Diagnosis Of HIV-associated Nephropathy Research Articles

Profiling Biomarkers in HIV Glomerular Disease - Potential for the Non-Invasive Diagnosis of HIVAN?

BackgroundThere is a wide spectrum of kidney pathology in human immunodeficiency virus (HIV) infection, affecting all structures of the kidney. The histology of HIV chronic kidney disease (CKD) is diverse, ranging from HIV-associated nephropathy (HIVAN) to focal glomerulosclerosis (FSGS), HIV-immune complex disease (HIV-ICD), other glomerulopathies and tubulo-interstitial nephritis. Definitive diagnosis is by kidney biopsy, an invasive procedure. However, serum and urinary biomarkers may be useful in predicting the histological diagnosis of HIVAN.PurposeWe wished to determine the utility of serum and urinary biomarkers in predicting the histological diagnosis of HIVAN.Patients and MethodsWe measured neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, transforming growth factor (TGF)-β isoforms and bone morphogenetic protein (BMP)-7 in the serum and urine in patients with different histological forms of HIV glomerular disease.ResultsIn HIVAN, we demonstrated increased levels of serum cystatin C and increased levels of serum and urinary NGAL. Urinary TGF-β1 and TGF-β2 levels were elevated in HIV-positive patients with CKD but were not significantly different in the different HIV histologies, while urinary BMP-7 levels were elevated in minimal change disease.ConclusionThis study confirmed the presence of increased serum and urinary biomarkers of tubular injury in patients with HIVAN, and increased urinary biomarkers of fibrosis in HIV CKD, and may indicate their value as a non-invasive diagnostic tool for the diagnosis of HIVAN.

Histological spectrum of renal disease in HIV/AIDS patients with significant proteinuria: An Indian perspective.

Background:Chronic kidney disease (CKD) has become epidemic in HIV/AIDS patients across Western and Eastern countries. HIV-associated nephropathy (HIVAN) has been consistently reported in studies from North America, Europe and African countries. However, studies from Asian countries are very sparse and differ strikingly in histological spectrum of renal disease, particularly in presence of HIVAN.Objectives:The study was carried out to in a teaching hospital from India to delineate the histological spectrum of renal disease and detect presence HIVAN in those with significant proteinuria (≥1gm/day).Patients and Methods:Urine analysis was done in 510 consecutive hospitalised HIV/AIDS patients after screening 640 such patients with age >18years. Patients with dipstick proteinuria ≥1+ were subjected to 24-hour urinary protein estimation. Renal biopsy was done in 10 patients with proteinuria ≥1gm/day.Results:Dipstick proteinuria ≥1+ was present in 29% patients. In patients undergoing kidney biopsy, the most frequent glomerular lesion was mesangial proliferative glomerulonephritis (30%) followed by HIVAN (20%). Tubulo-interstitial lesions were seen in 60% of biopsies. Pooled analysis of all the available kidney biopsy series from India revealed prevalence of HIVAN to be 16.5%.Conclusion:Contrary to the popular belief, HIVAN appears to be a common entity in this part of world too. High degree of clinical suspicion is required as diagnosis of HIVAN caries higher morbidity and mortality. Moreover, an early diagnosis and timely management can improve prognosis in such patients.

Urinary NGAL is a useful clinical biomarker of HIV-associated nephropathy

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is expressed by kidney tubules that are acutely damaged, but few studies have investigated the association of neutrophil gelatinase-associated lipocalin (NGAL) with different forms of chronic kidney disease (CKD). HIV-associated nephropathy (HIVAN) is a progressive form of CKD characterized by collapsing focal segmental glomerulosclerosis and microcytic tubular dilatation that typically leads to end-stage renal disease (ESRD). Previously, we reported that microcystic tubular dilatations specifically expressed NGAL RNA, implying that the detection of uNGAL protein could mark advanced HIVAN. To test this idea, we performed a comparative study of diverse proteinuric glomerulopathies in 25 patients who were HIV positive. Eighteen patients had HIVAN and seven had other glomerulopathies (four membranoproliferative glomerulonephritis, one membranous glomerulonephritis, one amyloid and one malarial GN). HIVAN and non-HIVAN patients did not differ with respect to age, ethnicity, serum creatinine, estimated GFR, proteinuria or the prevalence of hypocomplementemia (6 versus 29%, P = 0.18), but HIVAN patients were less likely to have HCV infections. HIVAN patients expressed 4-fold higher levels of uNGAL than the patients with other glomerulopathies [387 ± 338 versus 94 ± 101 μg/g urine creatinine (uCr), P = 0.02]. A cutpoint of 121.5 μg uNGAL/g uCr demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN, with an area under the receiver operator characteristic curve of 0.88. In summary, while HIVAN disease is currently diagnosed only by kidney biopsy, uNGAL can distinguish HIVAN from other proteinuric glomerulopathies in the HIV-infected patient, likely because of its specific expression from characteristic microcysts.

