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Objectives Current treatments are effective only in 30% of lupus nephritis patients emphasizing the need for novel therapeutic strategies. To develop mechanistic hypotheses and explore novel biomarkers, we analyzed the longitudinal urinary proteomic profiles in patients with lupus nephritis undergoing treatment. Methods We quantified 1,000 urinary proteins in 30 patients with lupus nephritis at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from lupus nephritis patients. Results Our analysis revealed multiple biological pathways including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization that could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with lupus nephritis as compared to controls without SLE. IL-16, CD163, and TGF-β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction of urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys. IL-16 producing cells were found at key sites of kidney injury. Conclusion Urine proteomics may profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.

AKI frequently occurs in patients with COVID-19, and kidney injury severe enough to require RRT is a common complication among patients who are critically ill. During the surge of the pandemic, there was a high demand for dialysate for continuous RRT, and this increase in demand, coupled with vulnerabilities in the supply chain, necessitated alternative approaches, including internal production of dialysate. Using a standard hemodialysis machine and off-the-shelf supplies, as per Food and Drug Administration guidelines, we developed a method for on-site dialysate production that is adaptable and can be used to fill multiple bags at once. The use of a central reverse osmosis unit, dedicated hemodialysis machine, sterile bags with separate ports for fill and use, and frequent testing will ensure stability, sterility, and—therefore—safety of the produced dialysate. The dialysate made in house was tested and it showed both stability and sterility for at least 30 hours. This detailed description of our process for generating dialysate can serve as a guide for other programs experiencing similar vulnerabilities in the demand versus supply of dialysate.

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. 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. 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

The coronavirus disease 2019 pandemic may require rationing of various medical resources if demand exceeds supply. Theoretical frameworks for resource allocation have provided much needed ethical guidance, but hospitals still need to address objective practicalities and legal vetting to operationalize scarce resource allocation schemata. To develop operational scarce resource allocation processes for public health catastrophes, including the coronavirus disease 2019 pandemic, five health systems in Maryland formed a consortium-with diverse expertise and representation-representing more than half of all hospitals in the state. Our efforts built on a prior statewide community engagement process that determined the values and moral reference points of citizens and health-care professionals regarding the allocation of ventilators during a public health catastrophe. Through a partnership of health systems, we developed a scarce resource allocation framework informed by citizens' values and by general expert consensus. Allocation schema for mechanical ventilators, ICU resources, blood components, novel therapeutics, extracorporeal membrane oxygenation, and renal replacement therapies were developed. Creating operational algorithms for each resource posed unique challenges; each resource's varying nature and underlying data on benefit prevented any single algorithm from being universally applicable. The development of scarce resource allocation processes must be iterative, legally vetted, and tested. We offer our processes to assist other regions that may be faced with the challenge of rationing health-care resources during public health catastrophes.

Inaugural consensus statements were developed and endorsed by the American College of Radiology (ACR) and National Kidney Foundation to improve and standardize the care of patients with kidney disease who have indication(s) to receive ACR-designated group II or group III intravenous gadolinium-based contrast media (GBCM). The risk of nephrogenic systemic fibrosis (NSF) from group II GBCM in patients with advanced kidney disease is thought to be very low (zero events following 4931 administrations to patients with estimated glomerular filtration rate [eGFR]

BACKGROUND/OBJECTIVES Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis (LN). The purpose of this study was to assess the effect of mycophenolate mofetil (MMF) on the timing of urine protein-to-creatinine ratio reaching 200 mg or less after starting MMF as initial therapy for class III, IV, or V in immunosuppressant-naive patients with LN. METHODS Patients who had a diagnosis of biopsy-proven LN were included in this cohort study. The initial dose of MMF was 1000 mg twice daily. If no improvement, it was increased to 1500 mg twice daily after 1 month. For statistical analysis, exact binomial distribution 95% confidence intervals were calculated. RESULTS Nine patients were identified. There were 3 patients with class III, 3 with class IV, 1 with class III to V, 1 with class II to V, and 1 with class V lupus nephritis. The majority were African Americans (70%). At baseline, proteinuria ranged between 0.41 and 4 g, and 88% had normal estimated glomerular filtration rate. Forty-four percent of patients reached 0.28 g of proteinuria within 8 weeks of starting MMF (95% confidence interval, 14%-79%), all of which maintained the same level of response and normal estimated glomerular filtration rate at 12 months. Thirty-three percent of patients achieved the American College of Rheumatology complete response at 8 weeks. CONCLUSIONS This study demonstrates that only a minority of immunosuppressant-naive LN patients achieved the American College of Rheumatology complete response at 8 weeks after initiation of MMF. A rapid decline in the proteinuria to 0.28 g within the first 8 weeks of the treatment correlated strongly with achieving the same level of response at 12 months.

