Several years after the emergence of the acquired immunodeﬁciency syndrome (AIDS) epidemic in the early 1980s, an association with renal disease was recognized. By 1984, reports described a distinctive form of focal segmental glomerulosclerosis (FSGS) in African Americans and Haitian immigrants with AIDS living in the large urban centers of New York and Miami. This new disease, initially called AIDS nephropathy, is now termed human immunodeﬁciency virus (HIV)- associated nephropathy (HIVAN) because the essential feature is infection with the HIV-1 virus, not the full clinical constellation of AIDS.
At present, approximately 800 to 900 new cases of HIVAN are reported to the U.S. Renal Database System (USRDS) each year. HIVAN is approximately tenfold more common in blacks than whites, indicating a strong racial predisposition based on genetic factors. It is clinically characterized by progressive renal insufﬁciency, often accompanied by proteinuria, nephrotic syndrome, and the ultrasonographic ﬁndings of enlarged, hyperechoic kidneys. The clinical picture reﬂects virus mediated podocyte injury and proliferation, which leads to collapsing focal segmental glomerulosclerosis with microcystic dilation of the tubules and interstitial ﬁbrosis and inﬂammation.
In the early years of the epidemic, before effective therapy, progression to end-stage renal disease (ESRD) or death was nearly universal, and by 1999 “AIDS nephropathy” had become the third leading cause of ESRD among adult African Americans aged 20 to 64 years. The widespread availability of combination antiretroviral therapy to treat HIV-1 infection, however, has changed the natural history and epidemiology of HIVAN. The incidence of new cases of HIVAN has been reduced and the rate of progression to renal failure has been slowed by antiretroviral therapy, which is now the mainstay of treatment.
Following the introduction of combination antiretroviral therapy, the incidence of ESRD attributed to HIVAN has reached a plateau in the United States; however, because HIV-infected patients are living longer with nephropathy, the prevalence of HIV-related ESRD continues to increase. Given a stable annual mortality rate and assuming a linear growth of the HIV epidemic among African Americans, it is projected that nearly 10,000 patients in the United States will be living with ESRD due to HIVAN by the year 2020. Emerging data from African populations indicate a high prevalence of kidney disease among HIV-infected individuals in sub-Saharan Africa, reaching 38% in Nigeria. As antiretroviral therapy becomes more available worldwide, it is likely that an increasing number of HIV-infected Africans will also be living with ESRD due to HIVAN.
HIVAN is caused by direct infection of renal epithelial cells by the HIV-1 virus, leading to viral gene expression. RNA in situ hybridization and DNA in situ polymerase chain reaction ampliﬁcation of speciﬁc HIV-1 genes from human renal biopsies have detected HIV-1 virus in the podocytes (glomerular visceral epithelial cells), the parietal epithelial cells lining Bowman’s capsule, and tubular epithelial cells. Individual patients are noted to have different HIV-1 quasispecies in their renal epithelium compared with their peripheral blood leukocytes, indicating the ability of the virus to replicate and undergo mutation within the renal epithelium. This process of error-prone viral replication allows the virus to change its coat and evade the host immune system. How the virus enters renal epithelial cells is uncertain because there is no evidence of renal epithelial expression of CD4 (the major HIV receptor in T helper cells) or the HIV-1 coreceptors, CXCR4 and CCR5. It is possible that HIV-1 infects renal epithelium via transcytosis from inﬁltrating lymphocytes.
