Stroke and kidney transplantation.

PURPOSE OF REVIEW: This review will focus on the epidemiological data, risk factors, and management of stroke before and after kidney transplant. Stroke is highly prevalent in waitlisted patients as well as kidney transplant recipients and is associated with impaired transplant outcomes. Multiple traditional, nontraditional, and transplanted risk factors increase the risk of stroke. RECENT FINDINGS: Although the risk of stroke is reduced after kidney transplantation compared with remaining on dialysis, the morbidity and mortality from stroke after transplantation remain significant. SUMMARY: Early screening for risk factors before and after a kidney transplant and following the Kidney Disease Improving Global Outcomes (KDIGO) management guidelines could minimize the incidence of stroke and transplant outcomes.

Defining the roles and responsibilities of the kidney transplant medical director: A necessary step for future training, mentoring, and professional development.

The management of a kidney transplant program has evolved significantly in the last decades to become a highly specialized, multidisciplinary standard of care for end-stage kidney disease. Transplant center job descriptions have similarly morphed with increasing responsibilities to address a more complex patient mix, increasing medical and surgical therapeutic options, and increasing regulatory burden in the face of an ever-increasing organ shortage. Within this evolution, the role of the Kidney Transplant Medical Director (KTMD) has expanded beyond the basic requirements described in the United Network for Organ Sharing bylaws. Without a clear job description, transplant nephrology trainees may be inadequately trained and practicing transplant nephrologists may face opaque expectations for the roles and responsibilities of Medical Director. To address this gap and clarify the key areas in which the KTMD interfaces with the kidney transplant program, American Society of Transplantation (AST) formed a Task Force of 14 AST KTMDs to review and define the role of the KTMD in key aspects of administrative, regulatory, budgetary, and educational oversight of a kidney transplant program.

Transplant administration-A survey of the roles and responsibilities of kidney and pancreas medical directors of US transplant centers.

The current American Society of Transplantation (AST) accredited transplant fellowship programs in the United States provide no structured formal training in leadership and administration which is essential for successfully running a transplant program. We conducted a survey of medical directors of active adult kidney and kidney-pancreas transplant programs in the United States about their demographics, training pathways, and roles and responsibilities. The survey was emailed to 183 medical directors, and 123 (67.2%) completed the survey. A majority of respondents were older than 50 years (61%), males (80%), and holding that position for more than 10 years (47%). Only 51% of current medical directors had taken that position after completing a one-year transplant fellowship, and 58% took on the role with no prior administrative or leadership experience. The medical directors reported spending a median 50%-75% of time in clinical responsibilities, 25%-50% of time in administration, and 0%-25% time in research. The survey also captured various administrative roles of medical directors vis-à-vis other transplant leaders. The study, designed to be the starting point of an improvement initiative of the AST, provided important insight into the demographics, training pathways, roles and responsibilities, job satisfaction, education needs, and training gaps of current medical directors.

Biomarkers of rejection in kidney transplantation.

PURPOSE OF REVIEW: To provide an update of the literature on the use of new biomarkers of rejection in kidney transplant recipients. RECENT FINDINGS: The kidney allograft biopsy is currently considered the gold standard for the diagnosis of rejection. However, the kidney biopsy is invasive and could be indeterminate. A significant progress has been made in discovery of new biomarkers of rejection, and some of them have been introduced recently for potential use in clinical practice including measurement of serum donor-derived cell free DNA, allo-specific CD154 + T-cytotoxic memory cells, and gene-expression 'signatures'. The literature supports that these biomarkers provide fair and reliable diagnostic accuracy and may be helpful in clinical decision-making when the kidney biopsy is contraindicated or is inconclusive. SUMMARY: The new biomarkers provide a promising approach to detect acute rejections in a noninvasive way.

Should Transplant Nephrology Pursue Recognition from the Accreditation Council for Graduate Medical Education (ACGME)?

