The human immunodeficiency virus (HIV) is a rapidly evolving virus that has been associated with renal disease since the early days of the HIV epidemic. Classically associated with collapsing focal segmental glomerulosclerosis, direct HIV related nephropathy can also manifest as HIV-immune-complex kidney disease and thrombotic microangiopathy. In recent years, with the advent of combination antiretroviral therapy and effective diffusion of these medications, patients are living longer lives without classic manifestations of the disease. Currently, disorders associated with nephrotoxicity of certain HIV therapies appear to be more prevalent, as well as a surge in non-infectious comorbidities, such as diabetes or hypertension, as etiologies of nephropathy in people living with HIV (PLWHIV). Renal disease remains one of the major causes of mortality in HIV infected patients, with a six-fold increase in mortality for those suffering from acute kidney injury (AKI) and chronic kidney disease (CKD). Furthermore, since HIV can infect and replicate within renal epithelial cells, a full virologic cure may only be feasible with complete eradication of the viral reservoir in the kidney as this compartment appears to act separately from the blood.
There is a diverse range of renal pathology in PLWHIV, such as lesions resulting directly from intrarenal HIV gene expression and injuries secondary to comorbidities, drug-induced nephrotoxicity, and immune dysregulation, among others. Renal disease associated with HIV infection is primarily a glomerular dominant disease that is further classified into two main categories: podocytopathies and immune complex-mediated disease. The major subtypes of podocytopathy that have been described in the setting of HIV infection are classic HIV-associated nephropathy (HIVAN), focal segmental glomerulosclerosis not otherwise specified, and the far less common, minimal change disease and diffuse mesangial hypercellularity. These are characterized by extensive podocyte foot process effacement and proteinuria mediated by direct HIV infection of renal epithelial cells, intrarenal viral gene expression, and dysregulation of host genes. Several forms of immune complex-mediated disease have been reported in PLWHIV. The causal relation is not well established yet, and secondary causes should be sought out in cases of post-infectious glomerulonephritis, lupus-like nephritis, IgA nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis, among others.
HIV-associated nephropathy incidence peaked in the mid-1990s, being reported in 3.5–10% of the HIV-infected population in the USA. It was primarily in individuals of African descent, but prevalence has been declining as a result of the widespread use of combined anti-retroviral treatments.
The expression of HIV-1 genes in the kidney epithelial cells is required for the development of HIVAN. The mechanism by which HIV infects renal epithelial cells remains unclear. The classical receptors necessary for entry of the virus into T cells and macrophages are absent from renal cells. Various studies have shown that macrophages and lymphocytes appear to be vectors necessary for renal epithelial cell transmission of HIV. Among these are CD209 antigen (DC-SIGN), which mediates HIV infection of dendritic cells, and lymphocyte antigen 75 (DEC-205), which may directly contribute to infection of renal tubular epithelial cells. Polymorphisms in APOL1 result in an increased risk of HIVAN. However, the mechanism by which these variations cause HIVAN is yet to be elucidated. It appears likely that the infection of renal tubular epithelial cells by HIV is mediated via transfer from leukocytes. Phagocytosis of apoptotic CD4+ T cells has also been proposed as a possible mechanism by which HIV accesses renal cells. The HIV proteins Vpr and Tat circulate in plasma and through proteoglycans, and lipid rafts have access to podocytes.
HIV-associated immune complex kidney disease
Many of the glomerular lesions associated with HIV-associated immune complex kidney disease (HIVICK) are routinely caused by co-infection with hepatitis B and C. Studies performed before the advent of combined antiretroviral therapy showed anti-HIV antibodies which may form immune complexes that could result in glomerulonephritis, but the mechanism and relevance in the post-antiretroviral era are unknown.
HIV-associated thrombotic microangiopathy
Thrombotic microangiopathy is a well-known complication of late-stage HIV/AIDS, but its incidence has decreased dramatically since the arrival of combined antiretroviral treatments. While its pathogenesis remains to be elucidated, it is postulated that the source of endothelial injury is the exposure to circulating viral proteins combined with other factors such as medications, proinflammatory molecules, and antiphospholipid antibodies.
