Impact of Prior Abdominal Procedures on Peritoneal Dialysis Catheter Outcomes: Findings From the North American Peritoneal Dialysis Catheter Registry.

RATIONALE & OBJECTIVE: A history of prior abdominal procedures may influence the likelihood of referral for peritoneal dialysis (PD) catheter insertion. To guide clinical decision making in this population, this study examined the association between prior abdominal procedures and outcomes in patients undergoing PD catheter insertion. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults undergoing their first PD catheter insertion between November 1, 2011, and November 1, 2020, at 11 institutions in Canada and the United States participating in the International Society for Peritoneal Dialysis North American Catheter Registry. EXPOSURE: Prior abdominal procedure(s) defined as any procedure that enters the peritoneal cavity. OUTCOMES: The primary outcome was time to the first of (1) abandonment of the PD catheter or (2) interruption/termination of PD. Secondary outcomes were rates of emergency room visits, hospitalizations, and procedures. ANALYTICAL APPROACH: Cumulative incidence curves were used to describe the risk over time, and an adjusted Cox proportional hazards model was used to estimate the association between the exposure and primary outcome. Models for count data were used to estimate the associations between the exposure and secondary outcomes. RESULTS: Of 855 patients who met the inclusion criteria, 31% had a history of a prior abdominal procedure and 20% experienced at least 1 PD catheter-related complication that led to the primary outcome. Prior abdominal procedures were not associated with an increased risk of the primary outcome (adjusted HR, 1.12; 95% CI, 0.68-1.84). Upper-abdominal procedures were associated with a higher adjusted hazard of the primary outcome, but there was no dose-response relationship concerning the number of procedures. There was no association between prior abdominal procedures and other secondary outcomes. LIMITATIONS: Observational study and cohort limited to a sample of patients believed to be potential candidates for PD catheter insertion. CONCLUSION: A history of prior abdominal procedure(s) does not appear to influence catheter outcomes following PD catheter insertion. Such a history should not be a contraindication to PD. PLAIN-LANGUAGE SUMMARY: Peritoneal dialysis (PD) is a life-saving therapy for individuals with kidney failure that can be done at home. PD requires the placement of a tube, or catheter, into the abdomen to allow the exchange of dialysis fluid during treatment. There is concern that individuals who have undergone prior abdominal procedures and are referred for a catheter might have scarring that could affect catheter function. In some institutions, they might not even be offered PD therapy as an option. In this study, we found that a history of prior abdominal procedures did not increase the risk of PD catheter complications and should not dissuade patients from choosing PD or providers from recommending it.

Population-wide eGFR percentiles in younger adults and clinical outcomes.

BACKGROUND AND HYPOTHESIS: Identifying meaningful estimated glomerular filtration rate (eGFR) reductions in younger adults (<65 years) could guide prevention efforts. To aid in interpretation and identification of young adults at risk, we examined the association of population-level eGFR percentiles relative to the median by age and clinical outcomes. METHODS: We conducted a retrospective cohort study of 8.7 million adults from Ontario, Canada from age 18 to 65 from 2008 to 2021 with an eGFR measure (both single outpatient value and repeat measures). We calculated median eGFR values by age and examined the association of reduced eGFR percentiles (≤10th, 5th, 2.5th and 1st) with outcomes using time to event models. Outcomes were a composite of all-cause mortality, major adverse cardiac outcomes (MACE) with/without heart failure (MACE+) and kidney failure as well as each component individually. RESULTS: From age 18 to 65, the median eGFR declined with age (range 128 to 90) and across percentiles [eGFR ranges 102 to 68 for ≤10th, 96 to 63 for ≤5th, 90 to 58 for ≤2.5th and 83 to 54 for 1st]. The adjusted rate for any adverse outcome was elevated at ≤ 10th percentile (HR 1.14 95%CI 1.10-1.18) and was consistent for all-cause mortality, MACE, MACE+ and predominant for kidney failure (HR 5.57 95%CI 3.79-8.19) compared to the median eGFR for age. Young adults with an eGFR in the lower percentiles were less likely to be referred to a specialist, have a repeat eGFR or albumin to creatinine ratio measure. CONCLUSIONS: eGFR values at the 10th percentile or lower based on a population-level distribution are associated with adverse clinical outcomes and in younger adults (18 to 39) this corresponds to a higher level of eGFR that may be underrecognized. Application of population-based eGFR percentiles may aid interpretation and improve identification of younger adults at risk.