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, Graphical abstract

The novel coronavirus disease 2019 (COVID‐19) is a highly infectious and rapidly spreading disease. There are limited published data on the epidemiology and outcomes of COVID‐19 infection among organ transplant recipients. After initial flulike symptoms, progression to an inflammatory phase may occur, characterized by cytokine release rapidly leading to respiratory and multiorgan failure. We report the clinical course and management of a liver transplant recipient on hemodialysis, who presented with COVID‐19 pneumonia, and despite completing a 5‐day course of hydroxychloroquine, later developed marked inflammatory manifestations with rapid improvement after administration of off‐label, single‐dose tocilizumab. We also highlight the role of lung ultrasonography in early diagnosis of the inflammatory phase of COVID‐19. Future investigation of the effects of immunomodulators among transplant recipients with COVID‐19 infection will be important.

BACKGROUND: Johns Hopkins was an early adopter of an in-house nephrology fellowship night float to improve work-life balance. Our study aimed to elucidate attitudes to guide fellowship structuring. METHODS: We performed a mixed-methods study surveying Johns Hopkins fellows, alumni, and faculty and conducting one focus group of current fellows. Surveys were developed through literature review, queried on a five-point Likert scale, and analyzed with t and ANOVA tests. The focus group transcript was analyzed by two independent reviewers. RESULTS: Survey response rates were 14 (100%) fellows, 32 (91%) alumni, and 17 (94%) faculty. All groups felt quality of patient care was good to excellent with no significant differences among groups (range of means [SD], 4.1 [0.7]–4.6 [0.7]; P=0.12), although fellows had a statistically significantly more positive view than faculty on autonomy (4.6 [0.5] versus 4.1 [0.3]; P=0.006). Fellows perceived a positive effect across all domains of night float on the day team experience (range, 4.2 [0.8]–4.6 [0.6]; P

Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing surveillance exists to assess real-world risk. Current labeling suggests dose reduction (maximum daily dose of 10 mg) for patients with severe CKD.Using deidentified electronic health record data, we analyzed 152,101 and 795,799 new users of rosuvastatin and atorvastatin, respectively, from 2011 to 2019. We estimated inverse probability of treatment-weighted hazard ratios (HRs) of hematuria, proteinuria, and kidney failure with replacement therapy (KFRT) associated with rosuvastatin. We reported the initial rosuvastatin dose across eGFR categories and evaluated for a dose effect on hematuria and proteinuria.Overall, we identified 2.9% of patients with hematuria and 1.0% with proteinuria during a median follow-up of 3.1 years. Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria (HR, 1.08; 95% confidence interval [95% CI], 1.04-1.11), proteinuria (HR, 1.17; 95% CI, 1.10-1.25), and KFRT (HR, 1.15; 1.02-1.30). A substantial share (44%) of patients with eGFR30 mL/min per 1.73 mCompared with atorvastatin, rosuvastatin was associated with increased risk of hematuria, proteinuria, and KFRT. Among patients with eGFR30 mL/min per 1.73 m

Objective Delayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. Methods A total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. Results At biopsy, 54 patients had UPCR Conclusion In this prospective study, three-quarters of patients with UPCR