Kidney transplant is not only the best treatment for patients with advanced kidney disease but it also reduces health care expenditure. The management of transplant patients is complex as they require special care by transplant nephrologists who have expertise in assessing transplant candidates, understand immunology and organ rejection, have familiarity with perioperative complications, and have the ability to manage the long-term effects of chronic immunosuppression. This skill set at the intersection of multiple disciplines necessitates additional training in Transplant Nephrology. Currently, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. In 2022, more than 40,000 patients were added to the kidney wait list and more than 25,000 received a kidney transplant. The Advancing American Kidney Health Initiative, passed in 2019, is aiming to double the number of kidney transplants by 2030 creating a need for additional transplant nephrologists to help care for them. Over the past decade, there has been a decline in the Nephrology-as well Transplant Nephrology-workforce due to a multitude of reasons. The American Society of Transplantation Kidney Pancreas Community of Practice created a workgroup to discuss the Transplant Nephrology workforce shortage. In this article, we discuss the scope of the problem and how the Accreditation Council for Graduate Medical Education recognition of Transplant Nephrology Fellowship could at least partly mitigate the Transplant Nephrology work force crisis.

A history of chronic opioid usage prior to kidney transplantation may be associated with increased mortality risk.

Chronic opioid usage (COU) for analgesia is common among patients with end-stage renal disease. In order to test whether a prior history of COU negatively affects post-kidney transplant outcomes, we retrospectively examined clinical outcomes in adult kidney transplant patients. Among 1064 adult kidney transplant patients, 452 (42.5%) reported the presence of various body pains and 108 (10.2%) reported a prior history of COU. While the overall death or kidney graft loss was not statistically different between patients with and without a history of COU, the cumulative mortality rate at 1, 3, and 5 years after transplantation, and during the entire study period, appeared significantly higher for patients with than without a history of COU (6.5, 18.5, and 20.4 vs. 3.2, 7.5, and 12.7%, respectively). Multivariate Cox regression analysis adjusted for potential confounding factors in entire cohorts and Cox regression analysis in 1:3 propensity-score matched cohorts suggest that a positive history of COU was significantly associated with nearly a 1.6- to 2-fold increase in the risk of death (hazard ratio 1.65, 95% confidence interval 1.04-2.60, and hazard ratio 1.92, 95% confidence interval 1.08-3.42, respectively). Thus, a history of chronic opioid usage prior to transplantation appears to be associated with increased mortality risk. Additional studies are warranted to confirm the observed association and to understand the mechanisms.

The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation.

Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan-Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pancreas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates.

Increase in proteinuria >200 mg/g after late rejection is associated with poor graft survival.

BACKGROUND: There is no information on the effects of proteinuria on outcomes following rejection. METHODS: We addressed this question in a retrospective study of 925 kidney transplant recipients between January 2003 and December 2007. Selection criteria were based on (i) biopsy proven diagnosis of a first episode of acute rejection, and (ii) available data on urine protein to creatinine (UPC) ratios at baseline (lowest serum creatinine before biopsy), time of biopsy and 1 month after biopsy. We examined the effects of a change in UPC (DeltaUPC = UPC 1 month after biopsy-baseline UPC) on outcomes. RESULTS: We identified 82 patients with both acute rejection and available data on proteinuria. Mean time (+/-SE) to acute rejection was 19 +/- 2.3 months, and patients were followed up for 38.7 +/- 2.6 months after transplant. Median DeltaUPC was 200 mg/g (95% confidence interval 0.00 to 0.300). Forty-two patients had a DeltaUPC > or =200 (high proteinuria group). Baseline characteristics were similar between high and low proteinuria groups except for more induction therapy with interleukin-2 receptor blockade in the former (71 vs. 47%, P = 0.04). Patient with DeltaUPC > or =200 had higher rates of graft loss (26 vs. 15%, P = 0.01) or combined graft loss or death (38 vs. 20%, P = 0.002 by log-rank). In univariate and multivariate Cox regression analyses, DeltaUPC > or =200 mg/g, sirolimus therapy 1 month after rejection and re-transplant status were significant factors associated with death-censored graft loss (hazard ratio (HR) 4.4, 14.9 and 6.2, P < or = 0.008) or combined graft loss or patient death (HR 3.8, 6.5 and 3.9, P < or = 0.03). Conclusions. An increase in proteinuria > or =200 mg/g after late acute rejection is associated with poor graft and patient outcomes. Clinical trials are needed to determine whether post-rejection anti-proteinuric strategies improve outcomes.

Transplantation in diabetic kidney failure patients: modalities, outcomes, and clinical management.

