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.

Percutaneous arteriovenous fistula creation in the management of severe Hemophilia A and end-stage kidney disease needing hemodialysis access, and beyond.

With the contemporary KDOQI, a patient-focused approach in vascular access care is emphasized more than ever when planning RRT. Nevertheless, functional vascular access continues to be the Achilles' heel for successful hemodialysis in specific patient sub-groups, such as the Hemophilia-A population. The newer percutaneous endovascular approach is a safer alternative when conventional surgical AVF poses high bleeding risks perioperatively, which subsequently prevents ESKD patients to have desired permanent dialysis access. This article presents the case of a 45-year-old male with severe Hemophilia-A, who has been dialysis-dependent due to diabetic kidney disease and hypertension. Due to the severity of his progressively worsening bleeding disorder, his previous surgeries to treat other comorbidities have been complicated and involved challenging peri-operative treatment courses that include blood and factor VIII infusions, bleeding wounds, along with prolonged hospital stays. With the fear of bleeding diathesis, a conventional surgical AVF was not pursued, which has left him with a prolonged tunneled CVC while not being considered a candidate for peritoneal dialysis. We offered the patient a left arm percutaneous endovascular AVF creation with the WavelinQ™ 4F Endo-AVF system as an alternative option for his permanent hemodialysis access. An Endo-AVF was created bloodlessly between the left radial artery and lateral radial vein percutaneously with only two 4-French accesses at left wrist. The patient has been receiving full sessions of hemodialysis with expected flow rates and free of the CVC since. Likely the first case of such utilization reported, the utilization of percutaneous Endo-AVF for this patient has suggested not only that the endovascularly created AVF offers a good alternative dialysis access for hemophilia A patient populations, but also due to this technology's unique features, it can be potentially employed in other situations, such as needs for reliable and chronic venous accesses and blood product exchanges.

Disseminated Nocardiosis in a Renal Transplant Recipient.

Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.

Favorable outcome of COVID-19 among African American (AA) renal transplant recipients in Detroit.

Transplant recipients are vulnerable to infections, including COVID-19, given their comorbidities and chronic immunosuppression. In this study, all hospitalized renal transplant recipients (RTR) with a positive nasal swab for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2) seen consecutively between 03/01/2020 and 05/01/2020 at the Detroit Medical Center were included. Data on demographics, clinical presentation, laboratory findings, management, and outcomes were collected. Twenty-five patients were included, all African American (AA) and deceased-donor transplant recipients. The most common presenting symptom was dyspnea, followed by fever, cough and diarrhea. Multifocal opacities on initial chest x-ray were seen in 52% patients and 44% of patients had a presenting oxygen saturation of less than or equal to 94%. Four patients (16%) required transfer to the intensive care unit, one required intubation and one expired. COVID-19-infected RTR in this cohort had low mortality of 4% (n = 1). Despite multiple comorbidities and chronic immunosuppression, our cohort of African American RTR had favorable outcomes compared to other reports on COVID-19 in RTR.

BK Virus Nephropathy: Prevalence, Impact and Management Strategies.

BK virus reactivation as a result of therapeutic immunosuppression following renal transplant can result in BK polyomavirus nephropathy and renal allograft loss. This is a complex and challenging clinical problem with a range of management options and practices reported in literature. The current standard for early diagnosis and treatment is surveillance by measuring viral DNA in blood using qPCR. Immunosuppression reduction is the cornerstone of effective management but is associated with a risk of acute rejection following treatment.

Utility of Serial Protocol Biopsies Performed After 1 Year in Predicting Long-Term Kidney Allograft Function According to Histologic Phenotype.