Objectives Pure membranous (class V) LN is considered a less aggressive phenotype, but tissue fibrosis and chronic kidney disease may still develop. This study aimed to elucidate the prognostic value of a history of class switch in pure membranous LN. Methods We included LN patients with at least two clinically indicated kidney biopsies. New onset of end stage kidney disease (ESKD) was defined as estimated glomerular filtration rate Results Among 220 patients (542 biopsies), 199 (90%) were female, and 118 (54%) were African American, 59 (27%) Caucasian, with median age of 28 years at the first kidney biopsy. Patients with pure class V in a first biopsy converted to proliferative LN in 41% of cases. Pure class V in a repeat biopsy was preceded by proliferative LN in 52%. Trajectory analysis of up to four repeat biopsies revealed that ISN class switch may happen at any time, even after multiple biopsies with the same class. New onset ESKD was observed within 2 years in 5/56 (9%) patients with pure class V in a repeat biopsy. All five patients had proliferative LN in the first biopsy (log rank P = 0.024). Conclusions The conversion from proliferative to membranous (and vice-versa) is frequent in SLE. It can occur at any time in the course of disease, limiting the prognostic value of the first biopsy. Evidence of prior proliferative LN is key as it is associated with higher risk of ESKD in non-proliferative LN.

Intravenous iodinated contrast media are commonly used with CT to evaluate disease and to determine treatment response. The risk of acute kidney injury (AKI) developing in patients with reduced kidney function following exposure to intravenous iodinated contrast media has been overstated. This is due primarily to historic lack of control groups sufficient to separate contrast-induced AKI (CI-AKI; ie, AKI caused by contrast media administration) from contrast-associated AKI (CA-AKI; ie, AKI coincident to contrast media administration). Although the true risk of CI-AKI remains uncertain for patients with severe kidney disease, prophylaxis with intravenous normal saline is indicated for patients who have AKI or an estimated glomerular filtration rate less than 30 mL/min/1.73 m2 who are not undergoing maintenance dialysis. In individual high-risk circumstances, prophylaxis may be considered in patients with an estimated glomerular filtration rate of 30–44 mL/min/1.73 m2 at the discretion of the ordering clinician.

ObjectivesIn lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.ConclusionsProcurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

This chapter discusses the continued high prevalence of renal disease in persons with HIV and the broad pathologic spectrum of renal disease, including medication-induced renal injury. It also allows the learner to understand the importance of screening and monitoring people with HIV for chronic kidney disease. Other topics discussed are the indications for nephrology referral and renal biopsy and potential targets of intervention for HIV-associated renal diseases. Treatment options for people with HIV who have end-stage renal disease, including dialysis and solid organ transplant, are also covered.

Introduction: Statin-induced rhabdomyolysis is a rare, but potentially life-threatening condition. It is unknown whether specific statins carry a greater risk of rhabdomyolysis and whether the risk differs between patients with and without chronic kidney disease (CKD). The objective of this study was to investigate the association of rosuvastatin use vs. atorvastatin use with the risk of rhabdomyolysis across CKD status. Hypothesis: Rosuvastatin use is associated with a higher risk of rhabdomyolysis as compared to atorvastatin use and the risk is greater among those with CKD than those without CKD. Methods: We identified adult patients who initiated rosuvastatin or atorvastatin between January 1, 2004 and December 31, 2018 and were free of end-stage kidney disease at the time of prescription in the Geisinger Health System. The association between rosuvastatin use and rhabdomyolysis was assessed using Cox proportional hazards regression models with an interaction between rosuvastatin use and CKD (i.e., estimated glomerular filtration rate 2 ) in an inverse probability of treatment weighted (IPTW) sample. Results: Of 8,748 rosuvastatin users (mean [SD] age, 59.7 [12.6] years; 49.8% female; 11.8% CKD) and 31,770 atorvastatin users (mean [SD] age, 59.1 [12.6] years; 48.2% female; 11.9% CKD), 0.7% and 0.4% patients developed rhabdomyolysis, respectively, during a median follow-up of 5.1 years. Rosuvastatin use was associated with a higher risk of rhabdomyolysis in patients with CKD (hazard ratio [HR], 3.29; 95% CI, 1.53-7.09), but not in those without CKD (HR, 1.29; 95% CI, 0.82-2.03; p-interaction=0.04). A higher risk of rhabdomyolysis associated with rosuvastatin use in lower eGFR was also observed in the analysis with continuous eGFR ( Figure ). Conclusions: The findings suggest that rosuvastatin use in patients with CKD may be associated with excess risk of rhabdomyolysis as compared to atorvastatin.

