Obesity impacts many inter-related, and sometimes conflicting, considerations for transplant practice. In this article, we describe an approach for applying available data on the importance of body composition to the kidney transplant population that separates implications for candidate selection, risk stratification among selected candidates, and interventions to optimize health of the individual. Transplant recipients with obesity defined by elevated body mass index (BMI) have been shown in many (but not all) studies to experience an array of adverse outcomes more commonly than normal-weight transplant recipients, including wound infections, delayed graft function, graft failure, cardiac disease, and increased costs. However, current studies have not defined limits of body composition that preclude clinical benefit from transplantation compared with long-term dialysis in patients who have passed a transplant evaluation. Formal cost-effectiveness studies are needed to determine if payers and society should be compensating centers for clinical and financial risks of transplanting obese end-stage renal disease patients. Recent studies also demonstrate the limitations of BMI alone as a measure of adiposity, and further research should be pursued to define practical measures of body composition that refine accuracy for outcomes prediction. Regarding individual management, observational registry studies have not found beneficial associations of pretransplant weight loss with patient or graft survival. However, association studies cannot distinguish purposeful from unintentional weight loss as a result of illness and comorbidity. Prospective evaluations of the impact of targeted risk modification efforts in this population including dietary changes, monitored exercise programs, and bariatric surgery are urgently needed.

Chimeric antigen receptor T cells (CAR‐T) are genetically modified T cells with a chimeric antigen receptor directed against a specific tumor‐associated antigen like CD19 in lymphoma. CAR‐T cells have shown encouraging activity against recurrent and refractory diffuse large B cell lymphomas (DLBCL). However concurrent use of immunosuppressive agents was prohibited in most CAR‐T trials effectively excluding patients with prior solid organ transplantation (SOT) and posttransplant lymphoproliferative disorders (PTLD). We report the outcomes for three patients with PTLD refractory to immunochemotherapy 10‐20 years after SOT who received CAR‐T therapy between January 2018 and December 2019. One patient had an orthotopic heart transplant, the second had a deceased donor kidney transplant, and the third had a pancreas after kidney transplant (PAK). All patients developed complications of CAR‐T therapy such as cytokine release syndrome, immune effector cell‐associated neurotoxicity syndrome, and acute kidney injury requiring renal replacement therapy in the two out of three patients. All patients expired after withdrawal of care due to lack of response to CAR‐T therapy. In addition, the PAK patient developed acute pancreatitis after CAR‐T therapy. This case series identifies the challenges of using CAR‐T therapy to manage refractory PTLD in SOT recipients and its possible complications.

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.

De novo thrombotic microangiopathy (TMA) after renal transplant is rare. Cytomegalovirus (CMV)-related posttransplant TMA has only been reported in 6 cases. We report an unusual case of a 75-year old woman who developed de novo TMA in association with CMV viremia. The recurrence of TMA with CMV viremia, resolution with treatment for CMV and the lack of correlation with a calcineurin inhibitor (CNI) in our case supports CMV as the cause of the TMA. What is unique is that the use of eculizumab without plasmapheresis led to prompt improvement in renal function. After a failure to identify a genetic cause for TMA and the clear association with CMV, eculizumab was discontinued. This case provides insight into the pathogenesis and novel treatment of de novo TMA, highlights the beneficial effects of complement inhibitors in this disease and shows that they can be safely discontinued once the inciting etiology is addressed.

Background: Despite advances in immune suppression, kidney allograft rejection and other injuries remain a significant clinical concern, particularly with regards to long-term allograft survival. Evaluation of immune activity can provide information about rejection status and help guide interventions to extend allograft life. Here we describe the validation of a blood gene expression classifier developed to differentiate immune quiescence from both T cell mediated rejection (TCMR) and antibody-mediated rejection (ABMR). Methods: A five-gene classifier (DCAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed on 56 peripheral blood samples and validated on two sample sets independent of the training cohort. The primary validation set comprised 98 quiescence samples and 18 rejection samples: 7 TCMR, 10 ABMR, and 1 mixed rejection. The second validation set included 8 quiescence and 11 rejections: 7 TCMR, 2 ABMR, and 2 mixed. AlloSure donor derived cell-free DNA was also evaluated. Results: AlloMap Kidney classifier scores in the primary validation set differed significantly between quiescence (median 9.49, IQR 7.68-11.53) and rejection (median 13.09, IQR 11.25-15.28), p < 0.001. In the second validation set, the cohorts were statistically different (p = 0.028) and the medians were similar to the primary validation set. The AUC for discriminating rejection from quiescence was 0.786 for the primary validation and 0.800 for the second validation. AlloMap Kidney results were not significantly correlated with AlloSure, although both were elevated in rejection. The ability to discriminate rejection from quiescence was improved when AlloSure and AlloMap Kidney were used together (AUC 0.894). Conclusion: Validation of AlloMap Kidney demonstrated the ability to differentiate between rejection and immune quiescence using a range of scores. The diagnostic performance suggests that assessment of the mechanisms of immunological activity is complementary to allograft injury information derived from AlloSure dd-cfDNA. Together, these biomarkers offer a more comprehensive assessment of allograft health and immune quiescence.

