Pre-Transplant Calcimimetic Use and Dose Information Improves the Accuracy of Prediction of Tertiary Hyperparathyroidism after Kidney Transplantation: A Retrospective Cohort Study.

Tertiary hyperparathyroidism (THPT) is characterized by elevated parathyroid hormone and serum calcium levels after kidney transplantation (KTx). To ascertain whether pre-transplant calcimimetic use and dose information would improve THPT prediction accuracy, this retrospective cohort study evaluated patients who underwent KTx between 2010 and 2022. The primary outcome was the development of clinically relevant THPT. Logistic regression analysis was used to evaluate pre-transplant calcimimetic use as a determinant of THPT development. Participants were categorized into four groups according to calcimimetic dose, developing two THPT prediction models (with or without calcimimetic information). Continuous net reclassification improvement (CNRI) and integrated discrimination improvement (IDI) were calculated to assess ability to reclassify the degree of THPT risk by adding pre-transplant calcimimetic information. Of the 554 patients, 87 (15.7%) developed THPT, whereas 139 (25.1%) received pre-transplant calcimimetic treatment. Multivariate logistic regression analysis revealed that pre-transplant calcimimetic use was significantly associated with THPT development. Pre-transplant calcimimetic information significantly improved the predicted probability accuracy of THPT (CNRI and IDI were 0.91 [p < 0.001], and 0.09 [p < 0.001], respectively). The THPT prediction model including pre-transplant calcimimetic information as a predictive factor can contribute to the prevention and early treatment of THPT in the era of calcimimetics.

Lung cancer after kidney transplantation: a 50-year experience at a single institution.

PURPOSE: To investigate the clinical characteristics of lung cancer that develops after kidney transplantation. METHODS: The clinical data of patients with lung cancer diagnosed after kidney transplantation were collected retrospectively. The medical records were extracted from our database. All patients underwent routine chest examination after kidney transplantation. RESULTS: In total, 17 lung tumors were detected in 15 (0.6%) of 2593 patients who underwent kidney transplantation at our institution. Eleven lung tumors were completely resected from a collective 10 patients (surgical group). The remaining five patients did not receive surgical treatment (nonsurgical group). The surgical group underwent wedge resection (n = 5), segmentectomy (n = 1), lobectomy (n = 3), and bilobectomy (n = 1). The pathological stages were 0 (n = 1), IA1 (n = 2), IA2 (n = 4), IA3 (n = 2), and IB (n = 1). The surgical group had a significantly better prognosis than the nonsurgical group. There were no perioperative complications related to kidney transplantation in either group. CONCLUSIONS: Routine chest examination would be useful for the early diagnosis and treatment of lung cancer after kidney transplantation. Moreover, surgical resection for early-stage lung cancer was associated with a better prognosis for kidney transplantation patients.

Optimal dose of rituximab in ABO-incompatible kidney transplantation in patients with low anti-A/B antibody titers: A single-center retrospective cohort study.

BACKGROUND: The clinical outcomes of ABO-incompatible (ABOi) kidney transplantation have improved with the introduction of desensitization therapy with rituximab. However, rituximab prevents not only antibody-mediated rejection (AMR) but also increases the risk of adverse events, such as infection. For ABOi kidney transplantation in patients with low anti-A/B antibody titers, we previously used a rituximab-free desensitization protocol and then initiated a single dose of 100 mg rituximab in 2016. We retrospectively compared the outcomes of ABOi kidney transplantation in patients with low anti-A/B antibody titers before and after the introduction of rituximab. METHODS: ABOi kidney transplantations (n = 142) in patients with low anti-A/B antibody titers between 2007 and 2021 were included. Patients were divided into two groups (with and without rituximab) for desensitization. The primary outcomes were the incidence of acute AMR and infection. RESULTS: Sixty-six patients were desensitized without rituximab (rituximab-free group), and 76 were pretreated with 100 mg rituximab (rituximab group) before transplantation. The incidence of acute AMR was significantly lower in the rituximab group than in the rituximab-free group (.0% [0/76] vs. 7.6% [5/66], respectively; p = .047). Post-transplantation anti-A/B antibody titers were also lower in the rituximab group than in the rituximab-free group. There was no significant difference in the incidence of adverse events, including infections, between the two groups. CONCLUSION: In ABOi kidney transplantation patients with low anti-A/B antibody titers, the desensitization protocol with a single dose of 100 mg rituximab was effective in preventing acute AMR without increasing the risk of other adverse events.

