Multiple facets of HIV-associated renal disease

Clinical Investigation Multiple facets of HIV-associated renal disease D.R. da Silva1  I.C. Gluz1  J. Kurz1  G.G. Thomé1  R. Zancan1  R.N. Bringhenti2  P.G. Schaefer2  M. dos Santos1  E.J.G. Barros1  F.V. Veronese1  1Serviço de Nefrologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil 2Serviço de Patologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil ABSTRACT HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003). In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥200 cells/mm3 was associated with better renal function after 2 years of follow-up. Key words: HIV; Renal disease; Proteinuria; Collapsing focal segmental glomerulosclerosis; CD4 cell count; Chronic kidney disease Introduction In 2014, the Brazilian Ministry of Health estimated there were 734,000 people living with HIV/AIDS in Brazil, corresponding to a prevalence of 0.4% (1). HIV-associated renal involvement was first described in 1984 (2 3 4), and since then several forms of HIV-associated nephropathy have been described (5 6 7 8 9 10 11 12 13 14) resulting from the direct effects of virus infection on the kidneys or indirect effects of intercurrent illness or medications. In the 80's, the clinical spectrum of HIV-associated renal disease was described as nephrotic and nephritic syndrome, acute kidney injury (AKI), chronic kidney disease (CKD), and non-nephrotic proteinuria (14). The classical HIV-associated nephropathy (HIVAN) is known to occur more frequently among HIV-infected individuals of African descent, and its clinical manifestations include nephrotic proteinuria, hematuria, rapidly progressive renal failure, and hypertension. HIVAN is characterized histologically by a collapsing focal segmental glomerulosclerosis (FSGS) (2,6,10,14). A non-collapsing FSGS and immune complex-mediated glomerulonephritis (ICGN) have been described, such as membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, membranous nephropathy, IgA nephropathy and lupus-like glomerulonephritis (5,) as well as thrombotic microangiopathy (8,9). Other HIV-associated conditions, including bacterial or viral infections and nephrotoxicity of antiretroviral therapy (ART), induce specific kidney damage such as acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) (8,10). Lastly, kidney injury caused by amyloidosis, diabetes mellitus, and hypertension are also part of the spectrum of HIV-associated renal diseases (8) because they are comorbidities that nowadays develop owing to the increased survival of these patients. For example, CKD is currently considered an independent risk factor for mortality in HIV patients (15 16). Renal biopsy is indicated in HIV patients when they present significant signs of kidney damage for accurate diagnosis of the underlying cause, appropriate treatment, and prognosis (8 10,15,). Treating patients with HIVAN using ART, corticosteroids, cyclosporin and/or angiotensin inhibitors may reduce proteinuria and preserve kidney function as reported by Elewa et al. (11) and Kalayjian (17) in their review studies. However, the benefits of ART and other drug treatments on non-HIVAN lesions are not yet clear (6,10,11,17). Undoubtedly, the treatment of different co-morbidities that develop in aging HIV patients, such as hypertension, diabetes, and non-AIDS diseases is of paramount importance for their longer survival. This study aimed to describe the findings of renal biopsies in HIV patients, correlating histopathological results and clinical presentation, and to search for predictors of CKD progression and death. Material and Methods Patient selection This retrospective cohort study included 61 HIV patients (64% male, mean age 45 years) who had a kidney biopsy done for acute, acute-on-chronic or chronic kidney failure of unknown etiology, pathological proteinuria with or without hematuria, nephrotic syndrome or nephritic syndrome. These patients were attended at a teaching hospital in Southern Brazil, and were selected throughout the period of January 2004 to December 2014. Patients on chronic dialysis treatment and kidney transplant recipients were excluded, as well as those with incomplete medical records. This study was approved by the Research Ethics Committee of Hospital de Clínicas de Porto Alegre. Demographic characteristics and clinical data The patients' demographic characteristics, clinical presentation, comorbidities, presence of viral co-infections and active infections of any origin at the time of renal biopsy were collected. Renal biopsy specimens were routinely examined by two nephropathologists from our institution. HIVAN was defined by the presence of collapsing glomerular lesions, podocyte proliferation, microcystic tubular dilatation and flattening and atrophy of tubular cells (18). The histological diagnosis of FSGS in the absence of these features was defined as non-collapsing FSGS. The following laboratory data were collected: serum creatinine (automated Jaffe method, Modular Analytics, Roche Diagnostics, Germany); estimated glomerular filtration rate (eGFR) using the CKD-EPI formula; and serum albumin and proteinuria determined by urine protein-to-creatinine ratio (Pr/Cr) in a random urine sample. Chronic kidney disease stage was established according to Kidney Disease Improving Global Outcomes classification (19) for (...truncated)