Challenges in the management of the kidney allograft: from decline to failure: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In March 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a virtual Controversies Conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of a failing allograft, 4 broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure trajectory; immunosuppression strategies; management of medical and psychological complications, and patient factors; and choice of kidney replacement therapy or supportive care following graft loss. Identifying and paying special attention to individuals with failing allografts was felt to be important in order to prepare patients psychologically, manage immunosuppression, address complications, prepare for dialysis and/or retransplantation, and transition to supportive care. Accurate prognostication tools, although not yet widely available, were embraced as necessary to define allograft survival trajectories and the likelihood of allograft failure. The decision of whether to withdraw or continue immunosuppression after allograft failure was deemed to be based most appropriately on risk-benefit analysis and likelihood of retransplantation within a few months. Psychological preparation and support was identified as a critical factor in patient adjustment to graft failure, as was early communication. Several models of care were noted that enabled a medically supportive transition back to dialysis or retransplantation. Emphasis was placed on the importance of dialysis-access readiness before initiation of dialysis, in order to avoid use of central venous catheters. The centrality of the patient to all management decisions and discussions was deemed to be paramount. Patient "activation," which can be defined as engaged agency, was seen as the most effective way to achieve success. Unresolved controversies, gaps in knowledge, and areas for research were also stressed in the conference deliberations.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Practicing With Uncertainty: Kidney Transplantation During the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic required transplant nephrologists, surgeons, and care teams to make decisions about the full spectrum of transplant program operations and clinical practices in the absence of experience or data. Initially, across the country, there was a reduction in kidney transplant procedures and a striking pause in the conduct of living donation and living-donor transplant surgeries. Aspects of candidate evaluation and follow-up rapidly converted to telehealth. Months into the pandemic, much has been learned from experiences worldwide, yet many questions remain. In this Perspective, we reflect on some of the practice decisions made by the transplant community in the initial response to the pandemic and consider lessons learned, including those related to the risks, benefits, and logistical considerations of proceeding with versus delaying deceased-donor transplantation, living donation, and living-donor transplantation during the pandemic. We review the evolution of therapeutic strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their use in transplant recipients, current consensus related to immunosuppression management in infected transplant recipients, and emerging information on vaccination against SARS-CoV-2. We share our thoughts on research priorities, discuss the areas in which we are still practicing with uncertainty, and look ahead to the next phase of the pandemic response.

Recipient Obesity and Kidney Transplant Outcomes: A Mate-Kidney Analysis.

RATIONALE & OBJECTIVE: The impact of extreme recipient obesity on long-term kidney transplant outcomes has been controversial. This study sought to evaluate the association of various levels of recipient obesity on kidney transplantation outcomes by comparing mate-kidney recipient pairs to address possible confounding effects of donor characteristics on posttransplant outcomes. STUDY DESIGN: Nationwide observational cohort study using mate-kidney models. SETTING & PARTICIPANTS: In analysis based on the Organ Procurement and Transplant Network/United Network of Organ Sharing database, 44,560 adult recipients of first-time deceased-donor kidney transplants from 2001 through 2016 were paired by donor. PREDICTORS: Recipient body mass index (BMI) categorized as 18-25 (n = 12,446), >25-30 (n = 15,477), >30-35 (n = 11,144; obese), and >35 (n = 5,493; extreme obesity) kg/m2. OUTCOMES: Outcomes included patient survival, graft survival, death-censored graft survival, delayed graft function (DGF), and hospital length of stay. ANALYTICAL APPROACH: Conditional logistic regression and stratified proportional hazards models were used to compare outcomes as odds ratios and hazard ratios (HRs), adjusted for recipient and transplant factors, using recipients with a BMI >35 kg/m2 as a reference. RESULTS: At a median follow-up of 3.9 years, adjusted odds ratios for DGF were 0.42 (95% CI, 0.36-0.48), 0.55 (95% CI, 0.48-0.62), and 0.73 (95% CI, 0.64-0.83) for BMI 18-25, >25-30, and >30-35 kg/m2, respectively (P < 0.001 for all). Death-censored graft failure was less frequent for BMI ≤25 and >25-30 kg/m2 (HRs of 0.66 [95% CI, 0.59-0.74] and 0.79 [95% CI, 0.70-0.88], respectively; P < 0.001 for both), but not for BMI >30-35 kg/m2 (HR, 0.91 [95% CI, 0.81-1.02]; P = 0.09). Length of stay and patient survival did not differ by recipient BMI. LIMITATIONS: Observational study with limited detail regarding potential confounders. CONCLUSIONS: Despite an increased risk of DGF likely unrelated to donor organ quality, long-term transplant outcomes among recipients with a BMI >35 kg/m2 are similar to those among recipients with a BMI >30-35 kg/m2, supporting a flexible approach to kidney transplantation candidacy in candidates with extreme obesity.

