The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single-center randomized, double-blind, placebo-controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1-month posttransplant. The primary endpoint was the change in eGFR from baseline to 12-month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12-month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m² (95% CI; −0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m² (95% CI, −0.02 to 3.7) in the placebo group, with no significant between-group difference (−0.7 mL/min/1.73 m² [95% CI; −3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR <45 mL/min/1.73 m² (P_interaction <0.05, between-group difference; −4.3 mL/min/1.73 m² [95% CI; −7.3 to −1.3]). The degree of IFTA, changes in urine albumin-to-creatinine ratio, or adverse events including hypercalcemia and infections requiring hospitalization did not differ between groups. In conclusion, cholecalciferol supplementation did not affect eGFR change compared to placebo among incident KTRs. These findings do not support cholecalciferol supplementation for improving allograft function in incident KTRs. Clinical trial registry: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as UMIN000020597 (please refer to the links below). UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000023776     

COVID‐19 in kidney transplant recipients

There is minimal information on coronavirus disease 2019 (COVID‐19) in immunocompromised individuals. We have studied 10 patients treated at 12 adult care hospitals. Ten kidney transplant recipients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by polymerase chain reaction, and 9 were admitted. The median age was 57 (interquartile range [IQR] 47‐67), 60% were male, 40% Caucasian, and 30% Black/African American. Median time from transplant to COVID‐19 testing was 2822 days (IQR 1272‐4592). The most common symptom was fever, followed by cough, myalgia, chills, and fatigue. The most common chest X‐ray and computed tomography abnormality was multifocal patchy opacities. Three patients had no abnormal findings. Leukopenia was seen in 20% of patients, and allograft function was stable in 50% of patients. Nine patients were on tacrolimus and a mycophenolic antimetabolite, and 70% were on prednisone. Hospitalized patients had their antimetabolite agent stopped. All hospitalized patients received hydroxychloroquine and azithromycin. Three patients died (30%), and 5 (50%) developed acute kidney injury. Kidney transplant recipients infected with COVID‐19 should be monitored closely in the setting of lowered immunosuppression. Most individuals required hospitalization and presenting symptoms were similar to those of nontransplant individuals.     

Late graft failure after kidney transplantation as the consequence of late versus early events

Beyond the first posttransplant year, 3% of kidney transplants fail annually. In a prospective, multicenter cohort study, we tested the relative impact of early versus late events on risk of long‐term death‐censored graft failure (DCGF). In grafts surviving at least 90 days, early events (acute rejection [AR] and delayed graft function [DGF] before day 90) were recorded; serum creatinine (Cr) at day 90 was defined as baseline. Thereafter, a 25% rise in serum Cr or new‐onset proteinuria triggered graft biopsy (index biopsy, IBx), allowing comparison of risk of DCGF associated with early events (AR, DGF, baseline serum Cr >2.0 mg/dL) to that associated with later events (IBx). Among 3678 patients followed for 4.7 ± 1.9 years, 753 (20%) had IBx at a median of 15.3 months posttransplant. Early AR (HR = 1.77, P < .001) and elevated Cr at Day 90 (HR = 2.56, P < .0001) were associated with increased risk of DCGF; however, later‐onset dysfunction requiring IBx had far greater impact (HR = 13.8, P < .0001). At 90 days, neither clinical characteristics nor early events distinguished those who subsequently did or did not undergo IBx or suffer DCGF. To improve long‐term kidney allograft survival, management paradigms should promote prompt diagnosis and treatment of both early and later events.     

Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review

Solid organ transplant (SOT) is frequently complicated by cancers, which render immunosuppression challenging. Immune checkpoint inhibitors have emerged as treatments for many cancers. Data are lacking regarding efficacy and rejection risk in the SOT population. We conducted a systematic literature review and analyzed 83 cases of immune checkpoint inhibitor use for cancer in SOT. Two thirds of these patients received anti–programmed death ligand 1 therapy, 15.7% received anti–cytotoxic T lymphocyte–associated protein 4 therapy, and 10.8% received a combination. Allograft rejection occurred in 39.8% of patients, leading to end‐stage organ failure in 71.0% of cases. Outcomes were similar across organs and immunotherapy regimens. The use of immunosuppressants other than steroids, time since transplant, and prior episodes of rejection were associated with the risk of rejection. The median overall survival of patients was 36 weeks. Most of the deaths were related to cancer progression. In nonkidney recipients, graft rejection was strongly associated with worse survival. At the end of the study, 19.3% of the patients were alive, free from rejection and tumor progression. This study highlights the difficult tradeoff facing oncologists and transplant specialists managing transplant recipients with cancer, and the need for prospective data and novel biomarkers for identifying the patients likely to benefit from immunotherapy in the SOT setting.     

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte‐depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti‐thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2‐receptor antagonists (IL2‐RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1‐year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2‐Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte‐depletion induction when the anticipated risk of DGF is increased.     

