Publications by authors named "Mohamed G Atta"

97 Publications

Long-term kidney function and survival in recipients of allografts from living kidney donors with hypertension: a national cohort study.

Transpl Int 2021 Jun 15. Epub 2021 Jun 15.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Allografts from living kidney donors with hypertension may carry subclinical kidney disease from the donor to the recipient and, thus, lead to adverse recipient outcomes. We examined eGFR trajectories and all-cause allograft failure in recipients from donors with versus without hypertension, using mixed-linear and Cox regression models stratified by donor age. We studied a US cohort from 1/1/2005 to 6/30/2017; 49 990 recipients of allografts from younger (<50 years old) donors including 597 with donor hypertension and 21 130 recipients of allografts from older (≥50 years old) donors including 1441 with donor hypertension. Donor hypertension was defined as documented predonation use of antihypertensive therapy. Among recipients from younger donors with versus without hypertension, the annual eGFR decline was -1.03 versus -0.53 ml/min/m (P = 0.002); 13-year allograft survival was 49.7% vs. 59.0% (adjusted allograft failure hazard ratio [aHR] 1.23; 95% CI 1.05-1.43; P = 0.009). Among recipients from older donors with versus without hypertension, the annual eGFR decline was -0.67 versus -0.66 ml/min/m (P = 0.9); 13-year allograft survival was 48.6% versus 52.6% (aHR 1.05; 95% CI 0.94-1.17; P = 0.4). In secondary analyses, our inferences remained similar for risk of death-censored allograft failure and mortality. Hypertension in younger, but not older, living kidney donors is associated with worse recipient outcomes.
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http://dx.doi.org/10.1111/tri.13947DOI Listing
June 2021

Thrombotic microangiopathy versus class IV lupus nephritis in systemic lupus erythematosus.

J Nephrol 2021 Mar 10. Epub 2021 Mar 10.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Kidney involvement is common in patients with systemic lupus erythematosus (SLE). This study investigates the clinical and prognostic characteristics of thrombotic microangiopathy (TMA) compared to class IV lupus nephritis in SLE patients.

Methods: A retrospective review of patients who underwent kidney biopsy, with a primary diagnosis of SLE and TMA between June 2006 and September 2018 was conducted. Those patients were subsequently compared to patients with class IV lupus nephritis between January 2018 and December 2018. Demographics, laboratory, and serological data at the time of biopsy were abstracted.

Results: Among 214 SLE patients records screened, 27 were included in the final analysis. Eight patients had lupus-related TMA without evidence of active lupus nephritis, while 19 patients had class IV lupus nephritis without evidence of TMA. TMA patients had significantly higher lactate dehydrogenase levels (718 ± 499 vs. 264 ± 107.7 U/L, p = 0.009), serum C3 (100.6 ± 39.3 vs. 65.8 ± 27 mg/dL, p = 0.049), white blood cell count (14743.8 ± 7933.3 vs. 5807.9 ± 2053.2 × 10E3/uL, p < 0.001), and total bilirubin (0.8 ± 0.5 vs. 0.3 ± 0.1 mg/dL, p = 0.007) in addition to significantly lower platelet counts (158.4 ± 88.6 vs. 240.3 ± 100.3 × 10E3/uL, p = 0.03), and haptoglobin (68.8 ± 116.1 vs. 166.8 ± 95.4 mg/dL, p = 0.03). After a median follow-up time of 53 weeks, 3 patients with TMA were dialysis-dependent (37.5%), compared with none in class IV lupus nephritis patients (p = 0.002).

Conclusions: TMA-associated SLE has worse prognosis compared to class IV lupus nephritis. An array of laboratory and pathological findings may be of value in discriminating between those two entities.
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http://dx.doi.org/10.1007/s40620-021-01010-4DOI Listing
March 2021

Low-Level Proteinuria in Systemic Lupus Erythematosus.

Kidney Int Rep 2020 Dec 18;5(12):2333-2340. Epub 2020 Sep 18.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Introduction: In patients with systemic lupus erythematosus (SLE) without concurrent active urinary sediment or unexplained acute kidney injury (AKI), current guidelines recommend performing a kidney biopsy in those with at least 500 mg/24-hour (European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association [EULAR/ERA-EDTA]) or 1000 mg/24-hour (American College of Rheumatology [ACR]) proteinuria. To evaluate the relevance of these indications, we studied histopathologic findings in patients with SLE with proteinuria below these cutoffs.

Methods: We retrospectively reviewed the clinical, laboratory and histological characteristics of patients with SLE with <1000 mg/24-hour proteinuria (or mg/g urinary protein-to-creatinine ratio [UPCR]) who underwent their first kidney biopsy between 2003 and 2018.

Results: We identified 87 patients with SLE with proteinuria less than 1000 mg/24-hour (or mg/g UPCR); 52 of 87 (60%) with isolated proteinuria, that is, without AKI or active urinary sediment (hematuria). Histologic evidence of lupus nephritis (LN) was present in 40 of 52 (76%). Of the 40 patients with LN, 12 had class I or II, 14 had class III or IV, 8 had class V, 6 had a combined proliferative and membranous LN. Non-lupus diagnoses included focal segmental glomerulosclerosis, acute interstitial nephritis, and others. Patient's age, low C3, low C4, and positivity for anti-double-stranded DNA (anti-dsDNA) antibodies predicted the histological diagnosis of LN on univariate logistic regression; however, a multivariate model including these parameters as independent covariates failed to predict LN.

