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Background Performing catheter-care observations in outpatient hemodialysis facilities are one of the CDC9s core interventions, which have been proven to reduce bloodstream infections. However, staff have many competing responsibilities. Efforts to increase and streamline the process of performing observations are needed. We developed an electronic catheter checklist, formatted for easy access with a mobile device, and conducted a pilot project to determine the feasibility of implementing it in outpatient dialysis facilities. Methods The tool contained the following content: (1) patient education videos; (2) catheter-care checklists (connection, disconnection, and exit-site care); (3) prepilot and postpilot surveys; and (4) a pilot implementation guide. Participating hemodialysis facilities performed catheter-care observations on either a weekly or monthly schedule and provided feedback on implementation of the tool. Results The pilot data were collected from January 6 through March 12, 2020, at seven participating facilities. A total of 954 individual observations were performed. The catheter-connection, disconnection, and exit-site steps were performed correctly for most individual steps; however, areas for improvement were (1) allowing for appropriate antiseptic dry time, (2) avoiding contact after antisepsis, and (3) applying antibiotic ointment to the exit site. Postpilot feedback from staff was mostly favorable. Use of the electronic checklists facilitated patient engagement with staff and was preferred over paper checklists, because data are easily downloaded and available for use in facility Quality Assurance and Performance Improvement (QAPI) meetings. The educational video content was a unique learning opportunity for both patients and staff. Conclusions Converting the CDC9s existing catheter checklists to electronic forms reduced paperwork and improved the ease of collating data for use during QAPI meetings. An additional benefit was the educational content provided on the tablet, which was readily available for viewing by patients and staff while in the hemodialysis facility.

Background Patients with ESKD who are on chronic hemodialysis have a high burden of comorbidities that may place them at increased risk for adverse outcomes when hospitalized with COVID-19. However, data in this unique patient population are limited. The aim of our study is to describe the clinical characteristics and short-term outcomes in patients on chronic hemodialysis who require hospitalization for COVID-19. Methods We performed a retrospective study of 114 patients on chronic hemodialysis who were hospitalized with COVID-19 at two major hospitals in the Bronx from March 9 to April 8, 2020 during the surge of SARS-CoV-2 infections in New York City. Patients were followed during their hospitalization through April 22, 2020. Comparisons in clinical characteristics and laboratory data were made between those who survived and those who experienced in-hospital death; short-term outcomes were reported. Results Median age was 64.5 years, 61% were men, and 89% were black or Hispanic. A total of 102 (90%) patients had hypertension, 76 (67%) had diabetes mellitus, 63 (55%) had cardiovascular disease, and 30% were nursing-home residents. Intensive care unit (ICU) admission was required in 13% of patients, and 17% required mechanical ventilation. In-hospital death occurred in 28% of the cohort, 87% of those requiring ICU, and nearly 100% of those requiring mechanical ventilation. A large number of in-hospital cardiac arrests were observed. Initial procalcitonin, ferritin, lactate dehydrogenase, C-reactive protein, and lymphocyte percentage were associated with in-hospital death. Conclusions Short-term mortality in patients on chronic hemodialysis who were hospitalized with COVID-19 was high. Outcomes in those requiring ICU and mechanical ventilation were poor, underscoring the importance of end-of-life discussions in patients with ESKD who are hospitalized with severe COVID-19 and the need for heightened awareness of acute cardiac events in the setting of COVID-19. Elevated inflammatory markers were associated with in-hospital death in patients with ESKD who were hospitalized with COVID-19.

Bloodstream infections are an important cause of hospitalizations, morbidity, and mortality in patients receiving hemodialysis. Eliminating bloodstream infections in the hemodialysis setting has been the focus of the Centers for Disease Control and Prevention (CDC) Making Dialysis Safer for Patients Coalition and, more recently, the CDC's partnership with the American Society of Nephrology's Nephrologists Transforming Dialysis Safety Initiative. The majority of vascular access-associated bloodstream infections occur in patients dialyzing with central vein catheters. The CDC's core interventions for bloodstream infection prevention are the gold standard for catheter care in the hemodialysis setting and have been proven to be effective in reducing catheter-associated bloodstream infection. However, in the United States hemodialysis catheter-associated bloodstream infections continue to occur at unacceptable rates, possibly because of lapses in adherence to strict aseptic technique, or additional factors not addressed by the CDC's core interventions. There is a clear need for novel prophylactic therapies. This review highlights the recent advances and includes a discussion about the potential limitations and adverse effects associated with each option.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.