Once the HIV-1 virus enters renal epithelium, it expresses viral genes that can cause cellular injury by inducing dysregulation of host genes. The HIV-1 genome contains a total of nine genes, including genes that encode structural proteins (gag, pol, env), regulatory proteins (tat and rev), and accessory proteins (vif, vpr, vpu, nef). The use of genetically engineered mice has identiﬁed several genes as particularly important in HIVAN pathogenesis, namely nef (which augments viral replication and infectivity) and vpr (which transports the HIV-1 preintegration complex into the nucleus and induces cell cycle arrest). In the podocyte, expression of nef activates signaling cascades that disrupt the actin cytoskeleton, causing foot process effacement and failure to maintain the normal ﬁltration barrier. Heavy glomerular proteinuria and nephrotic syndrome ensue. The infected podocytes revert to a more immature phenotype resembling that seen in proliferating podocytes during glomerular development. The inability of the podocyte to maintain its normal mature phenotype leads to cellular dedifferentiation, proliferation, and glomerular tuft collapse. The dysregulation of tubular epithelial cells by viral infection, compounded by the tubular injury caused by severe proteinuria, leads to tubular microcyst formation, interstitial ﬁbrosis, and progressive renal failure. Tubular expression of vpr causes G2 cell cycle arrest and impairs cytokinesis of tubular epithelial cells, leading to increased chromosomal copy number. As a result, infected tubular epithelial cells appear hypertrophied with atypical enlarged nuclei.
Host factors are also critical to disease pathogenesis. The vast majority of patients with HIVAN are of African descent. Recently, a candidate gene has been linked to the development of HIVAN in this group: APOL1, encoding apolipoprotein L-1, located on human chromosome 22. An APOL1 variant appears to have emerged in the African population through a broad evolutionary sweep by conferring selective advantage against infection by Trypanosoma brucei rhodesiense, a parasite that causes sleeping sickness. APOL1 encodes a serum factor contained in high density lipo- protein particles that lyses the trypanosomal organism. The evolutionary selection of this genetic variant is analogous to the emergence of hemoglobin mutations that confer protection against malaria at the price of increased susceptibility to hemoglobinopathy and sickle cell anemia. In the case of APOL1, protection against trypanosomal infection comes at the cost of increased susceptibility to HIVAN and other forms of FSGS, although the renal cellular mechanisms are unknown. Like the mutations underlying sickle cell disease and trait, APOL1’s protective effect against infection is dominant (present in heterozygotes), whereas the association with host disease is recessive (occurring in homozygotes).
PRESENTATION AND DIAGNOSIS
In the early years of the AIDS epidemic, before anti-retroviral therapy, the classic clinical presentation of HIVAN was rapidly progressive renal failure accompanied by moderate to severe nephrotic-range proteinuria, bland urinary sediment, and the ultrasound ﬁndings of large, highly echogenic kidneys. Patients progressed to ESRD within several months.
Although some cases have been reported in the setting of asymptomatic HIV infection or acute HIV seroconversion, HIVAN is typically a complication of advanced HIV disease. Thus HIV-infected patients who develop nephrotic-range proteinuria and have a CD4 cell count less than 200 cells/mm3 should be strongly suspected of having HIVAN. A renal biopsy is required to establish the diagnosis and exclude other causes of renal dysfunction and proteinuria, including numerous HIV-related glomerular diseases, non-HIV-related renal diseases, and medication nephrotoxicity. Other glomerular lesions encountered in the HIV-infected patient include thrombotic microangiopathy, immune complex-mediated glomerular disease (such as membranoproliferative or membranous glomerulonephritis related to coinfection with hepatitis C or hepatitis B viruses, acute postinfectious glomerulonephritis, lupus-like nephritis, and IgA nephropathy). These immune complex forms of glomerulonephritis are more common in HIV-infected Caucasians than African Americans. Other renal biopsy ﬁndings in the age of antiretroviral therapy include hypertensive arterio- nephrosclerosis and diabetic nephropathy.
In the acute phase, untreated HIVAN typically causes a dramatic pattern of collapsing FSGS. Glomerular capillary lumina are occluded by an implosive wrinkling and collapse of the glomerular basement membranes that is more often global than segmental. Tuft collapse is accompanied by prominent hypertrophy and hyperplasia of the overlying podocytes (visceral epithelial cells), which have enlarged; open vesicular nuclei with frequent nucleoli; and occasional mitotic ﬁgures. The podocyte cytoplasm is typically vacuolated, containing intracytoplasmic protein resorption (hyaline) droplets. Exuberant visceral and parietal epithelial cell proliferation can form pseudocrescents that obliterate the urinary space. Eventually, the glomerular tuft retracts into a tight, solidiﬁed ball crowned by enlarged, vacuolated visceral epithelial cells.