Conclusions: Patients with SLE with low-level proteinuria may have significant lupus- or non-lupus-related kidney disease with management implications. There was a significant burden of severe forms of LN. The presence of LN was not predicted by laboratory abnormalities. Based on our findings, we suggest current guidelines be revised to expand kidney biopsy indications to include isolated proteinuria of any grade.
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http://dx.doi.org/10.1016/j.ekir.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710831PMC
December 2020

Therapeutic advances in Fabry disease: The future awaits.

Biomed Pharmacother 2020 Nov 23;131:110779. Epub 2020 Sep 23.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Fabry disease (FD) is an X-linked disorder caused by mutations in GLA gene responsible for coding of the lysosomal enzyme alpha-galactosidase A(α-GAL). The resultant accumulation of globotriaosylceramide (Gb-3) leads to multisystemic disease including progressive chronic kidney disease, hypertrophic cardiomyopathy, stroke, angiokeratomas and corneal whorls. Current treatments include enzyme replacement therapy (ERT), along with recent advent of chaperone therapy. ERT has not shown to have dramatic improvement in outcomes for all organ systems, with benefit mostly seen in kidney disease and reduction in left ventricular hypertrophy. ERT, however, is associated with formation of anti-drug antibodies and requirement of long-term venous access, while chaperone therapy can only be used in amenable mutations. A multitude of therapies are now under investigation in various phases of clinical trials. These include pegylated form of α-GAL (pegunigalsidase alpha), gene therapy (both in-vivo and ex-vivo methods), mRNA therapy (inducing production of α-GAL) and substrate reduction therapy (inhibitors of glucosylceramide synthase leading to reduction of Gb-3). This review encapsulates literature pertaining to current and investigational therapies for FD.
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http://dx.doi.org/10.1016/j.biopha.2020.110779DOI Listing
November 2020

Cross-Sectional and Longitudinal Performance of Creatinine- and Cystatin C-Based Estimating Equations Relative to Exogenously Measured Glomerular Filtration Rate in HIV-Positive and HIV-Negative Persons.

J Acquir Immune Defic Syndr 2020 12;85(4):e58-e66

Department of Pediatrics, University of Rochester Medical Center, Rochester, NY.

Background: Reliable estimates of glomerular filtration rate (GFR) are important in the clinical management of HIV-positive patients. Data on the performance of widely used estimating equations (eGFR) relative to exogenously measured GFR are sparse in this population.

Methods: We evaluated cross-sectional and longitudinal accuracy and bias of eGFR, based on creatinine and cystatin C, relative to disappearance of infused iohexol from plasma (iGFR) in a cohort of participants followed annually for up to 7 years.

Results: A total of 222 HIV-positive and 139 HIV-negative participants contributed 1240 visits with valid iGFR and eGFR measures. Estimated GFR based on both creatinine and cystatin C performed the best. Estimated GFR based on creatinine alone overestimated iGFR by 9 mL·min·1.73 m on average and was significantly less accurate in HIV-positive than HIV-negative individuals. The performance of equations based on either creatinine alone or cystatin C alone were significantly affected by participant factors (eg, non-suppressed HIV RNA, nadir CD4 count, hepatitis C virus coinfection). The average iGFR slope was -4% per year in HIV-positive participants. In both HIV-positive and HIV-negative participants, eGFR slope measures were generally unbiased but inaccurate, with only 60%-74% of observations falling within ±5% points of iGFR slope.

Conclusions: Both creatinine and cystatin C have limitations as GFR indices in HIV-positive individuals. Estimated GFR based on both creatinine and cystatin C performed best in our study and may be preferred in HIV-positive persons with kidney disease or comorbidities that place them at high risk for kidney disease.
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http://dx.doi.org/10.1097/QAI.0000000000002471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301492PMC
December 2020

Persistent Interferon Production by Double Negative T Cells and Collapsing Focal Segmental Glomerulosclerosis.

Nephron 2021 15;145(1):85-90. Epub 2020 Oct 15.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA,

Collapsing glomerulopathy has multiple associations, including viral infections, medications like bisphosphonates and interferon, autoimmune diseases, and genetic predisposition. We report a case of collapsing focal segmental glomerulosclerosis associated with persistently high levels of interferon gamma produced by T-cell receptor αβ (+), CD4- CD8- (double negative) T lymphocytes that progressed despite treatment and improvement of other cytokine levels. Double negative T cells are elevated and activated in autoimmune lymphoproliferative syndrome (ALPS). Production of elevated interferon gamma levels from double negative T cells in ALPS despite treatment provides insight to the pathophysiology of collapsing glomerulopathy, guiding future research for collapsing glomerulopathy.
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http://dx.doi.org/10.1159/000510759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785627PMC
October 2020

Pharmacotherapeutic options for kidney disease in HIV positive patients.

Expert Opin Pharmacother 2021 Jan 21;22(1):69-82. Epub 2020 Sep 21.

Division of Nephrology, Johns Hopkins University , Baltimore, MD, US.

Introduction: Since the developmentof combined antiretroviral therapy (cART), HIV-associated mortality and the incidence of HIV-associated end-stage kidney disease (ESKD) has decreased. However, in the United States, an increase in non-HIV-associated kidney diseases within the HIV-positive population is expected.