Background COVID-19 mortality disproportionately affects the Black population in the United States (US). To explore this association a cohort study was undertaken. Methods We assembled a cohort of 505,992 patients receiving ambulatory care at Bronx Montefiore Health System (BMHS) between 1/1/18 and 1/1/20 to evaluate the relative risk of hospitalization and death in two time-periods, the pre-COVID time-period (1/1/20–2/15/20) and COVID time-period (3/1/20–4/15/20). COVID testing, hospitalization and mortality were determined with the Black and Hispanic patient population compared separately to the White population using logistic modeling. Evaluation of the interaction of pre-COVID and COVID time periods and race, with respect to mortality was completed. Findings A total of 9,286/505,992 (1.8%) patients were hospitalized during either or both pre-COVID or COVID periods. Compared to Whites the relative risk of hospitalization of Black patients did not increase in the COVID period (p for interaction=0.12). In the pre- COVID period, compared to Whites, the odds of death for Blacks and Hispanics adjusted for comorbidity was statistically equivalent. In the COVID period compared to Whites the adjusted odds of death for Blacks was 1.6 (95% CI 1.2–2.0, p = 0.001). There was a significant increase in Black mortality risk from pre-COVID to COVID periods (p for interaction=0.02). Adjustment for relevant clinical and social indices attenuated but did not fully explain the observed difference in Black mortality. Interpretation The BMHS COVID experience demonstrates that Blacks do have a higher mortality with COVID incompletely explained by age, multiple reported comorbidities and available metrics of sociodemographic disparity. Funding N/A

Tunneled central venous catheters used for the provision of hemodialysis are associated with excess morbidity and mortality. Catheter related exit site and blood stream infections are major risks of their use. Although catheter-avoidance is the best strategy to reduce infections and mortality in the hemodialysis population, the use of catheters remains unacceptably high. In this review, the existing clinical practice guidelines for the prevention of hemodialysis catheter associated infections are outlined, and a comprehensive evidenced-based summary of interventions is provided. This includes details about the use of topical antimicrobial ointments and dressings, intranasal ointment application, prophylactic use of antibiotic and non-antibiotic catheter lock solutions, and catheter hub devices for the prevention of catheter blood stream infections.

Central venous catheters are used frequently in patients on hemodialysis as a bridge to a permanent vascular access. They are prone to frequent complications, including catheter-related bloodstream infection, catheter dysfunction, and central vein obstruction. There is a compelling need to develop new drugs or devices to prevent central venous catheter complications. We convened a multidisciplinary panel of experts to propose standardized definitions of catheter end points to guide the design of future clinical trials seeking approval from the Food and Drug Administration. Our workgroup suggests diagnosing catheter-related bloodstream infection in catheter-dependent patients on hemodialysis with a clinical suspicion of infection (fever, rigors, altered mental status, or unexplained hypotension), blood cultures growing the same organism from the catheter hub and a peripheral vein (or the dialysis bloodline), and absence of evidence for an alternative source of infection. Catheter dysfunction is defined as the inability of a central venous catheter to (1) complete a single dialysis session without triggering recurrent pressure alarms or (2) reproducibly deliver a mean dialysis blood flow of >300 ml/min (with arterial and venous pressures being within the hemodialysis unit parameters) on two consecutive dialysis sessions or provide a Kt/V≥1.2 in 4 hours or less. Catheter dysfunction is defined only if it persists, despite attempts to reposition the patient, reverse the arterial and venous lines, or forcefully flush the catheter. Central vein obstruction is suspected in patients with >70% stenosis of a central vein by contrast venography or the equivalent, ipsilateral upper extremity edema, and an existing or prior history of a central venous catheter. There is some uncertainty about the specific criteria for these diagnoses, and the workgroup has also proposed future high-priority studies to resolve these questions.

Background Classification and treatment decisions in lupus nephritis (LN) are largely based on renal histology. Single-cell RNA sequencing (scRNAseq) analysis may accurately differentiate types of renal involvement at the transcriptomic level, and better inform treatment decisions and prognosis. Methods scRNAseq was performed on kidney and non-lesional skin tissue collected from 20 SLE patients undergoing a clinically indicated renal biopsy. Cell types were determined using principal component analysis and t-distributed stochastic neighbor embedding (tSNE) plotting, resulting in the definitive identification of keratinocytes, tubular cells, mesangial cells, fibroblasts, endothelial cells, and leukocytes. Results LN patients expressed upregulated IFN response genes in both their tubular cells and keratinocytes. This IFN response signature in tubular cells predicted poor response to therapy 6 months post-biopsy. Tubular cells of non-responder patients also expressed upregulated extracellular matrix proteins and fibrotic markers (figure 1A and 1B). Using logistic regression analysis, a 4-gene tubular fibrosis score was created and able to predict response to treatment with an area under curve of 0.9 (figure 1C). Keratinocytes of non-responders also upregulated certain extracellular matrix genes and this response was not observed in peripheral blood mononuclear cells. Differential expression analysis between histology classes indicated an upregulation of IFN and TNF signaling in the tubular cells of patients with proliferative LN compared with membranous. Conclusions scRNAseq from 2–10 mm of renal biopsy tissue in SLE can differentiate between the different classes of LN, and provide important insights into potential pathogenic mechanisms. Further, changes in the skin of LN patients can provide a useful source of biomarkers and may reflect important information concerning concurrent kidney pathological events. Funding Source(s): This work was supported by the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public-private partnership (AbbVie, Arthritis Foundation, Bristol-Myers Squibb, Foundation for the National Institutes of Health, Lupus Foundation of America, Lupus Research Alliance, Merck Sharp and Dohme, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, Rheumatology Research Foundation, Sanofi, and Takeda Pharmaceuticals) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, and UM2-AR067678).

Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). Design, setting, participants, & measurements We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC)

Lupus nephritis (LN) occurs in up to 50% of patients with systemic lupus erythematosus (SLE), and is a major contributor to mortality and morbidity. LN presents as a highly heterogeneous disease both in histopathology and response to therapy. The molecular and cellular processes leading to renal damage and to the heterogeneity of the disease are not well understood. To elucidate the processes underpinning the heterogeneity of LN, we applied singlecell RNA-sequencing (scRNA-seq) to renal biopsies from LN patients. Skin biopsies were evaluated as a source of biomarkers for monitoring kidney disease. Type-I interferon (IFN) response signatures were identified in tubular cells and keratinocytes, differentiating LN patients from healthy controls. Non-responders associated with higher IFN signatures in both tissue compartments. Moreover, non-response was also associated with a fibrotic signature in the tubular cells. Receptor-ligand interaction analysis indicated that the fibrotic process is likely mediated by FGF receptors with the initiating signal originating from infiltrating leukocytes. Differential expression analysis of tubular cells between proliferative and membranous LN pointed to several fibrosis-relevant pathways, which may offer insight into their histological differences. In summary, scRNA-seq was applied to LN to deconstruct its heterogeneity and provide novel targets for personalized approaches to therapy.

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Understanding healthcare providers' preferences, values, and beliefs around AVF eligibility is important to explain variability in practice. We conducted a survey of international surgeons, using hypothetical patient scenarios, to assess resources used, variables, perceived barriers, and absolute contraindications to access creation. A total of 134 surgeons completed the survey. Venous duplex ultrasound mapping (VDUM) was offered to all patients by 90% of US, 68% Canadian, and 63% European respondents. VDUM altered clinical decision less than 25% of the time for 33% American, 48% Canadian, and 85% European surgeons. Increased comorbidities and previous failed access were deterrents to AVF creation as was vessel size. Second choice access was the AV graft in the US and Europe and the catheter in Canada. Absolute contraindications to AVF creation included patient life expectancy

Central venous catheter-related infections have been associated with high morbidity, mortality, and costs. Catheter use in chronic hemodialysis patients has been recognized as distinct from other patient populations who require central venous access, leading to recent adaptations in guidelines-recommended diagnosis for catheter-related bacteremia (CRB). This review will discuss the epidemiology and pathogenesis of hemodialysis CRB, in addition to a focus on interventions that have favorably affected CRB outcomes. These include: (1) the use of prophylactic topical antimicrobial ointments at the catheter exit site, (2) the use of prophylactic catheter locking solutions for the prevention of CRB, (3) strategies for management of the catheter in CRB, and (4) the use of vascular access managers and quality initiative programs.

In the United States, over 340,000 patients have end-stage renal disease treated by hemodialysis (HD) and are dependent on a reliable vascular access. In over 80% of patients initiating HD, this access is the central venous catheter (CVC). Although the CVC has many advantages that make it desirable for dialysis initiation—ease of insertion, unnecessary maturation time, and availability for immediate use—it is not without significant disadvantages. The substantial morbidity and mortality associated with CVC use has been well documented in the literature. 1 , 2 Initiating and maintaining HD patients using a CVC is suboptimal from the perspective of both patient care and associated long-term costs. Yet, in the United States, the most common HD access-related event is replacement of any vascular access type with a CVC. 3 Although in recent years greater effort has be made to reduce CVC use, some patients are unable to have a functioning arteriovenous fistula or graft created due to exhaustion of vessels from previous permanent accesses or limiting comorbidities. In patients dependent on long-term CVC use, the primary problems are due to malfunction (‘poor flows') or infection. Catheter malfunction leads to inadequate dialysis, the need for costly and inconvenient intervention, and reduced quality of life. This review will focus on the etiology, prevention, and management of CVC-related malfunction.

Purpose To determine the association between the initial hemodialysis (HD) vascular access type and short-term changes in inflammation markers. Methods This is a prospective, observational study in incident chronic kidney disease (CKD) (stages 4 and 5) patients receiving their first HD vascular access. Serum samples were obtained pre-access placement, and 1 week, and 1 month post-access insertion. Samples were tested for high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) using ELISA. Patients with known inflammatory states (infection, malignancy, connective tissue disorders, organ transplantation and those on immune modulating agents) were excluded. The hsCRP and IL-6 values were transformed into logarithmic scale. Chi-square analysis, independent and paired t-tests were performed where appropriate, and a two-way ANOVA with time as a repeated measure was also performed. Significance was determined at p=0.05. Results One-month follow-up data was obtained in 48 patients (arteriovenous fistula (AVF), n=10; tunneled catheter (TC), n=28; arteriovenous graft (AVG), n=10). A significant increase in both hsCRP (pConclusions In CKD patients, TC and AVG insertion result in a transient state of inflammation 1 week post-operatively, which is not observed after AVF surgery. Whether this is a persistent phenomenon after TC insertion requires a larger, longitudinal study.