Role of HIV-1 DNA levels as clinical marker of HIV-1-associated nephropathies

HIV-associated nephropathy (HIVAN) is usually diagnosed in virologically uncontrolled infected patients. However, HIVAN can occur in some cases with undetectable HIV-1 RNA levels. We suggested that intracellular HIV-1 proviral DNA load can be used as a marker in this particular patient population. Renal tissue HIV-1 proviral DNA, peripheral blood mononuclear cells (PBMCs) HIV-1 proviral DNA, plasma HIV-1 RNA and peripheral blood CD4-positive lymphocyte counts were quantified and assessed in 100 HIV-1-infected individuals (49 with undetectable HIV-1 RNA level viraemia) who underwent a kidney biopsy for renal abnormalities in a prospective study. A proviral DNA load was detected in patients with HIV-1-associated nephropathy with a negative plasma viral RNA load. None of the patients with a proviral DNA load of <10 copies/1.5×10(5) PBMCs had HIVAN. In renal tissue, proviral DNA load was detected in all patients with HIVAN. PBMC HIV-1 proviral DNA load is potentially the optimal clinical marker to exclude the diagnosis of HIVAN. On the other hand, cellular incorporation of HIV-1 within the kidney is a requisite for the development of this disorder.

Urinary NGAL Marks Cystic Disease in HIV-Associated Nephropathy

Nephrosis and a rapid decline in kidney function characterize HIV-associated nephropathy (HIVAN). Histologically, HIVAN is a collapsing focal segmental glomerulosclerosis with prominent tubular damage. We explored the expression of neutrophil gelatinase-associated lipocalin (NGAL), a marker of tubular injury, to determine whether this protein has the potential to aid in the noninvasive diagnosis of HIVAN. We found that expression of urinary NGAL was much higher in patients with biopsy-proven HIVAN than in HIV-positive and HIV-negative patients with other forms of chronic kidney disease. In the HIV-transgenic mouse model of HIVAN, NGAL mRNA was abundant in dilated, microcystic segments of the nephron. In contrast, urinary NGAL did not correlate with proteinuria in human or in mouse models. These data show that marked upregulation of NGAL accompanies HIVAN and support further study of uNGAL levels in large cohorts to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related tubular damage.

Nephrotic range proteinuria and CD4 count as noninvasive indicators of HIV-associated nephropathy

PurposeHuman immunodeficiency virus (HIV)-associated nephropathy is a common and serious cause of progressive renal insufficiency in patients with HIV, frequently presenting with nephrotic range proteinuria. The purpose of this study is to document the histopathologic diagnoses seen in HIV-positive patients with and without nephrotic range proteinuria and to evaluate the predictive value of both nephrotic range proteinuria and CD4 count in diagnosing HIV-associated nephropathy. MethodsWe performed a cross-sectional, single-center study of all 107 HIV-positive patients who had both a renal biopsy and urine protein measurement between 1995 and 2002. Nephrotic range proteinuria was defined as a urine protein-to-creatinine ratio > 3 or a 24-hour urine protein > 3 g. Clinical and laboratory characteristics of those patients with and without HIV-associated nephropathy were compared. Sensitivity, specificity, and positive and negative predictive values of nephrotic range proteinuria in the diagnosis of HIV-associated nephropathy were determined. ResultsFifty-five biopsied patients had nephrotic range proteinuria, among whom 29 (53%) were diagnosed with HIV-associated nephropathy. Among the remaining patients, 12 had non-HIV-associated nephropathy focal segmental glomeruloscerlosis, 3 had membranoproliferative glomerulonephritis, 2 had AA Amyloid, 2 had diabetic nephropathy, and 7 had other diagnoses. Sensitivity, specificity, and positive and negative predictive values of nephrotic proteinuria in the diagnosis of HIV-associated nephropathy were 73%, 61%, 53%, and 79%, respectively. The patients with HIV-associated nephropathy had a significantly higher creatinine (8.2 mg/dL vs 2.5 mg/dL, P < .001) and a lower CD4 count (158 count/mm3 vs 349 count/mm3, P < .01) at the time of biopsy. Although significantly more patients with HIV-associated nephropathy had a CD4 count below 200 (P = .03), among those with a CD4 count below 200, 10 of 30 patients (33%) had diagnoses other than HIV-associated nephropathy. Injection drug use, presence of hepatitis C, and hypertension were not associated with HIV-associated nephropathy. ConclusionOur results suggest that HIV patients with nephrotic range proteinuria warrant a kidney biopsy because the presence of nephrotic range proteinuria, even in the presence a low CD4 count, does not establish the diagnosis of HIV-associated nephropathy.