Immunosuppressive therapy for IgA nephropathy in children.

BACKGROUND: IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis. It is a heterogeneous disease with different presentations and high morbidity. Thirty per cent of adults and 20% of children (followed into adulthood) will have a 50% decline in kidney function or develop kidney failure after 10 years. OBJECTIVES: To determine the benefits and harms of immunosuppressive therapy for the treatment of IgAN in children. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 03 October 2023 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) investigating the treatment of IgAN in children with immunosuppressive therapies compared to placebo, no treatment, supportive care, standard therapy (Japanese protocol), other immunosuppressive therapies or non-immunosuppressive therapies. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias. Random effects meta-analyses were used to summarise estimates of treatment effects. Treatment effects were expressed as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and the mean difference (MD) and 95% CI for continuous outcomes. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs and the ROBIN-I tool for NRSIs. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). MAIN RESULTS: This review included 13 studies with 686 participants. Ten RCTs included 334 children and 191 adults, and three NRSIs included 151 participants, all children. Most participants had mild kidney disease. The risk of bias was unclear for most of the domains relating to allocation concealment, blinding of participants, personnel, and outcome assessment. In children with IgAN, it is uncertain if corticosteroid (steroid) therapy, compared to placebo reduces proteinuria (1 study, 64 children and young adults: RR 0.47, 95% CI 0.13 to 1.72; low certainty evidence) or the decline in estimated glomerular filtration rate (eGFR) (1 study, 64 children and young adults: RR 0.47, 95% CI 0.09 to 2.39; low certainty evidence). It is uncertain if steroids reduce proteinuria compared to supportive care (2 studies, 61 children: RR 0.04, 95% CI -0.83 to 0.72; low certainty evidence). Adverse events associated with steroid therapy were not assessed due to heterogeneity in steroid protocols, including dose and duration, and lack of systematic assessment for adverse events in the included studies. Azathioprine, mycophenolate mofetil, mizoribine, or cyclophosphamide alone or in combination with steroid therapy had uncertain effects on improving proteinuria or preventing eGFR decline in children with IgAN. Fish oil, vitamin E and tonsillectomy had uncertain effects on improving proteinuria or preventing eGFR decline. Effects of other immunosuppressive therapies, secondary outcomes and adverse events were not assessed due to insufficient data. AUTHORS' CONCLUSIONS: There is a lack of high-quality evidence to guide the management of IgAN in children. There is no evidence to indicate that steroids, other immunosuppressive therapies, or tonsillectomy, when added to optimal supportive care, prevent a decline in eGFR or proteinuria in children with IgAN. Available studies were few, with small numbers, low-quality evidence, high or uncertain risk of bias, did not systematically assess harms associated with treatment, or report net benefits or harms. Severe cases and atypical presentations of IgAN were not included in the reviewed studies, and our findings cannot be generalised to these situations.

Global variability of vascular and peritoneal access for chronic dialysis.

AIM: Vascular and peritoneal access are essential elements for sustainability of chronic dialysis programs. Data on availability, patterns of use, funding models, and workforce for vascular and peritoneal accesses for dialysis at a global scale is limited. METHODS: An electronic survey of national leaders of nephrology societies, consumer representative organizations, and policymakers was conducted from July to September 2018. Questions focused on types of accesses used to initiate dialysis, funding for services, and availability of providers for access creation. RESULTS: Data from 167 countries were available. In 31 countries (25% of surveyed countries), >75% of patients initiated haemodialysis (HD) with a temporary catheter. Seven countries (5% of surveyed countries) had >75% of patients initiating HD with arteriovenous fistulas or grafts. Seven countries (5% of surveyed countries) had >75% of their patients starting HD with tunnelled dialysis catheters. 57% of low-income countries (LICs) had >75% of their patients initiating HD with a temporary catheter compared to 5% of high-income countries (HICs). Shortages of surgeons to create vascular access were reported in 91% of LIC compared to 46% in HIC. Approximately 95% of participating countries in the LIC category reported shortages of surgeons for peritoneal dialysis (PD) access compared to 26% in HIC. Public funding was available for central venous catheters, fistula/graft creation, and PD catheter surgery in 57%, 54% and 54% of countries, respectively. CONCLUSION: There is a substantial variation in the availability, funding, workforce, and utilization of vascular and peritoneal access for dialysis across countries regions, with major gaps in low-income countries.

Global variations in funding and use of hemodialysis accesses: an international report using the ISN Global Kidney Health Atlas.