Areas Covered: In this review, the authors highlight the risk factors for kidney disease within an HIV-positive population and provide the current recommendations for risk stratification and for the monitoring of its progression to chronic kidney disease (CKD), as well as, treatment. The article is based on literature searches using PubMed, Medline and SCOPUS.

Expert Opinion: The authors recommend clinicians (1) be aware of early cART initiation to prevent and treat HIV-associated kidney diseases, (2) be aware of cART side effects and discriminate those that may become more nephrotoxic than others and require dose-adjustment in the setting of eGFR ≤ 30ml/min/1.73m, (3) follow KDIGO guidelines regarding screening and monitoring for CKD with a multidisciplinary team of health professionals, (4) manage other co-infections and comorbidities, (5) consider changing cART if drug induced toxicity is established with apparent eGFR decline of ≥ 10ml/min/1.73m or rising creatinine (≥0.5mg/dl) during drug-drug interactions, and (6) strongly consider kidney transplant in appropriately selected individuals with end stage kidney failure.
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http://dx.doi.org/10.1080/14656566.2020.1817383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855280PMC
January 2021

Eosinophilia and risk of incident end stage kidney disease.

BMC Nephrol 2020 01 13;21(1):14. Epub 2020 Jan 13.

Division of Nephrology, Johns Hopkins University, 1830 Monument Street, Suite 416, Baltimore, Maryland, 21287, USA.

Background: Eosinophils in kidney disease are poorly understood and are often incidental findings on kidney biopsy. Eosinophilia in blood and renal biopsy tissue is associated with a host of immune and non-immune kidney diseases. The significance of eosinophilia in renal diseases has not been well addressed. We evaluated the presence of peripheral eosinophilia (> 4% of blood leukocytes) with biopsy tissue eosinophilia and their association with end-stage-kidney-disease (ESKD).

Methods: A nested case-control (2:1) of patients who underwent kidney biopsies at Johns Hopkins Hospital and Medical University of South Carolina from 2004 to 2018 were included in the study. From the 616 eligible patients, 178 patients were identified through the registry of kidney biopsies as 18 years or older without missing biopsy reports or hematology results. Controls (n = 154) had no ESKD at the time of case (n = 24) designation and were assembled using incident density sampling and matched on age and sex. The association of peripheral eosinophilia (> 4% of peripheral blood leukocytes) with the risk of progression to ESKD was evaluated using conditional logistic model after adjusting for clinical demographics.

Results: Among 178 patients, 65 (37%) had peripheral eosinophilia and 113 (63%) had no eosinophilia. Compared to patients without eosinophilia, patients with peripheral eosinophilia were notably male and had a higher serum creatinine at the time of their biopsy. Peripheral eosinophilia was associated with higher risk of ESKD (OR 15.9 [1.9, 134.7]) adjusted for patient demographics including hypertension, proteinuria and eGFR at the time of kidney biopsy. Peripheral eosinophilia had a significant linear association with kidney tissue eosinophils, 22 (standard deviation [SD] 20) per high power field (hpf) in 4-10% peripheral eosinophilia, 19 (SD 18) per hpf in ≥10% eosinophilia and 3 (SD 7) per hpf in no eosinophilia (P <  0.001).

Conclusions: Peripheral eosinophilia is an independent predictor of tissue eosinophilia and subsequent progression to ESKD. Peripheral eosinophilia may be an early biomarker for underlying inflammation and disease, but further studies to investigate this clinical association are warranted.
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http://dx.doi.org/10.1186/s12882-020-1685-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958669PMC
January 2020

Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial.

J Inherit Metab Dis 2019 05 8;42(3):534-544. Epub 2019 Apr 8.

Department of Haematology, LSDU, Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, London, UK.

Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α-galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half-life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open-label, 3-month dose-ranging study, followed by a 9-month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment-emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half-life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m at baseline, remaining stable throughout treatment. Three patients developed treatment-induced IgG ADAs; following 1 year's treatment, all became ADA-negative. Nearly all treatment-emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity.
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http://dx.doi.org/10.1002/jimd.12080DOI Listing
May 2019

Association of HIV Suppression With Kidney Disease Progression Among HIV-Positive African Americans With Biopsy-Proven Classic FSGS.

J Acquir Immune Defic Syndr 2018 12;79(5):639-643

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: In the era of combined antiretroviral therapy, classic focal segmental glomerulosclerosis (FSGS) is the most common histopathological finding in African American HIV-positive patients with kidney disease. We sought to determine whether HIV suppression is associated with lower risk of progression to end-stage renal disease (ESRD) among HIV-positive African Americans with biopsy-confirmed classic FSGS.

Methods: HIV-positive African Americans who underwent kidney biopsies at a single tertiary hospital between January 1996 and June 2011 were confirmed as having classic FSGS by the presence of segmental glomerulosclerosis without features of HIV-associated nephropathy. Multivariable Cox proportional hazards models were used to examine the independent association of viral suppression (HIV-RNA < 400 copies per milliliter at biopsy) with time to progression to ESRD.