HIV-associated nephropathy is defined as a collapsing glomerulopathy and associated tubulointerstitial disease, which may include tubular microcysts and inflammation of the interstitium. Diffuse effacement of podocyte foot process and endothelial tubular inclusions are mainstays when examined by electron microscopy. Staining for IgM, C3, and C1q in collapsed segments and mesangial areas is common by immunofluorescence.
HIV-associated nephropathy classically presents with a swift decline in GFR and proteinuria in the nephrotic range. Other manifestations of nephropathy, such as peripheral edema of the lower extremities and hypertension, are uncommon in this population. Since concomitant conditions and infections are likely in this population, the importance of ruling out other etiologies should be emphasized.
Guidelines from the HIV Medicine Association of the Infectious Diseases Society of America state that screening for HIV nephropathy in HIV positive patients should include serum creatinine and estimated glomerular filtration rate (GFR) along with urinalysis or a quantitative measure of proteinuria at baseline when antiretroviral therapy (ART) is initiated or changed, and at least twice a year in stable HIV-infected patients. Imaging modalities, such as ultrasonography of the kidneys, has been evaluated as a possible noninvasive test for the diagnosis of HIVAN. Studies have shown that high scores of renal echogenicity were strong predictors for HIVAN, while low scores could effectively rule it out. While this appears to be useful in specific settings, most of the patients suffering from HIVAN have echogenicity scores that fall between those two values. A kidney biopsy is often the only means of achieving a definitive diagnosis. Indications for biopsy remain the same as for the general population. The decision to perform kidney biopsy should take into consideration the clinical presentation, the likelihood of alternate diagnosis, the therapeutic options, and the risks associated with the procedure.
Currently, combination antiretroviral therapy (cART) induced nephropathy is a far more common disease than HIVAN. Differentiating patients with HIVAN versus cART induced nephropathy is important, as management is different. Besides history and physical examination findings, patients with HIVAN present with CD4 count <200 cells/mm, viral load >400 copies/mL, a rapid decline in renal function, proteinuria >300 mg/24h, hyaline or proteinaceous casts on urinalysis and large-sized kidneys with intense cortical echogenicity. On the other hand, cART induced nephropathy presents in patients with CD4 count >200 cells/mm, viral load <400 copies/mL, proteinuria <30 mg/24h, indolent decline in renal function, hematuria or leukocyturia, needle or rod-like crystals on urine microscopy and unremarkable ultrasound findings.
Since HIVAN is associated with a high risk for progression to end-stage renal disease (ESRD) and increased mortality, treatment should not be delayed. Combined antiretroviral therapy continues to be the mainstay of treatment for HIVAN, as it has been shown to reduce the likelihood of progression into ESRD. Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) is also important since it has been shown to improve renal survival and should be considered as an adjunct to cART in HIVAN. In patients with refractory renal impairment after cART and RAAS blockade treatment, steroids can be added as an adjunct, but data supporting them as primary treatment is weak, and the side effect profile is broad. It is important to adjust cART therapy to renal function as some have been shown to directly affect renal function, such as tenofovir, atazanavir, and indinavir. In those who progress to ESRD, renal replacement therapy remains the mainstay of management, and renal transplantation can be considered as the evidence demonstrates it is effective in patients with controlled HIV.
Before the advent of combined antiretroviral therapy, HIVAN was an aggressive disease that resulted in rapid progression to end-stage renal disease within 2-4 months. Currently, the prognosis is more favorable. However, patients with HIVAN consistently do worse than patients with other causes of renal disease.
HIV-associated nephropathy is an aggressive disease that will result in end-stage renal disease if no treatment is initiated. Patients should be encouraged to be compliant with antiretroviral medications and to follow with their primary care clinician and nephrologist on a regular basis.
HIVAN is classically manifested as focal segmental glomerulosclerosis. The natural course of the condition is rapid progression to end-stage renal disease in 2-4 months. Combined antiretroviral therapy is the mainstay treatment because it hastens progression and improves renal survival. Currently, other etiologies of kidney disease, such as hypertension and diabetes, are more common than HIVAN due to the advent of cART and improved survival in patients infected with HIV.