BACKGROUND: There is a lack of contemporary data describing global variations in vascular access for hemodialysis (HD). We used the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to highlight differences in funding and availability of hemodialysis accesses used for initiating HD across world regions. METHODS: Survey questions were directed at understanding the funding modules for obtaining vascular access and types of accesses used to initiate dialysis. An electronic survey was sent to national and regional key stakeholders affiliated with the ISN between June and September 2022. Countries that participated in the survey were categorized based on World Bank Income Classification (low-, lower-middle, upper-middle, and high-income) and by their regional affiliation with the ISN. RESULTS: Data on types of vascular access were available from 160 countries. Respondents from 35 countries (22% of surveyed countries) reported that > 50% of patients started HD with an arteriovenous fistula or graft (AVF or AVG). These rates were higher in Western Europe (n = 14; 64%), North & East Asia (n = 4; 67%), and among high-income countries (n = 24; 38%). The rates of > 50% of patients starting HD with a tunneled dialysis catheter were highest in North America & Caribbean region (n = 7; 58%) and lowest in South Asia and Newly Independent States and Russia (n = 0 in both regions). Respondents from 50% (n = 9) of low-income countries reported that > 75% of patients started HD using a temporary catheter, with the highest rates in Africa (n = 30; 75%) and Latin America (n = 14; 67%). Funding for the creation of vascular access was often through public funding and free at the point of delivery in high-income countries (n = 42; 67% for AVF/AVG, n = 44; 70% for central venous catheters). In low-income countries, private and out of pocket funding was reported as being more common (n = 8; 40% for AVF/AVG, n = 5; 25% for central venous catheters). CONCLUSIONS: High income countries exhibit variation in the use of AVF/AVG and tunneled catheters. In low-income countries, there is a higher use of temporary dialysis catheters and private funding models for access creation.

Age and memory B cells at baseline are associated with risk of relapse and memory B-cell reappearance following anti-CD20 treatment in pediatric frequently-relapsing/steroid-dependent nephrotic syndrome.

B-cell depleting anti-CD20 monoclonal antibodies, such as rituximab, have proven efficacy in children with frequently-relapsing/steroid-dependent nephrotic syndrome (FR/SDNS). However, drug-free remission is variable and specific baseline markers predictive of relapse after anti-CD20 treatment are still being defined. To clarify these, we performed a bicentric observational study in a large cohort of 102 children and young adults with FR/SDNS treated with anti-CD20 monoclonal antibodies (rituximab and ofatumumab). Sixty-two patients (60.8%) relapsed during a 24-month period (median [interquartile range] relapse-free survival, 14.4 months [7.9-24.0]). A lower risk of relapse was significantly associated with an older age (over 9.8 years, hazard ratio, 0.44; 95% confidence interval, 0.26-0.74) and a higher risk of relapse was significantly associated with higher circulating levels of memory B cells (1.14; 1.09-1.32) at time of anti-CD20 infusion, independent of time elapsed from onset, previous anti-CD20 treatment, type of administered anti-CD20 monoclonal antibodies, and previous or maintenance oral immunosuppression. Patients younger than 9.8 years at anti-CD20 infusion had a subsequent higher recovery of total, transitional, mature-naïve and memory B-cell subsets independent of previous anti-CD20 treatment and maintenance immunosuppression. Significantly, younger age and higher circulating levels of memory B cells at time of anti-CD20 infusion were also independently associated with the recovery of memory B cells by linear mixed-effects modelling. Thus, both younger age and higher circulating levels of memory B cells at time of infusion are independently associated with a higher risk of relapse and an earlier recovery of memory B cells following anti-CD20 treatment in children with FR/SDNS.