Results: Of the 55 HIV-positive African Americans with classic FSGS, 26 had suppressed viral loads at the time of biopsy. Compared to viremic patients, those who were virally suppressed had a significantly higher mean CD4 cell count (452 vs. 260 cell/mm, respectively; P = 0.02) and median estimated glomerular filtration rate (53.5 vs 35.5 mL/min/1.73 m, respectively; P = 0.002). Adjusting for sex and baseline CD4 cell count, estimated glomerular filtration rate, and proteinuria, those with HIV-RNA levels <400 copies per milliliter at baseline had a 75% lower risk of progressing to ESRD (hazard ratio = 0.25; 95% CI: 0.07 to 0.88) during a median follow-up time of 2.70 years (interquartile range: 0.80-5.15 years).

Conclusions: HIV suppression is associated with significantly lower risk of progression to ESRD among HIV-infected African Americans with classic FSGS, supporting the potential role of combined antiretroviral therapy for this histopathology in addition to HIV-associated nephropathy among HIV-positive individuals.
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http://dx.doi.org/10.1097/QAI.0000000000001860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231978PMC
December 2018

Role of Apolipoprotein L1 in Human Parietal Epithelial Cell Transition.

Am J Pathol 2018 11 8;188(11):2508-2528. Epub 2018 Sep 8.

Immunology and Inflammation Center, Feinstein Institute for Medical Research and Zucker School of Medicine at Hofstra-Northwell, Manhasset, New York. Electronic address:

Human parietal epithelial cells (PECs) are progenitor cells that sustain podocyte homeostasis. We hypothesized that the lack of apolipoprotein (APO) L1 ensures the PEC phenotype, but its induction initiates PEC transition (expression of podocyte markers). APOL1 expression and down-regulation of miR193a coincided with the expression of podocyte markers during the transition. The induction of APOL1 also stimulated transition markers in human embryonic kidney cells (cells with undetectable APOL1 protein expression). APOL1 silencing in PECs up-regulated miR193a expression, suggesting the possibility of a reciprocal feedback relationship between APOL1 and miR193a. HIV, interferon-γ, and vitamin D receptor agonist down-regulated miR193a expression and induced APOL1 expression along with transition markers in PECs. Luciferase assay suggested a putative interaction between miR193a and APOL1. Since silencing of APOL1 attenuated HIV-, vitamin D receptor agonist-, miR193a inhibitor-, and interferon-γ-induced expression of transition markers, APOL1 appears to be a critical functional constituent of the miR193a- APOL1 axis in PECs. This notion was confirmed by further enhanced expression of PEC markers in APOL1 mRNA-silenced PECs. In vivo studies, glomeruli in patients with HIV, and HIV/APOL1 transgenic mice had foci of PECs expressing synaptopodin, a transition marker. APOL1 likely regulates PEC molecular phenotype through modulation of miR193a expression, and APOL1 and miR193a share a reciprocal feedback relationship.
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http://dx.doi.org/10.1016/j.ajpath.2018.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222279PMC
November 2018

HIV-associated nephropathy: links, risks and management.

HIV AIDS (Auckl) 2018 25;10:73-81. Epub 2018 May 25.

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Despite the decreased incidence of human immunodeficiency virus (HIV)-associated nephropathy due to the widespread use of combined active antiretroviral therapy, it remains one of the leading causes of end-stage renal disease (ESRD) in HIV-1 seropositive patients. Patients usually present with low CD4 count, high viral load and heavy proteinuria, with the pathologic findings of collapsing focal segmental glomerulosclerosis. Increased susceptibility exists in individuals with African descent, largely due to polymorphism in gene. Other clinical risk factors include high viral load and low CD4 count. Advanced kidney disease and nephrotic range proteinuria have been associated with progression to ESRD. Improvement in kidney function has been observed after initiation of combined active antiretroviral therapy. Other treatment options, when clinically indicated, are inhibition of the renin-angiotensin system and corticosteroids. Further routine management approaches for patients with chronic kidney disease should be implemented. In patients with progression to ESRD, kidney transplant should be pursued, provided that viral load control is adequate. Screening for the presence of kidney disease upon detection of HIV-1 seropositivity in high-risk populations is recommended.
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http://dx.doi.org/10.2147/HIV.S141978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975615PMC
May 2018

Clinical Pharmacology in HIV Therapy.

Clin J Am Soc Nephrol 2019 03 29;14(3):435-444. Epub 2018 May 29.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.

The success of combination antiretroviral therapy in the treatment of HIV-1-positive individuals has shifted clinical attention toward combination antiretroviral drug regimens that optimize tolerability, long-term safety, and durable efficacy. Wherever patients have access to treatment, morbidity and mortality are increasingly driven by non-HIV-associated comorbidities, which may be observed earlier than in age-matched controls and despite the best available combination antiretroviral therapy. Similarly, HIV-1-positive individuals are now diagnosed and treated earlier with anticipated lifelong therapy. The contribution of specific antiretroviral agents to long-term morbidity and mortality is dependent on the pharmacologic characteristics of these agents, and it is increasingly important in this context.
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http://dx.doi.org/10.2215/CJN.02240218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419290PMC
March 2019

Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2018 03 3;93(3):545-559. Epub 2018 Feb 3.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge of the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.
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http://dx.doi.org/10.1016/j.kint.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983378PMC
March 2018

Pharmacotherapy and treatment options for HIV-associated nephropathy.