Background Kidney disease and dialysis significantly impact cognitive function across the age spectrum. Cognitive training (CT) and/or exercise training (ET) are promising approaches to preserve cognitive function among community-dwelling older adults, but have not been tested for cognition preservation in hemodialysis patients of all ages. In this manuscript, we summarize the protocol for the Interventions Made to Preserve Cognitive Function Trial (IMPCT). Methods We will perform a 2 × 2 factorial randomized controlled trial (RCT) of eligible adult (≥18 years) hemodialysis initiates (n = 200) to test whether intradialytic CT (brain games on a tablet PC), ET (foot peddlers) and combined CT + ET while undergoing hemodialysis preserves executive function compared to standard of care (SC). Participants will engage in the interventions to which they are randomized for 6 months. The primary objective is to compare, among interventions, the 3-month change in executive function measured using the Trail Making Test A (TMTA) and B (TMTB); specifically, executive function is calculated as TMTB-TMTA to account for psychomotor speed. This primary outcome was selected based on findings from our pilot study. The secondary objectives are to compare the risk of secondary cognitive outcomes, ESKD-specific clinical outcomes, and patient-centered outcomes at 3-months and 6-months. All data collection and interventions are conducted in the dialysis center. Discussion We hypothesize that receiving intradialytic CT or ET will better preserve executive function than SC but receiving combined CT + ET, will be the most effective intervention. The current trial will be an important step in understanding how intradialytic interventions might preserve cognitive health. Trial Registration Clinicaltrials.Gov (Date: 8/6/18): # NCT03616535. Protocol Version: 10 (April 2020). Funding: NIDDK R01DK114074.

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology, which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology is needed in order to understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways. Here, we analyzed the patterns of 1000 urine protein biomarkers in 30 patients with active lupus nephritis. We found that patients stratify over a chemokine gradient inducible by IFN-γ. Higher values identified patients with proliferative lupus nephritis. After integrating the urine proteomics with the single-cell transcriptomics of kidney biopsies, we observed that the urinary chemokines defining the gradient were predominantly produced by infiltrating CD8(+) T cells, along with natural killer and myeloid cells. The urine chemokine gradient significantly correlated with the number of kidney-infiltrating CD8(+) cells. These findings suggest that urine proteomics can capture the complex biology of the kidney in lupus nephritis. Patient-specific pathways could be noninvasively tracked in the urine in real time, enabling diagnosis and personalized treatment.

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has both a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology is needed to understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways. Here, we analyzed the patterns of 1000 urine protein biomarkers in 30 patients with active lupus nephritis. We found that patients stratify over a chemokine gradient inducible by interferon-gamma. Higher values identified patients with proliferative lupus nephritis. After integrating the urine proteomics with the single-cell transcriptomics of kidney biopsies, it was observed that the urinary chemokines defining the gradient were predominantly produced by infiltrating CD8 T cells, along with natural killer and myeloid cells. The urine chemokine gradient significantly correlated with the number of kidney-infiltrating CD8 cells. These findings suggest that urine proteomics can capture the complex biology of the kidney in lupus nephritis. Patient-specific pathways may be noninvasively tracked in the urine in real time, enabling diagnosis and personalized treatment.