Significant advances in immunosuppressive therapies have been made in renal transplantation, leading to increased allograft and patient survival. Despite improvement in overall patient survival, patients continue to require management of persistent post-transplant hyperparathyroidism. Medications that treat persistent hyperparathyroidism include vitamin D, vitamin D analogues, and calcimimetics. Medication side effects such as hypocalcemia or hypercalcemia, and adynamic bone disease, may lead to a decrease in the drugs. When medical management fails to control persistent post-transplant hyperparathyroidism, treatment is a parathyroidectomy. Surgical techniques are not uniform between centers and surgeons. Undergoing the surgery may include a subtotal technique or a technique including total parathyroid gland resection with partial heterotopic gland reimplantation. In addition, there are possible post-surgical complications. The ideal treatment for persistent post-transplant hyperparathyroidism is the treatment and prevention of the condition while patients are being managed for their late-stage chronic kidney disease and end-stage renal disease.

SummaryCoronary heart disease (CHD) is the leading cause of death in Western civilizations, in particular in chronic kidney disease (CKD) patients. Serum total cholesterol and LDL have been linked to the development of atherosclerosis and progression to CHD in the general population. However, the reductions of total and LDL cholesterol in the dialysis population have not demonstrated the ability to reduce the morbidity, mortality, and cost burden associated with CHD. The patients at greatest risk include those with pre-existing CHD, a CHD-risk equivalent, or multiple risk factors. However, data in the dialysis population are much less impressive, and the relationship between plasma cholesterol, cholesterol reduction, use of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, and reduction in incidence of CHD or effect on progression of renal disease have not been proven. Adverse event information from published trials indicates that agents within this class share similar tolerability and adverse event profiles. Hepatic transaminase elevations may occur in 1 to 2% of patients and is dose related. Myalgia, myopathy, and rhabodmyolysis occur infrequently and are more common in kidney transplant patients and patients with CKD. This effect appears to be dose related and may be precipitated by administration with agents that inhibit cytochrome P-450 isoenzymes. Caution should be exercised when coadministering any statin with drugs that metabolize through cytochrome P-450 IIIA-4 in particular fibrates, cyclosporine, and azole antifungals. Elderly patients with CKD are at greater risk of adverse drug reactions, and therefore the lowest possible dose of statins should be used for the treatment of hyperlipidemia.

Patients with stage 5 chronic kidney disease usually develop secondary hyperparathyroidism with concomitant parathyroid gland hyperplasia. Following renal transplantation, parathyroid glands usually undergo slow involution, resulting in lower parathyroid hormone (PTH) levels and abatement of hypercalcemia and hypophosphatemia. A subset of patients has more severe hyperparathyroidism posttransplant, and develops persistent and significant hypercalcemia.In this issue of the American Journal of Transplantation, Evenepoel et al report the results of a placebo-controlled trial of cinacalcet for management of posttransplant hypercalcemia due to persistent hyperparathyroidism (1). They demonstrate that cinacalcet normalizes serum calcium and lowers PTH. The study randomized 114 patients with severe hyperparathyroidism (mean PTH 318 pg/mL) and hypercalcemia (mean calcium 11.3 mg/dL) an average of 7 months posttransplant. Consistent with prior smaller studies, cinacalcet lowered PTH, normalized serum calcium and increased phosphorus, while placebo treatment led to no significant changes in these parameters. Gastrointestinal side effects from cinacalcet were expected and observed, but the discontinuation rate was quite low.After 1 year of treatment, the cinacalcet group had several other outcomes similar to placebo treatment: no improvement in bone mineral density (BMD) at the distal one-third radius, femoral neck or lumbar spine, and no improvement in biomarkers of high bone turnover (1). Both groups had comparable and stable estimated GFR, allaying concerns raised previously. Following withdrawal of cinacalcet, serum calcium and PTH levels were similar in the cinacalcet and placebo groups, suggesting cinacalcet did not hasten parathyroid gland involution (1).This trial illustrates a biochemical response to cinacalcet, with improvement in hypercalcemia and PTH. However, the duration of follow-up was too short, and the study population too small to examine fracture incidence. Unlike other patients with primary hyperparathyroidism, most renal transplant recipients do not routinely have high bone turnover (2). Bone biopsies in 17 patients (not treated with cinacalcet) with hypercalcemia and hyperparathyroidism 0.6-12 years posttransplant showed eight had osteitis fibrosa (high bone turnover), seven had adynamic bone disease (low bone turnover) and one each had mixed uremic osteodystrophy and osteomalacia (2).Given the high prevalence of low bone turnover in transplant patients with hypercalcemia and hyperparathyroidism, use of cinacalcet (or parathyroidectomy) may exacerbate bone disease, despite normalizing serum calcium. A prospective study performing bone biopsies in 10 patients with hypercalcemia and hyperparathyroidism for an average of 2 years postrenal transplant found low bone turnover present in 4 of 10 prior to cinacalcet (3). After 18-24 months of cinacalcet therapy, 8 of 10 had low bone turnover, including five with undetectable bone formation rates. As in the Evenepoel et al trial, these investigators found cin...