Expert Opin Pharmacother 2018 01 26;19(1):39-48. Epub 2017 Dec 26.

a Johns Hopkins Department of Medicine , Division of Nephrology , Baltimore , MD , US.

Introduction: Human immunodeficiency virus (HIV) remains a worldwide disease with significant mortality and morbidity. There are a multitude of HIV-related kidney diseases including HIV-associated nephropathy (HIVAN) most prominently. The risk of developing HIVAN increases with decreasing CD4 count, higher viral load, and based on genetic factors. The mortality rate for those with HIVAN-end stage renal disease (ESRD) remains 2.5-3 times higher than ESRD patients without HIVAN.

Areas Covered: The epidemiology of HIVAN, particularly risk assessment, will be explored in this review. Further, the pathogenesis of HIVAN, from viral-specific renal expression to the role of genetics as well as characteristic renal pathology will be described. Diagnosis and management of HIVAN will be addressed, with an emphasis on various treatment strategies including medication, dialysis, and kidney transplantation.

Expert Opinion: HIVAN is associated with a high risk for progression to ESRD and increased mortality. The backbone of HIVAN therapy remains combined anti-retroviral therapy (cART), while adjunctive therapies including RAAS blockade and prednisone, should be considered. In those who progress to ESRD, dialysis remains the mainstay of management, though increasing evidence has demonstrated that kidney transplantation can be effective in those with controlled HIV disease.
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http://dx.doi.org/10.1080/14656566.2017.1416099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381591PMC
January 2018

Lupus Nephritis: Current Treatment Paradigm and Unmet Needs.

Rev Recent Clin Trials 2018;13(2):105-113

Johns Hopkins Department of Medicine, Division of Nephrology, Baltimore, MD, United States.

Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterized by chronic inflammation, which can result in a multitude of systemic or organ-limited manifestations, including the skin, lungs, heart, and kidney. SLE nephritis is present in an average of 38% of patients at the time of diagnosis, and may occur as the initial presentation of disease with progression to End-Stage Renal Disease (ESRD) in roughly 10-20% of patients.

Methods: A review of the current literature was undertaken to investigate the evolution of treatment of SLE nephritis based on randomized trials and robust observational studies. We aimed to provide a timeline of the development of current induction and maintenance therapy, as well as the development of novel targeted therapies, all leading to current guidelines.

Results: Based on all available current data on standard of care therapies for SLE nephritis, there is at best a complete remission rate of 50-60%, and roughly 13-25% of patients experience periods of relapse during maintenance therapy for SLE nephritis. Therefore, the need for newer, targeted therapies has been the focus of many current, ongoing clinical trials.

Conclusion: Standard induction and maintenance therapies at present are anti-proliferative and nonspecific, that is, interfering with the process of autoantigen presentation and activation of autoreactive leukocytes. However, newer agents with specific T-cell, B-cell, or proteasome targets are currently being investigated.
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http://dx.doi.org/10.2174/1574887112666171123113200DOI Listing
December 2018

Allogeneic Mesenchymal Stem Cells for Treatment of AKI after Cardiac Surgery.

J Am Soc Nephrol 2018 01 16;29(1):260-267. Epub 2017 Oct 16.

Department of Anesthesia, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario

AKI after cardiac surgery remains strongly associated with mortality and lacks effective treatment or prevention. Preclinical studies suggest that cell-based interventions may influence functional recovery. We conducted a phase 2, randomized, double-blind, placebo-controlled trial in 27 centers across North America to determine the safety and efficacy of allogeneic human mesenchymal stem cells (MSCs) in reducing the time to recovery from AKI after cardiac surgery. We randomized 156 adult subjects undergoing cardiac surgery with evidence of early AKI to receive intra-aortic MSCs (AC607; =67) or placebo (=68). The primary outcome was the time to recovery of kidney function defined as return of postintervention creatinine level to baseline. The median time to recovery of kidney function was 15 days with AC607 and 12 days with placebo (25th, 75th percentile range, 10-29 versus 6-21, respectively; hazard ratio, 0.81; 95% confidence interval, 0.53 to 1.24; =0.32). We did not detect a significant difference between groups in 30-day all-cause mortality (16.7% with AC607; 11.8% with placebo) or dialysis (10.6% with AC607; 7.4% with placebo). At follow-up, 12 patients who received AC607 and six patients who received placebo had died. Rates of other adverse events did not differ between groups. In these patients with AKI after cardiac surgery, administration of allogeneic MSCs did not decrease the time to recovery of kidney function. Our results contrast with those in preclinical studies and provide important information regarding the potential effects of MSCs in this setting.
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http://dx.doi.org/10.1681/ASN.2016101150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748899PMC
January 2018

Tenofovir alafenamide nephrotoxicity in an HIV-positive patient: A case report.

Medicine (Baltimore) 2017 Sep;96(36):e8046

Department of Medicine Department of Pathology, Johns Hopkins University, Baltimore, MD.

Rationale: Tenofovir alafenamide (TAF) is novel prodrug of Tenofovir, a nucleotide reverse transcriptase inhibitor. TAF is less nephrotoxic than its predecessor prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir causes mitochondrial dysfunction and tubular injury when there is elevated accumulation in proximal tubule cells. TAF's unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage. TAF has not been associated with the histologic markers of tenofovir-associated nephrotoxicity that are seen with TDF, such as dysmorphic mitochondria in proximal tubule cells. Here, we report a patient with dysmorphic mitochondria on kidney biopsy after initiating therapy with TAF.