Laparoscopic sleeve gastrectomy improves renal transplant candidacy and posttransplant outcomes in morbidly obese patients

Morbid obesity is a barrier to kidney transplantation due to inferior outcomes, including higher rates of new‐onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. Laparoscopic sleeve gastrectomy (LSG) increases transplant eligibility by reducing BMI in kidney transplant candidates, but the effect of surgical weight loss on posttransplantation outcomes is unknown. Reviewing single‐center medical records, we identified all patients who underwent LSG before kidney transplantation from 2011‐2016 (n = 20). Post‐LSG kidney recipients were compared with similar‐BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed‐rank test were used to compare groups. Among post‐LSG patients, mean BMI ± standard deviation (SD) was 41.5 ± 4.4 kg/m² at initial encounter, which decreased to 32.3 ± 2.9 kg/m² prior to transplantation (P < .01). No complications, readmissions, or mortality occurred following LSG. After transplantation, one patient (5%) experienced DGF, and no patients experienced NODAT. Allograft and patient survival at 1‐year posttransplantation was 100%. Compared with non‐LSG patients, post‐LSG recipients had lower rates of DGF (5% vs 20%) and renal dysfunction–related readmissions (10% vs 27.5%) (P < .05 each). Perioperative complications, allograft survival, and patient survival were similar between groups. These data suggest that morbidly obese patients with end‐stage renal disease who undergo LSG to improve transplant candidacy, achieve excellent posttransplantation outcomes.     

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation

Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and “real world” CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant—ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.     

Collagenofibrotic glomerulopathy in a kidney transplant recipient: A first report

Collagenofibrotic glomerulopathy (CG) is a rare disease characterized by the deposition of collagen type 3 fibrils in the glomeruli. Patients may have proteinuria, hematuria, and/or renal dysfunction. CG is considered a progressive disease with variable rates of progression. The definitive diagnosis is made by electron microscopy with the presence of characteristic subendothelial and mesangial curved, comma-like, banded collagen type 3 fibers of 40–65 nm periodicity. We are reporting the first case of CG in a kidney transplant recipient with kidney disease of unknown cause.     

Association of time-updated plasma calcium and phosphate with graft and patient outcomes after kidney transplantation

Disturbances in calcium-phosphate homeostasis are common after kidney transplantation. We aimed to assess the relationship between deregulations in plasma calcium and phosphate over time and mortality and death-censored graft failure (DCGF). In this prospective cohort study, we included kidney transplant recipients with ≥2 plasma calcium and phosphate measurements. Data were analyzed using time-updated Cox regression analyses adjusted for potential confounders including time-updated kidney function. We included 2769 patients (mean age 47 ± 14 years, 42.3% female) with 138 496 plasma calcium and phosphate levels (median [IQR] 43 [31–61] measurements per patient). During follow-up of 16.3 [8.7–25.2] years, 17.2% developed DCGF and 7.9% died. Posttransplant hypercalcemia was associated with an increased risk of mortality (1.63 [1.31–2.00], p < 0.0001), but not with DCGF. Hyperphosphatemia was associated with both DCGF (2.59 [2.05–3.27], p < .0001) and mortality (3.14 [2.58–3.82], p <  .0001). Only the association between hypercalcemia and mortality remained significant in sensitivity analyses censored by a simultaneous eGFR <45 mL/min/1.73 m². Hypocalcemia and hypophosphatemia were not consistently associated with either outcome. Posttransplant hypercalcemia, even in the presence of preserved kidney function, was associated with an increased mortality risk. Associations of hyperphosphatemia with DCGF and mortality may be driven by eGFR.     

Multiple myeloma derived from a kidney transplant donor who also developed myeloma after kidney donation

Patients who undergo kidney transplantation are at increased risk of cancer due to the long‐term use of immunosuppressive treatment. Postrenal transplant cancers usually originate from recipient cells, but donor‐related cancers have been rarely reported. We report the case of 49‐year‐old woman who developed multiple myeloma of donor origin 7 years after kidney transplantation. The donor was the mother of the recipient and also developed multiple myeloma 1 year after kidney donation. The diagnosis of multiple myeloma was based on IgG lambda monoclonal protein and the infiltration of plasma cells in bone marrow. The renal biopsy did not reveal plasmacytoma in the transplanted kidney. Epstein‐Barr virus DNA load was negative in peripheral blood. The patient responded to lenalidomide and dexamethasone, and subsequently received autologous stem cell transplantation. Donor chimerism was detected in the recipient marrow by short tandem repeat analysis; however, studies of Ig gene rearrangement were inconclusive due to insufficient DNA quality. The chromosomal abnormalities in the two myelomas were different. This case suggests that donor cells with myeloma‐initiating potential can be transferred to a recipient via a renal graft and can lead to the development of donor‐derived multiple myeloma in the recipient under immunosuppression.     

Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor‐specific antibodies in the first year of kidney transplantation

De novo donor‐specific antibodies (dnDSAs) have been associated with reduced graft survival. Tacrolimus (TAC)–based regimens are the most common among immunosuppressive approaches used in in clinical practice today, yet an optimal therapeutic dose to prevent dnDSAs has not been established. We evaluated mean TAC C₀ (tacrolimus trough concentration) and TAC time in therapeutic range for the risk of dnDSAs in a cohort of 538 patients in the first year after kidney transplantation. A mean TAC C₀ < 8 ng/mL was associated with dnDSAs by 6 months (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.32–4.79, P = .005) and by 12 months (OR 2.32, 95% CI 1.30–4.15, P = .004), and there was a graded increase in risk with lower mean TAC C₀. TAC time in the therapeutic range of <60% was associated with dnDSAs (OR 2.05, 95% CI 1.28‐3.30, P = .003) and acute rejection (hazard ratio [HR] 4.18, 95% CI 2.31–7.58, P < .001) by 12 months and death‐censored graft loss by 5 years (HR 3.12, 95% CI 1.53–6.37, P = .002). TAC minimization may come at a cost of higher rates of dnDSAs, and TAC time in therapeutic range may be a valuable strategy to stratify patients at increased risk of adverse outcomes.     

Plasma cell diseases and organ transplant: A comprehensive review

Plasma cell diseases are a class of hematologic diseases that are sometimes present as preexisting diagnoses prior to organ transplantation, causative factors leading to a need for organ transplantation, or may occur posttransplant as part of the spectrum of posttransplant lymphoproliferative disorders. Herein, we review the most common plasma cell diseases, both as coexisting with other causes of organ failure, but also as a primary underlying cause for organ failure. In many cases, treatment of the underlying clonal disease may be indicated before proceeding with organ transplant. This review aims to provide current and relevant data regarding the management of these conditions in the organ transplant patient, for transplant providers, and those who take care of these patients.     

Posttransplant proteinuria due to Apolipoprotein E2 deposition in a kidney allograft

Lipoprotein deposition disorders limited to the kidney and causing proteinuria are rare. We present a case of nephrotic range proteinuria presenting within 4 months after deceased donor renal transplantation in a patient with end-stage kidney disease presumed secondary to hypertension. Two transplant kidney biopsies were performed sixteen weeks after transplantation, and one year after the first biopsy, both showing lipoprotein deposits in the glomeruli, progressive focal segmental glomerulosclerosis, and effacement of visceral foot processes. The patient had a normal lipid profile. Based on previous case reports of Apolipoprotein E variants causing proteinuria in native kidneys, Apolipoprotein E genotyping was performed. Genotyping showed Apolipoprotein E2 homozygosity. This Apolipoprotein E variant has been associated with lipoprotein deposition, proteinuria, and progressive kidney disease in the native kidneys. However, this is the first case of Apolipoprotein E2 homozygosity-related kidney disease in a transplant recipient. The patient was treated with fenofibrate, angiotensin enzyme inhibition, and angiotensin receptor blockade with reduction in proteinuria, and he kept good stable kidney function.     

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management

The objective of this review is to explore the available literature on solid renal masses (SRMs) in transplant allograft kidneys to better understand the epidemiology and management of these tumors. A literature review using PubMed was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) methodology. Fifty‐six relevant studies were identified from 1988 to 2015. A total of 174 SRMs in 163 patients were identified, with a mean tumor size of 2.75 cm (range 0.5–9.0 cm). Tumor histology was available for 164 (94.3%) tumors: clear cell renal cell carcinoma (RCC; 45.7%), papillary RCC (42.1%), chromophobe RCC (3%), and others (9.1%). Tumors were managed by partial nephrectomy (67.5%), radical nephrectomy (19.4%), percutaneous radiofrequency ablation (10.4%), and percutaneous cryoablation (2.4%). Of the 131 patients (80.3%) who underwent nephron‐sparing interventions, 10 (7.6%) returned to dialysis and eight (6.1%) developed tumor recurrence over a mean follow‐up of 2.85 years. Of the 110 patients (67.5%) who underwent partial nephrectomy, 3.6% developed a local recurrence during a mean follow‐up of 3.12 years. The current management of SRMs in allograft kidneys mirrors management in the nontransplant population, with notable findings including an increased rate of papillary RCC and similar recurrence rates after partial nephrectomy in the transplant population despite complex surgical anatomy.     

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66–0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66–0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = −0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.     

Impact of ureteral stricture and treatment choice on long‐term graft survival in kidney transplantation

We aimed to evaluate the influence of urological complications occurring within the first year after kidney transplantation on long‐term patient and graft outcomes, and sought to examine the impact of the management approach of ureteral strictures on long‐term graft function. We collected data on urological complications occurring within the first year posttransplant. Graft survivals, patient survival, and rejection rates were compared between recipients with and without urological complications. Male gender of the recipient, delayed graft function, and donor age were found to be significant risk factors for urological complications after kidney transplantation (P < .05). Death censored graft survival analysis showed that only ureteral strictures had a negative impact on long‐term graft survival (P = .0009) compared to other complications. Death censored graft survival was significantly shorter in kidney recipients managed initially with minimally invasive approach when compared to the recipients with no stricture (P = .001). However, graft survival was not statistically different in patients managed initially with open surgery (P = .47). Ureteral strictures following kidney transplantation appear to be strongly negatively correlated with long‐term graft survival. Our analysis suggests that kidney recipients with ureteral stricture should be managed initially with open surgery, with better long‐term graft survival.