Operational challenges in the COVID-19 era: Asymptomatic infections and vaccination timing.

The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented challenges for solid organ transplant programs. While transplant activity has largely recovered, appropriate management of deceased donor candidates who are asymptomatic but have positive nucleic acid testing (NAT) for SARS-CoV-2 is unclear, as this result may reflect active infection or prolonged viral shedding. Furthermore, candidates who are unvaccinated or partially vaccinated continue to receive donor offers. In the absence of robust outcomes data, transplant professionals at US adult kidney transplant centers were surveyed (February 13, 2021 to April 29, 2021) to determine community practice (N: 92 centers, capturing 41% of centers and 57% of transplants performed). The majority (97%) of responding centers declined organs for asymptomatic NAT+ patients without documented prior infection. However, 32% of centers proceed with kidney transplant in NAT+ patients who were at least 30 days from initial diagnosis with negative chest imaging. Less than 7% of programs reported inactivating patients who were unvaccinated or partially vaccinated. In conclusion, despite national recommendations to wait for negative testing, many centers are proceeding with kidney transplant in patients with positive SARS-CoV-2 NAT results due to presumed viral shedding. Furthermore, few centers are requiring COVID-19 vaccination prior to transplantation at this time.

Patient-reported outcome measures for life participation in kidney transplantation: A systematic review.

For many patients with end-stage kidney disease, transplantation improves survival and quality of life compared with dialysis. However, complications and side effects in kidney transplant recipients can limit their ability to participate in activities of daily living including work, study, and recreational activities. The aim of this study was to identify the characteristics, content, and psychometric properties of the outcome measures used to assess life participation in kidney transplant recipients. We searched MEDLINE, Embase, PsycINFO, and CINAHL from inception to July 2018 for all studies that reported life participation in kidney transplant recipients. Two authors identified instruments measuring life participation and reviewed for characteristics. In total, 230 studies were included: 19 (8%) randomized trials, 17 (7%) nonrandomized trials, and 194 (85%) observational studies. Across these studies, we identified 29 different measures that were used to assess life participation. Twelve (41%) measures specifically assessed aspects of life participation (eg, disability assessment, daily activities of living), while 17 (59%) assessed other constructs (eg, quality of life) that included questions on life participation. Validation data to support the use of these measures in kidney transplant recipients were available for only 7 measures. A wide range of measures have been used to assess life participation in kidney transplant recipients, but validation data supporting the use of these measures in this population are sparse. A content relevant and validated measure to improve the consistency and accuracy of measuring life participation in research may inform strategies for transplant recipients to be better able to engage in their life activities.

The Epidemiologic Burden of Tacrolimus Variability among Kidney Transplant Recipients in the United States.