BackgroundIn 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.MethodsHIV-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.ResultsOf 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

Objectives This study sought to compare a continuous infusion diuretic strategy versus an intermittent bolus diuretic strategy, with the addition of low-dose dopamine (3 μg/kg/min) in the treatment of hospitalized patients with heart failure with preserved ejection fraction (HFpEF). Background HFpEF patients are susceptible to development of worsening renal function (WRF) when hospitalized with acute heart failure; however, inpatient treatment strategies to achieve safe and effective diuresis in HFpEF patients have not been studied to date. Methods In a prospective, randomized, clinical trial, 90 HFpEF patients hospitalized with acute heart failure were randomized within 24 h of admission to 1 of 4 treatments: 1) intravenous bolus furosemide administered every 12 h; 2) continuous infusion furosemide; 3) intermittent bolus furosemide with low-dose dopamine; and 4) continuous infusion furosemide with low-dose dopamine. The primary endpoint was percent change in creatinine from baseline to 72 h. Linear and logistic regression analyses with tests for interactions between diuretic and dopamine strategies were performed. Results Compared to intermittent bolus strategy, the continuous infusion strategy was associated with higher percent increase in creatinine (continuous infusion: 16.01%; 95% confidence interval [CI]: 8.58% to 23.45% vs. intermittent bolus: 4.62%; 95% CI: −1.15% to 10.39%; p = 0.02). Low-dose dopamine had no significant effect on percent change in creatinine (low-dose dopamine: 12.79%; 95% CI: 5.66% to 19.92%, vs. no-dopamine: 8.03%; 95% CI: 1.44% to 14.62%; p = 0.33). Continuous infusion was also associated with greater risk of WRF than intermittent bolus (odds ratio [OR]: 4.32; 95% CI: 1.26 to 14.74; p = 0.02); no differences in WRF risk were seen with low-dose dopamine. No significant interaction was seen between diuretic strategy and low-dose dopamine (p > 0.10). Conclusions In HFpEF patients hospitalized with acute heart failure, low-dose dopamine had no significant impact on renal function, and a continuous infusion diuretic strategy was associated with renal impairment. (Diuretics and Dopamine in Heart Failure With Preserved Ejection Fraction [ROPA-DOP]; NCT01901809)

Introduction Cognitive decline is common and increases mortality risk in hemodialysis patients. Intradialytic interventions like cognitive training (CT) and exercise training (ET) may preserve cognitive function. Methods We conducted a pilot randomized controlled trial of 20 hemodialysis patients to study the impact of 3 months of intradialytic CT (tablet-based brain games) (n = 7), ET (foot peddlers) (n = 6), or standard of care (SC) (n = 7) on cognitive function. Global cognitive function was measured by the Modified Mini Mental Status Exam (3MS), psychomotor speed was measured by Trail Making Tests A and B (TMTA and TMTB), and executive function was assessed by subtracting (TMTB − TMTA). Lower 3MS scores and slower TMTA and TMTB times reflected worse cognitive function. P values for differences were generated using analysis of variance, and 95% confidence intervals (CIs) and P values were generated from linear regression. Results Patients with SC experienced a decrease in psychomotor speed and executive function by 3 months (TMTA: 15 seconds; P = 0.055; TMTB: 47.4 seconds; P = 0.006; TMTB − TMTA; 31.7 seconds; P = 0.052); this decline was not seen among those with CT or ET (all P > 0.05). Compared with SC, the difference in the mean change in 3MS score was −3.29 points (95% CI: −11.70 to 5.12; P = 0.42) for CT and 4.48 points (95% CI: −4.27 to 13.22; P = 0.30) for ET. Compared with SC, the difference in mean change for TMTA was −15.13 seconds (95% CI: −37.64 to 7.39; P = 0.17) for CT and −17.48 seconds (95% CI: −41.18 to 6.22; P = 0.14) for ET, for TMTB, the difference was −46.72 seconds (95% CI: −91.12 to −2.31; P = 0.04) for CT and −56.21 seconds (95% CI: −105.86 to −6.56; P = 0.03) for ET, and for TMTB – TMTA, the difference was −30.88 seconds (95% CI: −76.05 to 14.28; P = 0.16) for CT and −34.93 seconds (95% CI: −85.43 to 15.56; P = 0.16) for ET. Discussion Preliminary findings of our pilot study suggested that cognitive decline in psychomotor speed and executive function is possibly prevented by intradialytic CT and ET. These preliminary pilot findings should be replicated.