Variations in Incidence and Prognosis of Stage 4 CKD Among Adults Identified Using Different Algorithms: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Clinical guidelines define chronic kidney disease (CKD) as abnormalities of kidney structure or function for>3 months. Assessment of the duration criterion may be implemented in different ways, potentially impacting estimates of disease incidence or prevalence in the population, individual diagnosis, and treatment decisions, especially for more severe cases. We investigated differences in incidence and prognosis of CKD stage G4 identified by 1 of 4 algorithms. STUDY DESIGN: Population-based cohort study in Alberta, Canada. SETTING & PARTICIPANTS: Residents>18 years old with incident CKD stage G4 (eGFR 15-29mL/min/1.73m2) diagnosed between April 1, 2015, and March 31, 2018, based on administrative and laboratory data. EXPOSURE: Four outpatient eGFR-based algorithms, increasing in stringency, for defining cohorts with CKD G4 were evaluated: (1) a single test, (2) first eGFR<30mL/min/1.73m2 and a second eGFR 15-29mL/min/1.73m2 measured>90 days apart (2 tests), (3) ≥2 eGFR measurements of<30mL/min/1.73m2 sustained for>90 days (qualifying period) and the last eGFR in the qualifying period of 15-29mL/min/1.73m2 (relaxed sustained), and (4) ≥2 consecutive measurements of 15-29mL/min/1.73m2 for>90 days (rigorous sustained). OUTCOME: Time to the earliest of death, eGFR improvement (a sustained increase in eGFR to≥30mL/min/1.73m2 for>90 days and>25% increase from the index eGFR), or kidney failure. ANALYTICAL APPROACH: For each of the 4 cohorts, incidence rates and event-specific cumulative incidence functions at 1 year from cohort entry were estimated. RESULTS: The incidence rates of CKD G4 decreased as algorithms became more stringent, from 190.7 (single test) to 79.9 (rigorous sustained) per 100,000 person-years. The 2 cohorts based on sustained reductions in eGFR were of comparable size and 1-year event-specific probabilities. The 2 cohorts based on a single test and a 2-test sequence were larger and experienced higher probabilities of eGFR improvement. LIMITATIONS: A short follow-up period of 1 year and a predominantly White population. CONCLUSIONS: The use of more stringent algorithms for defining CKD G4 results in substantially lower estimates of disease incidence, the identification of a group with a lower probability of eGFR improvement, and a higher risk of kidney failure. These findings can inform implementation decisions of disease definitions in clinical reporting systems and research studies. PLAIN-LANGUAGE SUMMARY: Although guidelines recommend>3 months to define chronic kidney disease (CKD), the methods for defining specific stages, particularly G4 (eGFR 15-29mL/min/1.73m2) when referral to nephrology services is recommended, have been implemented differently across studies and surveillance programs. We studied differences in incidence and prognosis of CKD G4 cohorts identified by 4 algorithms using administrative and outpatient laboratory databases in Alberta, Canada. We found that, compared with a single-test definition, more stringent definitions resulted in a lower disease incidence and identified a group with worse short-term kidney outcomes. These findings highlight the impact of the choice of algorithm used to define CKD G4 on disease burden estimates at the population level, on individual prognosis, and on treatment/referral decisions.

Patient and Clinician Perspectives on Shared Decision Making in Vascular Access Selection: A Qualitative Study.

RATIONALE & OBJECTIVE: Collaborative approaches to vascular access selection are being increasingly encouraged to elicit patients' preferences and priorities where no unequivocally superior choice exists. We explored how patients, their caregivers, and clinicians integrate principles of shared decision making when engaging in vascular access discussions. STUDY DESIGN: Qualitative description. SETTING & PARTICIPANTS: Semistructured interviews with a purposive sample of patients, their caregivers, and clinicians from outpatient hemodialysis programs in Alberta, Canada. ANALYTICAL APPROACH: We used a thematic analysis approach to inductively code transcripts and generate themes to capture key concepts related to vascular access shared decision making across participant roles. RESULTS: 42 individuals (19 patients, 2 caregivers, 21 clinicians) participated in this study. Participants identified how access-related decisions follow a series of major decisions about kidney replacement therapy and care goals that influence vascular access preferences and choice. Vascular access shared decision making was strengthened through integration of vascular access selection with dialysis-related decisions and timely, tailored, and balanced exchange of information between patients and their care team. Participants described how opportunities to revisit the vascular access decision before and after dialysis initiation helped prepare patients for their access and encouraged ongoing alignment between patients' care priorities and treatment plans. Where shared decision making was undermined, hemodialysis via a catheter ensued as the most readily available vascular access option. LIMITATIONS: Our study was limited to patients and clinicians from hemodialysis care settings and included few caregiver participants. CONCLUSIONS: Findings suggest that earlier, or upstream, decisions about kidney replacement therapies influence how and when vascular access decisions are made. Repeated vascular access discussions that are integrated with other higher-level decisions are needed to promote vascular access shared decision making and preparedness.

Social determinants of health and the transition from advanced chronic kidney disease to kidney failure.