BACKGROUND: Within-patient tacrolimus level variability >30% has been shown to be a risk factor for de novo donor-specific antibody formation and death-censored graft failure among kidney transplant recipients. The burden of tacrolimus variability and the correlation between variability and subtherapeutic tacrolimus levels were examined in a large national data set. METHODS: All tacrolimus levels drawn at LabCorp® facilities in the United States with a diagnosis code for kidney transplant between November 2011 and September 2017 were examined, excluding values that could represent new allografts. Tacrolimus variability was calculated if at least 3 levels were available. The percentage of subtherapeutic (<4.0 ng/dL) tacrolimus levels (%subT) was also calculated. Interdependence between %subT and tacrolimus variability was assessed with correlation analysis and linear regression. RESULTS: There were 410,257 tacrolimus levels among 27,375 patients, who had 11 (interquartile range [IQR] 6-20) tacrolimus levels over a median follow-up of 26.5 (IQR 12.8-46.1) months. Median tacrolimus variability was 30.6%, and 51.6% of patients exceeded 30% variability. Median %subT was 11.1% (IQR 0-30.8%), and 34.3% of patients had no subtherapeutic levels. The correlation coefficient between tacrolimus variability and %subT was 0.253 (p< 0.001). In linear regression, tacrolimus variability increased 1.86% for each 10% increase in %subT (p < 0.001), but R-squared for this model was only 0.06. CONCLUSION: More than half of established kidney transplant patients from a large national sample exhibited levels of tacrolimus variability that have been associated with inferior transplant outcomes. Tacrolimus variability has a weak association with subtherapeutic levels, but represents a more complicated constellation of clinical factors.

Implementing core outcomes in kidney disease: report of the Standardized Outcomes in Nephrology (SONG) implementation workshop.

There are an estimated 14,000 randomized trials published in chronic kidney disease. The most frequently reported outcomes are biochemical endpoints, rather than clinical and patient-reported outcomes including cardiovascular disease, mortality, and quality of life. While many trials have focused on optimizing kidney health, the heterogeneity and uncertain relevance of outcomes reported across trials may limit their policy and practice impact. The international Standardized Outcomes in Nephrology (SONG) Initiative was formed to identify core outcomes that are critically important to patients and health professionals, to be reported consistently across trials. We convened a SONG Implementation Workshop to discuss the implementation of core outcomes. Eighty-two patients/caregivers and health professionals participated in plenary and breakout discussions. In this report, we summarize the findings of the workshop in two main themes: socializing the concept of core outcomes, and demonstrating feasibility and usability. We outline implementation strategies and pathways to be established through partnership with stakeholders, which may bolster acceptance and reporting of core outcomes in trials, and encourage their use by end-users such as guideline producers and policymakers to help improve patient-important outcomes.

Establishing a Core Outcome Measure for Fatigue in Patients on Hemodialysis: A Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop Report.

Fatigue is one of the most highly prioritized outcomes for patients and clinicians, but remains infrequently and inconsistently reported across trials in hemodialysis. We convened an international Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) consensus workshop with stakeholders to discuss the development and implementation of a core outcome measure for fatigue. 15 patients/caregivers and 42 health professionals (clinicians, researchers, policy makers, and industry representatives) from 9 countries participated in breakout discussions. Transcripts were analyzed thematically. 4 themes for a core outcome measure emerged. Drawing attention to a distinct and all-encompassing symptom was explicitly recognizing fatigue as a multifaceted symptom unique to hemodialysis. Emphasizing the pervasive impact of fatigue on life participation justified the focus on how fatigue severely impaired the patient's ability to do usual activities. Ensuring relevance and accuracy in measuring fatigue would facilitate shared decision making about treatment. Minimizing burden of administration meant avoiding the cognitive burden, additional time, and resources required to use the measure. A core outcome measure that is simple, is short, and includes a focus on the severity of the impact of fatigue on life participation may facilitate consistent and meaningful measurement of fatigue in all trials to inform decision making and care of patients receiving hemodialysis.

Preeclampsia Risks in Kidney Donors and Recipients.