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1–associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR ¼ 5.0, 95% CI ¼ 3.5–7.1; P ¼ 4 � 10 � 23 , n ¼ 852). This association extended to hypertensive ESKD (OR ¼ 2.2, 95% CI ¼ 1.5–3.4; n ¼ 433), but not type 2 diabetic ESKD (n ¼ 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.

The management of tunneled cuffed catheter (TCC)-associated bacteremias varies among nephrologists. To determine whether patient outcomes after TCC-associated bacteremia can be improved by modifying the management model, we performed an interventional controlled trial comparing a collaborative team model, intervention (INT), with the usual physician-managed model, usual care (UC).INT consisted of an infection manager who worked closely with nephrologists and dialysis staff and made treatment recommendations using the available published guidelines at the time of the study's conception (Dialysis Outcomes Quality Initiative guideline no. 26, 1997) and additional literature-based recommendations. Nephrologists made the final treatment decisions. TCC-associated bacteremia was physician managed in the UC group.Two hundred twenty-three episodes of TCC-associated bacteremia occurred in 7 outpatient hemodialysis units during the 2-year study period. The INT was associated with a significantly lower incidence of recurrent bacteremia with the same organism (INT, 6% versus UC, 18%; odds ratio, 0.28; 95% confidence interval, 0.09 to 0.8; P = 0.015) and death from sepsis (INT, 0% versus UC, 6%; P0.02). In INT units, there was a 45% decrease in the practice of TCC salvage (TCC not removed; P = 0.05). Antibiotic prescribing practices (final antibiotic selection, dose, and duration of therapy) were improved in INT units compared with UC units. By using multivariate analysis, the INT was associated with a 73% decrease in the combined outcome of recurrent bacteremia or septic death (P0.02).Implementation of a collaborative team model for the management of TCC-associated bacteremic episodes is associated with improvement in the quality of heath care delivery and patient outcomes.

Background. Infection is a serious complication of tunnelled cuffed catheter (TCC) use and is associated with high complication and mortality rates. Although attempts at TCC salvage after bacteraemia have been associated with high rates of recurrent bacteraemia, there have been no large studies in which multivariate analysis has been performed to control for confounding factors such as infecting organisms, diabetes, etc. Methods. A prospective observational study was performed in chronic HD patients dialyzing with a TCC at seven outpatient HD centers. All patients diagnosed with TCC bacteraemia were observed for 3 months following initial presentation and outcomes were recorded. Results. During the 2.5 year study period, 226 patients had an episode of TCC bacteraemia that met inclusion criteria, and 3 month follow-up data were available in 219 episodes. Treatment failure, defined as recurrent TCC bacteraemia with the same organism or death from sepsis, occurred in 26 patients (12%). Infectious complications (such as endocarditis, osteomyelitis, etc.) occurred in 16 patients (7%), bacteraemia with a different organism occurred in 19 patients (9%), and death from sepsis occurred in eight patients (4%). Significant predictors of treatment failure (by univariate analysis) were TCC salvage, and infection with Staphylococcus aureus, (OR ¼ 4.2, P ¼ 0.002; and OR ¼ 3.3, P ¼ 0.02, respectively). TCC salvage, when used in episodes of S. aureus bacteraemia, was associated with an 8-fold higher risk of treatment failure (P ¼ 0.001). The presence of an abnormal TCC exit site was associated with a significantly higher rate of death from sepsis, (OR ¼ 7, P ¼ 0.001). Outcomes (treatment failure and infectious complications) did not differ among bacteraemic episodes where the TCC was exchanged over a guidewire compared to those in which the TCC was immediately removed followed by delayed reinsertion. In the multivariate analysis, adjusted for potential confounding covariates, the only significant predictors of treatment failure after an episode of TCC bacteraemia were TCC salvage (OR ¼ 5.4, P ¼ 0.003), and S. aureus (OR ¼ 4.2, P ¼ 0.002). In a multivariate analysis, controlling for TCC management, the only variable that was significantly associated with the development of an infectious complication was infection with S. aureus (OR ¼ 3.5, P ¼ 0.02). Conclusions. We have shown, using multivariate analysis and adjusting for potential confounding factors, that the use of TCC salvage and S. aureus are independent risk factors for treatment failure after an episode of TCC bacteraemia, and that S. aureus is an independent risk factor for developing an infectious complication. An infected-appearing TCC exit site is associated with a higher mortality rate. Episodes of TCC bacteraemia treated using TCC salvage are associated with the highest treatment failure rates. TCC guidewire exchange can be an acceptable practice, unless severe exit site or tunnel infection is present.

