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Although glomerular damage caused by diabetic nephropathy was thought to be irreversible, in recent years, there have been reports on improvement in glomerular damage with strict glycemic control. However, few reports are available on the pathologic course after renal transplantation of donor-derived grafts with findings of diabetic nephropathy. A 53-year-old woman underwent an ABO blood-type compatible living-donor renal transplant. The recipient had no history of diabetes, and fasting blood glucose and hemoglobin A1c levels were both normal. The donor was a 57-year-old male who had received treatment for type 2 diabetes mellitus for 10 years. Transplant renal biopsy performed 1 h after revascularization showed mesangial matrix expansion and arterial hyalinosis due to diabetic nephropathy. The blood glucose level was within the normal range after transplantation. Mesangial matrix expansion and arterial hyalinosis disappeared in allograft biopsy samples 7 years after transplantation. We observed significant improvement in the pathological findings of donor-derived diabetic nephropathy after renal transplantation in the subsequent follow-ups.

A 64-year-old man with nephrotic syndrome was admitted to another hospital where his renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) with monoclonal immunoglobulin (Ig) G, subclass 1, κ light chain (IgG1κ) deposition on immunofluorescence (IF). Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) was suspected due to monoclonal IgG1κ deposits and the absence of hematological abnormalities. However, the typical PGNMID phenotype was not observed by electron microscopy. Instead, an organized and striated muscle-like structure was observed in the subendothelial space. Since a 2-year treatment with immunosuppressants did not improve his proteinuria, a second biopsy was performed at our hospital. It showed an MPGN-like phenotype; however, monoclonal Ig deposits on IF were no longer observed. One year after the second biopsy, he developed ESRD. Thus, he underwent living kidney transplantation from his wife. Allograft biopsy was performed as proteinuria was observed 3 months after transplantation, which again showed an MPGN-like phenotype with monoclonal IgG1κ deposits. The observed electron-dense deposits were similar to those in the native biopsies. Accordingly, the patient was diagnosed with recurrent MPGN. Adding methylprednisolone pulse therapy to conventional immunosuppressants did not improve the patient’s renal function or proteinuria. He died of Legionella pneumonia 8 months after transplantation. Considering the patient’s histological findings of MPGN with monoclonal IgG1κ deposits and early recurrence of glomerulonephritis after transplantation, he was diagnosed with PGNMID with novel electron-dense deposits.

We report the failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer. A 76-year-old man was admitted to our hospital for evaluation of an elevated serum prostate specific antigen (PSA) level (191.10 ng/ml) in August 2011. He was diagnosed with T3aN0M1b prostate adenocarcinoma. A combined androgen blockade using luteinizing hormone-releasing hormone agonist (the 1-month depot of leuprorelin acetate) and antiandrogen was administered. Due to liver dysfunction, antiandrogens, both bicalutamide and flutamide, were stopped. The 1-month depot was switched to the 3-month depot in May 2013, but the patient complained of induration and abscess at the infection site. Leuprorelin acetate was replaced by goserelin acetate. Because no adverse event appeared after injection of the 1-month depot of goserelin acetate, the 3-month depot was administered in October 2013. The PSA level increased gradually, and the testosterone level was greater than 50 ng/dl, that is, above castrate range. The 3-month depot of both leuprorelin acetate and goserelin acetate was not effective for this patient. For this reason, the 1-month depot of leuprorelin acetate was started resulting in a rapid decrease in PSA and testosterone levels. Thereafter, androgen depriving therapy could be continued. Androgen deprivation therapy is the standard treatment for patients with advanced prostate cancer and luteinizing hormone-releasing hormone aims to suppress serum testosterone to castrate range. We recommend assessing the serum testosterone levels during luteinizing hormone-releasing hormone agonist therapy for monitoring treatment efficacy and verifying progression when the PSA level increases.

The excess mortality of COVID-19 solid organ transplant recipients (SOTRs) throughout the pandemic remains unclear. This prospective cohort study based on the Japanese nationwide registry included 1,632 SOTRs diagnosed with COVID-19 between February 1, 2020, and July 31, 2022, categorized based on dominant phases of variants of concern (VOC): Waves 1–3 (Beta), 4 (Alpha), 5 (Delta), 6 (Omicron BA.1/BA.2), and 7 (Omicron BA.5). Excess mortality of COVID-19-affected SOTRs was analyzed by calculating standardized mortality ratios (SMRs). Overall, 1,632 COVID-19-confirmed SOTRs included 1,170 kidney, 408 liver, 25 lung, 20 heart, 1 small-intestine, and 8 multiorgan recipients. Although disease severity and all-cause mortality decreased as VOC transitioned, SMRs of SOTRs were consistently higher than those of the general population throughout the pandemic, showing a U-shaped gap that peaked toward the Omicron BA.5 phase; SMR (95% CI): 6.2 (3.1–12.5), 4.0 (1.5–10.6), 3.0 (1.3–6.7), 8.8 (5.3–14.5), and 21.9 (5.5–87.6) for Waves 1–3 (Beta), Wave 4 (Alpha), Wave 5 (Delta), Wave 6 (Omicron BA.1/2), and Wave 7 (Omicron BA.5), respectively. In conclusion, COVID-19 SOTRs had greater SMRs than the general population across the pandemic. Vaccine boosters, immunosuppression optimization, and other protective measures, particularly for older SOTRs, are paramount.

