Parathyroid carcinoma in a dialysis patient definitively diagnosed after parathyroidectomy for uncontrolled secondary hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) is a well-known complication in chronic kidney disease patients undergoing maintenance dialysis. In 2006, the Japanese Society for Dialysis Therapy recommended parathyroidectomy (PTx) for medically resistant SHPT cases, resulting in an increase in the performance of PTx. However, after calcimimetics were added to the treatment options in 2008, the number of cases requiring PTx has decreased. Presented here is the case of a dialysis patient with SHPT under medical treatment with calcimimetics, who was normocalcemic but showed persistently high levels of parathyroid hormone (PTH), suggesting the possibility of parathyroid carcinoma. Parathyroid carcinoma is a very rare endocrine malignancy characterized by hypercalcemia and increased PTH level. With appropriately performed PTx at the proper time, the definitive diagnosis was made and the patient has not developed any recurrences or metastases to date. In cases of SHPT refractory to medical therapy, the possibility of parathyroid carcinoma should be considered as an alternative. We report a case in which parathyroid carcinoma was diagnosed after appropriate conversion from medical therapy to PTx with reference to ultrasonographic images.

Outcome of surgical parathyroidectomy for tertiary hyperparathyroidism in kidney transplant recipients: tertiary hyperparathyroidism should not be ignored, for the sake of precious allografts.

Tertiary hyperparathyroidism is a complication of kidney transplantation. This complicated condition carries over from the dialysis period and varies according to the function of the transplanted allograft. Treatments include pharmacotherapy (mainly using calcimimetics) and parathyroidectomy, but calcimimetics are currently not covered by the national insurance system in Japan. Two types of parathyroidectomy can be performed: subtotal parathyroidectomy; and total parathyroidectomy with partial autograft. Both types can be expected to improve hypercalcemia. Concerns about the postoperative deterioration of allograft function are influenced by preoperative allograft function, which is even more likely to be affected by early surgery after kidney transplantation. In general, transient deterioration of allograft function after surgery is not expected to affect graft survival rate in the medium to long term. Tertiary hyperparathyroidism in kidney transplant recipients negatively impacts allograft and patient survival rates, and parathyroidectomy can be expected to improve prognosis in both kidney recipients and dialysis patients. However, studies offering high levels of evidence remain lacking.

Effect of Mammalian Target of Rapamycin Inhibition on Activated Regulatory T-Cell Expansion in Kidney Transplantation.

BACKGROUND: The mammalian target of rapamycin (mTOR) plays a critical role in the host immune response in organ transplantation. This study evaluates the regulatory benefits of mTOR inhibitors in kidney transplant recipients (KTRs). METHODS: The mTOR-dependent immune-regulating effects in KTRs were evaluated by examining T-cell subsets among peripheral blood mononuclear cells from 79 KTRs. Recipients included an early introduction of everolimus (EVR) and reduced-exposure tacrolimus group (n = 46) and a standard tacrolimus-based without EVR (non-EVR) group (n = 33). RESULTS: Trough concentrations of tacrolimus at 3 months and 1 year were significantly lower in the EVR group than the non-EVR group (both P < .001). In addition, the respective proportions of patients without estimated glomerular filtration rate < 20% in the EVR and non-EVR groups were 100% and 93.3% at 1 year, 96.3% and 89.7% at 2 years, and 96.3% and 89.7% at 3 years after blood collection, respectively (P = .079). The frequencies of CD3+ T cells and CD4+ T cells among peripheral blood mononuclear cells were comparable between groups. Total CD25highCD127-CD4+ regulatory T (Treg) cells were similar in the EVR and non-EVR groups. In contrast, circulating CD45RA-CD25highCD127-CD4+ activated Treg cells were significantly higher in the EVR group (P= .008). CONCLUSION: These results suggest that the early introduction of mTOR benefits long-term kidney graft function and circulating activated Treg-cell expansion in KTRs.

Immunological imprint on peripheral blood in kidney transplant recipients after two doses of SARS-CoV-2 mRNA vaccination in Japan.

The immunological imprint after two doses of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) mRNA vaccination for patients after kidney transplantation (KTx) remain unclear. This study included KTx recipients and volunteer healthy controls (HCs) who received two doses of SARS-CoV-2 mRNA vaccine (Pfizer BioNTech) from January 2021 to December 2021. We analyzed safety within 21 days after each vaccination dose and compared the immune response in peripheral blood mononuclear cells (PBMCs) between the two groups. No graft rejection was observed throughout this study. Adverse events were generally observed within 5 days. The KTx group exhibited a significantly lower degree of symptoms between doses 1 and 2 (P < 0.001). Increases in activated subsets of T and B cells expressing human leukocyte antigen (HLA)-DR and/or CD38 were observed in the HC group after dose 2 (both P < 0.001), with the greatest increases in HLA-DR+CD8+ T cells and CD38+CD19+ B cells (P = 0.042 and P = 0.031, respectively). In addition, PD1+CD8+ T cells-but not PD1+CD4+ T cells-increased significantly in the HC group (P = 0.027). In the KTx group, however, activated HLA-DR+, CD38+, and PD1+ cells remained at baseline levels. Immunoglobulin (Ig)G against SARS-CoV-2 was detected in only four KTx recipients (13.3%) after dose 2 (P < 0.001). Multivariate logistic regression analyses revealed that ΔHLA-DR+CD8+ T cells and ΔCD38+CD19+ B cells were significantly associated with IgG formation (both P = 0.02). SARS-CoV-2 mRNA vaccine generates impaired cellular and humoral immunity for KTx recipients. Results indicate the need for modified vaccination strategies in immunocompromised KTx recipients.