Short-term outcomes of second kidney transplantation compared with those of first transplantation in Japanese patients: a single-center, retrospective, observational study.

BACKGROUND: Among patients who undergo kidney transplantation, a subsequent second kidney transplantation (TX2) is often necessary. The TX2 outcomes remain controversial, however, and only limited data are available on clinical outcomes of TX2 in Japanese patients. This study aimed to assess graft and patient survival rates of TX2 and compared these rates with those of first kidney transplantation (TX1) in Japanese patients. METHODS: Of the 898 kidney transplantations performed between 2010 and 2019 at our institution, 33 were TX2. We performed survival analysis using weighted Kaplan-Meier analysis and Cox proportional hazards analysis with propensity score matching, specifically inverse probability of treatment weighting (IPTW). RESULTS: Death-censored graft survival (DCGS) rates at 1, 3, and 5 years for the TX1 versus TX2 groups were 99.3, 97.9, and 95.0% versus 100, 96.0, and 91.2%, respectively. Overall survival (OS) rates at 1, 3, and 5 years for the TX1 versus TX2 groups were 99.4, 98.9, and 97.8% versus 100, 100, and 94.4%, respectively. Using the log-rank test, IPTW-weighted Kaplan-Meier curves showed no significant differences for TX1 versus TX2 in DCGS (p = 0.535) and OS (p = 0.302). On Cox proportional hazards analysis for TX2 versus TX1, the IPTW-adjusted hazard ratio (HR) for DCGS was 1.75 (95% CI, 0.28-10.9; p = 0.550) and for OS was 2.71 (95% CI, 0.40-18.55; p = 0.311). CONCLUSIONS: For patients who require TX2, this treatment is an acceptable option based on the short-term outcomes data for DCGS and OS.

Persistent hyperparathyroidism after preemptive kidney transplantation.

BACKGROUND: Long-term dialysis vintage is a predictor of persistent hyperparathyroidism (HPT) after kidney transplantation (KTx). Recently, preemptive kidney transplantation (PKT) has increased. However, the incidence, predictors, and clinical implications of HPT after PKT are unclear. Here, we aimed to elucidate these considerations. METHODS: In this retrospective cohort study, we enrolled patients who underwent PKT between 2000 and 2016. Those who lost their graft within 1 year posttransplant were excluded. HPT was defined as an intact parathyroid hormone (PTH) level exceeding 80 pg/mL or hypercalcemia unexplained by causes other than HPT. Patients were divided into two groups based on the presence of HPT 1 year after PKT. The primary outcome was the predictors of HPT after PKT, and the secondary outcome was graft survival. RESULTS: Among the 340 consecutive patients who underwent PKT, 188 did not have HPT (HPT-free group) and 152 had HPT (HPT group). Multivariate logistic regression analysis revealed that pretransplant PTH level (P < 0.001; odds ratio [OR], 5.480; 95% confidence interval [CI], 2.070-14.50) and preoperative donor-estimated glomerular filtration rate (P = 0.033; OR, 0.978; 95% CI, 0.957-0.998) were independent predictors of HPT after PKT. Death-censored graft survival was significantly lower in the HPT group than that in the HPT-free group (90.4% vs. 96.4% at 10 years, P = 0.009). CONCLUSIONS: Pretransplant PTH levels and donor kidney function were independent predictors of HPT after PKT. In addition, HPT was associated with worse graft outcomes even after PKT.

Immunological risk and complement genetic evaluations in early onset de novo thrombotic microangiopathy after living donor kidney transplantation: A Japanese multicenter registry.