Due to the aggressive nature of HIVAN, prompt diagnosis and treatment should be made in cases of suspected disease. An interprofessional team approach will improve patient outcomes. The team should include a primary care provider, a nephrologist, and an infectious disease specialist. Frequent renal function testing as per HIV association guidelines should be followed in every patient with HIV. Biopsy should be considered after considering alternative diagnosis and the risks associated with the procedure. An interventional radiologist and pathologist will need to be a part of the team at this point. CD4 count and viral load should not be measures to take into consideration for the initiation of cART in patients with HIVAN.
|||Hou J,Nast CC, Changing concepts of HIV infection and renal disease. Current opinion in nephrology and hypertension. 2018 May; [PubMed PMID: 29337702]|
|||Heron JE,Bagnis CI,Gracey DM, Contemporary issues and new challenges in chronic kidney disease amongst people living with HIV. AIDS research and therapy. 2020 Mar 16; [PubMed PMID: 32178687]|
|||Rosenberg AZ,Naicker S,Winkler CA,Kopp JB, HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment. Nature reviews. Nephrology. 2015 Mar; [PubMed PMID: 25686569]|
|||Waheed S,Atta MG, Predictors of HIV-associated nephropathy. Expert review of anti-infective therapy. 2014 May; [PubMed PMID: 24655211]|
|||Ross MJ, Advances in the pathogenesis of HIV-associated kidney diseases. Kidney international. 2014 Aug; [PubMed PMID: 24827777]|
|||Medapalli RK,He JC,Klotman PE, HIV-associated nephropathy: pathogenesis. Current opinion in nephrology and hypertension. 2011 May; [PubMed PMID: 21358326]|
|||Swanepoel CR,Atta MG,D'Agati VD,Estrella MM,Fogo AB,Naicker S,Post FA,Wearne N,Winkler CA,Cheung M,Wheeler DC,Winkelmayer WC,Wyatt CM, Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney international. 2018 Mar; [PubMed PMID: 29398134]|
|||D'Agati V,Appel GB, HIV infection and the kidney. Journal of the American Society of Nephrology : JASN. 1997 Jan; [PubMed PMID: 9013459]|
|||Menez S,Hanouneh M,McMahon BA,Fine DM,Atta MG, Pharmacotherapy and treatment options for HIV-associated nephropathy. Expert opinion on pharmacotherapy. 2018 Jan; [PubMed PMID: 29224373]|
|||Gameiro J,Jorge S,Lopes JA, HIV and renal disease: a contemporary review. International journal of STD [PubMed PMID: 29343165]|
|||Risk factors for kidney disease among HIV-1 positive persons in the methadone program., Matłosz B,Pietraszkiewicz E,Firląg-Burkacka E,Grycner E,Horban A,Kowalska JD,, Clinical and experimental nephrology, 2018 Sep 14 [PubMed PMID: 30218298]|
|||Prevalence of risk factors for chronic kidney disease in South African youth with perinatally acquired HIV., Frigati L,Mahtab S,Nourse P,Ray P,Perrazzo S,Machemedze T,Agyei NA,Cotton M,Myer L,Zar H,, Pediatric nephrology (Berlin, Germany), 2018 Sep 15 [PubMed PMID: 30219929]|
|||Lucas GM,Ross MJ,Stock PG,Shlipak MG,Wyatt CM,Gupta SK,Atta MG,Wools-Kaloustian KK,Pham PA,Bruggeman LA,Lennox JL,Ray PE,Kalayjian RC, Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Nov 1; [PubMed PMID: 25234519]|
|||Kumar N,Perazella MA, Differentiating HIV-associated nephropathy from antiretroviral drug-induced nephropathy: a clinical challenge. Current HIV/AIDS reports. 2014 Sep [PubMed PMID: 24924830]|
|||Bigé N,Lanternier F,Viard JP,Kamgang P,Daugas E,Elie C,Jidar K,Walker-Combrouze F,Peraldi MN,Isnard-Bagnis C,Servais A,Lortholary O,Noël LH,Bollée G, Presentation of HIV-associated nephropathy and outcome in HAART-treated patients. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2012 Mar; [PubMed PMID: 21745806]|