BACKGROUND: The transition from chronic kidney disease (CKD) to kidney failure is a vulnerable time for patients, with suboptimal transitions associated with increased morbidity and mortality. Whether social determinants of health are associated with suboptimal transitions is not well understood. METHODS: This retrospective cohort study included 1070 patients with advanced CKD who were referred to the Ottawa Hospital Multi-Care Kidney Clinic and developed kidney failure (dialysis or kidney transplantation) between 2010 and 2021. Social determinant information, including education level, employment status and marital status, was collected under routine clinic protocol. Outcomes surrounding suboptimal transition included inpatient (versus outpatient) dialysis starts, pre-emptive (versus delayed) access creation and pre-emptive kidney transplantation. We examined the association between social determinants of health and suboptimal transition outcomes using multivariable logistic regression. RESULTS: The mean age and estimated glomerular filtration rate were 63 years and 18 ml/min/1.73 m2, respectively. Not having a high school degree was associated with higher odds for an inpatient dialysis start compared with having a college degree {odds ratio [OR] 1.71 [95% confidence interval (CI) 1.09-2.69]}. Unemployment was associated with higher odds for an inpatient dialysis start [OR 1.85 (95% CI 1.18-2.92)], lower odds for pre-emptive access creation [OR 0.53 (95% CI 0.34-0.82)] and lower odds for pre-emptive kidney transplantation [OR 0.48 (95% CI 0.24-0.96)] compared with active employment. Being single was associated with higher odds for an inpatient dialysis start [OR 1.44 (95% CI 1.07-1.93)] and lower odds for pre-emptive access creation [OR 0.67 (95% CI 0.50-0.89)] compared with being married. CONCLUSIONS: Social determinants of health, including education, employment and marital status, are associated with suboptimal transitions from CKD to kidney failure.

Health related quality of life during dialysis modality transitions: a qualitative study.

BACKGROUND: Modality transitions represent a period of significant change that can impact health related quality of life (HRQoL). We explored the HRQoL of adults transitioning to new or different dialysis modalities. METHODS: We recruited eligible adults (≥ 18) transitioning to dialysis from pre-dialysis or undertaking a dialysis modality change between July and September 2017. Nineteen participants (9 incident and 10 prevalent dialysis patients) completed the KDQOL-36 survey at time of transition and three months later. Fifteen participants undertook a semi-structured interview at three months. Qualitative data were thematically analyzed. RESULTS: Four themes and five sub-themes were identified: adapting to new circumstances (tackling change, accepting change), adjusting together, trading off, and challenges of chronicity (the impact of dialysis, living with a complex disease, planning with uncertainty). From the first day of dialysis treatment to the third month on a new dialysis therapy, all five HRQoL domains from the KDQOL-36 (symptoms, effects, burden, overall PCS, and overall MCS) improved in our sample (i.e., those who remained on the modality). CONCLUSIONS: Dialysis transitions negatively impact the HRQoL of people with kidney disease in various ways. Future work should focus on how to best support people during this time.

Calculated versus measured albumin-creatinine ratio to predict kidney failure and death in people with chronic kidney disease.

Albumin-to-creatinine ratio (ACR), the preferred method to quantify proteinuria, can be calculated from urine dipstick protein or protein-to-creatinine ratio (PCR). The performance of calculated vs. measured ACR in predicting kidney failure and death without kidney failure in people with chronic kidney disease (CKD) is unknown. Here, we used population-based data from Alberta, Canada, to identify adults with incident moderate-severe CKD (sustained for more than 90 days) from 2008-04-01 to 2017-03-31, who had same-day measures of ACR and urine dipstick (ACR-dipstick cohort) or PCR (ACR-PCR cohort) in the two years before cohort entry. We followed participants until 2019-03-31 and trained competing risk models of kidney failure and death without kidney failure including age, sex, estimated glomerular filtration rate, diabetes, cardiovascular disease, and either measured or calculated ACR. Model performance was tested in cohorts created using the same algorithm in Manitoba, Canada. The ACR-dipstick and ACR-PCR cohorts included 18,731 and 4,542 people (training cohorts) and 821 and 1,831 people (testing cohorts), respectively. In internal and external testing, there was closer agreement between predictions based on measured vs. PCR-calculated ACR than between those based on measured vs. dipstick-calculated ACR. The dipstick-calculated ACR had higher Brier scores than measured ACR from year three for both outcomes, indicating worsening calibration. Models including measured or calculated ACR had similar discrimination: year one-to-five area under the receiver operating characteristic curve of 83-89% for kidney failure and 69-75% for mortality. Thus, if confirmed in different ethnic groups, calculated ACR can be used for risk predictions when the measured ACR is not available. PCR-calculated ACR may have superior performance to dipstick-calculated ACR.

