. HIVAN is observed predominantly among African Americans and is the third leading cause of ESRD among black persons aged 20-64 years. Most patients with HIVAN are young black males, and approximately 50% are intravenous addicts. HIVAN is observed more often in men than in women, with a male-to-female ratio of 10:1. The mean age of persons with HIVAN is 33 years. PATHOGENESISSection 4 of 11
Experiments using transgenic mice perhaps provided the strongest evidence for a direct role of HIV type 1 (HIV-1) in the development of HIVAN. Researchers created transgenic mice by inserting HIV DNA constructs into the mice genomes. The mice developed proteinuria and had a histological picture similar to that observed in patients with HIVAN. A genetic or environmental cofactor that has not yet been identified is required for patients to develop this disease, which may explain the racial predilection for this disease among black persons. The cellular target for developing HIVAN is likely the renal glomerular and tubular epithelium. Using in situ hybridization and polymerase chain reaction assays to detect HIV-1 DNA and mRNA, investigators have shown that renal glomerular and tubular epithelial cells are productively infected by HIV-1 in patients with HIVAN, arguing strongly for localized replication of HIV-1 in the kidney and the existence of a renal viral reservoir. Further, circularized viral DNA, a marker of recent nuclear import of full-length, reverse-transcribed RNA, has been detected in kidney biopsy samples from patients with HIVAN, suggesting active replication in renal tissue. However, the mechanisms of virus-induced renal injury remain undetermined. Peculiar histopathological features of HIVAN are the enhanced proliferation and the loss of differentiation markers of glomerular epithelial cells. In one study, HIV-1 infection was shown to kill renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase activation and Fas up-regulation, suggesting that apoptosis of nonlymphoid cells can be directly induced by HIV-1. The net and long-standing glomerular and tubular epithelial cell damage leads to proteinuria, glomerulosclerosis, and tubulointerstitial scarring. The role of cytokines is not established, and, although their presence is not essential for the development of HIVAN, cytokines may modify the progression of infection or a patient's susceptibility to infection. The levels of cytokines are increased in renal biopsy samples from patients with HIVAN. In one study, mesangial and tubular cell production of interleukin-6 and tumor necrosis factor-alpha was shown to be a potent stimulus for HIV-1 expression in HIV-1–infected monocytes. Viral replication in response to cytokines may play an important role in the pathogenesis of HIVAN. GENETICSSection 5 of 11
The reason behind the increased predilection among black persons is not clear. In general, black persons have a higher incidence of other renal diseases (eg, diabetic nephropathy, lupus, abuse); therefore, they may have an underlying genetic predisposition to severe renal disease, regardless of the etiology. The type of host response to the HIV infection itself may be what determines who develops nephropathy. HISTOLOGYSection 6 of 11
On ultrasound images or when examined by tomography, HIVAN patients have enlarged and echogenic kidneys. This may result from prominent interstitial expansion by cellular infiltrate and markedly dilated tubules containing voluminous casts. Findings from light microscopy of kidney biopsy tissue are diagnostic in most cases. The most common histologic light microscopy finding is a collapsing form of focal segmental glomerulosclerosis. The glomerular capillary tuft is collapsed (see Media file 1) and may be segmentally or globally sclerosed. Visceral epithelial cells are hypertrophied and form a characteristic pseudocrescent in the Bowman space. Tubulointerstitial scarring, atrophy, and marked dilatation of the tubules (microcystic dilatations) are usually present (see Media file 2). Immunofluorescent microscopy helps identify positive staining for albumin and immunoglobulin G in epithelial cells and for immunoglobulin M, C3, and, occasionally, immunoglobulin A, in mesangial or sclerotic areas. Electron microscopy reveals wrinkling of the basement membranes, epithelial cell proliferation, and focal foot process effacement. Tubuloreticular structures in the glomerular endothelial cells (see Media file 3) consisting of ribonucleoprotein and membrane, the synthesis of which is stimulated by alpha-interferon, is highly predictive of HIVAN CLINICAL FEATURESSection 7 of 11
