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.

Clinical Experience with Extended-Release Tacrolimus in Older Adult Kidney Transplant Recipients: A Retrospective Cohort Study.

BACKGROUND: Extended-release tacrolimus (LCP-Tac) prescribing information states that there is insufficient data in older adult patients from which to make recommendations on use in this population. This study sought to provide information on de novo use of LCP-Tac in the older adult kidney transplant population. METHODS: This single-center retrospective study had two distinct objectives; to determine if weight-based doses of LCP-Tac differ based on recipient age and to compare safety and efficacy between LCP-Tac and immediate-release tacrolimus (IR-Tac) in older adult transplant recipients. Data was obtained through electronic chart review up to 2 years after transplant with censoring for graft loss and death. RESULTS: Weight-based doses were compared between patients aged ≥ 65 years (n = 84), 36-64 years (n = 64), and ≤35 years (n = 44). LCP-Tac weight-based doses were lower at all time points in patients ≥ 65 years of age. Both age and race significantly impacted required dose on linear regression. The doses required to achieve therapeutic tacrolimus troughs were significantly lower in all age groups compared with the current FDA de novo dosing recommendation. In the older adult population, graft outcomes and infectious and metabolic complications were compared between recipients of LCP-Tac (n = 84) and IR-Tac (n = 42). Within this cohort, there were no differences between LCP-Tac and IR-Tac on graft function, rejection, graft loss, death, cytomegalovirus viremia, BK viremia, hypertension, diabetes, alopecia, or tremor up to 2 years after transplant. CONCLUSIONS: Older adult recipients required significantly lower LCP-Tac doses compared with younger recipients and with the FDA-labeled starting dose. There were no differences in graft outcomes or adverse effects in older adult patients who received LCP-Tac versus IR-Tac.

Poor Outcomes With the Use of Checkpoint Inhibitors in Kidney Transplant Recipients.

BACKGROUND: Checkpoint inhibitors are now frequently used for oncologic conditions. The impact of these therapies in solid organ transplant recipients was not assessed in clinical trials. Subsequent case reports highlight the major detrimental interactions of checkpoint inhibitors and the high risk of allograft rejection with their use. Patient outcomes have not been assessed in long-term follow-up. METHODS: We conducted a retrospective review of kidney transplant recipients with metastatic cancer who received checkpoint inhibitors at a single center between April 2015 and May 2018. RESULTS: Six kidney transplant recipients with metastatic cancers that were not responding to first-line treatments met study criteria. These include 2 with squamous cell cancers, 2 with melanoma, 1 with renal cell cancer, and 1 with adenocarcinoma of the lung. Four patients received anti-programmed cell death protein-1 (PD-1) antibody and 2 received a combination of anticytotoxic T-lymphocyte-associated protein 4 and anti-PD-1 antibodies. Three out of 6 patients developed acute kidney injury. Two were biopsy-proven acute rejections with subsequent graft failures. The third was attributed to rejection, but improved after discontinuing the checkpoint inhibitor. Five out of 6 patients had cancer progression and only 1 patient had remission. CONCLUSIONS: Providers and patients need to be aware of the high risk of rejection and the poor remission rate with the use of checkpoint inhibitors in kidney transplant patients. More research is warranted to assess the optimal maintenance immunosuppression during the use of checkpoint inhibitor therapy that would not diminish the chances of remission.

Immunoglobulin isotype switching of antibodies to vimentin is associated with development of transplant glomerulopathy following human renal transplantation.