Human or Chimeric Monoclonal Anti-CD20 Antibodies for Children with Nephrotic Syndrome: A Superiority Randomized Trial.

BACKGROUND: The chimeric anti-CD20 monoclonal antibody rituximab is effective in steroid-dependent and calcineurin inhibitor-dependent forms of nephrotic syndrome, but many patients relapse at 1 year. Because ofatumumab, a fully human anti-CD20 monoclonal antibody, has a more extended binding site and higher affinity to CD20 compared with rituximab, it might offer superior efficacy in these patients. METHODS: We designed a single-center randomized clinical trial to compare the long-term efficacy of ofatumumab versus rituximab in children and young adults with nephrotic syndrome maintained in remission with prednisone and calcineurin inhibitors. We randomized 140 children and young adults (aged 2-24 years) to receive intravenous ofatumumab (1.50 mg/1.73 m2) or rituximab (375 mg/m2). After infusions, oral drugs were tapered and withdrawn within 60 days. The primary outcome was relapse at 1 year, which was analyzed following the intent-to-treat principle. The secondary endpoint was relapse within 24 months from infusion, on the basis of urine dipstick and confirmed by a urine protein-to-creatinine ratio <200. RESULTS: At 12 months, 37 of 70 (53%) participants who received ofatumumab experienced relapse versus 36 of 70 (51%) who received rituximab (odds ratio [OR], 1.06; 95% confidence interval [95% CI], 0.55 to 2.06). At 24 months, 53 of 70 (76%) participants who received ofatumumab experienced relapse, versus 46 of 70 (66%) who received rituximab (OR, 1.6; 95% CI, 0.8 to 3.3). The two groups exhibited comparable B cell subpopulation reconstitution and did not differ in adverse events. CONCLUSIONS: A single dose of ofatumumab was not superior to a single dose of rituximab in maintaining remission in children with steroid-dependent and calcineurin inhibitor-dependent nephrotic syndrome. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT02394119) and https://www.clinicaltrialsregister.eu/ctr-search/search (2015-000624-28).

Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial.

BACKGROUND: A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. METHODS: We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. RESULTS: At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. CONCLUSIONS: This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

NSAID prescriptions in kidney transplant recipients.

BACKGROUND: Guidelines recommend that non-steroidal anti-inflammatory drugs (NSAIDs) be avoided in kidney transplant recipients due to potential nephrotoxicity. It is unclear whether physicians are following these recommendations. METHODS: We conducted a retrospective cohort study of adult kidney transplant recipients from 2008 to 2017 in Alberta, Canada. We determined the frequency and prescriber of NSAID prescriptions, the proportion with serum creatinine and potassium testing post-fill, and the incidence of acute kidney injury (AKI, serum creatinine increase of ≥ 50% or ≥ 26.5 µmol/L from baseline) and hyperkalemia (potassium ≥ 5.5 mmol/L) within 14 and 30 days. RESULTS: Of the 1730 kidney transplant recipients, 189 (11%) had at least one NSAID prescription over a median follow-up of 5 years (IQR 2-9) (280 unique prescriptions). The majority were prescribed by family physicians (67%). Approximately 25% and 50% of prescriptions had serum creatinine and potassium testing within 14 and 30 days, respectively. Of those with lab measurements within 14 days, 13% of prescriptions were associated with AKI and 5% had hyperkalemia. CONCLUSIONS: Contrary to guidelines, one in 10 kidney transplant recipients are prescribed an NSAID, and most do not get follow-up testing of graft function and hyperkalemia. These findings call for improved education of patients and primary care providers.

Secular Changes in Mortality and Hospitalization over Time in People with Kidney Failure or Severe CKD as Compared with Other Noncommunicable Diseases.