BACKGROUND: Thrombotic microangiopathy (TMA) after kidney transplantation (KTx), particularly early onset de novo (dn) TMA, requires immediate interventions to prevent irreversible organ damage. This multicenter study was performed to investigate the allogeneic clinical factors and complement genetic background of dnTMA after KTx. METHODS: Perioperative dnTMA after KTx within 1 week after KTx were diagnosed based on pathological or/and hematological criteria at each center, and their immunological backgrounds were researched. Twelve aHUS-related gene variants were examined in dnTMA cases. RESULTS: Seventeen recipients (15 donors) were enrolled, and all dnTMA cases were onset within 72-h of KTx, and 16 of 17 cases were ABO incompatible. The implementation rate of pre-transplant plasmaphereses therapies were low, including cases with high titers of anti-A/anti-B antibodies. Examination of aHUS-related gene variants revealed some deletions and variants with minor allele frequency (MAF) in Japan or East Asian genome databases in genes encoding alternative pathways and complement regulatory factors. These variants was positive in 8 cases, 6 of which were positive in both recipient and donor, but only in one graft loss case. CONCLUSIONS: Although some immunological risks were found for dnTMA after KTx, only a few cases developed into TMA. The characteristic variations revealed in the present study may be novel candidates related to dnTMA in Japanese or Asian patients, but not pathogenic variants of aHUS. Future studies on genetic and antigenic factors are needed to identify factors contributing to dnTMA after KTx.

Two-year outcomes of low-exposure extended-release tacrolimus and mycophenolate mofetil regimen in de novo kidney transplantation: A multi-center randomized controlled trial.

BACKGROUND: Once-daily extended-release tacrolimus (TACER) is commonly administered following kidney transplantation (KTx); however, its optimal dosage remains unknown. METHODS: In this multi-center, randomized controlled trial, 62 living donor KTx recipients were assigned to either standard-exposure (SE; n = 32) or low-exposure (LE; n = 30) TACER (Graceptor®, Astellas Pharm Inc.) groups. All patients received basiliximab and mycophenolate mofetil (MMF). The primary outcomes were acute rejection, graft/patient survival, and the secondary outcomes were incidence of cytomegalovirus infection, and de novo donor-specific antibodies (dnDSA) production. RESULTS: The tacrolimus trough level and estimated area under the blood concentration-time curve (eAUC) were significantly higher in SE than in LE (SE vs. LE; 1 year: 5.0 ± 0.9 ng/ml and 206.9 ± 26.8 ng h/ml vs. 3.4 ± 1.0 ng/ml and 153.9 ± 26.4 ng h/ml; 2 years: 4.8 ± 1.0 ng/ml and 204.9 ± 30.1 ng h/ml vs. 3.8 ± 0.9 ng/ml and 164.4 ± 27.0 ng h/ml). In contrast, the dosage and eAUC of MMF did not differ between groups. Two-year graft and patient survival rates were 100% in both groups, and acute rejection rates were 0% and 10% in the SE and LE, respectively (p = 0.11). The mean estimated glomerular filtration rates did not differ between the groups. Cytomegalovirus infection was slightly lower in the LE (SE: 12.5% and LE: 6.7%, p = 0.37). In the LE, four cases of dnDSA were noted within 2 years of transplantation; no case was observed in the SE (p = 0.034). CONCLUSIONS: Although the LE TACER regimen showed similar rates of acute rejection, as well as graft and patient survival compared with SE after KTx, LE was significantly more associated with dnDSA. Further investigation of its long-term effect on graft survival is warranted. (University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000033089).

Risk factors for subchondral insufficiency fracture of the femoral head in renal transplant patients.

INTRODUCTION: Risk factors associated with subchondral insufficiency fracture (SIF) of the femoral head have not been established. The aim of the present study was to determine the incidence and risk factors for SIF of the femoral head following renal transplantation (RT). MATERIALS AND METHODS: We analyzed the cases of 681 RT patients (mean age at surgery: 49.5 ± 13.6 years, 249 women, 432 men) to determine the incidence of SIF. Hip magnetic resonance imaging (MRI) was performed 6 months post-RT. The following potential predictors of SIF were evaluated: (1) patient's condition at RT: bone mineral density (BMD), pre-RT laboratory values including calcium (Ca), phosphorus (P), calcium-phosphorus product (Ca × P), and intact parathyroid hormone; the patient and donor's blood relationship; and mismatching number of human leukocyte antigens (HLAs), and (2) post-RT dosage(s) of steroid(s), the immunosuppressive regimen, and the incidence of acute rejection. RESULTS: SIF was observed in 15 hips (13 patients, 1.9%). We successfully matched 39 patients without SIF. A multivariate logistic regression analysis adjusted for cumulative dosages of steroids, revealed the following were risk factors for SIF: osteoporosis (OR: 11.4, p = 0.046), lumbar BMD (OR: 0.003, p = 0.038), pre-RT serum P (OR 2.68, p = 0.004), and pre-RT serum Ca × P (OR: 1.11, p = 0.005). CONCLUSION: Since osteoporosis, the lumbar BMD, serum P, and serum Ca × P were identified as risk factors for a post-RT SIF, these factors should be evaluated before RT for the prediction of the SIF risk.

Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation.

AIM: Bacterial and fungal infections are serious, life-threatening conditions after kidney transplantation. The development of oral/oesophageal candidiasis after kidney transplantation is not a reported risk factor for subsequent severe infection. This study was performed to investigate the relationship between oral/oesophageal candidiasis after kidney transplantation and the development of subsequent infection requiring hospitalization. METHODS: This retrospective study included 522 consecutive patients who underwent kidney transplantation at Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital from 1 January 2010 to 1 February 2019. Ninety-five percentage of patients were living donor transplant recipients. Visual examination was performed to detect oral candidiasis, beginning immediately after kidney transplantation; upper gastrointestinal endoscopy was performed 8-10 months after kidney transplantation. Twenty-five patients developed candidiasis (Candida-onset group) and 497 did not (non-Candida-onset group). The follow-up periods were 67 (37-86) months in the Candida-onset group and 55 (34-89) months in the non-Candida-onset group. Severe infection was defined as bacterial or fungal infection requiring hospitalization; viral infections were excluded. RESULTS: Severe infection developed in 9/25 (36%) patients in the Candida-onset group and in 77/497 (15%) patients in the non-Candida-onset group (p = .006). Binomial logistic analysis revealed that Candida infection (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.06-6.06; p = .037) and use of rituximab (OR 1.81, 95% CI 1.12-2.93; p = .016) were significant predictors of subsequent severe infection. CONCLUSION: Oral/oesophageal candidiasis is a risk factor for severe infection after kidney transplantation and suggests an over-immunosuppressive state, which should prompt evaluation of immunosuppression.

Elevated parathyroid hormone one year after kidney transplantation is an independent risk factor for graft loss even without hypercalcemia.

BACKGROUND: Hypercalcemic hyperparathyroidism has been associated with poor outcomes after kidney transplantation (KTx). However, the clinical implications of normocalcemic hyperparathyroidism after KTx are unclear. This retrospective cohort study attempted to identify these implications. METHODS: Normocalcemic recipients who underwent KTx between 2000 and 2016 without a history of parathyroidectomy were included in the study. Those who lost their graft within 1 year posttransplant were excluded. Normocalcemia was defined as total serum calcium levels of 8.5-10.5 mg/dL, while hyperparathyroidism was defined as when intact parathyroid hormone levels exceeded 80 pg/mL. The patients were divided into two groups based on the presence of hyperparathyroidism 1 year after KTx. The primary outcome was the risk of graft loss. RESULTS: Among the 892 consecutive patients, 493 did not have hyperparathyroidism (HPT-free group), and 399 had normocalcemic hyperparathyroidism (NC-HPT group). Ninety-five patients lost their grafts. Death-censored graft survival after KTx was significantly lower in the NC-HPT group than in the HPT-free group (96.7% vs. 99.6% after 5 years, respectively, P < 0.001). Cox hazard analysis revealed that normocalcemic hyperparathyroidism was an independent risk factor for graft loss (P = 0.002; hazard ratio, 1.94; 95% confidence interval, 1.27-2.98). CONCLUSIONS: Normocalcemic hyperparathyroidism 1 year after KTx was an independent risk factor for death-censored graft loss. Early intervention of elevated parathyroid hormone levels may lead to better graft outcomes, even without overt hypercalcemia.

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 (Pinteraction <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.

Everolimus-facilitated calcineurin inhibitor reduction in Asian de novo kidney transplant recipients: 2-year results from the subgroup analysis of the TRANSFORM study.