Systemic lupus erythematosus (SLE), a disorder of the immune system, is potentially curable by allogeneic bone marrow transplantation (alloBMT). Until recently, alloBMT was limited by donor availability and toxicity. Reduced intensity conditioning (RIC) combined with post-transplantation cyclophosphamide (PTCy) has improved the availability and safety of alloBMT permitting its exploration in severe-refractory autoimmune illnesses. We report the six-year follow-up of a young female whose refractory SLE-associated nephrosis resolved after RIC alloBMT with PTCy.

[This corrects the article DOI: 10.1371/journal.pone.0082028.].

Endocrine-disrupting chemicals, such as phthalates, are an unexamined potential risk factor for bacterial vaginosis (BV) and warrant investigation because hormones affect BV. We examined the association between phthalate exposure and BV in the National Health and Nutrition Examination Survey, 2001-2004. BV outcomes were defined as intermediate (Nugent score of 4-6) and positive (7-10). Phthalate metabolites, including monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), and di(2-ethylhexyl) phthalate (DEHP) metabolites, were measured in urine. Among 854 women with complete data, multinomial logistic regression revealed that concentrations of MnBP (Q4 vs. Q1 OR = 3.01, 95% CI 1.76-5.15, p-trend0.001) and ΣDEHP metabolites (Q4 OR = 2.55, 95% CI 1.45-4.47, p-trend = 0.03) were associated with Nugent-score BV, although only MnBP was significant after adjustment for confounders. Associations were null after adjustment for urinary creatinine (MnBP Q4 OR = 1.11, 95% CI 0.63-1.96; ΣDEHP Q4 OR = 0.72, 95% CI 0.37-1.39). Future work should further examine these relationships using direct measurements of intravaginal phthalates exposures.

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.

Background Tenofovir disoproxil fumarate (TDF) may cause acute kidney injury and proximal tubular dysfunction. However, no detailed studies document urinary phosphate wasting as a marker of TDF-induced tubulopathy. Methods Records of HIV-infected patients with presumed TDF toxicity were reviewed. We describe the characteristics and clinical course of 15 patients who had documented elevated (>20%) fractional excretion of phosphate (FEphos). Results Patients were predominantly Caucasian and male (73 and 80%, respectively), with a mean age of 56 years (range 38–76). Of the 15 patients, 11 had a estimated glomerular filtration rate (eGFR) of >90 mL/min/1.732 at time of TDF initiation. The mean duration of TDF therapy prior to diagnosis of TDF toxicity was 64 months. Mean FEphos was 34% (range 20–62). The mean eGFR at TDF initiation was 104 mL/min/1.73 m2 [standard deviation (SD) 17.0] with a gradual decline to 69 mL/min/1.73 m2 (SD 19.0) by the time of TDF discontinuation. Of 10 patients with repeated FEphos after TDF discontinuation, 9 had improvement of their FEphos. Of these individuals, 6 had normalization of their FEphos. Estimated GFR improved in 12 patients after discontinuation of TDF, though importantly, none returned to their baseline eGFR. Conclusions Urinary phosphate wasting is a sensitive marker for TDF-induced proximal tubulopathy and is associated with unrecognized and permanent renal function decline. Tubular dysfunction can develop after years of TDF therapy in those with normal kidney function at the time of drug initiation. This suggests that continuing vigilance be maintained in all those on TDF.

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 patient 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 treatment of HIVAN focusing on ESRD progression, 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 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.

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.

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.

The association between cardiovascular disease and acute renal failure (ARF) and acute-on-chronic renal failure is less well defined. In the cardiac intensive care unit (CICU), the presence of ARF imparts a significant mortality. The predominant aetiology of ARF in the CICU relates to hypotension, although other causes are certainly involved too, and both contrast nephropathy and cholesterol embolisation may be associated with percutaneous coronary intervention. Despite the availability of renal replacement therapies, preventative measures remain the most important element of management. Specific therapy includes management of the patient’s volume status, vasoactive medication and renal replacement therapy in the way of dialysis. In the setting of acute renal failure, both patient and renal outcome is improved with the early involvement of a nephrological service.