OBJECTIVES: Prognostic implications of early protocol biopsies have been studied; however, the value of late protocol biopsy in predicting graft outcome has not been well defined. Here, we compared the effects of early and late protocol biopsy histologic findings in stable kidney allografts and aimed to understand the significance of "borderline" rejection on allograft function. MATERIALS AND METHODS: We studied 261 biopsies from 159 renal transplant recipients who were on a steroid-free, calcineurin inhibitor and mycophenolate mofetil regimen and who received transplants between 2004 and 2012 with mean follow-up of 5 years. Early (between 3 and 9 mo) and subsequent late (between 12 and 24 mo) protocol biopsies were performed. Biopsies were classified as normal, interstitial fibrosis and/or tubular atrophy, subclinical acute rejection with interstitial fibrosis and/or tubular atrophy, and borderline rejection with interstitial fibrosis and/or tubular atrophy. A linear mixed-effects model was used to determine the effects of early and late protocol biopsies on estimated glomerular filtration rate changes, with baseline time for estimated glomerular filtration rate fixed at 12 months. RESULTS: The adjusted model showed that estimated glomerular filtration rate at 3 months, donor age, delayed graft function, and early protocol biopsies were associated with baseline estimated glomerular filtration rate at 12 months. Estimated glomerular filtration rate changes over time were associated with findings of interstitial fibrosis and/or tubular atrophy at early biopsy and subclinical acute rejection and borderline rejection at late biopsy. At last follow-up, final estimated glomerular filtration rate was significantly associated with interstitial fibrosis and/or tubular atrophy at early biopsy and with subclinical acute rejection at late biopsy. CONCLUSIONS: Although early protocol biopsy predicted baseline estimated glomerular filtration rate, late biopsy was important for predicting changes in function over time. In addition, a diagnosis of "borderline" rejection on protocol biopsies predicted long-term graft function.

BK Virus in Kidney Transplant: Current Concepts, Recent Advances, and Future Directions.

BK virus nephropathy is a challenging clinical problem in kidney transplant recipients with wide range of surveillance and management practices, based on individual experience. BK virus reactivation in kidney transplant recipients can result in BK virus nephropathy and graft loss. The most effective strategy for early diagnosis and treatment of BK virus nephropathy is regular monitoring for BK virus, currently achieved by quantification of viral DNA in blood by quantitative polymerase chain reaction. Immunosuppression reduction remains the mainstay of treatment; however, viral clearance is often followed by acute rejection, likely secondary to a delay between immune reconstitution and viral clearance. Impaired cell-mediated immune response to BK virus has been shown to correlate with progression to BK virus nephropathy, while reconstitution of this response correlates with resolution of nephropathy. There is recent research to support monitoring BK virus-specific cell-mediated immune response as a predictor of disease progression and resolution. In this article, we review the current concepts and recent developments in understanding BK virus-associated disease in the context of kidney transplant and outline areas for future research.

Alemtuzumab (Campath-1H) experience in kidney transplantation what we have learned; current practices; and scope for the future?

PURPOSE OF REVIEW: Alemtuzumab (Campath) usage as a preconditioning agent in kidney transplantation has gained considerable interest in the recent future. Alemtuzumab is currently available only by special request from Sanofi through its Campath distribution program. It is restricted to transplant programs with prior and continued experience with the agent. There may be a resurgence of interest for the utilization of this agent because of its ease of administration, and less cost and comparable or improved outcome in comparison to other induction agents. RECENT FINDINGS: Alemtuzumab when combined with standard calcineurin inhibitor and mycophenolate mofetil is well tolerated and efficacious as an induction therapy and allows for long-term steroid avoidance in high-risk renal transplant recipients. SUMMARY: The transplant community has advanced through a learning curve with the use of alemtuzumab over time; starting from an agent that was tried out to induce proper tolerance, minimization of nephrotoxic calcineurin inhibitors, and currently as a comparable depletional therapy that can reduce acute rejection in high-risk kidney transplant recipients.

Extended release once a day tacrolimus.

PURPOSE OF REVIEW: This article provides an update of the literature on the use of extended release once-daily tacrolimus in solid organ transplant recipients. RECENT FINDINGS: Medication nonadherence occurs in a substantial proportion of patients posttransplant and is associated with worse outcomes. Multiple daily dosing is associated with an increased risk for nonadherence. Several studies have indicated once-daily dosing of medications and reduced complexity improve medication adherence. The extended release formulations of tacrolimus have been developed with the potential benefits of improving adherence, and hence safety and outcomes. Astagraf XL™ (Advagraf in Europe) and Envarsus XR. are the two extended release once-daily tacrolimus formulations that have recently become available for clinical use and provide promising alternatives to the treatment choices available for immunosuppression in solid organ transplant recipients. SUMMARY: Although extended release tacrolimus shows promise in improving patient adherence to transplant medication therapy, further studies are needed to confirm improved compliance and to assess long-term safety and efficacy.

Evaluation of a Renal Transplant Program for Incarcerated ESRD Patients.