Diabetes mellitus (DM) is a common and devastating disease, affecting up to 19.3 million Americans. It is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. Diabetic patients with ESRD have a high incidence of cardiovascular disease and death. For those kidney transplant patients with no history of DM prior to transplantation, the development of new onset diabetes after transplantation (NODAT) also poses a serious threat to both graft and patient survival. Kidney transplantation is the best renal replacement option for diabetic ESRD and has the potential to halt the progression of cardiovascular diseases. Early referral for transplant evaluation is essential for pre-emptive or early kidney transplantation in this cohort of patients. In type 1 DM patients with ESRD, simultaneous pancreas and kidney transplantation (SPK) should be encouraged; and in patients facing prolonged waiting time for SPK transplantation but with an available living donor, living donor kidney transplantation followed by pancreas after kidney transplantation (PAK) is a suitable alternative. Islet transplantation in type 1 diabetics is deemed experimental by Medicare, and easy access to this modality remains restricted to qualified patients enrolled in clinical trials or with private insurance. The optimal management of kidney transplant patients with pre-existent DM or NODAT involves a multi-pronged approach consisting of pharmacological and nonpharmacological intervention to address all potential cardiovascular risk factors such as glycemic and lipid control, blood pressure control, weight loss, and smoking cessation. Finally, re-transplantation should be recommended in suitable kidney transplant patients when the kidney allograft demonstrates continuous and progressive decline in function.

Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient.

Atypical hemolytic uremic syndrome, or the nondiarrheal form of hemolytic uremic syndrome, is a rare disorder typically classified as familial or sporadic. Recent literature has suggested that approximately 50% of patients have mutations in factor H (CFH), factor I (CFI), or membrane cofactor protein (encoded by CD46). Importantly, results of renal transplantation in patients with mutations in either CFH or CFI are dismal, with recurrent disease leading to graft loss in the majority of cases. We describe an adult renal transplant recipient who developed recurrent hemolytic uremic syndrome 1 month after transplantation. Bidirectional sequencing of CFH, CFI, and CD46 confirmed that the patient was heterozygous for a novel missense mutation, a substitution of a serine reside for a tyrosine residue at amino acid 369, in CFI. This report reemphasizes the importance of screening patients with atypical hemolytic uremic syndrome for mutations in these genes before renal transplantation and shows the challenges in the management of these patients.

Bisphosphonates and bone fractures in long-term kidney transplant recipients.

BACKGROUND: There is little information on the role of bisphosphonates and bone mineral density (BMD) measurements for the follow-up and management of bone loss and fractures in long-term kidney transplant recipients. METHODS: To address this question, we retrospectively studied 554 patients who had two BMD measurements after the first year posttransplant and compared outcomes in patients treated, or not with bisphosphonates between the two BMD assessments. Kaplan-Meier survival and stepwise Cox regression analyses were performed to examine fracture-free survival rates and the risk-factors associated with fractures. RESULTS: The average time (+/-SE) between transplant and the first BMD was 1.2+/-0.05 years. The time interval between the two BMD measurements was 2.5+/-0.05 years. There were 239 and 315 patients in the no-bisphosphonate and bisphosphonate groups, respectively. Treatment was associated with significant preservation of bone loss at the femoral neck (HR 1.56, 95% CI 1.21-2.06, P=0.0007). However, there was no association between bone loss at the femoral neck and fractures regardless of bisphosphonate therapy. Stepwise Cox regression analyses showed that type-1 diabetes, baseline femoral neck T-score, interleukin-2 receptor blockade, and proteinuria (HR 2.02, 0.69, 0.4, 1.23 respectively, P<0.01), but not bisphosphonates, were associated with the risk of fracture. CONCLUSIONS: Bisphosphonates may prevent bone loss in long-term kidney transplant recipients. However, these data suggest a limited role for the initiation of therapy after the first posttransplant year to prevent fractures.

CKD stage-to-stage progression in native and transplant kidney disease.