PURPOSE OF REVIEW: To review the studies and practice guidelines on the preeclampsia risks in kidney donors and recipients. RECENT FINDINGS: There is a small increased risk of gestational hypertension and preeclampsia in pregnancies that follow kidney donation. Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline (2017) and the 2015 American Society of Transplantation (AST) consensus conference statement recommends counseling kidney donors about this increased risk. There is no observed increase in fetal complications or eclampsia post-kidney donation. Preeclampsia is more commonly observed in kidney transplant recipients than the general population and these patients should be co-managed with an obstetrician with experience in managing high risk pregnancies. Although preeclampsia has not been found to have a deleterious effect on renal graft function, it can cause premature delivery. Risk calculators have been proposed and an elevated pre-pregnancy creatinine seems to be an important risk. KDIGO Clinical Practice Guidelines (2009) recommends attempting pregnancy when kidney function is stable with proteinuria of less than 1 g per day. The use of novel biomarkers for preeclampsia has not been published in this population. Preeclampsia is an important concern for female kidney donors and recipients of child-bearing age. These individuals should be appropriately counseled.

Pregnancy in chronic kidney disease and kidney transplantation.

Chronic kidney disease (CKD) affects up to 6% of women of childbearing age in high income countries, and is estimated to affect 3% of pregnant women. Advanced renal dysfunction, proteinuria, hypertension, and poorly controlled underlying primary renal disease are all significant risks for adverse maternal, fetal, and renal outcomes. In order to achieve the best outcomes, it is therefore of paramount importance that these pregnancies are planned, where possible, to allow the opportunity to counsel women and their partners in advance and to optimize these risks. These pregnancies should be deemed high risk and they require close antenatal monitoring from an expert multidisciplinary team. We discuss the effect of pregnancy on CKD, and also current guidelines and literature with specific reference to transplantation, autoimmune disease, and medication use in pregnancy. We also discuss the benefits of prepregnancy counseling and give practical recommendations to advise pregnant women with renal disease.

Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach - a retrospective analysis.

Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 104 to >25 × 106 BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 103 to 4.3 × 106 copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.

Patient-Reported Barriers to the Prekidney Transplant Evaluation in an At-Risk Population in the United States.

BACKGROUND: Despite our knowledge of barriers to the early stages of the transplant process, we have limited insight into patient-reported barriers to the prekidney transplant medical evaluation in populations largely at-risk for evaluation failure. METHODS: One-hundred consecutive adults were enrolled at an urban, Midwestern transplant center. Demographic, clinical, and quality of life data were collected prior to patients visit with a transplant surgeon/nephrologist (evaluation begins). Patient-reported barriers to evaluation completion were collected using the Subjective Barriers Questionnaire 90-days after the initial medical evaluation appointment (evaluation ends), our center targeted goal for transplant work-up completion. RESULTS: At 90 days, 40% of participants had not completed the transplant evaluation. Five barrier categories were created from the 85 responses to the Subjective Barriers Questionnaire. Patient-reported barriers included poor communication, physical health, socioeconomics, psychosocial influences, and access to care. In addition, determinants for successful evaluation completion included being of white race, higher income, free of dialysis, a lower comorbid burden, and reporting higher scores on the Kidney Disease Quality of Life subscale role-emotional. CONCLUSION: Poor communication between patients and providers, and among providers, was the most prominent patient-reported barrier identified. Barriers were more prominent in marginalized groups such as ethnic minorities and people with low income. Understanding the prevalence of patient-reported barriers may aid in the development of patient-centered interventions to improve completion rates.

Motivations, Challenges, and Attitudes to Self-management in Kidney Transplant Recipients: A Systematic Review of Qualitative Studies.

BACKGROUND: Kidney transplantation offers better outcomes compared to dialysis, but requires patients to adhere to an ongoing and complex self-management regimen. Medication nonadherence remains a leading cause of transplant loss, and inadequate self-management undermines transplantation and other health outcomes. We aimed to describe kidney transplant recipients' motivations, challenges, and attitudes toward self-management. STUDY DESIGN: Systematic review and thematic synthesis of qualitative studies. SETTING & POPULATION: Kidney transplant recipients. SEARCH STRATEGY & SOURCES: MEDLINE, EMBASE, PsycINFO, and CINAHL were searched to October 2014. ANALYTICAL APPROACH: Thematic synthesis. RESULTS: 50 studies involving 1,238 recipients aged 18 to 82 years across 19 countries were included. We identified 5 themes: empowerment through autonomy (achieving mastery, tracking against tangible targets, developing bodily intuition, routinizing and problem solving, and adaptive coping), prevailing fear of consequences (inescapable rejection anxiety, aversion to dialysis, minimizing future morbidity, trivialization and denial, and defining acceptable risks), burdensome treatment and responsibilities (frustrating ambiguities, inadvertent forgetfulness, intrusive side effects, reversing ingrained behaviors, and financial hardship), overmedicalizing life (dominating focus, evading patienthood, and succumbing to burnout), and social accountability and motivation (demonstrating gratitude toward medical team, indebtedness to donor, and peer learning). LIMITATIONS: Non-English articles were excluded. CONCLUSIONS: Self-efficacy and social accountability are motivators for self-management, although adherence can be mentally and physically taxing. Multicomponent interventions incorporating personalized care planning, education, psychosocial support, decision aids, and self-monitoring tools may foster self-management capacity and improve transplantation outcomes.