HIVAN patients typically present with a nephrotic syndrome consisting of nephrotic-range proteinuria (>3.5 g/d), azotemia, hypoalbuminemia, and hyperlipidemia. Edema is uncommon in HIVAN, yet many authors think this is a characteristic of HIVAN. The salt losing propensity and high oncotic pressure contributed by marked hypergammaglobulinemia in these patients have been suggested as possible explanations for this puzzling observation. The CD4 count in these patients is usually depressed below 200 cells/µL, but HIVAN has been reported in patients with higher CD4 counts. The prognosis for renal survival is worse in patients with clinical AIDS, especially if their CD4 count is less than 50 cells/µL. Patients with HIVAN are not typically hypertensive, even in the face of renal insufficiency, and their kidneys are usually normal-to-large and highly echogenic on ultrasonography images. Routine urinalysis may occasionally reveal findings of nonnephrotic proteinuria in patients being evaluated for other medical conditions. The urinalysis reveals microhematuria, leukocytes, hyaline casts, and oval fat bodies, but no cellular casts. Serum complement levels are normal. In one study, the rate of progression from the initial presentation to ESRD was 2.5 months in the pre-HAART (highly active antiretroviral therapy) era. With the introduction of HAART in 1996-1997, the traditional natural history of rapid progression of HIVAN has been slowed significantly. HAART therapy has been shown to retard the progression of renal disease in persons with HIVAN. Electrolyte abnormalities, such as hyponatremia and hyperkalemia, may be observed in patients with HIVAN and may reflect an increase in total body water (from the nephrotic syndrome, syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) or hyporeninemic hypoaldosteronism, respectively. SIADH may be a result of concomitant pulmonary infection or persistent nausea from medications or gastrointestinal disease. Hyporeninemic hypoaldosteronism, a cause of type IV renal tubular acidosis manifesting as hyperkalemia with normal anion gap metabolic acidosis, is much more common when renal insufficiency is present. Most HIV medications are well tolerated, even in the presence of renal insufficiency. The potential toxicity of the nucleoside reverse transcriptase inhibitors (ie, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine) is uniformly type B lactic acidosis; however, didanosine may cause electrolyte abnormalities, such as hypokalemia, hyponatremia, hypermagnesemia, and hyperuricemia, and stavudine may cause hyperuricemia. Except for nevirapine, which may cause lactic acidosis, the nonnucleoside reverse transcriptase inhibitors (ie, nevirapine, delavirdine, efavirenz) have no reported significant renal toxicity. As a class, the protease inhibitors (ie, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir) are known to precipitate nephrolithiasis. A classic form of this is indinavir crystalluria, which occurs independently of renal function; however, the stones resolve after cessation of indinavir therapy. Enfuvirtide (Fuzeon) is the first of a new class of fusion inhibitors that stops the virus from entering cells. Enfuvirtide has no known renal effects for creatinine clearance of greater than 35 mL/min. Therefore, dose adjustment should be made in patients receiving nucleoside reverse transcriptase inhibitors when the glomerular filtration rate falls below 50 mL/min. Patients receiving nonnucleoside reverse transcriptase inhibitors may also receive a dose adjustment when the glomerular filtration rate falls below 50 mL/min. No dose adjustment is required for patients taking protease inhibitors. Some drugs used to treat opportunistic infections in HIV disease may also cause nephrotoxicity or electrolyte abnormalities (see Media file 4). INDICATIONS FOR BIOPSYSection 8 of 11
The decision to obtain a biopsy sample is somewhat controversial in the general medical community. Even if a patient presents with the classic clinical features of HIVAN, clinical consideration is predictive of the biopsy diagnosis in only 55-60% of patients. Therefore, to distinguish HIVAN from other forms of renal disease (eg, immune complex glomerulonephritis, immunoglobulin A nephropathy), patients who are seropositive for HIV require a renal biopsy. The typical practice is to obtain a renal biopsy specimen if the patient's daily protein excretion is greater than 1 gram. TREATMENTSection 9 of 11