BACKGROUND: Few new treatments have been developed for kidney failure or CKD in recent years, leading to perceptions of slower improvement in outcomes associated with CKD or kidney failure than for other major noncommunicable diseases. METHODS: Our retrospective cohort study included 548,609 people with an incident noncommunicable disease, including cardiovascular diseases, diabetes, various cancers, and severe CKD or kidney failure treated with renal replacement (KF-RRT), treated in Alberta, Canada, 2004-2015. For each disease, we assessed presence or absence of 8 comorbidities; we also compared secular trends in relative (compared to a referent year of 2004) and absolute risks of mortality and mean annual days in the hospital associated with each disease after 1 year and 5 years. RESULTS: Comorbidities increased significantly in number over time for all noncommunicable diseases except diabetes, and increased most rapidly for CKD and KF-RRT. Significant but relatively small reductions over time in the risk ratio of mortality at 1 year occurred for nearly all noncommunicable diseases. Secular trends in the absolute risk of mortality were similar; CKD and KF-RRT had a relatively favorable ranking at 1 year. Breast cancer, KF-RRT, diabetes, and colorectal cancer displayed the largest relative reductions in number of hospital days at 1 year. Significant absolute reductions in the number of hospital days were observed for both KF-RRT and CKD; the former had the highest absolute reduction among all noncommunicable diseases. Results were similar at 5 years. CONCLUSIONS: We observed secular reductions in mortality and annual hospital days at 1 year and 5 years among incident patients with KF-RRT and severe CKD, as well as several other common noncommunicable diseases.

Estimating Urine Albumin-to-Creatinine Ratio from Protein-to-Creatinine Ratio: Development of Equations using Same-Day Measurements.

BACKGROUND: Urine albumin-to-creatinine ratio (ACR) and protein-to-creatinine ratio (PCR) are used to measure urine protein. Recent guidelines endorse ACR use, and equations have been developed incorporating ACR to predict risk of kidney failure. For situations in which PCR only is available, having a method to estimate ACR from PCR as accurately as possible would be useful. METHODS: We used data from a population-based cohort of 47,714 adults in Alberta, Canada, who had simultaneous assessments of urine ACR and PCR. After log-transforming ACR and PCR, we used cubic splines and quantile regression to estimate the median ACR from a PCR, allowing for modification by specified covariates. On the basis of the cubic splines, we created models using linear splines to develop equations to estimate ACR from PCR. In a subcohort with eGFR<60 ml/min per 1.73 m2, we then used the kidney failure risk equation to compare kidney failure risk using measured ACR as well as estimated ACR that had been derived from PCR. RESULTS: We found a nonlinear association between log(ACR) and log(PCR), with the implied albumin-to-protein ratio increasing from <30% in normal to mild proteinuria to about 70% in severe proteinuria, and with wider prediction intervals at lower levels. Sex was the most important modifier of the relationship between ACR and PCR, with men generally having a higher albumin-to-protein ratio. Estimates of kidney failure risk were similar using measured ACR and ACR estimated from PCR. CONCLUSIONS: We developed equations to estimate the median ACR from a PCR, optionally including specified covariates. These equations may prove useful in certain retrospective clinical or research applications where only PCR is available.

Changes in kidney function follow living donor nephrectomy.

Better understanding of kidney function after living donor nephrectomy and how it differs by donor characteristics can inform patient selection, counselling, and follow-up care. To evaluate this, we conducted a retrospective matched cohort study of living kidney donors in Alberta, Canada between 2002-2016, using linked healthcare administrative databases. We matched 604 donors to 2,414 healthy non-donors from the general population based on age, sex, year of cohort entry, urban residence and the estimated glomerular filtration rate (eGFR) before cohort entry (nephrectomy date for donors and randomly assigned date for non-donors). The primary outcome was the rate of eGFR change over time (median follow-up seven years; maximum 15 years). The median age of the cohort was 43 years, 64% women, and the baseline (pre-donation) eGFR was 100 mL/min/1.73 m2. Overall, from six weeks onwards, the eGFR increased by +0.35 mL/min/1.73 m2 per year (95% confidence interval +0.21 to +0.48) in donors and significantly decreased by -0.85 mL/min/1.73 m2 per year (-0.94 to -0.75) in the matched healthy non-donors. The change in eGFR between six weeks to two years, two to five years, and over five years among donors was +1.06, +0.64, and -0.06 mL/min/1.73 m2 per year, respectively. In contrast to the steady age-related decline in kidney function in non-donors, post-donation kidney function on average initially increased by 1 mL/min/1.73 m2 per year attributable to glomerular hyperfiltration, which began to plateau by five years post-donation. Thus, the average change in eGFR over time is significantly different between donors and non-donors.

Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial.