The clinical characteristics and antiretroviral dosing patterns of HIV-infected patients receiving dialysis

Human immunodeficiency virus (HIV)-related renal disease is the third leading cause of end-stage renal disease (ESRD) among African Americans aged 24 to 60 years. This study describes the clinical characteristics and antiretroviral dosing patterns of HIV-infected patients receiving dialysis to define the clinical needs of this growing population. Demographic and clinical information was collected on all HIV-infected patients incident to dialysis after January 1, 1998 until January 1, 2001 at five medical centers. The cohort was described overall and by subgroups based on hepatitis status, CD4 lymphocyte count, and use of antiretroviral therapy. Continuous and categoric variables were compared using either the Wilcoxon rank sum or Student t test and Fisher's exact or chi-square tests, as appropriate. A total of 89 patients were included, 55 of whom were alive at the time of data collection. The mean age was 44.6 years (range, 22.7 to 66.9 years), 74.2% were male, and 83.2% patients were African Americans. While only 45.9% of patients undergoing renal biopsy were diagnosed with HIV-associated nephropathy (HIVAN), the majority of patients who had not undergone biopsy carried the clinical diagnosis of HIVAN (69.8%, P = 0.03). Of the cohort, 19.7% tested hepatitis B surface antigen positive, and 67.1% had reactive antibody tests for hepatitis C. Patients with hepatitis C were more likely to have experienced intravenous drug use as a risk behavior for HIV acquisition (OR 8.2; 95% CI 2.39, 27.9; P = 0.001] and to be older (OR 1.1 per year of age; 95% CI 1.02, 1.2; P = 0.01). A total of 60.7% of patients were receiving antiretroviral medication at last follow-up. Among patients alive and receiving antiretroviral medications at the time of data collection, absolute CD4+ count rose (268 vs. 339 cells/mL, P = 0.03), while among patients alive, but not receiving antiretroviral medications, absolute CD4+ count did not change (389 vs. 392 cells/mL, P = 0.11) during similar periods of follow-up. No difference was seen between initial and current HIV RNA levels for either group. Among patients receiving antiretroviral medications, there were significant variations in dosing regimens. The greatest variation was seen in the prescribing patterns of lamivudine with a 12-fold difference among patients. The projected growth of the HIV-infected ESRD population requires a better understanding of the clinical needs of this population. The high prevalence of coinfection with hepatitis C as well as the wide variations in dosing patterns for antiretroviral medications are areas that require further investigation to minimize morbidity and mortality among this group.

Recent progress in HIV-associated nephropathy.

The classic kidney disease of HIV infection, HIV-associated nephropathy (HIVAN), is an aggressive form of collapsing focal segmental glomerulosclerosis with accompanying tubular and interstitial lesions. HIVAN was first described among African-Americans and Haitian immigrants with advanced HIV disease, an early suggestion of a strong genetic association. This genetic susceptibility was recently linked to polymorphisms on chromosome 22 in individuals of African descent. The association with advanced HIV infection and evidence from HIV-transgenic mice suggested the possibility that HIV directly infects the kidney and that specific HIV gene expression induces host cellular pathways that are responsible for HIVAN pathogenesis. Although combination antiretroviral therapy has substantially reduced the impact of HIVAN in the United States, continued growth of the HIV epidemic in susceptible African populations may have important public health implications. This article reviews recent progress in the pathogenesis...

Protease inhibitors are associated with a slowed progression of HIV-related renal diseases.