Antiretroviral therapyThe best course of treatment involves a collaborative effort between a nephrologist and an HIV disease specialist. The current standard is to initiate aggressive antiretroviral therapy (ie, HAART) for all patients with advanced or symptomatic HIV disease, defined as a CD4 count of fewer than 350 cells/µL or a high viral load. A recent report from the USRDS shows that the incidence of HIVAN appears to be declining since the introduction of HAART. Renal dosing of antiretroviral therapy and adjustments for creatinine clearance are as follows: Nucleoside reverse transcriptase inhibitors
Protease inhibitors
Nonnucleoside reverse transcriptase inhibitors
CorticosteroidsA number of case reports suggest that corticosteroids offer some short-term benefit. In one report, results from a pretreatment and posttreatment kidney biopsy suggested that the improvement in renal function was associated with a reduced number of lymphocytes and macrophages infiltrating the interstitium. In another report, 20 patients were treated with prednisone at 60 mg/d for 2-11 weeks, followed by a slow taper. After a follow-up of 44 weeks, 8 patients required maintenance dialysis, 11 died from complications, and 7 were alive and not longer had ESRD. Angiotensin-converting enzyme inhibitorsIn patients with advanced renal insufficiency, captopril was noted to improve renal survival for a mean of 37-150 days. More recently, in a prospective follow-up of 44 patients, the median renal survival of patients who received fosinopril was 479.5 days, with only one patient developing ESRD. All untreated control subjects progressed to ESRD, with a median renal survival of 146.5 days (P <0.0001). The exact mechanism of action of this class of drugs is unknown, but it may be related to a hemodynamic effect, a reduction in the transglomerular passage of serum proteins, and an antiproliferative effect mediated, in part, by inhibiting transforming growth factor-beta. Use angiotensin-converting enzyme inhibitors if patients do not have hyperkalemia. CyclosporineSome reports on pediatric populations suggest that cyclosporine can be effective in reducing the proteinuria observed in persons with HIVAN. The usefulness of cyclosporine therapy for HIVAN warrants further study. Promising therapeutic strategies in animal studiesAnimal research shows promising results for retarding renal disease progression in HIVAN. In one study, the use of a cyclin-dependent kinase inhibitor decreased visceral epithelial cell proliferation in HIV-infected mice. In another study, blockade of nuclear factor kappa beta (a cell signaling pathway), in mice, resulted in increased lifespan and kidney and lean body mass preservation. These benefits were associated with a reduction of CD45(+) cells infiltrating the kidneys, amelioration of the renal architecture, and reduced level of circulating inflammatory cytokines. Further studies are needed to determine the role of these inhibitors on human HIVAN. Dialysis and transplantationPatients who progress to ESRD remain a clinical challenge. Physicians must anticipate progressive renal disease in patients with HIVAN and set a goal for placing an arteriovenous fistula in a timely manner for future use in hemodialysis. In current practice, hemodialysis is the accepted modality of ESRD therapy in this population. Because of increased susceptibility to infections, peritoneal dialysis has not been widely advocated. For the same reason, the general theory is that immunosuppression after kidney transplantation would pose a substantive risk of opportunistic infections in this population. As such, kidney transplantation in these patients is still considered experimental, with only few transplant centers considering cadaver kidney transplantation in compliant, stable patients with no prior opportunistic infections who have an undetectable viral load and a CD4 count of fewer than 300 cells/µL. Anecdotal reports of small samples of this selected group of patients with HIVAN suggest no extra risk of opportunistic infections; however, until larger studies are performed, transplantation in persons with HIVAN remains relatively contraindicated. In one study, 1- and 2-year actuarial patient survival was 85% and 82%, respectively, and graft survival was 75% and 71%, respectively. Plasma HIV-1 RNA remained undetectable, and CD4 counts remained in excess of 400 cells/µL with no evidence of AIDS for up to 2 years. These results were comparable to other high-risk populations receiving kidney transplantation. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Article Last Updated: Jan 30, 2007 | ||||||||||||||||||||||||||||