Background. Pseudomonas is regarded as a particularly lethal bacterial isolate. High mortality rates have been reported in episodes of Pseudomonas sepsis when associated with visceral infections as seen in immuno-suppressed, hospitalized patients. In comparison, lower mortality rates have been reported with catheter-associated Pseudomonas bacteraemia in non-dialysis patients. The purpose of this study was to determine the risk factors and the outcomes for episodes of Pseudomonas bacteraemia associated with the use of tunnelled cuffed haemodialysis catheters (TCCs) in a chronic out-patient population. Methods. We performed a prospective observational study in seven chronic haemodialysis units over a 2.5 year period. Patients who were diagnosed as having their initial TCC-associated bacteraemia within the study period were followed for 3 months. All episodes of Pseudomonas TCC bacteraemia were identified, and univariate analyses were performed to compare Pseudomonas bacteraemia with non-Pseydinibas bacteraemia. Results. During the study period, 219 episodes of TCC bacteraemia were identified; 18 had a Pseudomonas isolate (8%). Pseudomonas bacteraemia episodes were associated with a significantly higher risk of not receiving appropriate initial antibiotics (odds ratio = 3.6, P=0.02). There were no deaths in the Pseudomonas bacteraemia group, whereas 19% died in the non-Pseudomonas group. The TCC was removed in 89% of Pseudomonas bacteraemias. There were no significant risk factors for acquiring a Pseudomonas isolate, and no difference in recurrent bacteraemia or infectious complication rates between the groups. Conclusions. In haemodialysis patients with a TCC-associated Pseudomonas bacteraemia, outcomes are remarkably good. This may be because the source of Pseudomonas infection was removed in most cases. Initial antibiotic coverage lacking anti-Pseudomonas activity was not associated with increased mortality.

We report the identification of a novel Wilms tumor suppressor gene mutation in a 5-month-old girl who presented with unilateral Wilms tumor (WT) and renal diffuse mesangial sclerosis typical of Denys-Drash syndrome (DDS). The patient did not have ambiguous genitalia and the karyotype (by amniocentesis) was 46, XX. A de novo constitutional heterozygous mutation in WT1 gene exon 9 coding for the third zinc-finger (1163G--A, C388Y) was identified. This mutation affects a cysteine residue involved in the coordination of the zinc atom, confirming the importance of these residues in the biological function of WT1 protein.

Infection rates in tunneled-cuffed catheters (TCC) are reported to be higher in immunocompromised patients. The purpose of this study was to evaluate TCC-associated infection rates in patients with HIV infection (HIV+). Data were collected in 40 HIV + patients and 41 controls (C), and in 118 TCC (HIV+, 58; C, 60) for 28,146 catheter days (HIV+, 16,227; C, 11,919). There were no significant differences in the TCC bacteremia rates (HIV+, 2.23 versus C, 2.53 per 1000 TCC days, P: = NS) or in the TCC exit site infection rates (HIV+, 2.20 versus C, 2.24 per 1000 TCC days, P: = NS) between the groups. The number of TCC removed due to infection was also similar, (HIV+ versus C: 17 versus 15%, P: = NS). In the HIV+ group, the association of hepatitis B surface antigenemia with TCC exit site infection was dependent on the history of injection drug use. Black race was a significant risk factor for higher TCC exit site infection rates, whereas prophylactic antibiotic use and high CD4 count were significantly associated with lower TCC exit site infection rates. None of the factors significantly predicted bacteremia rate in either group (HIV+ or C). In comparison to controls, HIV+ patients had a fivefold increased risk of having a Gramnegative organism (P: = 0.02) and a sevenfold increased risk of a fungal isolate (P: = 0.08), although the latter finding was not statistically significant. HIV infection is not a significant risk factor for TCC-associated infection but is associated with a higher prevalence of Gram-negative and fungal species.

Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies. Background Mature podocytes are growth-arrested because of the expression of cyclin-dependent kinase inhibitors. Under pathological conditions, podocytes may undergo mitosis, but not cell division. Exceptions to this rule are collapsing glomerulopathies (CGs), including HIV-associated nephropathy (HIVAN) and idiopathic CG, where podocytes undergo a dysregulation of their differentiated phenotype and proliferate. Methods To shed light on the mechanism underlying podocyte proliferation in CG, we analyzed the expression of the proliferation marker Ki-67, cyclins (A, D1), cyclin-dependent kinase inhibitors (p27, p57), and podocyte differentiation marker synaptopodin in eight cases of HIVAN and two cases of idiopathic CG. Normal fetal and adult kidneys served as controls. Results Both HIVAN and idiopathic CG showed a marked reduction in the expression of p27, p57, and cyclin D1 (absent in 69, 62, and 80% of all glomeruli, respectively). Cyclin A and Ki-67 were expressed in 11 and 29% of all glomeruli. Moreover, there was partial loss of synaptopodin and cyclin D1 expression in nonaffected glomeruli. Conclusions The loss of p27 and p57 leading to expression of cyclin A may account for the activation of podocyte proliferation in CG. Furthermore, the loss of cyclin D1 from histologically normal glomeruli suggests a possible role of cyclin D1 in mediating the dysregulation of the podocyte cell cycle in CG. These novel findings offer insight into the molecular regulation of mature podocyte differentiation. Podocyte proliferation in CG provides evidence in support of a previously underestimated plasticity of mature podocytes.