Lessons: This case suggests that at risk individuals may experience tubular mitochondrial injury from lower concentrations of tenofovir with TAF.
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http://dx.doi.org/10.1097/MD.0000000000008046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393094PMC
September 2017

Predictors of Acute Renal Injury Study (PARIS) among HIV-positive individuals: design and methods.

BMC Nephrol 2017 Sep 7;18(1):289. Epub 2017 Sep 7.

San Francisco and San Francisco VA Health Care System, Kidney Health Research Collaborative, University of California, 1450 Clement St., 111A1, San Francisco, 94121, CA, USA.

Background: Acute kidney injury (AKI), which is common among HIV-positive individuals, may contribute to the excess burden of chronic kidney disease (CKD) in this patient population; however, conventional clinical methods to detect AKI do not capture kidney injury sufficiently early to prevent irreversible damage. Further, large observational and interventional studies of AKI generally exclude HIV-positive persons in spite of their disproportionate risk.

Methods: The Predictors of Acute Renal Injury Study (PARIS) is a prospective observational cohort study among HIV-positive individuals established to determine the ability of candidate kidney injury biomarkers to predict future hospitalized clinical AKI, to characterize hospitalized subclinical AKI, and to discern the risk of progressive kidney disease following subclinical and clinical AKI. Among the candidate kidney injury markers, we will select the most promising to translate into a clinically viable, multiplex panel of urinary biomarkers which we will integrate with clinical factors to develop a model prognostic of risks for AKI and subsequent kidney function decline. This study has a targeted enrollment of 2000 participants. The overall follow-up of participants consists of two phases: 1) a 5-year active follow-up phase which involves serial evaluations at enrollment, annual clinic visits, and among participants who are hospitalized during this period, an evaluation at index hospitalization and 3 and 12 months post-hospitalization; and 2) a subsequent passive follow-up phase for the duration that the participant receives medical care at The Johns Hopkins Hospital.

Discussions: This study will serve as an important resource for future studies of AKI by establishing a repository with both ambulatory and inpatient biospecimens, a resource that is currently lacking in existing HIV clinical cohorts and studies of AKI. Upon completion of this study, the resulting prognostic model which will incorporate results from the multiplex HIV-AKI Risk Pane could serve as a pharmacodynamic endpoint for early phase therapeutic candidates for AKI.
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http://dx.doi.org/10.1186/s12882-017-0696-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590192PMC
September 2017

Kidney Disease in HIV: Moving beyond HIV-Associated Nephropathy.

J Am Soc Nephrol 2017 Nov 7;28(11):3142-3154. Epub 2017 Aug 7.

Kidney Health Research Collaborative, Department of Medicine, University of California, San Francisco, California;

In developed countries, remarkable advances in antiretroviral therapy have transformed HIV infection into a chronic condition. As a result, HIV-associated nephropathy, the classic HIV-driven kidney lesion among individuals of African descent, has largely disappeared in these regions. However, HIV-positive blacks continue to have much higher rates of ESRD than HIV-positive whites, which could be attributed to the renal risk variants. Additionally, HIV-positive individuals face adverse consequences beyond HIV itself, including traditional risk factors for CKD and nephrotoxic effects of antiretroviral therapy. Concerns for nephrotoxicity also extend to HIV-negative individuals using tenofovir disoproxil fumarate-based pre-exposure prophylaxis for the prevention of HIV infection. Therefore, CKD remains an important comorbid condition in the HIV-positive population and an emerging concern among HIV-negative persons receiving pre-exposure prophylaxis. With the improved longevity of HIV-positive individuals, a kidney transplant has become a viable option for many who have progressed to ESRD. Herein, we review the growing knowledge regarding the renal risk variants in the context of HIV infection, antiretroviral therapy-related nephrotoxicity, and developments in kidney transplantation among HIV-positive individuals.
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http://dx.doi.org/10.1681/ASN.2017040468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661296PMC
November 2017

Rhabdomyolysis in an HIV cohort: epidemiology, causes and outcomes.

BMC Nephrol 2017 Jul 17;18(1):242. Epub 2017 Jul 17.

Department of Medicine/Division of Nephrology, Johns Hopkins University Hospital and School of Medicine, 1830 E. Monument Street - Suite 416, Baltimore, MD, 21205, USA.

Background: The Literature on rhabdomyolysis in the HIV-positive population is sparse and limited. We aimed to explore the incidence, patient characteristics, etiologies and outcomes of rhabdomyolysis in a cohort of HIV-positive patients identified through the Johns Hopkins HIV clinical registry between June 1992 and April 2014.

Methods: A retrospective analysis of 362 HIV-positive patients with non-cardiac CK elevation ≥1000 IU/L was performed. Both inpatients and outpatients were included. Incidence rate and potential etiologies for rhabdomyolysis were ascertained. The development of acute kidney injury (AKI, defined as doubling of serum creatinine), need for dialysis, and death in the setting of rhabdomyolysis were determined. Logistic regression was used to evaluate the association of peak CK level with the development of AKI.