'Suspended in a paradox'-patient attitudes to wait-listing for kidney transplantation: systematic review and thematic synthesis of qualitative studies.

Patients on waiting lists for kidney transplantation have higher mortality rates and have specific anxieties about their eligibility, process, and outcomes of wait-listing. We aimed to describe patient experiences and attitudes to wait-listing for kidney transplantation. Electronic databases were searched to September 2014. Thematic synthesis was used to analyze the findings. From 22 studies (n = 795 patients), we identified six themes: accepting the only option (chance to regain normality, avoiding guilt, impulsive decision-making); maintaining hope (determined optimism, appreciating a fortuitous gift, enduring for optimal outcomes, trust in clinical judgment); burden of testing (strenuous commitment, losing the battle, medical mistrust); permeating vulnerability (eligibility enigma, being threatened, angst of timing uncertainty, desperate urgency, living in limbo, spiraling doubt and disappointment, residual ambivalence); deprived of opportunity (unfairly dismissed, unexpected disqualification, self-resignation and acceptance, jealousy, suspicious of inequity); and moral guilt (awaiting someone's death, questioning deservingness). The waiting list offered hope of restored normality. However, the demands of workup, uncertainty about eligibility, and waiting times that exceeded expectations impelled patients to disillusionment, despair, and suspicion of inequity. Managing patient expectations and ensuring transparency of wait-listing and allocation decisions may allay patient disappointment and skepticism, to improve patient satisfaction and treatment outcomes.

Determinants of frequent Internet use in an urban kidney transplant population in the United States: characterizing the digital divide.

CONTEXT: The Internet is a staple of electronic communication and is essential to the emerging telemonitoring and health information technology interventions for adults with chronic diseases. OBJECTIVE: To identify determinants of frequent Internet use in an urban kidney transplant population in the United States. DESIGN: A single center, cross-sectional survey study. SETTING: An urban Midwestern transplant center. PARTICIPANTS: 78 pretransplant and 177 posttransplant patients. MAIN OUTCOME MEASURES: Frequent Internet use, defined as using the Internet more than 5 hours per week. RESULTS: Only 38% of participants reported being frequent Internet users. Non-Hispanic blacks and participants who reported their race/ethnicity as "other" were significantly less likely than whites to report being frequent Internet users. Women were 59% less likely than men to be frequent users of the Internet. Those who reported having kidney disease for more than 3 years were more likely to report being frequent Internet users. As education increased, Internet use increased. As age increased, Internet use decreased. CONCLUSION: Alternatives to electronic information sources and/or additional resources should be considered for those who may fall in the so-called digital divide.

Validation of a Core Patient-Reported Outcome Measure for Life Participation in Kidney Transplant Recipients: the SONG Life Participation Instrument.