Life-threatening digoxin toxicity may be effectively treated with digoxin-specific antibody fragments (Fab). However, in end-stage renal disease, the digoxin-Fab complexes persist in the circulation and dissociate, potentially resulting in rebounding free digoxin levels and the recurrence of symptomatic toxicity. To prevent this rebound phenomenon, plasma exchange (PE) has been implemented for the removal of the digoxin-Fab complexes in renal failure. However, there is only one case report describing its use in this setting. To better determine the optimal timing of PE after Fab administration, we performed two PE treatments (each preceded by Fab) in a patient with acute renal failure and acute digoxin poisoning. The admission serum digoxin level was 21 ng/mL. The timing of the PE treatments relative to Fab dosing was as follows: the first PE was performed 26 hours post-Fab, and the second PE was performed 2.5 hours post-Fab. The plasma ultrafiltrate digoxin concentration was 2.5-fold greater when PE was performed 2.5 hours versus 26 hours after Fab administration (19.9 versus 8.1 ng/mL). The combined total amount of digoxin removed in the ultrafiltrate plasma was minimal (0.13 mg), less than 1% of the total amount of ingested drug. We conclude that the optimal timing of PE is within the first 3 hours after Fab administration. Although PE is efficacious for removing digoxin-Fab complexes, thus preventing rebound digoxin toxicity, it is not efficacious for improving total digoxin clearance because of the large apparent volume of distribution of digoxin (5 to 8 L/kg).

Reports of human immunodeficiency virus-associated nephropathy (HIVAN) occurring in Hispanics, females and heterosexuals are scarce. We reviewed 858 charts from our total HIV population to determine the prevalence and epidemiology of HIVAN at our center, and to evaluate the renal and patient survival among individual groups, according to race, sex and HIV risk factor. The prevalence of HIVAN was low (1.9%), relative to other centers (4–13%). Although Hispanics accounted for 56% of the HIV population, only 38% of HIVAN patients were Hispanic. The absolute risk of HIVAN in blacks was 3.6%, and in Hispanics was 1.3%. The relative risk of blacks vs. Hispanics was 2.8% (p < 0.04). Women and men were represented equally in both the HIVAN and HIV populations. The mean (± SE) rate of decline in glomerular filtration rate was 3.7 ± 0.9 ml/min/month, and patient survival following the onset of HIVAN was 23.6 ± 4.8 months. We found no difference in renal or patient survival between individual groups. In summary, the risk of HIVAN in Hispanics is similar to that for whites. Male sex is not an independent risk factor. Both renal and patient survival are similar in blacks and Hispanics, and in men compared to women.

Therapeutic plasma exchange is a treatment modality used in a variety of disease states, some of which are characterized by renal involvement (ie, Goodpasture's syndrome, multiple myeloma, cryoglobulinemia, and thrombotic thrombocytopenic purpura). To investigate the safety of this procedure we evaluated all patients receiving plasma-pheresis at the University of Connecticut from January 1988 to June 1991. Sixty-eight adverse reactions occurred in 699 treatments, resulting in an incidence of 9.7%. The most frequent complications were symptoms of hypocalcemia, hypovolemia, and anaphylactoid reactions. The incidence of hypocalcemic symptoms was lowered with the prophylactic administration of calcium. Without calcium prophylaxis the incidence of symptoms was 9.1% (six in 66 treatments), whereas with calcium prophylaxis the incidence was reduced to 1% (six in 633 treatments) (P < 0.01). Treatments in which albumin was administered as volume replacement were associated with fewer adverse reactions when compared with those using fresh-frozen plasma (1.4% v 20%). Our experience, combined with the 15,658 procedures reported in the literature, reveals that serious complications do not commonly occur. These are characterized by cardiovascular events (0.2%), respiratory events (0.2%), and anaphylactoid reactions (0.25%). Hemorrhage and infection are rare, each occurring at a rate of 0.02%. Death was reported in eight of 15,658 procedures (0.05%). We conclude that therapeutic plasma exchange is relatively safe and alterations in plasma proteins generally are well tolerated. Prophylactic calcium administration lowers the incidence of hypocalcemic symptoms. Adverse reactions are associated more commonly with the administration of fresh-frozen plasma.

Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-nine-fold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P = 0.01) and faster progression to ESRD (P < 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIV-infected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.