Renal transplantation (Tx) improves mortality and morbidity but is limited by availability of suitable organs. Clinical and economic impact of a Tx program for end-stage renal disease (ESRD) prisoners was evaluated. Wait list time and patient and organ survival rates were assessed. Twelve of the 104 ESRD prisoners at a prison dialysis unit were activated; 9 transplanted, 2 released active on the United Network for Organ Sharing list, and 1 died after listing. Kidneys from antibody-positive hepatitis C (HepC) donors were given to consenting HepC antibody-positive recipients. The average waiting period was 6.6 months for HepC-positive kidney recipients and 49.6 months for others. Compared with costs of continuing dialysis, Tx resulted in substantial savings. Patients with HepC experienced good graft and survival rates when given grafts from HepC donors, suggesting that transplantation is a viable, cost-effective option for the incarcerated patient with ESRD including those who have chronic HepC infection.

Alemtuzumab induction in simultaneous pancreas and kidney transplantation.

BACKGROUND: Alemtuzumab (AZ) is a monoclonal anti-CD52 antibody used as an induction agent in organ transplantation. Few studies have analyzed this agent in the context of simultaneous kidney-pancreas transplantation (SPKT). METHODS: We examined US registry data of SPKT recipient outcomes from January 2002 to October 2009 stratified by induction agent including AZ, other T-cell-depleting agents combined (T cell), IL2 receptor blockade (IL-2RAb), and no induction (none). RESULTS: Of 6860 SPKT recipients, induction therapy was AZ in 10%, T cell in 49%, IL-2RAb in 18%, and none in 22%. On multivariate analysis, there were no significant differences in overall patient survival, pancreas or renal allograft survival, or delayed renal graft function for the three induction groups compared with no induction. Rehospitalization within six months of transplantation occurred more often with AZ (51%) T cell (52%), and IL-2RAB (45%) compared with none (41%; p < 0.0001). On multivariate analysis, there was a significant higher odds of six-month rehospitalization with AZ (aOR 1.40, 95%CI 1.14-1.71), IL-2RAb (aOR 1.20, 95%CI 1.01-1.42-1.20), and other T-cell-depleting agents (aOR 1.50, 95%CI 1.31-1.73) compared with none. Median length of stay was significantly shorter in the AZ (8 d) compared with the IL-2RAb (9 d), T cell (10 d), and none (10 d) groups (p < 0.0001). CONCLUSIONS: There are no differences in patient, pancreas or renal allograft survival using AZ induction. AZ may confer an advantage in the perioperative period as evidenced by a decreased hospital length of stay. However, this benefit may be lost due to more frequent rehospitalizations.

Outcomes and survival analysis of old-to-old simultaneous pancreas and kidney transplantation.

Outcomes of old-donor simultaneous pancreas-kidney transplantation (SPKT) have not been thoroughly studied. Scientific Registry of Transplant Recipients data reported for SPKT candidates receiving dialysis wait-listed between 1993 and 2008 (n = 7937) were analyzed for outcomes among those who remained listed (n = 3301) and of SPKT recipients (n = 4636) using multivariable time-dependent regression models. Recipients were stratified by donor/recipient age (cutoff 40 years) into: young-to-young (n = 2099), young-to-old (n = 1873), old-to-young (n = 293), and old-to-old (n = 371). The overall mortality was 12%, 14%, 20%, and 24%, respectively, for those transplanted, and 50% for those remaining on the waiting list. On multivariable analysis, old-donor SPKT was associated with significantly higher overall risks of patient death, death-censored pancreas, and kidney graft failure in both young (73%, 53%, and 63% increased risk, respectively) and old (91%, 124%, and 85% increased risk, respectively) recipients. The adjusted relative mortality risk was similar for recipients of old-donor SPKT compared with wait-listed patients including those who subsequently received young-donor transplants (aHR 0.95; 95% CI 0.78, 1.12) except for candidates in OPOs with waiting times ≥604 days (aHR 0.65, 95% CI 0.45-0.94). Old-donor SPKT results in significantly worse graft survival and patient mortality without any waiting-time benefit as compared to young-donor SPKT, except for candidates with expected long waiting times.

Use of anti-CD20 antibody in the treatment of post-transplant glomerulonephritis.