OBJECTIVE: We analyzed the efficacy and safety of an everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) versus mycophenolic acid with standard-exposure CNI (MPA+sCNI) regimen in Asian patients from the TRANSFORM study. METHODS: In this 24-month, open-label study, de novo kidney transplant recipients (KTxRs) were randomized (1:1) to receive EVR+rCNI or MPA+sCNI, along with induction therapy and corticosteroids. RESULTS: Of the 2037 patients randomized in the TRANSFORM study, 293 were Asian (EVR+rCNI, N = 136; MPA+sCNI, N = 157). At month 24, EVR+rCNI was noninferior to MPA+sCNI for the binary endpoint of estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2 or treated biopsy-proven acute rejection (27.0% vs. 29.2%, P = .011 for a noninferiority margin of 10%). Graft loss and death were reported for one patient each in both arms. Mean eGFR was higher in EVR+rCNI versus MPA+sCNI (72.2 vs. 66.3 ml/min/1.73 m2 , P = .0414) even after adjusting for donor type and donor age (64.3 vs. 59.3 ml/min/1.73 m2 , P = .0582). Overall incidence of adverse events was comparable. BK virus (4.4% vs. 12.1%) and cytomegalovirus (4.4% vs. 13.4%) infections were significantly lower in the EVR+rCNI arm. CONCLUSION: This subgroup analysis in Asian de novo KTxRs demonstrated that the EVR+rCNI versus MPA+sCNI regimen provides comparable antirejection efficacy, better renal function, and reduced viral infections (NCT01950819).

The importance of kidney volume as a marker in the assessment of living-donor kidney transplantation in Japan.

BACKGROUND: In living kidney transplantation, predicting the risk of end-stage kidney disease in the organ donors though crucial remains to be resolved. Thus, any useful biomarker to predict kidney outcome would be highly desirable to safeguard donors. METHODS: This retrospective study was conducted at Nagoya Daini Red Cross Hospital to confirm whether an increase in preserved kidney volume (PKV) was a predict marker of proteinuria. A change of PKV before and 1 year after kidney donation was measured, and its association with proteinuria 3 years after the donation was analyzed. RESULTS: A total of 119 kidney donors who met the Japanese donor guideline were enrolled. The mean age was 57.4 years, 46.2% were male. The mean values of the variables before kidney donation (baseline) were: BMI levels: 23.4 kg/m2, BSA-adjusted PKV: 132.9 cm3/1.73 m2, and estimated glomerular filtration rate (eGFRave): 82.9 mL/min/1.73 m2. A positive correlation was noted between BSA-adjusted PKV and eGFRave (r = 0.61, p < 0.001). BSA-adjusted PKV increased by 19.5% 1 year after donation, and the median urine protein was 0.04 g/gCre. Linear regression analyses showed that change of PKV and BSA-adjusted PKV before the donation were significantly associated with proteinuria 3 years after donation. CONCLUSION: Change of PKV and BSA-adjusted PKV before donation is important factors for proteinuria after donation under the Japanese donor guidelines. Further studies are needed to confirm whether these factors are associated with renal survival after donation.

Kidney function of Japanese children undergoing kidney transplant with preemptive therapy for cytomegalovirus infection.

BACKGROUND: Cytomegalovirus (CMV) infection is one of the major factors that affect morbidity and mortality in kidney transplant (KTx) patients. The rate of CMV seropositivity in children before KTx is lower than that in adults; therefore, pediatric KTx patients have a higher risk of CMV infection. In Japanese pediatric KTx patients, preemptive therapy for CMV infection is a main conventional therapy. This study investigated whether this preemptive treatment would affect kidney function at 2 years post-KTx. METHODS: A total of 163 patients, that is approximately half of the Japanese pediatric KTx patients nationwide, were recruited to participate in our study. We compared the values of the sequential estimated glomerular filtration rate (eGFR) at two years post-KTx and other influencing factors in CMV viremia, CMV disease, and no-infection groups. RESULTS: Cytomegalovirus infection after KTx occurred in 75 patients (46.0%), 38.7% of whom developed CMV disease. The sequential eGFR values post-KTx did not differ significantly between the three groups. CMV infection was not significantly correlated with other factors, other infections (including Epstein-Barr [EB] virus infection), acute rejection (AR), or adverse events. Only prolonged duration of total hospitalization was significantly associated with CMV infection (P = .002). In the multivariate analysis, younger age, CMV infection, and adverse effects were independently significantly related to prolonged total hospitalization. CONCLUSION: Preemptive therapy for CMV infection evidenced by viremia and disease did not significantly influence kidney function in Japanese pediatric KTx patients at two years after the operation.