Tubulo-interstitial disease is an invariable component of HIVAN and often appears out of proportion to the degree of glomerular injury. In addition to tubular atrophy, interstitial ﬁbrosis, edema, and inﬂammation, there are also widespread tubular degenerative and regenerative changes, including acute tubular epithelial injury and hypertrophy with enlarged hyperchromatic nuclei, prominent nucleoli, mitotic ﬁgures, and focal apoptosis. Distended tubules containing loose protein- aceous casts form tubular microcysts, which may be numerous and account for the enlarged appearance of the kidneys on radiographic imaging or gross examination.
By immunoﬂuorescence, there are no immune complex type deposits. Segmental to global staining for IgM, C3, and less commonly C1 is frequently observed in the collapsing segments. These immune reactants are nonspeciﬁcally trapped in areas of sclerosis.
By electron microscopy, the glomerular capillaries are narrowed by wrinkling and retraction of the glomerular basement membranes. The overlying podocytes are markedly hypertrophied with severe foot process effacement, disruption of the actin cytoskeleton, focal cellular detachment, and intracytoplasmic protein resorption droplets. No typical immune type of electron dense deposits are observed. The glomerular endothelial cells contain characteristic tubulo-reticular inclusions, also known as “interferon footprints.” These 24 nm structures are located in dilated cisternae of smooth endoplasmic reticulum and constitute a marker of HIV infection that can be found in endothelial cells and lymphocytes throughout the body. Importantly, tubulo-reticular inclusions are not a speciﬁc feature of HIVAN and may be found in HIV-infected patients without nephropathy, as well as in patients with systemic lupus erythematosus, hepatitis C, or other viral infections. Endothelial tubuloreticular inclusions have become less common in renal biopsies from patients with HIVAN who are receiving antiretroviral therapy, consistent with a treatment-induced reduction in viral burden and associated cytokine dysregulation.
A biopsy picture of collapsing glomerulopathy is not speciﬁc for HIVAN. Differential diagnosis of the collapsing variant of FSGS includes primary (idiopathic) FSGS; infections by viruses such as parvovirus B19, SV40 or CMV; erythrophagocytosis syndrome; interferon therapy; pamidronate toxicity; acute vasoocclusive injury; and rare familial forms.
The introduction of combination antiretroviral therapy in 1996 was followed by a decline in the incidence of HIVAN and in the number of new cases of ESRD attributed to HIVAN in the United States. Some case reports demonstrated histologic improvement of the glomerular collapse and tubular injury on repeat renal biopsies following antiretroviral therapy, paralleling improvements in renal function and proteinuria. In addition, antiretroviral therapy has been found to delay the course of renal failure and prolong renal survival.
Recent guidelines consider HIVAN an indication for the initiation of antiretroviral therapy, irrespective of CD4 cell count. Highly active antiretroviral therapy typically includes combinations of drugs from several classes, including nucleoside and nucleotide reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors. Therapy with ACE inhibitors or angiotensin receptor blockers may be added to reduce proteinuria and slow disease progression. Corticosteroids have been used as adjunct therapy in patients with aggressive disease or severe interstitial inﬂammation. Patients with HIVAN approaching ESRD can be maintained on hemodialysis or peritoneal dialysis. Select patients with remote HIVAN and well-controlled HIV infection are potential candidates for kidney transplantation.
The natural history of untreated HIVAN was once rapid progression to ESRD. At present, however, both proteinuria and renal function can stabilize following antiretroviral therapy, with relatively slow disease progression. Patients who develop HIVAN while on anti-retroviral therapy often exhibit a milder form of FSGS that lacks collapsing features.