BACKGROUND: Kidney half-life and inter-stage progression rates in native chronic kidney disease (CKD) and CKD-transplant (CKD-T) remain unknown. METHODS: We examined stage-to-stage progression/regression rates in patients with CKD (n = 601) and CKD-T (n = 431) between 1991 and 2001. Kidney function was estimated by Cockcroft-Gault and MDRD eGFR formulae. Kaplan-Meier analyses determined progression and regression half-lives, defined as the time required for 50% of kidneys to advance towards a higher or lower stage of CKD, respectively. RESULTS: Most (67%) of the patients were in stage 3. Patients with native CKD were more likely to progress compared to CKD-T (inter-stage progression rates 12 vs 4 cases per 100 patient-years, P < 0.0001). Accordingly, estimated glomerular filtration rate (eGFR)-based progression half-lives were significantly shorter in CKD compared to CKD-T [6 vs 9.6 years, P < 0.0001, hazard ratio (HR) 3.1, 95% confidence interval (CI) = 2.5-3.7]. Creatinine clearance (CCR)-based stage half-lives were 7.2 months shorter in each group (5.4 and 9 years in CKD and CKD-T, respectively). Despite slower progression rates in patients with transplant kidney disease, adjusted patient survival rates were significantly decreased in CKD-T compared to CKD. Only Scr and CCR-based formulae were significantly associated with patient and allograft outcomes in the CKD-T group. Moreover, death rates were not different in stage 3 compared to stage 2 CKD-T, suggesting that eGFR and the current staging classification have a limited value to predict patient death in this cohort. CONCLUSION: Kidney half-lives per stage of CKD may be a novel tool to examine disease progression.

Disease progression and outcomes in type 1 diabetic kidney transplant recipients based on posttransplantation CKD staging.

BACKGROUND: Disease progression rates and outcomes per stage of kidney disease in kidney transplant recipients with type 1 diabetes mellitus are unknown. STUDY DESIGN: Single-center retrospective cohort study. SETTINGS & PARTICIPANTS: 276 kidney transplant recipients with type 1 diabetes mellitus and a functioning graft at 1 year posttransplantation. PREDICTORS: Stage of chronic kidney disease at 1 year posttransplantation, donor source, and other clinical characteristics (covariates). OUTCOMES & MEASUREMENTS: Slope of creatinine clearance, weighted average slopes of creatinine clearance in a subgroup of 60 patients, death-censored allograft and patient survival rates. RESULTS: The median rate of creatinine clearance decrease after the first posttransplantation year was -1.6 mL/min/y (95% confidence interval [CI], -1.97 to -1.30) during a median follow-up of 8.4 years (95% CI, 8.13 to 8.84). The slope was significantly greater in stages 1 to 2 (-1.7 mL/min/y; 95% CI, -2.2 to -1.4) than stage 3 (-1.2 mL/min/y; 95% CI, -1.9 to -0.6; P = 0.0003). However, chronic kidney disease stage and donor source had no significant effect on death-censored allograft survival and patient survival rates. There were 23 deaths and 31 allograft losses in patients with stages 1 to 2 compared with 19 deaths and 18 allograft losses in those with stage 3. Univariate and multivariable Cox regression analyses showed that semiquantitative proteinuria of 1 or greater, mean arterial pressure, hematocrit of 33% or less, and calcineurin-inhibitor use were associated with decreased allograft survival, and age and hemoglobin A(1c) level of 7% or greater were significant risk factors for patient death regardless of donor type and stage of kidney function. LIMITATIONS: Generalizability to other settings; study power. CONCLUSION: All forms of kidney transplantation in patients with type 1 diabetes mellitus progressed at similar rates regardless of chronic kidney disease stage at 1 year posttransplantation. Age, anemia, hemoglobin A(1c) level, proteinuria, hypertension, and calcineurin-inhibitor use were associated with decreased allograft and patient outcomes.

Drug insight: maintenance immunosuppression in kidney transplant recipients.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease, in part because of ongoing efforts towards improving immunosuppressive strategies. Although calcineurin inhibitors remain the mainstay of immunosuppression in kidney transplant recipients, within this class of drug there has been a shift from use of ciclosporin to use of tacrolimus. Mycophenolate mofetil and mycophenolate sodium are now the antimetabolites of choice. A new class of drugs (inhibitors of mammalian target of rapamycin) that includes sirolimus is being increasingly used in stable kidney transplant recipients. New data, however, indicate that a more cautious approach to the use of this drug is warranted. Many transplant centers are now using steroid avoidance, minimization and withdrawal protocols. The impact of these different drugs and therapeutic strategies on outcomes has to be weighed against their immunosuppressive benefit. As more and more community-based nephrologists and primary care physicians are becoming involved in the care of stable kidney transplant recipients, it is important for these clinicians to familiarize themselves with novel immunosuppressive drugs and their pharmacokinetic properties.

The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients.

Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.

Current outcomes of chronic active antibody mediated rejection - A large single center retrospective review using the updated BANFF 2013 criteria.