Post-transplant glomerulonephritis (PTGN) accounts for 4-10% of late graft loss. Six consecutive patients who developed PTGN 3-72 months post-transplant presented to our center with deteriorating kidney function and proteinuria. Three had focal segmental glomerulosclerosis; one had membranoproliferative glomerulonephritis Type 1; one recurrent membranous nephropathy; and one recurrent immunoglobin A nephropathy. All six were treated with an aggressive immunosuppression regimen including rituximab, pulse steroids and/or maximization of mycophenolic acid and calcineurin inhibitor therapy. Four of the six patients received plasma exchange. The patients were followed for a minimum of nine months after treatment. Proteinuria decreased from 7.2 ± 4.4 to 1.4 ± 1.5g (p = 0.04), while mean estimated glomerular filtration rate was 31.2 ± 13.1 and 42.5 ± 21.7 mL/min (p = 0.07) at nine months. No adverse events were noted. These observations suggest that immune modulating therapy may be of benefit in the treatment of PTGN.

Kidney transplantation and pregnancy.

PURPOSE OF REVIEW: The purpose of this review is to improve the basis upon which advice on pregnancy is given to renal transplant recipients in the reproductive age group. The review attempts to impart up-to-date evidence-based information on the predictable outcome and the risk of pregnancy after kidney transplantation. RECENT FINDINGS: A current change in the consensus opinion of American Society of Transplantation regarding timing of pregnancy after transplantation. There are conflicting data regarding the utility of drug monitoring and dose adjustments of immunosuppressive medications during pregnancy and breast feeding. There is a recent change in the U.S. Food and Drug Administration category of mycophenolate mofetil from pregnancy Class C to D based on recent adverse fetal and neonatal outcome. SUMMARY: Counseling regarding pregnancy should be an integral part of caring for the kidney transplant patient in the reproductive age group. Ethical concerns exist about advising pregnancy and fertility treatment for a woman whose life expectancy may be affected by outcome of pregnancy. Toxic effects of newer immunosuppressive medications exposed in utero and during breast feeding and its long-term effects in the offspring have to be clearly defined. The need for longitudinal studies and multicenter observational studies cannot be over emphasized to help answer our considerable gaps in this area.

TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen.

We have previously demonstrated that transforming growth factor-beta(1) (TGF-beta(1)) rapidly activates the mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK signaling cascade, leading to the induction of type I collagen synthesis in mouse glomerular mesangial cells (Wang L, Ma R, Flavell RA, Choi ME. J Biol Chem 277: 47257-47262, 2002). In the present study, we investigated the functional role of upstream TGF-beta-activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) in the TGF-beta(1) signaling cascade. Rapid activation of endogenous TAK1 activity by TGF-beta(1) was observed in mouse mesangial cells. Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-beta(1) stimulation, whereas a dominant-negative mutant of TAK1 (TAK1DN) suppressed TGF-beta(1)-induced activation of MKK3 and p38 MAPK. Moreover, constitutive expression of TAK1DN reduced steady-state protein levels of MKK3 and p38 MAPK as well as MKK3 phosphorylation. Increased p38alpha MAPK activity by ectopic expression of either TAB1 or wild-type p38alpha MAPK resulted in enhanced TGF-beta(1)-induced type I collagen expression. In contrast, constitutive expression of TAK1DN inhibited collagen induction. Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.

Calcium channel blockers, endothelial dysfunction, and combination therapy.

Endothelial dysfunction complicates hypertension and is a precursor of atherosclerosis. It is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide (NO), and an increase in the activity of vasoconstrictors, including angiotensin (Ang) II and reactive oxygen species (ROS). To the extent that cardiovascular disease is characterized by an imbalance between NO, Ang II, and ROS in the endothelium, modulating the activity of these vasoactive substances has important implications for both the treatment of hypertension and the prevention of atherosclerosis and end organ damage. Accumulating experimental and clinical data suggest that a multitherapy antihypertensive regimen that includes inhibitors of the renin-angiotensin system and calcium channel antagonists may further reduce cardiovascular risk via greater improvements in endothelial function, in addition to the well-documented blood pressure lowering effects. Experimental studies in small and large coronary arteries and in aorta indicate that the calcium channel blocker, amlodipine, stimulates NO generation. These drug-specific actions beyond blood pressure lowering may exert cardio- and vasculoprotective effects by preventing the maladaptive changes that accompany hypertension, namely endothelial dysfunction, upregulation of proinflammatory molecules, vascular smooth muscle cell (VSMC) growth and migration, and increased extracellular matrix deposition, mechanisms that lead to atherosclerotic cardiovascular disease. These effects compliment those of other classes of antihypertensive agents and also 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), which have also been demonstrated to ameliorate the damaging consequences of endothelial dysfunction and thus reduce the incidence of cardiovascular events.