Renal disease associated with HIV infection may present as fluid-electrolyte and acid-base abnormalities, acute renal failure, coincidental renal disorders, or a glomerulopathy directly related to underlying HIV infection, the so-called HIV-associated nephropathy (HIVAN). Originally observed in patients with AIDS and referred to as AIDS-associated nephropathy, recent studies have described the characteristic renal changes of HIVAN in both asymptomatic HIV-infected individuals and those with early symptomatic HIV disease, thereby broadening the definition to include all HIV-infected patients. With the advent of the potent protease inhibitor indinavir, renal stones have been reported with increasing frequency. Up to 4% of indinauir recipients experience flank pain, with or without hematuria, while on therapy. Crystallization of drug in the renal collecting system leads to development of “sludge,” or frank stones, resulting in renal colic.
Fluid, Electrolyte, and Acid-Base Disorders
Fluid-electrolyte disorders are common in patients with advanced HIV infection. Hyponatremia is noted in up to 40% of hospitalized AIDS patients and occurs in the setting of both hypovolemia and euvolemia. Hypovolemia, most often due to gastrointestinal fluid losses, is the most common cause of hyponatremia among this group of patients.
The syndrome of inappropriate antidiuretic hormone release (SIADH) is responsible for the majority of cases of euvolemic hyponatremia and is most often due to underlying Pneumocystis carinii infection, malignancy, or central nervous system (CNS) disease. The presence of hyponatremia is associated with increased morbidity and mortality, especially in conjunction with certain opportunistic infections, such as cryptococcosis.
Adrenal insufficiency is a less frequent cause of hyponatremia. Although abnormalities of the adrenal glands are frequently reported at autopsy, overt adrenal insufficiency occurs in < 5% of patients. The typical findings of hyponatremia, hyperkalemia, non-anion gap metabolic acidosis, hypovolemia, renal salt wasting, and mild renal insufficiency are usually present in some combination.
Drugs are an important cause of fluid and electrolyte disorders in HIV-infected patients and can mimic the abnormalities associated with adrenal dysfunction. Hyperkalemia and non-anion gap metabolic acidosis have been noted in patients receiving parenteral pentamidine. Amphotericin B is associated with hypokalemia, hypomagnesia, renal tubular acidosis, and renal insufficiency. Foscarnet therapy is associated with decreased levels of ionized calcium and, on occasion, renal insufficiency. Nucleotide analogs, such as cidofovir and adefovir, are associated with renal insufficiency and electrolyte disorders. A Fanconi-like proximal renal tubule disorder, characterized by hypophosphatemia and creatinine elevation, has been observed frequently in patients receiving adefovir; the incidence of this disorder increases dramatically after 24 weeks of adefovir therapy. Chemotherapeutic agents used to treat AIDS-associated malignancies may lead to fluid and electrolyte disturbances through direct nephrotoxicity or gastrointestinal losses associated with prolonged vomiting or diarrhea.
Acute Renal Failure
As with most chronic illnesses, acute renal dysfunction may develop as a complication in the management of HIV-infected patients. Prerenal azotemia often results from hypovolemia secondary to poor fluid intake, increased gastrointestinal losses, or both. Acute tubular necrosis can be ischemic in origin, usually secondary to hypotension or sepsis, or due to nephrotoxic agents. Acute interstitial nephritis is another complication associated with drugs used to treat HIV-related diseases. A listing of agents with nephrotoxic potential commonly used in HIV-infected patients is presented in
Opportunistic infections, invasion of renal parenchyma with lymphoma or Kaposi’s sarcoma, and amyloidosis, which occurs as a complication of subcutaneous narcotic abuse, all may result in interstitial nephritis. Other renal lesions, such as hepatitis B-induced membranous glomerulonephritis, IgA nephropathy, acute glomerulonephritis secondary to bacterial infection, direct infection of the renal parenchyma with cytomegalovirus (CMV), fungi, or mycobacteria, and the hemolytic-uremic syndrome have all been associated with renal dysfunction in HIV-infected individuals. The diagnosis and management of acute renal failure are no different in HIV-infected patients than in their uninfected counterparts.
HIVAN was first established as a unique clinical entity in 1984. Originally called AIDS-associated nephropathy (AAN), many investigators questioned whether AAN was indeed a unique manifestation of AIDS or simply represented heroin-associated nephropathy (HAN) occurring in intravenous drug users (IVDUs) who also happened to be infected with HIV. Although the lesions and clinical manifestations of HAN are similar to those of AAN, further studies have established clear distinctions between the two entities. Of note, AAN occurs in individuals, including children, who have never used intravenous drugs. Indeed, nearly half of the cases presenting with the manifestations of AAN have early (asymptomatic or minimally symptomatic) HIV disease. Therefore, HIVAN has replaced AAN as the most appropriate name for this entity.
The first cases of HIVAN were described in major urban centers, such as New York and Miami, which also had many IVDUs among their HIV patient population. In contrast, centers whose HIV population consisted primarily of Caucasian homosexual and bisexual men, such as San Francisco and the National Institutes of Health, were not observing the renal changes of HIVAN in their patients, thereby implying that HIVAN was a manifestation of HAN. More recent epidemiologic data indicate that 50% of patients with HIVAN are IVDUs, with the remaining cases occurring in homosexual and bisexual men, immigrants from Haiti, women who have acquired HIV from heterosexual contacts, and children born to infected mothers, many of whom did not use intravenous drugs.
Over 90% of patients with HIVAN are black. No explanation regarding the high prevalence of cases among blacks has been established, although many investigators have speculated that cofactors such as superimposed infection(s) or specific immune response genes may be responsible.