The differential diagnosis of proteinuria and hematuria in pregnancy is broad and includes active lupus nephritis. Identification of the correct diagnosis often has a profound therapeutic impact on not only the mother but also the fetus. To date, relatively few reports exist on the role of renal biopsy during pregnancy among women with systemic lupus erythematosus (SLE). We present a case series of 11 pregnant women with SLE who underwent a renal biopsy to evaluate a presumptive flare of lupus nephritis. The electronic medical record was retrospectively analyzed for pre-biopsy serum creatinine, proteinuria, hematuria, antinuclear antibodies (ANA), and antibodies to double-stranded DNA (anti-dsDNA); histologic findings on renal biopsy; and the clinical course of each mother and fetus. From 2001 to 2012, 11 pregnant women with SLE flares during pregnancy underwent a renal biopsy at an academic tertiary medical center. At the time of biopsy, median gestational age was 16 weeks (range 9 to 27), median serum creatinine was 0.6 mg/dl (interquartile range 0.5 to 0.9), six (55%) had hematuria, and all had proteinuria >500 mg/24 hours. Proliferative lupus nephritis was found in 10 (91%) of 11 biopsies (five with ISN/RPS Class III; five with ISN/RPS Class IV). All but one individual underwent a change in management guided by information gleaned from renal biopsy. No apparent biopsy-related complications occurred to mother or fetus. Three women elected to terminate their pregnancy; although many factors were involved, the findings on renal biopsy informed the decision-making process. Among the remaining cases, there were three pre-term deliveries, one fetus with complete heart block, one in utero demise, and one maternal death. Renal biopsy is helpful at informing the management of patients with lupus nephritis during pregnancy.

Summary Background and objectives HIV-associated nephropathy (HIVAN) is well described, but the clinical features of a group of renal pathologies characterized by Ig or immune complex depositions referred to as HIV-associated immune complex kidney disease (HIVICK) have not been well established. The objective of this study is to assess risk factors for HIVICK compared with contemporaneous control participants. Design, setting, participants, & measurements A nested case-control study of 751 HIV-infected patients followed from January 1996 to June 2010 was conducted. Groups were compared using the chi-squared test or rank-sum analysis. Conditional logistic regression was used to estimate odds ratios (ORs) for HIVICK. Incidences of overall ESRD and with/without combined antiretroviral therapy (cART) exposure were calculated. Results HIVICK patients were predominantly African American (92%). Compared with matched controls, patients with HIVICK were more likely to have HIV RNA >400 copies/ml (OR, 2.5; 95% confidence interval [95% CI], 1.2 to 5.2), diabetes (OR, 2.8; 95% CI, 1.1 to 6.8), and hypertension (OR, 2.3; 95% CI, 1.2 to 4.5). Compared with HIVAN, patients with HIVICK had more antiretroviral therapy exposure, lower HIV viral loads, and higher CD4 and estimated GFR. ESRD was less common in the HIVICK versus the HIVAN group (30% versus 82%; P Conclusions HIVICK was predominantly observed in African-American patients and associated with advanced HIV disease. ESRD incidence is lower in HIVICK patients compared with those with HIVAN. Unlike HIVAN, cART use was not associated with the incidence of ESRD in HIVICK.

BACKGROUND Monitoring kidney function is important in HIV-positive persons, but creatinine-based estimates of glomerular filtration rate (GFR) have limitations. There are little to no data available assessing GFR trends in HIV-positive persons using a gold-standard measure of GFR. METHODS We measured GFR based on iohexol plasma disappearance (iGFR) annually for 3 years in nondiabetic, HIV-negative and HIV-positive volunteers with normal estimated kidney function. We used mixed linear models to evaluate factors associated with baseline iGFR and iGFR slope. RESULTS One hundred HIV-negative and 191 HIV-positive, predominantly black individuals (median age 49 years) participated in the study and completed a total of 960 iGFR assessments over a median of 36 months. Despite similar estimated GFR at baseline, average iGFR values were lower in HIV-positive compared with HIV-negative participants (103.2 vs. 110.8, ml/min/1.73 m, P = 0.004). However, subsequent iGFR slope was not significantly different in HIV-positive and HIV-negative participants. In the HIV-positive group, the presence of carotid plaque and hepatitis C virus coinfection were associated with significantly lower iGFR values at baseline. A nonsuppressed HIV RNA level at baseline was associated with a significantly more rapid iGFR decline compared with individuals with HIV RNA less than 400 copies/ml (-4.69 vs. -1.31 ml/min per 1.73 m per year, P = 0.005). Other factors significantly associated with iGFR slope included albuminuria and glycosylated hemoglobin. CONCLUSION Compared with HIV-negative persons, HIV-positive participants had significantly lower baseline iGFR, despite similar estimated GFR in the two groups. Nonsuppressed HIV RNA at baseline was associated with a more rapid iGFR decline over 3 years.