Results: Three hundred sixty two cases of rhabdomyolysis were identified in a cohort of 7079 patients with a 38,382 person years follow-up time. The incidence rate was nine cases per 1000 person-years (95% CI: 8.5-10.5). Infection was the most common etiology followed by compression injury and drug/alcohol use. One-third of cases had multiple potential etiologies. AKI developed in 46% of cases; 20% of which required dialysis. Thirteen percent died during follow-up. After adjustment, AKI was associated with higher CK (OR 2.05 for each 1-log increase in CK [95% CI: 1.40-2.99]), infection (OR 5.48 [95% CI 2.65-11.31]) and higher HIV viral load (OR 1.22 per 1-log increase [95% CI: 1.03-1.45]).

Conclusion: Rhabdomyolysis in the HIV-positive population has many possible causes and is frequently multifactorial. HIV-positive individuals with rhabdomyolysis have a high risk of AKI and mortality.
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http://dx.doi.org/10.1186/s12882-017-0656-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512985PMC
July 2017

Hyperuricemia after orthotopic liver transplantation: divergent associations with progression of renal disease, incident end-stage renal disease, and mortality.

BMC Nephrol 2017 03 27;18(1):103. Epub 2017 Mar 27.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Although hyperuricemia is common after orthotopic liver transplantation (OLT), its relationship to mortality, progressive kidney disease, or the development of end stage renal disease (ESRD) is not well-described.

Methods: Data from 304 patients undergoing OLT between 1996 and 2010 were used to assess the association of mean serum uric acid (UA) level in the 3-months post-OLT with mortality, doubling of creatinine, and ESRD incidence. Post-OLT survival to event outcomes according to UA level and eGFR was assessed using the Kaplan Meier method and multivariate Cox proportional hazards models.

Results: Mean UA level among the 204 patients with an eGFR level ≥60 ml/min/1.73 m was 6.4 mg/dl compared to 7.9 mg/dl among the 100 patients with eGFR <60 (p < 0.0001). During a median of 4.6 years of follow-up, mortality rate, doubling of creatinine, and ESRD incidence were 48.9, 278.2, and 20.7 per 1000 person-years, respectively. In the first 5 years of follow-up, elevated UA was associated with mortality (Hazard Ratio, HR = 1.7; p = 0.045). However, among those with eGFR ≥ 60, UA level did not predict mortality (HR = 1.0; p = 0.95), and among those with eGFR < 60, elevated UA was a strong predictor of mortality (HR = 3.7[1.1, 12.0]; p = 0.03). UA was not associated with ESRD, but was associated with doubling of creatinine among diabetics (HR = 2.2[1.1, 4.3]; p = 0.025).

Conclusion: In this post-OLT cohort, hyperuricemia independently predicted mortality, particularly among patients with eGFR < 60, and predicted doubling of creatinine among diabetics.
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http://dx.doi.org/10.1186/s12882-017-0518-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369182PMC
March 2017

Longitudinal Assessment of Proximal Tubular Dysfunction in HIV Seropositive and Seronegative Persons: Correlates and Implications.

J Acquir Immune Defic Syndr 2017 05;75(1):45-51

*Internal Medicine Residency Training Program, Johns Hopkins Bayview Medical Center, Baltimore, MD; †Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; ‡Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; §Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; ‖Kidney Health Research Collaborative, San Francisco VA Medical Center and University of California, San Francisco, CA; and ¶Department of Pediatrics, University of Rochester Medical Center, Rochester, NY.

Background: Proximal tubular dysfunction (PTD) is common in HIV-positive persons and has been associated with tenofovir disoproxil fumarate (TDF). However, few studies have assessed the natural history PTD in HIV-positive and -negative individuals, or the association of PTD with the subsequent trajectory of directly measured glomerular filtration rate (mGFR).

Methods: We followed 192 HIV-positive and 100 HIV-negative, nondiabetic participants for 3 years. We measured 3 PTD markers (normoglycemic glycosuria, fractional excretion of phosphorus, and tubular proteinuria) and mGFR (by iohexol disappearance from serum) annually. We used univariate and multivariate generalized estimating equation logistic regression to identify factors associated with PTD across all visits and linear mixed effects models to assess the association between baseline PTD and mGFR slope.

Results: Compared with HIV-negative participants, HIV-positive persons that were not taking antiretroviral therapy were at increased risk of PTD (adjusted odds ratio 3.33; 95% confidence interval: 1.65 to 6.71), whereas those taking a TDF-based or a TDF-sparing regimen were not at significantly increased risk of PTD. Among HIV-positive participants, uncontrolled viremia was a strong correlate of PTD. Forty-nine of 55 (89%) participants with PTD at baseline had at least 1 subsequent visit without PTD. There was no association between baseline PTD and rate of decline in mGFR over time.

Conclusions: Poorly controlled HIV may be a stronger risk factor for PTD than TDF use. The individual-level variability of the PTD markers over time was high, potentially limiting their usefulness for routine screening in unselected patients. Baseline PTD was not associated with subsequent mGFR slope.
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http://dx.doi.org/10.1097/QAI.0000000000001302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388566PMC
May 2017

Hypertensive disorders in pregnancy.

World J Nephrol 2016 Sep;5(5):418-28

Casey Berry, Mohamed G Atta, Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.