BACKGROUND: Immune responses to tissue-restricted self-antigens are thought to play a role in chronic rejection after solid organ transplantation. De novo development of antibodies (Abs) to vimentin have been reported to be associated with interstitial fibrosis/tubular atrophy after kidney transplant, and it has been suggested that immunoglobulin isotype switching of Abs to vimentin may occur during this process. We aimed to determine the correlation between immunoglobulin isotype switching of Abs to vimentin and development of transplant glomerulopathy (TG) after kidney transplant, and to determine whether citrullinated modification of vimentin is required for de novo anti-vimentin development. METHODS: Sera were collected from 24 patients with TG (diagnosed on biopsy), 24 matched stable kidney transplant recipients (KTxRs) and 22 normal healthy subjects who did not undergo transplant. Serum vimentin Abs concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Immunoglobulin isotypes of anti-vimentin were determined using isotype-specific Abs conjugated with horseradish peroxidase. Samples were considered positive to vimentin Abs if the values were above mean+2× standard deviations of the levels in the healthy control subjects. Specificities of anti-vimentin for mutated citrullinated vimentin and anti-mutated citrullinated vimentin were measured by ELISA. RESULTS: In this retrospective analysis of 24 KTxRs with TG, 16/24 (67%) patients with biopsy-proven TG developed Abs to vimentin (645±427ng/ml). In contrast, only 4/24 (17%) stable KTxRs had detectable Abs to vimentin (275±293ng/ml; p=0.001). Of the patients with TG, 15/24 (63%) developed Abs to vimentin of IgG isotype (572±276ng/ml), whereas only 6/24 (25%) stable KTxRs (310±288ng/ml) had anti-vimentin of IgG isotype (p=0.002). However, no significant difference was noted in the concentration of IgM isotype anti-vimentin between KTxRs with TG (9/24 [38%], 407±401ng/ml) and stable KTxRs (5/24 [21%], 348±439ng/ml; p=0.631). The serum concentration of Abs specific for the mutated form of citrullinated vimentin was not significantly different between KTxRs with TG and stable KTxRs. CONCLUSIONS: Patients with biopsy-proven TG demonstrated significantly increased levels of anti-vimentin Abs of the IgG isotype compared with stable KTxRs. Anti-vimentin in stable KTxRs was primarily of IgM isotype. Therefore, the observed isotype switching of anti-vimentin from IgM to IgG isotype strongly suggests ongoing immune responses to vimentin in KTxRs diagnosed with TG. Furthermore, as opposed to patients with rheumatoid arthritis (who develop immune responses primarily to citrullinated vimentin), KTxRs diagnosed with TG developed immune responses to non-citrullinated vimentin, suggesting that modification of vimentin protein via citrullination is not required for the de novo anti-vimentin response seen in patients with TG.

ABO incompatible renal transplants and decreased likelihood for developing immune responses to HLA and kidney self-antigens.

Immune responses to HLA and tissue-restricted self-antigens (SAgs) have been proposed to play a role in the pathogenesis of renal allograft (KTx) rejection. However, ABO incompatible (ABOi) KTx recipients (KTxR) following depletion of antibodies (Abs) to blood group antigens had fewer rejections. To determine the mechanisms, pre- and post-transplant sera from ABOi (n=18) and ABO-compatible (ABOc) (n=45) KTxR were analyzed for Abs against HLA class I and II by LABScreen single antigen assay. The development of Abs to SAgs was measured by ELISA. Immunity to Collagen IV (Col-IV) and cytokines induced were measured by ELISPOT. While 8/45 (18%) ABOc KTxR developed new donor specific antibodies to HLA (DSA) following transplantation, 0/18 ABOi KTxR developed DSA. ABOi KTxR failed to develop Abs to kidney SAgs (Col-IV and fibronectin (FN)). In contrast, 7 ABOc KTxR developed Abs to both Col-IV and FN. Col-IV stimulation of lymphocytes from ABOc KTxR demonstrated increased IFNγ, IL-17 and decreased IL-10. In contrast ABOi recipients following stimulation with antigens resulted in more IL10 and reduced IFN-γ and IL17 production. At one year, the GFR in ABOi KTxR were significantly better (p<0.04) than ABOc KTxR. De novo DSA and immune responses to SAgs are reduced or absent in ABOi KTxR which we propose leads to less acute rejection and better long term function following ABOi KTx.