While angiotensin-con-verting enzyme inhibitors and zidovudine may improve the course of the most common HIV-related renal disease, HIV-associated nephropathy (HIVAN), the effect of anti-retroviral combination therapy on this and other HIV-related renal diseases has not been assessed. This study describes the clinical course of HIV-related renal diseases and the effect of protease inhibitors on their progression. This retrospective cohort study reviews the clinical course of 19 patients with a clinical or biopsy-proven diagnosis of HIVAN or other HIV-related renal diseases. Groups progressing and not progressing to ESRD were compared using longitudinal analyses to assess the association between creatinine clearance and clinical and therapeutic factors. The cohort consisted of 16 African-Americans, 2 Caucasians and 1 Native American. Their modes of HIV infection were intravenous drug use (7), a history of men having sex with men (3) and heterosexual behavior (5). Patients were followed for a median of 16.6 months. Seven patients reached ESRD. Loss of creatinine clearance over time did not differ among genders, races, or patients with different modes of HIV infection. Longitudinal analyses demonstrated an association between protease inhibitors and prednisone and a slower decline in creatinine clearance in multivariable models (p = 0.04 and 0.003, respectively). The epidemiology and clinical course of HIV-related renal diseases is more heterogeneous than previously described. This study suggests a benefit to the use of protease inhibitors and prednisone on the progression of these nephropathies.

Observations on HIV-Associated Renal Disease in the Era of Highly Active Antiretroviral Therapy

Renal disease in patients infected with HIV has evolved to include several lesions, including HIV-associated nephropathy (HIV-AN), which can promote progressive loss of renal function. Although angiotensin-converting enzyme inhibitors and corticosteroids are beneficial in selected patients, the effect of highly active antiretroviral therapy (HAART) on renal function is currently being explored. We undertook a retrospective study to determine the types of renal lesions present in patients infected with HIV with renal insufficiency and/or proteinuria during the era of HAART availability and the effect of HAART on renal outcomes in these patients. Patients with HIV infection referred to the renal clinic from July 1996 through December 2000 were evaluated. Patient characteristics and data were collected including CD4 count, viral load, serum creatinine, blood pressure, proteinuria, renal ultrasound, and biopsy results, and treatment with HAART. Study endpoints were doubling of serum creatinine, initiation of dialysis, or death. Twenty-three patients met study criteria, 13 received HAART, and 10 did not. Baseline characteristics were similar except for renal function parameters, viral loads, and CD4 counts. A variety of lesions were noted on 12 renal biopsies. A clinical diagnosis of HIV-AN was made in the other 11 patients. Only 2 patients receiving HAART before renal evaluation were noted to have HIV-AN. In the HAART group, none of the patients, including those with HIV-AN, developed a doubling of serum creatinine. In the non-HAART group, all patients manifested a doubling of serum creatinine, 2 patients died, and 8 patients required dialysis. A variety of renal lesions are noted in patients infected with HIV during the HAART era. Patients who received HAART maintained stable renal function, whereas patients who did not required dialysis therapy or died with advanced renal failure. It seems that HAART may improve renal outcomes in patients with HIV and renal disease.

Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients

Previous studies have reported that approximately 10% of the patients with human immunodeficiency virus (HIV) infection develop HIV-associated nephropathy (HIVAN). However, over the last decade, morbidity and mortality as a result of HIV-1 infection has remarkably decreased with the availability of potent new antiretroviral drugs. We therefore determined the prevalence of HIVAN from autopsy data of HIV-infected patients in more recent years (1992 to 1997). Autopsy reports of 389 patients were reviewed. In reports suggestive of possible HIVAN, slides of renal tissue were retrieved and reviewed again to ensure appropriate classification. The criteria for the diagnosis of HIVAN were focal segmental glomerulosclerosis with collapse of the glomerular tuft in some glomeruli, extensive tubular ectasia, and significant tubulointerstitial disease. Of 389 autopsy reports, 54% of the patients were black, 35% were white, and 11% were Hispanic. Thirty-three percent of the patients had a history of intravenous drug abuse. The mean CD4 count of the patients was 54 ± 91/μL (mean ± SD). In 27 cases, typical features of HIVAN were found based on the criteria used, accounting for an overall HIVAN prevalence of 6.9% (27 of 389 autopsies). Because the overwhelming majority of these patients were black (93%), the prevalence in blacks was 12% (25 of 209 autopsies). We conclude that although mortality and morbidity from HIV infection is decreasing, HIVAN remains an important complication of HIV infection in blacks, even in recent years.