Introduction: Life participation has been established as a critically important core for trials in kidney transplantation. We aimed to validate a patient-reported outcome measure for life participation in kidney transplant recipients. Methods: A psychometric evaluation of the Standardized Outcomes in Nephrology life participation (SONG-LP) measure was conducted in adult kidney transplant recipients. The measure includes 4 items of life participation (leisure, family, work, and social) each with a 5-point Likert scale. Each item is scored from 0 (never) to 4 (always) and the summary measure score the average of each item. Results: A total of 249 adult kidney transplant recipients from 20 countries participated. The SONG-LP instrument demonstrated internal consistency (Cronbach's α = 0.87; 95% confidence intervals [CI]: 0.83-0.90, baseline) and test-retest reliability over 1 week (intraclass correlation coefficient of 0.62; 95% CI: 0.54-0.70). There was moderate to high correlation (0.65; 95% CI: 0.57-0.72) with the PROMIS Ability to Participate in Social Roles and Activities Short Form 8a that assessed a similar construct, and moderate correlation with measures that assessed related concepts (i.e., EQ5D 0.57; 95% CI: 0.49-0.65), PROMIS Cognitive Functional Abilities Subset Short Form 4a (0.40; 95% CI: 0.29-0.50). Conclusion: The SONG-LP instrument is a simple, internally consistent, reliable measure for kidney transplant recipients and correlates with similar measures. Routine incorporation in clinical trials will ensure consistent and appropriate assessment of life participation for informed patient-centered decision-making.

CKD-mineral and bone disorder management in kidney transplant recipients.

Kidney transplantation, the most effective treatment for the metabolic abnormalities of chronic kidney disease (CKD), only partially corrects CKD-mineral and bone disorders. Posttransplantation bone disease, one of the major complications of kidney transplantation, is characterized by accelerated loss of bone mineral density and increased risk of fractures and osteonecrosis. The pathogenesis of posttransplantation bone disease is multifactorial and includes the persistent manifestations of pretransplantation CKD-mineral and bone disorder, peritransplantation changes in the fibroblast growth factor 23-parathyroid hormone-vitamin D axis, metabolic perturbations such as persistent hypophosphatemia and hypercalcemia, and the effects of immunosuppressive therapies. Posttransplantation fractures occur more commonly at peripheral than central sites. Although there is significant loss of bone density after transplantation, the evidence linking posttransplantation bone loss and subsequent fracture risk is circumstantial. Presently, there are no prospective clinical trials that define the optimal therapy for posttransplantation bone disease. Combined pharmacologic therapy that targets multiple components of the disordered pathways has been used. Although bisphosphonate or calcitriol therapy can preserve bone mineral density after transplantation, there is no evidence that these agents decrease fracture risk. Moreover, bisphosphonates pose potential risks for adynamic bone disease.

Renal impairment and clinical outcomes of Clostridium difficile infection in two randomized trials.

BACKGROUND/AIMS: Patients with chronic kidney disease (CKD) have increased risk for Clostridium difficile infection (CDI) and for subsequent mortality. We determined the effect of CKD on response to treatment for CDI. METHODS: This is a post hoc analysis of two randomized controlled phase 3 trials that enrolled patients with CDI. Patients received either fidaxomicin 200 mg b.i.d. or vancomycin 125 mg q.i.d. for 10 days. Univariate and multivariate analyses compared end points by treatment received and CKD stage. RESULTS: At baseline, 27, 21, and 9% of the patients had stage 2 (60-89 ml/min/1.73 m(2)), stage 3 (30-59), and stage 4 or higher (<30) CKD. Cure rates were similar for normal (91%) and stage 2 CKD (92%), but declined to 80% for stage 3 and to 75% for stage 4 CKD (p < 0.001 for trend). Time to resolution of diarrhea (TTROD) increased with stage 3 and stage 4 CKD. CDI recurrence rates 4 weeks after treatment were 16, 20, 27, and 24% for normal, stage 2, stage 3, and stage 4 or higher CKD, respectively. Mortality increased with CKD stage. In multivariate analyses, stage 3 or higher CKD correlated with lower odds of cure, greater chance of recurrence, and lower odds of sustained response 28 days after treatment. Initial cure rates were similar in the vancomycin or fidaxomicin groups; however, the rate of recurrence was higher following vancomycin treatment independent of renal function. The presence of immunosuppression did not alter this effect. CONCLUSION: Progressive CKD is associated with increased TTROD, lower cure rates, and higher recurrence rates with treatment of CDI.