Background. The contribution of the hemodialysis (HD) vascular access type to inflammation is unclear. Methods. We conducted a prospective observational study in an incident HD population. C-reactive protein (CRP), interleukin-6 (IL-6), and interferon-γ-induced protein (IP-10) were measured before and at 6-time points after access placement for 1 year. Results. Sixty-four incident HD patients were included (tunneled catheter (TC), 𝑛 = 4 0 , arteriovenous fistula (AVF), 𝑛 = 1 4 , and arteriovenous graft (AVG), 𝑛 = 1 0 ). A mixed effects model was performed to adjust for age, sex, race, coronary artery disease, diabetes mellitus, infections, access thrombosis, initiation of HD, and days after access surgery. In comparison to AVFs, the presence of a TC was associated with significantly higher levels of CRP ( 𝑃 = 0 . 0 3 ), IL-6 ( 𝑃 = 0 . 0 7 ), and IP-10 ( 𝑃 = 0 . 0 3 ). The presence of an AVG was associated with increases in CRP ( 𝑃 = 0 . 0 1 ) and IP-10 ( 𝑃 = 0 . 0 7 ). Conclusions. Patients who initiate HD with a TC or an AVG have a heightened state of inflammation, which may contribute to the excess 90-day mortality after HD initiation.

Background. There is marked variation in the use of the arteriovenous fistula (AVF) across programmes, regions and countries not explained by differences in patient demographics or comorbidities. The lack of clear criteria of who should or should not get a fistula may contribute to this, as well as barriers to creating AVFs. Methods. We conducted a survey of Canadian and American nephrologists to assess the patient variables considered to determine the timing and type of access requested. Perceived barriers and absolute contraindications to access were also collected. Results. An immediate referral for a fistula was more highly preferred when patients are

This Practice Point commentary discusses the findings and limitations of a meta-analysis that evaluated the use of prophylactic antibiotics for hemodialysis catheters. Use of prophylactic topical antibiotics at the catheter exit site was associated with a significant reduction in catheter-related bacteremia, exit-site infections, catheter removals due to secondary complications, hospitalizations for infection, and patient mortality. Use of prophylactic intraluminal antibiotic instillation was associated with a significantly reduced risk of catheter-related bacteremia and need for catheter removal. This commentary highlights the issues that should be considered when interpreting and generalizing these results, including the variability of antibiotic type and catheter type (nontunneled vs tunneled), the use of co-interventions in the various trials, and potential publication bias. The known benefits of prophylactic antibiotic use in patients with hemodialysis catheters are strongly supported by this meta-analysis.

Wilms’ tumor gene ( WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular scarring. To test whether genetic variations in WT1 and WIT1 (gene immediately 5′ to WT1) associate with focal segmental glomerulosclerosis (FSGS), patients with biopsy-proven idiopathic and HIV-1-associated FSGS were enrolled in a multicenter study. We genotyped SNP rs6508 located in WIT1 exon 1, three SNPs (rs2301250, rs2301252, rs2301254) in the promoter shared by WT1 and WIT1, rs2234590 in exon 6, rs2234591 in intron 6, rs16754 in exon 7, and rs1799937 in intron 9 of WT1. Cases ( n = 218) and controls ( n = 281) were compared in the African American population. Stratification by HIV-1 infection status showed that SNPs rs6508, rs2301254, and rs1799937 were significantly associated with FSGS [rs6508 odds ratio (OR) 1.82, P = 0.006; rs2301254 OR 1.65, P = 0.049; rs1799937 OR 1.91, P = 0.005] in the non-HIV-1 group and rs2234591 (OR 0.234, P = 0.011) in the HIV-1 group. Haplotype analyses in the population revealed that seven SNPs were associated with FSGS; five SNPs had the highest contingency score [−log10( P value) = 13.57] in the HIV-1 group. This association could not be explained by population substructure. We conclude that SNPs in WT1 and WIT1 genes are significantly associated with FSGS, suggesting that variants in these genes may mediate pathogenesis by altering WT1 function. Furthermore, HIV-1 infection status interacts with genetic variations in both genes to influence this phenotype. We speculate that nephropathy liability alleles in WT1 pathway genes cause podocyte dysfunction and glomerular scarring.

Aims: In the existing literature, there is a paucity of data regarding large atrial thrombus (AT) formation occurring as a complication of tunneled cuffed hemodialysis catheter (TCC) use. This study was performed to determine the risk factors, mortality and the appropriate management of TCC-AT. Methods: We report 6 new cases of TCC-AT and have amalgamated these data with data from 16 previously published cases of TCC-AT found by performing a PubMed literature search (total of 22 cases). Demographic data were collected prospectively over 2 years in 85 consecutive patients initiating hemodialysis who were using a TCC as their primary vascular access, so that comparisons could be made between the 6 patients with TCC-AT versus all patients with a TCC at our center. Results: In patients with TCC-AT, the mean time from TCC insertion was 4.5 months, and infection was present at the time of diagnosis in 68% of cases. The mean thrombus size was 3.7 cm, range 1.5 - 8 cm. All but 1case were visualized by echocardiography; the remaining case required magnetic resonance imaging. Management included TCC removal and thrombectomy (n = 9), TCC removal and anticoagulation (AC) (n = 6), TCC removal alone (n = 5), and no intervention (n = 2). The overall mortality was 27%, and 5 of the 6 deaths (83%) occurred in patients with bacteremia. The mortality associated with each management strategy was as follows: TCC removal and thrombectomy (0%), TCC removal and AC (33%), TCC removal alone (40%), and no intervention (100%). Conclusions: AT is a serious complication of TCC use in hemodialysis patients and may be associated with a high mortality rate. TCC-AT may occur more commonly than previously reported and therefore warrants a high index of suspicion.