Comparison of Pre- and Post-transplant Parathyroidectomy in Renal Transplant Recipients and the Impact of Parathyroidectomy Timing on Calcium Metabolism and Renal Allograft Function: A Retrospective Single-Center Analysis.

BACKGROUND: The effect of parathyroidectomy (PTx) timing on serum calcium (Ca) levels and renal functions in renal transplant recipients with severe hyperparathyroidism (HPT) remains unclear. We retrospectively aimed to investigate and compare the clinical data of patients who underwent pre- and post-transplant PTx and elucidated the impact of PTx timing on serum Ca levels and renal graft outcomes after renal transplantation (RTx). METHODS: During January 2000-December 2016, 53 and 55 patients underwent post-transplant PTx (Post-RTx group) and pretransplant PTx (Pre-RTx group), respectively. The serum Ca levels and estimated glomerular filtration rate (eGFR) were assessed in both groups. RESULTS: At the end of the follow-up, the serum Ca levels were significantly higher and the incidence of hypocalcemia was significantly lower in the Pre-RTx group than in the Post-RTx group [9.5 vs. 8.9 mg/dL, P < 0.001; 14.5% vs. 34.0%, P = 0.024]. The decrease in the eGFR 12-36 months after RTx was more significant in the Post-RTx group than in the Pre-RTx group (-13.8% vs. -0.9%; P = 0.001). A logistic regression involving age, sex, dialysis period, and serum parathormone level revealed that post-transplant PTx is an independent risk factor for persistent hypocalcemia at the end of the follow-up (P = 0.034) and for a >20% decrease in the eGFR 12-36 months after RTx (P = 0.029). CONCLUSIONS: In renal transplant candidates with severe HPT, pretransplant PTx should be considered to prevent persistent hypocalcemia and deterioration of the renal graft function.

Two-year retrospective study of the effect of preemptive kidney transplantation and pretransplant mineral bone factors on calcium in post-kidney transplant recipients.

BACKGROUND: Preemptive kidney transplantation (PEKT) incidence has recently increased in Japan. The effect of PEKT and mineral bone factors before kidney transplantation (KTx) on long-term calcium (Ca) levels remains unknown. METHODS: Eighty-one consecutive patients at Nagoya Daini Red Cross Hospital were included in this study (PEKT group with 41 patients and non PEKT group with 40 patients). Ca metabolism, including intact fibroblast growth factor 23 (iFGF23), were measured before KTx and intact parathyroid hormone (iPTH), and corrected Ca (cCa) were measured before KTx and 6 months (M), 12 M, and 24 M after KTx. RESULTS: In PEKT group, cCa levels at 24 M were higher from the baseline level. At baseline, cCa levels had a positive correlation with iFGF23 levels (r = 0.51; p < 0.001) and a negative correlation with iPTH levels (r = 0.51; p < 0.001). The cCa difference between baseline and 24 M was 0.8 ± 0.6 mg/dL in PEKT group and 0.3 ± 0.7 mg/dL in non-PEKT group (p = 0.001). A multivariate linear regression analysis showed iFGF23 and iPTH at baseline in entire groups were useful markers on calcium levels at 24 M. However, in PEKT group, both markers were found to be not associated with Ca at 24 M, whereas in non PEKT group, iPTH was the only effective marker. CONCLUSIONS: This study suggested that iFGF23 and iPTH may be useful markers of the calcium status after KTx. However, no correlation was noted in PEKT group.

Incidence and risk factors for osteonecrosis of the hip in renal transplant patients: a prospective single-centre study.