BACKGROUND: Children with multidrug-resistant nephrotic syndrome (MRNS) are exposed to drug toxicity (steroids/calcineurin inhibitors (CNI)/mycophenolate mofetil (MMF)) and have an increased risk of kidney disease progression. In small case series, the fully humanized anti-CD20 antibody ofatumumab (OFA) induced remission in children with MRNS when at high dose (10,300 mg/1.73 m2) and partial remission at standard dose (1000 mg/1.73 m2). METHODS: This double-blind randomized placebo-controlled trial tested the efficacy of single infusion OFA in children with proven MRNS and initial chronic renal failure (eGFR [median/range] 119/38-155 ml/min/1.73 m2 in Placebo arm vs. 65/19-103 ml/min/1.73 m2 Intervention). Children who had been resistant to a combination of CNI and steroids, with or without MMF or rituximab, were randomized to receive single infusion OFA (1500 mg/1.73 m2) (Intervention arm) or normal saline (Placebo arm). We assessed complete or partial remission of proteinuria after 3 months (primary outcome), and after 6 and 12 months (secondary outcomes), as well as progression to end-stage kidney disease. RESULTS: After 13 of the planned 50 children (25%) were randomized, the data safety and monitoring board recommended study termination for futility. All 13 children remained nephrotic. Renal function worsened in 5 children (2 in Intervention arm, 3 in Placebo arm) who required renal replacement therapy during the study period. Circulating CD20 was reduced following OFA infusion and remained low for > 3 months. CONCLUSIONS: OFA given in one single infusion of 1500 mg/1.73 m2 doses does not induce remission in MRNS. Regimens based on higher OFA doses should be tested in clinical trials. TRIAL REGISTRATION: https://clinicaltrials.gov: NCT02394106.

Rituximab for very low dose steroid-dependent nephrotic syndrome in children: a randomized controlled study.

BACKGROUND: Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, randomized controlled trial was designed to test whether the monoclonal antibody rituximab is non-inferior to steroids in maintaining remission in juvenile forms of SDNS and how long remission may last (EudraCT:2008-004486-26). METHODS: We enrolled 30 children 4-15 years who had developed SDNS 6-12 months before and were maintained in remission with low prednisone doses (0.1-0.4 mg/Kg/day). Participants were randomized following a non-inferiority design to continue prednisone alone (n 15, controls) or to add a single intravenous infusion of rituximab (375 mg/m2, n 15 intervention). Prednisone was tapered in both arms after 1 month. Children assigned to the control arm were allowed to receive rituximab to treat disease relapse. RESULTS: Proteinuria increased at 3 months in the prednisone group (from 0.14 to 1.5 g/day) (p < 0.001) and remained unchanged in the rituximab group (0.14 g/day). Fourteen children in the control arm relapsed within 6 months. Thirteen children assigned to rituximab (87%) were still in remission at 1 year and 8 (53%) at 4 years. Responses were similar in children of the control group who received rituximab to treat disease relapse. We did not record significant adverse events. CONCLUSIONS: Rituximab was non-inferior to steroids for the treatment of juvenile SDNS. One in two children remains in remission at 4 years following a single infusion of rituximab, without significant adverse events. Further studies are needed to clarify the superiority of rituximab over low-dose corticosteroid as a treatment of SDNS.

Pharmacological interventions for heart failure in people with chronic kidney disease.

BACKGROUND: Approximately half of people with heart failure have chronic kidney disease (CKD). Pharmacological interventions for heart failure in people with CKD have the potential to reduce death (any cause) or hospitalisations for decompensated heart failure. However, these interventions are of uncertain benefit and may increase the risk of harm, such as hypotension and electrolyte abnormalities, in those with CKD. OBJECTIVES: This review aims to look at the benefits and harms of pharmacological interventions for HF (i.e., antihypertensive agents, inotropes, and agents that may improve the heart performance indirectly) in people with HF and CKD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies through 12 September 2019 in consultation with an Information Specialist and using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials of any pharmacological intervention for acute or chronic heart failure, among people of any age with chronic kidney disease of at least three months duration. DATA COLLECTION AND ANALYSIS: Two authors independently screened the records to identify eligible studies and extracted data on the following dichotomous outcomes: death, hospitalisations, worsening heart failure, worsening kidney function, hyperkalaemia, and hypotension. We used random effects meta-analysis to estimate treatment effects, which we expressed as a risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias using the Cochrane tool. We applied the GRADE methodology to rate the certainty of evidence. MAIN RESULTS: One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow-up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta-analyses. In acute heart failure, the effects of adenosine A1-receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported. In chronic heart failure, the effects of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I2 = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta-blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I2 = 0%; moderate certainty evidence). Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I2 = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta-blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I2 = 87%; low certainty evidence). Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I2 = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I2 = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta-analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies. The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported. Effects of anti-arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies. AUTHORS' CONCLUSIONS: The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.