Post-kidney transplant soluble Klotho levels are determined by pretransplant soluble Klotho levels in both living donors and recipients.

BACKGROUND: Soluble Klotho (sKl), the free form of membrane-bound Klotho predominantly expressed in the kidney, is detectable in serum and may have multiple pleiotropic effects. Patients with end-stage kidney disease are possibly sKl deficient, and kidney transplantation is the treatment of choice in these patients; however, little is known about changes in posttransplant sKl level and the factors influencing these changes. METHODS: We conducted a prospective longitudinal study to examine changes in posttransplant sKl level in recipients for 12 months after living-donor kidney transplantation and analyzed correlations between posttransplant changes in sKl levels and various influencing factors in both recipients and donors. RESULTS: 29 kidney transplant recipients and their living donors were included for analysis. The results showed that sKl levels transiently decreased at 1 week posttransplant but progressively increased thereafter for 12 months. Multivariable linear regression analysis showed that body surface area-adjusted donor sKl levels were associated with posttransplant increases in recipient sKl levels at 12 months. In addition, pretransplant recipient sKl levels and body surface area-adjusted donor sKl levels were identified as an independent predictor of 12-month posttransplant sKl levels. CONCLUSION: Pretransplant sKl levels in both kidney recipients and living donors are a strong determinant of sKl levels after kidney transplantation.

CD45RA-CD25highCD127-CD4+ activated regulatory T cells are correlated with de novo donor-specific anti-HLA antibody formation after kidney transplantation in standard immunosuppression.

Although de novo donor-specific anti-HLA antibodies (dnDSA) remain a barrier for human kidney transplantation (KTx), the role of regulatory T (Treg) cells in dnDSA formation remains unknown. To address this question, we evaluated Treg cell subsets in peripheral blood mononuclear cells in 15 healthy volunteers and 59 KTx recipients using flow cytometric analysis. The post-transplant CD25highCD127-CD4+ Treg cells in KTx recipients were down-regulated compared with those of healthy volunteers (P < .001). Among them, 11 KTx recipients showed dnDSA formation, which was associated with lower frequencies of CD25highCD127-CD4+ Treg cells (P = .040). Furthermore, of the total Treg cell population, CD45RA-CD25highCD127-CD4+ activated Treg (aTreg) cells were significantly dominant in patients with dnDSA (P = .038), but not CD45RA+CD25highCD127-CD4+ resting Treg cells (P = .961). In contrast, non-donor-specific anti-HLA antibody formation was not associated with CD45RA- aTreg cells (P = .772). Multivariate logistic regression analyses revealed that CD45RA- aTreg cells were independently associated with dnDSA formation (Odds ratio = 6.69, P = .040). These findings indicate that CD45RA- aTreg cells are strongly associated with dnDSA formation in KTx recipients and might be an important risk factor of antibody-mediated rejection before clinical diagnosis.

Correction to: Preventive effect of early introduction of everolimus and reduced­exposure tacrolimus on renal interstitial fibrosis in de novo living­donor renal transplant recipients.

In the Original publication of the article, the co-author name has been misspelled as "Yousuke Nakagawa".

Preventive effect of early introduction of everolimus and reduced-exposure tacrolimus on renal interstitial fibrosis in de novo living-donor renal transplant recipients.

BACKGROUND: To improve the long-term outcomes following renal transplantation, prevention of renal-allograft interstitial fibrosis (IF), mainly due to calcineurin inhibitors, is an important therapeutic target. Everolimus (EVR) was reported to have antifibrotic effects. We aimed to investigate the safety, efficacy, and IF of our modified immunosuppressive regimen, which includes early introduction of EVR and reduced-exposure tacrolimus (Tac) (EVR group), and compare it with the standard-exposure tacrolimus-based regimen (Tac group) in de novo living-donor renal recipients. METHODS: In this retrospective, single-center cohort study, we compared the 2-year clinical courses between the two groups according to intention to treat. Additionally, in patients in whom biopsies were obtained at 1 h, 3 months, and 12 months post-transplant, we compared IF between the groups using imaging analysis. RESULTS: Overall, 47 patients were included (EVR group, n = 22; Tac group, n = 25). There were no significant differences in renal function and incidences of rejection and viral infections between the groups at the 2-year post-transplant follow-up. However, pathologic imaging analysis (n = 34) revealed chronological progression of IF in the Tac group during the first year post-transplant and no changes in the EVR group (fibrosis rate at 3 months: 20.8 vs. 13.6%, p < 0.001; at 12 months: 24.7 vs. 14.7%, p < 0.001, respectively). CONCLUSION: Our modified immunosuppressive regimen may have an antifibrotic effect on transplanted kidneys without loss of safety and efficacy.