Renal disease in persons with HIV has been a major cause of morbidity and mortality since the onset of the epidemic. HIV nephropathy (HIVAN) was the most common form of kidney disease initially seen, but in the post-antiretroviral therapy (ART) era it is much less common. Other renal conditions associated with HIV infection include immune complex disease and classic focal segmental glomerulosclerosis. The pathologic spectrum of renal disease in patients with HIV is extensive. Some conditions, including HIVAN, improve following treatment of the virus with ART. Acute kidney injury is much more common in HIV-infected patients and is associated with a sixfold increase in mortality. Patients with HIV are also much more likely to require renal replacement therapy, including dialysis and renal transplantation. ART may also contribute to renal disease in patients with HIV.

To determine whether mean arterial blood pressure excursions below the lower limit of cerebral blood flow autoregulation during cardiopulmonary bypass are associated with acute kidney injury after surgery.Tertiary care medical center.Four hundred ten patients undergoing cardiac surgery with cardiopulmonary bypass.Prospective observational study.None.Autoregulation was monitored during cardiopulmonary bypass by calculating a continuous, moving Pearson's correlation coefficient between mean arterial blood pressure and processed near-infrared spectroscopy signals to generate the variable cerebral oximetry index. When mean arterial blood pressure is below the lower limit of autoregulation, cerebral oximetry index approaches 1, because cerebral blood flow is pressure passive. An identifiable lower limit of autoregulation was ascertained in 348 patients. Based on the RIFLE criteria (Risk, Injury, Failure, Loss of kidney function, End-stage renal disease), acute kidney injury developed within 7 days of surgery in 121 (34.8%) of these patients. Although the average mean arterial blood pressure during cardiopulmonary bypass did not differ, the mean arterial blood pressure at the limit of autoregulation and the duration and degree to which mean arterial blood pressure was below the autoregulation threshold (mm Hg × min/hr of cardiopulmonary bypass) were both higher in patients with acute kidney injury than in those without acute kidney injury. Excursions of mean arterial blood pressure below the lower limit of autoregulation (relative risk 1.02; 95% confidence interval 1.01 to 1.03; p0.0001) and diabetes (relative risk 1.78; 95% confidence interval 1.27 to 2.50; p = 0.001) were independently associated with for acute kidney injury.Excursions of mean arterial blood pressure below the limit of autoregulation and not absolute mean arterial blood pressure are independently associated with for acute kidney injury. Monitoring cerebral oximetry index may provide a novel method for precisely guiding mean arterial blood pressure targets during cardiopulmonary bypass.

Background While urine flow rate ≤0.5 ml kg−1 h−1 is believed to define oliguria during cardiopulmonary bypass (CPB), it is unclear whether this definition identifies risk for acute kidney injury (AKI) . The purpose of this retrospective study was to evaluate if urine flow rate during CPB is associated with AKI. Methods Urine flow rate was calculated in 503 patients during CPB. AKI in the first 48 h after surgery was defined by the Kidney Disease: Improving Global Outcomes classification. Adjusted risk factors associated with AKI and urine flow rate were assessed. Results Patients with AKI [n=149 (29.5%)] had lower urine flow rate than those without AKI (P Conclusions Urine flow rate during CPB Clinical trial registration ClinicalTrials.gov NCT00769691 and NCT00981474.

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.