BACKGROUND: There is a lack of evidence about the risk factors associated with osteonecrosis of the femoral head (ONFH). PURPOSES: To determine the incidence and risk factors for ONFH following renal transplantation (RT). METHODS: In total, data of 681 RT patients (mean age at surgery, 49.5 ± 13.6 years; 249 women and 432 men) were evaluated to determine the incidence of ONFH. Hip magnetic resonance imaging (MRI) was performed six months after RT. The following potential predictors of ONFH were evaluated: (1) patient's condition at RT; laboratory test results including calcium (Ca), phosphorus (P), calcium-phosphorus product (Ca × P), and intact parathyroid hormone before RT; blood relationship between the patient and donor; and mismatching number of human leukocyte antigens (HLAs), especially HLA class I and class II and (2) dosages of steroids after RT, immunosuppressive regimen, and incidence of acute rejection. RESULTS: ONFH was observed in 30 hips (21 cases, 3.1%). We successfully matched 63 patients without ONFH. Multivariate logistic regression analysis, adjusted for cumulative dosages of steroids, revealed that mismatching number of HLA (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.10-2.36; p = 0.014), HLA class II (HR, 3.73; 95% CI, 1.46-9.56; p = 0.001), P before RT (HR, 1.62; 95% CI, 1.02-2.58; p = 0.041), and Ca × P  before RT (HR, 1.06; 95% CI, 1.01-1.11; p = 0.024) were risk factors for ONFH. CONCLUSION: A greater number of HLA mismatches, HLA class II, serum P, and serum Ca × P were risk factors for ONFH after RT. Therefore, these factors should be evaluated in order to predict ONFH after RT.

Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study.

TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2 was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = -0.3, 8.7; P = .006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2 ) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R- high-risk group (P < .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24 months. Clinicaltrials.gov number: NCT01950819.

Increased CD40L+PD-1+ follicular helper T cells (Tfh) as a biomarker for predicting calcineurin inhibitor sensitivity against Tfh-mediated B-cell activation/antibody production after kidney transplantation.

It is unclear to what extent the development of follicular helper T cells (Tfh) and de novo donor-specific human leukocyte antigen antibody (DSA) production could be influenced by immunosuppressive agents, particularly calcineurin inhibitor (CNI; cyclosporine or tacrolimus), after kidney transplantation. Here, the effects of immunosuppressive agents on Tfh-mediated B-cell activation and antibody production were investigated. In vitro circulating Tfh (cTfh; memory CD4+CXCR5+)/B-cell (CD19+) co-culture assays revealed that CNI considerably inhibited cTfh-mediated B-cell activation and IgG antibody secretion through the suppression of IL-21 and IL-2. Both IL-21 and CD40L up-regulated IL-2 receptors (CD25) on B cells, and anti-CD25 antibody induced apoptosis of activated B cells, resulting in the inhibition of IgG production. The frequency of cTfh-expressed CD40L and PD-1 was elevated in patients with de novo DSA 1 year after transplantation. The degree of inhibition by CNI was dependent on Staphylococcal enterotoxin B-induced CD40L+PD-1+ cTfh up-regulation level. Our data demonstrate that CD40L+PD-1+cTfh could be a marker to implicate individual difference in CNI sensitivity for Tfh-mediated B-cell activation in kidney transplantation.

The effect of maintaining high hemoglobin levels on long-term kidney function in kidney transplant recipients: a randomized controlled trial.

BACKGROUND: Posttransplant anemia may be a major determinant of chronic allograft nephropathy. However, the impact of correcting anemia on graft function remains controversial. METHODS: A 3-year follow-up of an open-label, multicenter, randomized controlled trial involving kidney transplantation recipients examined whether sustained maintenance of target hemoglobin (Hb) concentrations at a high level (12.5-13.5 g/dL, n = 64) with either darbepoetin alfa or epoetin beta pegol would slow the graft function decline rate as the primary efficacy endpoint, compared with maintenance of a low Hb concentration (10.5-11.5 g/dL, n = 63). RESULTS: The mean blood pressures in the two groups were well controlled throughout the study. In the high Hb group, mean Hb concentrations increased to >12 g/dL at 3 months, reaching the target range at 18 months. At the end of this study (36 months), the mean Hb concentration was 12.8 ± 0.7 g/dL in the high Hb group and 11.5 ± 1.2 g/dL in the low Hb group. The decline rate of the estimated glomerular filtration (eGFR) rate was considerably greater in the low Hb group (ΔeGFR, -5.1 ± 9.5 mL/min/1.73 m2) than in the high Hb group (-1.0 ± 8.4 mL/min/1.73 m2) (P = 0.02). Of note, only a few high Hb patients developed cardiovascular events and returned to hemodialysis, but the low Hb patients did not. CONCLUSION: This prospective study suggests that correcting anemia to the target Hb level range (12.5-13.5 g/dL) slows renal function deterioration by >3 years in the chronic phase of allograft nephropathy.