Renal injury or failure may occur in the context of pregnancy requiring special considerations with regard to fetal and maternal health. The condition of pregnancy itself may be a major factor in such injuries. In addition, for many young women previously known to be healthy, pregnancy may be the first presentation for routine urine and blood testing which may yield previously subclinical renal disease. As such, pregnancy may add complexity to considerations in the management of renal disease presenting coincidentally requiring knowledge of the physiologic changes and potential renal disorders that may be encountered during pregnancy.
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http://dx.doi.org/10.5527/wjn.v5.i5.418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011248PMC
September 2016

HIV, Cocaine Use, and Hepatitis C Virus: A Triad of Nontraditional Risk Factors for Subclinical Cardiovascular Disease.

Arterioscler Thromb Vasc Biol 2016 10 8;36(10):2100-7. Epub 2016 Sep 8.

From the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (G.M.L., M.G.A., D.M.F., M.M.E., K.Z.); Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (A.M.M.); and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison (J.H.S.).

Objective: We assessed cross-sectional and longitudinal associations of 3 nontraditional cardiovascular disease risk factors-HIV, cocaine use, and chronic hepatitis C virus infection-with 3 validated markers of subclinical cardiovascular disease: carotid artery plaque, albuminuria, and aortic pulse wave velocity in a well-characterized cohort.

Approach And Results: We measured carotid plaque at baseline and after 24 months, urine albumin/creatinine ratio every 6 months, and pulse wave velocity annually for up to 36 months in a predominantly black cohort of 292 participants (100 HIV negative and 192 HIV positive). Thirty-nine percent had chronic hepatitis C virus infection and 20%, 28%, and 52% were never, past, and current cocaine users, respectively. Sixteen percent, 47%, and 64% of those with none, 1 or 2, or all 3 nontraditional risk factors had ≥2 abnormal cardiovascular disease risk markers (P=0.001). In fully adjusted models that included all 3 nontraditional risk factors, HIV infection was independently associated with carotid plaque progression (increase in the number of anatomic segments with plaque), albuminuria (albumin-creatinine ratio >30 mg/g), albuminuria progression (doubling of albumin-creatinine ratio from baseline to a value >30 mg/g), and pulse wave velocity. Cocaine use was associated with an ≈3-fold higher odds of carotid plaque at baseline, and hepatitis C virus infection was significantly associated with a higher risk of carotid plaque progression.

Conclusions: These results suggest that HIV infection, cocaine use, and hepatitis C virus infection are important nontraditional risk factors for cardiovascular disease and highlight the need to understand the distinct and overlapping mechanisms of the associations.
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http://dx.doi.org/10.1161/ATVBAHA.116.307985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033718PMC
October 2016

Correlates and Longitudinal Renal and Cardiovascular Implications of FGF23 Levels in HIV-Positive Individuals.

PLoS One 2016 13;11(5):e0155312. Epub 2016 May 13.

Johns Hopkins University School of Medicine, Department of Medicine, Baltimore, MD, 21287, United States of America.

Fibroblast growth factor23 (FGF23), an early marker of kidney dysfunction, is associated with cardiovascular death. Its role in HIV-positive individuals is unknown. We measured FGF23 in 100 HIV-negative and 191 HIV-positive nondiabetic adults with normal baseline estimated glomerular filtration rate (GFR). We measured GFR by iohexol annually, albumin-creatinine ratio (ACR) every 6 months, as well as pulse wave velocity, carotid plaque, and carotid intima media thickness (IMT) at baseline and 2 years. Progressive albuminuria was defined as follow-up ACR ≥2-fold than baseline and ≥30 mg/g. Regression models assessed associations of FGF23 with baseline factors and longitudinal changes in disease markers. FGF23 levels were similar in HIV serostatus. Among HIV-positive persons, factors independently associated with higher baseline FGF23 levels included female (adjusted ratio of geometric means [95% CI],1.46 [1.21,1.76]), serum phosphorus (1.20 [1.03,1.40]), HCV (1.31 [1.10,1.56]) and non-suppressed HIV RNA (1.27 [1.01,1.76]). At baseline, FGF23 was not associated with GFR, albuminuria, carotid plaque, or carotid IMT in cross-sectionally adjusted analysis of HIV-positive individuals. However, higher baseline FGF23 was associated with progressive albuminuria (odds ratio1.48 [95% CI]:1.05,2.08) and a more rapid increase in IMT (13 μm/year, 95% CI,3,24). These findings suggest a role for FGF23 in HIV-positive populations in identifying patients at greater risk for cardiovascular and kidney disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866696PMC
July 2017

Renal Thrombotic Microangiopathy, Podocytopathy, and Chylous Ascites: A Hard-Nosed Diagnosis.

Am J Med 2016 Oct 3;129(10):e227-31. Epub 2016 May 3.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Md.

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http://dx.doi.org/10.1016/j.amjmed.2016.04.011DOI Listing
October 2016

Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy.

Clin J Am Soc Nephrol 2016 Feb 14;11(2):262-70. Epub 2015 Dec 14.

Departments of Medicine and.

Background And Objectives: Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high-risk genotype incrementally improved the prediction of these underlying lesions beyond conventional clinical factors.

Design, Setting, Participants, & Measurements: In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation.

Results: The addition of APOL1 genotype to HIV-related risk factors for kidney disease in a predictive model improved the prediction of non-HIV-associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology.

Conclusions: APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease.
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http://dx.doi.org/10.2215/CJN.07490715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741048PMC
February 2016
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