Is the Prevalence of HIV-Associated Nephropathy Decreasing?

Initial reports have suggested that approximately 10% of patients with HIV-infection develop HIV-associated nephropathy (HIVAN). It has also been predicted that by the end of the decade, HIVAN is likely to become a third leading cause of end-stage renal disease (ESRD) in African-Americans between the ages of 20–64 years. As the morbidity and mortality from HIV-infection has decreased in the last few years, it is possible that prevalence of HIVAN is also changing. We therefore screened HIV-1-infected patients followed in our hospital for HIVAN. A screening urinalysis was performed in 557 HIV-1-infected adult patients between March and May 1998. Of these, 252 were outpatients and 305 were Texas Department of Criminal Justice inmates (TDCJI). Demographic and laboratory data of these patients was obtained from the HIV patients’ database. Fifty percent of the patients were African-American, 36.6% were Caucasian and 12.7% were Hispanic. The mean age of patients was 37 ± 8 years. Seventy-nine percent of the patients were males and a history of intravenous drug abuse (IVDA) was present in 28%. Twenty-three percent of the patients were concomitantly infected with hepatitis C virus, 4.1% were positive for hepatitis B surface antigen, and rapid plasma reagin test for syphilis was positive in 9.1%. In 38 patients who had more than 100 mg/dl (2+) proteins on screening urinalysis, total urinary proteins were quantitated by collecting 24 h urine specimens. Fifteen of these patients had urinary proteins more than 1.5 g/day (12 patients >3.5 g/24 h and 3 patients >1.5 g/24 h). A renal biopsy was done in 14 of these patients and clinical diagnosis of HIVAN was made in one patient who refused biopsy. Renal biopsies revealed HIVAN [9], diabetic nephropathy [2], membranoproliferative glomerulonephritis [2], Fibrillary glomerulonephritis [1]. All 10 patients (5 TDCJI and 5 outpatients) with HIVAN were African-American. Two of these 10 patients had a history of IVDA and another two were concomitantly infected with hepatitis C virus. The plasma viral load (Pvl) and total CD4 count was not different in patients with or without HIVAN [(Pvl log 10.05 ± 1.39 vs. 9.9 ± 2.18 copies/ml, p = 0.78) (CD4: 187 ± 192 vs. 288 ± 249 cells/μl, p = 1.17) mean ± SD]. We conclude that in our HIV-infected population HIVAN exclusively affected African-Americans and the prevalence in them was 3.5%.

Pathology of HIV-associated nephropathy: A detailed morphologic and comparative study

Clinical and pathologic findings in the kidneys of 30 consecutive acquired immunodeficiency syndrome (AIDS) autopsies and in 34 consecutive renal biopsies performed on HIV infected patients at our institution between 1983 and 1987 were studied. To determine if the lesions of HIV-associated nephropathy have morphologic specificity, a subgroup of 13 biopsies with a diagnosis of HIV-associated nephropathy (HIVN) were compared to 13 biopsies each of heroin-associated nephropathy (HAN) and of idiopathic focal segmental glomerulosclerosis (IFSGS) matched for patient age, proteinuria and serum creatinine. A diagnosis of HIVN was made in 1 of 30 (3.3%) AIDS autopsies and 26 of 34 (76.5%) renal biopsies. When compared to HAN and IFSGS, HIVN had more globally "collapsed" glomeruli (P less than 0.001), less glomerular hyalinosis (P less than 0.02), more severe visceral epithelial cell swelling (P less than 0.05), more numerous visceral epithelial cell droplets (P less than 0.002), more prevalent and severe tubular microcystic dilatation (P less than 0.02), and tubular cell degenerative changes (P less than 0.001). Focal glomerular electron-dense deposits were present in 14 of 26 cases. Tubuloreticular inclusions were extremely numerous in glomerular and interstitial capillary endothelial cells as well as in interstitial leukocytes (P less than 0.001). Granular degeneration of nuclear chromatin was present in 10 of 26 cases. Nuclear bodies were more numerous in tubular and interstitial cells of HIVN (P less than 0.01), particularly type 3 (P less than 0.001). Reversal of tissue T4/T8 ratio was observed. We conclude that while no single morphologic feature of HIVN is specific, the combination of clinical and pathologic findings is quite distinctive and permits a presumptive diagnosis of HIVN in otherwise asymptomatic carriers.