Background. Immediate tunnelled, cuffed catheter (TCC) removal is the current standard of care when bacteraemia is associated with severe clinical symptoms. When minimal or no symptoms are present, the optimal strategy of TCC management is controversial. The following three strategies have been proposed: TCC 'salvage' (antibiotic administration without TCC removal), TCC exchange over a guidewire with antibiotics or immediate TCC removal with delayed reinsertion and antibiotics. Methods. We developed a decision analytic model to assess the cost-effectiveness of 'each strategy for episodes of TCC-associated bacteraemia presenting with minimal symptoms, in a hypothetical cohort of haemodialysis patients followed for a 3 month period. Data regarding the probability of treatment failure due to recurrent infection for each strategy, secondary infectious complications and patient mortality were obtained from existing clinical trials and from the 1998 United States Renal Data System database. Costs were substituted with the current 2000 New York hospital charges. Results. Tunnelled, cuffed catheter exchange over a guidewire was associated with a reduction in net charges of $5241 and $750 when compared with TCC salvage and immediate TCC removal, respectively. The expected 3 month patient survival for TCC guidewire exchange and immediate TCC removal were similar (93%), whereas survival for TCC salvage was worse (89%). Tunnelled, cuffed catheter guidewire exchange remained the most cost-effective strategy when the probability of treatment failure with recurrent bacteraemia in 3 months was

Type “B” lactic acidosis has been described in patients receiving the nucleoside analogs zidovudine, didanosine, and fialuridine. Lactic acidosis has also been described in 4 patients receiving combination therapy with stavudine and lamivudine. We describe the development of chronic type “B” lactic acidosis in 3 patients receiving stavudine as a single agent and in 2 patients receiving combination therapy with stavudine and either lamivudine or delavirdine, a nonnucleoside analog. All patients presented with abdominal pain, vomiting, and hepatic steatosis. Other signs of mitochondrial toxicity included pancreatitis and myopathy (2 cases). The mean duration of stavudine therapy was 9.4 months, and the mean observed peak lactate was mmol/L. After discontinuation of stavudine treatment, lactic acidosis level 5 SD 10.3 5 5 improved in 4 patients after 4‐60 weeks, and 1 patient died. Evaluations for other causes of lactic acidosis, including hypoxemia, malignancy, sepsis, and cardiogenic shock, were negative. Type “B” lactic acidosis is a rare but potentially life-threatening complication of nucleoside analog therapy and is often accompanied by other serious clinical manifestations of mitochondrial toxicity, such as hepatic steatosis, pancreatitis, and myopathy. This syndrome has been reported with single nucleoside analog therapy with zidovudine, didanosine, or fialuridine and with combination therapy with lamivudine and stavudine [1‐5]. We report 5 cases of stavudine-associated lactic acidosis; 2 are described in detail, and 3 additional cases are summarized in table 1.

Nephrogenic diabetes insipidus (NDI) is a well-documented complication of lithium use. The association of central diabetes insipidus (CDI) with lithium use is rare. We report a patient receiving chronic lithium therapy who presented with a transient CDI occurring in the setting of underlying chronic NDI. To the best of our knowledge, this is the first case of lithium-associated CDI and NDI presenting concurrently. Potential mechanisms regarding the pathophysiology of lithium-associated CDI are discussed. This case emphasizes the importance of the evaluation of lithium-associated polyuria with a direct measurement of plasma vasopressin, interpreted with simultaneous plasma and urine osmolality to secure the correct diagnosis and ensure appropriate therapeutic management.

A randomized trial of minidose warfarin for the prevention of late malfunction in tunneled, cuffed hemodialysis catheters.BackgroundMinidose warfarin (1 mg/day) has been associated with a 74% reduction in the thrombosis rate of central venous catheters used in oncology patients. To determine the efficacy of minidose warfarin on late malfunction caused by thrombosis or fibrin sheath formation in tunneled, cuffed catheters (TCC) used for hemodialysis (HD), we performed a randomized, placebo-controlled trial.MethodsOne hundred five chronic HD patients with TCCs were initially randomized. Of these, 85 (warfarin 41 and placebo 44) completed the first two weeks of the protocol and were followed for the first year of TCC life or until TCC removal.ResultsSixteen TCCs failed with late TCC malfunction, eight in each group. In a multivariate analysis, there was no significant effect of warfarin on thrombosis-free TCC survival or time to the first urokinase (UK) instillation for incipient thrombosis. The presence of a low hemoglobin (Hgb; 1.00. Patients with diabetes and those with a low Hgb or INR have a higher risk of late TCC malfunction.