BACKGROUND: The updated BANFF 2013 criteria has enabled a more standardized and complete serologic and histopathologic diagnosis of chronic active antibody mediated rejection (cAMR). Little data exists on the outcomes of cAMR since the initiation of this updated criteria. METHODS: 123 consecutive patients with biopsy proven cAMR (BANFF 2013) between 2006 and 2012 were identified. RESULTS: Patients identified with cAMR were followed for a median of 9.5 (2.7-20.3) years after transplant and 4.3 (0-8.8) years after cAMR. Ninety-four (76%) recipients lost their grafts with a median survival of 1.9 years after diagnosis with cAMR. Mean C4d and allograft glomerulopathy scores were 2.6 ± 0.7 and 2.2 ± 0.8, respectively. 53.2% had class II DSA, 32.2% had both class I and II, and 14.5% had class I DSA only. Chronicity score >8 (HR 2.9, 95% CI 1-8.4, p=0.05), DSA >2500 MFI (HR 2.8, 95% CI 1.1-6.8, p=0.03), Scr >3mg/dL (HR 3.2, 95% CI 1.6-6.3, p=0.001) and UPC >1g/g (HR 2.5, 95% CI 1.4-4.5, p=0.003) were associated with a higher risk of graft loss. CONCLUSIONS: cAMR was associated with poor graft survival after diagnosis. Improved therapies and earlier detection strategies are likely needed to improve outcomes of cAMR in kidney transplant recipients.

Preemptive kidney transplantation: has it come of age?

The benefits of preemptive kidney transplantation are manifold. By avoiding complications associated with dialysis, preemptive kidney transplantation offers significant benefits in terms of patient welfare and societal cost-saving. Patients transplanted preemptively also tend to enjoy better patient and graft survival, especially when done with a living-donor organ. While dialysis exposure limited to 6 to 12 months may not significantly impact post-transplant outcomes, longer period of dialysis has been shown to increase the risk of mortality, delayed graft function, acute rejection, and death-censored graft loss. The benefits of preemptive transplantation also extend to different age groups and end-stage kidney disease (ESKD) diagnoses. However, multiple barriers have prevented wider adoption of preemptive transplantation as the primary treatment of ESKD around the world. Timely preparation for ESKD and identification of living donors should be encouraged in all patients with advanced chronic kidney disease to increase the chance of preemptive transplantation.

Incidences of preformed and de novo donor-specific HLA antibodies and their clinicohistological correlates in the early course of kidney transplantation.

Our center started routine monitoring of preformed and de novo human leukocyte antigen donor-specific antibodies (DSA) in September 2010 using single antigen beads on the Luminex platform. Recipients with preformed DSA or other high immunological risk factors had serial DSA monitoring at 3, 6, and 12-months posttransplant, and low-risk recipients were screened only at 12-months. Surveillance biopsies were performed at 3, 6, and 12-months post-transplant for all recipients. In addition, for-cause biopsies and DSA testing were performed when clinically indicated for allograft dysfunction. Among 150 adult kidney and kidney/pancreas transplant recipients included in the analysis, 14% had preformed DSA and 7.8% of recipients without preformed DSA developed de novo DSA by 12-months. De novo DSA developed in 25% of recipients on cyclosporine compared to 5% of those on tacrolimus (p = 0.02). The incidences of acute rejection were 34%, 48%, and 70% in recipients with no DSA, with preformed DSA, and with de novo DSA, respectively (p = 0.05). In all recipients with de novo DSA and rejection, the first rejection episode preceded or was concurrent with the emergence of de novo DSA. Despite the difference in rejection incidences, the estimated glomerular filtration rate at 1-year was not significantly different between recipients with or without DSA.

Fibrogenesis in kidney transplantation: potential targets for prevention and therapy.

Kidney allograft fibrosis results from a reactive process mediated by humoral and cellular events and the activation of transforming growth factor beta1. It is a process that involves both parenchymal and graft infiltrating cells and can lead to organ failure if injury persists or if the response to injury is excessive. In this review, we will address the role of preventive and therapeutic strategies that target kidney allograft fibrogenesis. We conclude that in addition to preventive strategies, therapies based on bone morphogenetic protein 7, hepatocyte growth factor, connective tissue growth factor, and pirfenidone have shown promising results in preclinical studies. Clinical trials are needed to examine the effect of these therapies on long-term outcomes.