Pathology and Pathogenesis
Focal and segmental glomerulosclerosis (FSGS) is the characteristic renal lesion identified in patients with HIVAN, occurring in 80 to 90% of patients. On gross inspection, the kidneys usually are enlarged and the cortical surface is smooth, even in advanced uremia. Microscopic examination of early lesions reveals diffuse mesangial hyperplasia with minimal glomerular sclerosis over time. A variable number of glomeruli develop segmental sclerosis characterized by hyperplastic visceral epithelial cells with coarse cytoplasmic vacuoles, collapsed capillary walls or capillaries obliterated by protein deposits (hyalinosis), and foam cells (lipid-filled monocytes) in the lumina. Bowman spaces are usually dilated and tubular damage is universal. Microcystic dilation of tubules is a unique feature of HIVAN not reported in the FSGS of HAN. Interstitial changes consisting of mild edema with scattered mononuclear cells are usually evident in HIVAN kidneys but not nearly to the degree noted in HAN. Similarly, although interstitial fibrosis may be present in advanced HIVAN disease, it is not nearly as prominent as the marked interstitial fibrosis noted in HAN disease.
The etiology of HIVAN remains unknown; however, many investigators suspect that an infectious agent perhaps HIV itself, is responsible. Ultrastructural studies have demonstrated tubuloreticular structures in vascular endothelium as well as in circulating and tissue lymphocytes. Other findings, such as a large number of nuclear bodies existing as budding forms in renal and lymphoid tissues, have been interpreted by some investigators to suggest a viral etiology. In situ hybridization studies have demonstrated proviral HIV DNA in renal tubular and glomerular epithelial cells, implicating HIV as the causative agent. However, the predominance of HIVAN in blacks and the relative paucity of cases among Caucasian homosexual men suggest that other factors not yet identified must play a role in the pathogenesis of HIVAN.
HIVAN is characterized by the development of proteinuria, nephrotic syndrome, and rapidly progressive irreversible azotemia. The proteinuria is typically heavy and presents as an early manifestation. Untreated, the time to the development of end-stage renal disease (ESRD) from the initial diagnosis of proteinuria is 4 to 16 weeks in patients with HIVAN, compared to 20 to 40 months among patients with HAN. Another clinical distinction between HIVAN and HAN is the relative absence of significant hypertension among patients with HIVAN. Accelerated hypertension is a hallmark of HAN. Peripheral edema and anasarca are conspicuously absent in a large number of HIVAN patients with high-grade proteinuria and hypoalbuminemia.
Nephropathy has been documented in patients months to years before the onset of clinical symptoms of early symptomatic HIV disease or AIDS. HIVAN is being reported with increasing frequency among HIV-infected children and appears to be independent of the risk factors for HIV infection in their mothers. It is anticipated that the incidence of HIVAN will continue to grow and should be considered as a diagnostic possibility in any HIV-infected patient who presents with unexplained proteinuria regardless of the stage of disease.
Quantitative measurement of the amount of protein excreted in the urine along with estimation of the creatinine clearance via a 24-hour Urine collection should be performed early in the course of evaluation. Other reversible causes of renal insufficiency such as bacterial infection, crystalluria, and obstructive uropathy should be ruled out using urine culture, urinalysis, and ultrasonography. The kidneys are enlarged early in HIVAN and remain enlarged throughout the course of disease. Since a variety of other renal lesions, such as membranous nephropathy related to hepatitis B, membranoproliferative disease, and immune complex-related glomerular damage, may also present as nephrotic syndrome in HIV-infected patients, renal biopsy should be encouraged. The presence of the typical features of FSGS with tubular involvement as described above establishes the diagnosis of HIVAN when renal tissue is obtained.
Improved outcome, including reversal of renal insufficiency and marked reduction in proteinuria, has been reported with a number of interventions. The use of highly active antiretroviral therapy, usually consisting of a regimen containing a potent protein inhibitor, in combination with other modalities (e.g., conticosteroids or ACE-inhibitor therapy) is the cornerstone of therapy. Corticosteroids (60 mg prednisone daily over 2 to 6 weeks) have been shown to partially reverse the progressive azotemia and prevent the need for dialysis in a subgroup of patients. Several uncontrolled studies have demonstrated benefit of ACE-inhibitors, either captopril or fosinopril, in the treatment of biopsy-proven HIVAN. Outcomes were better among those receiving ACE-inhibitors along with potent antiretroviral therapy.
Nutritional support in the form of high-protein, high-calorie diets along with appropriate dosage adjustments of nephrotoxic drugs is crucial. Hemodialysis is of marginal benefit in prolonging survival of patients with advanced HIV disease once they have reached end-stage renal disease. Among patients with AIDS, hemodialysis provides significant prolongation of life. Patients who are asymptomatic or have early symptomatic HIV disease survive longer, with some patients living > 6 years on chronic hemodialysis. Peritoneal dialysis should be considered in patients who are suitable candidates.
Chronic ambulatory peritoneal dialysis (CAPD) may offer several advantages over hemodialysis, including avoiding leukopenia caused by the hemodialysis membranes, fewer problems with anemia, and theoretical advantages of less stimulation of HIV-infected T lymphocytes via membrane-induced cytokine release. A potential disadvantage of CAPD is the higher incidence of peritonitis. Renal transplantation is not considered a viable option in HIV-infected patients owing to the intensive immunosuppressive regimens required to prevent rejection. In some patients with advanced HIV infection or AIDS who develop HIVAN it may be appropriate to withhold dialysis support because of the generally poor prognosis. As always, such decisions should be individualized, taking into account the wishes of the patient, the family, and significant others.
Revision date: June 14, 2011
Last revised: by Jorge P. Ribeiro, MD