There are no previous reports directly evaluating immunologic conditions in tumor microenvironment including both bladder cancer (BCa) and upper urinary tract carcinoma (UTUC). In this study, we aimed to clarify the difference of immunity status and its clinical significance depending on the tumor site in urothelial carcinoma.

In Cushing syndrome, excessive glucocorticoids lead to metabolic disturbances, such as insulin resistance, adipocyte hypertrophy, and liver steatosis. In vitro experiments have highlighted the importance of adipocyte glucocorticoid receptor (GR), but its metabolic roles in vivo have not been fully elucidated in Cushing syndrome. In this study, using clinical samples from patients with Cushing syndrome and adipocyte-specific GR knockout (AGRKO) mice, we investigated the roles of adipocyte GR and its clinical relevance in Cushing syndrome. Under chronic treatment with corticosterone, AGRKO mice underwent healthy adipose expansion with diminished ectopic lipid deposition and improved insulin sensitivity. These changes were associated with Atgl-mediated lipolysis through a novel intronic glucocorticoid-responsive element. Additionally, integrated analysis with RNA sequencing of AGRKO mice and clinical samples revealed that healthy adipose expansion was associated with dysregulation of tissue remodeling, preadipocyte proliferation, and expression of the circadian gene. Thus, our study revealed the roles of adipocyte GR on healthy adipose expansion and its multiple mechanisms in Cushing syndrome.

Renal ischemia–reperfusion (I/R) injury is unavoidable in kidney transplantation (KTx) and frequently influences both short- and long-term allograft survival. Carbon monoxide (CO) has attracted attention as a medical gas with anti-inflammatory and anti-apoptotic effects. We investigated a new strategy for organ preservation using ex vivo application of high-pressure CO in an experimental rat KTx model. We preserved kidney grafts using a high-pressure chamber filled with mixed gases composed of CO and O2. We found that cold I/R injury resulted in progressive deterioration of renal graft function in University of Wisconsin solution, whereas CO significantly improved renal function. We confirmed that CO decreased oxidative stress and mRNA expression of proinflammatory cytokines and inhibited tubular apoptosis in the early phases. Western blot analysis demonstrated that CO increased phosphatidylinositol-3 kinase and phosphorylation of Akt and p38 mitogen-activated protein kinase. Furthermore, CO significantly alleviated tubular injury scores and suppressed the development of interstitial fibrosis at 100 days after KTx. Thus, high-pressure mixed CO and O2gases successfully preserved rat kidney grafts for 24 h by protecting tubular epithelial cells from apoptosis and inhibiting inflammation.

Ischemia-reperfusion injury (IRI) causes massive tissue damage. Renal IRI is the most common type of acute renal injury, and the defects caused by it may progress to chronic kidney disease (CKD). Rodent models of renal IRI, with various patterns, have been used to study the treatment of human kidney injury. A rat model of bilateral IRI, in which the bilateral kidney blood vessels are clamped for 60 min, is widely used, inducing both acute and chronic kidney disease. However, the molecular mechanisms underlying the effects of bilateral IRI on kidney cells have not yet been fully elucidated. This study aimed to perform a whole-transcriptome analysis of the IRI kidney using single-cell RNA sequencing. We found renal parenchymal cells, including those from the proximal tubule, the loop of Henle, and distal tubules, to be damaged by IRI. In addition, we observed significant changes in macrophage population. Our study delineated the detailed cellular and molecular changes that occur in the rat model of bilateral IRI. Collectively, our data and analyses provided a foundation for understanding IRI-related kidney diseases in rat models.

The introduction of cyclosporine (CsA) has improved graft survival, but it causes nephropathy, which limits its clinical utility. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia reperfusion injury as well as EPO. To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a CsA-induced nephropathy model. CsA caused renal dysfunction, while EPO/CEPO administration significantly improved renal function. EPO treatment significantly increased Hb concentration, while CEPO treatment neither enhanced nor reduced Hb concentration. CsA treatment induced tubular apoptosis, while EPO/CEPO administration inhibited it and increased PI3 kinase activation and Akt phosphorylation. In parallel, morphological assessment revealed that EPO/CEPO significantly reduced CsA-induced interstitial fibrosis and inhibited interstitial macrophage infiltration. In addition, real-time RT-PCR demonstrated that cortical mRNA levels of TGF-β1 and type I collagen were suppressed in the EPO/CEPO group. These results suggest a new therapeutic approach using CEPO to protect kidneys from CsA-induced nephropathy.

Renal ischemia-reperfusion (I/R) injury, which is unavoidable in renal transplantation, frequently influences both short- and long-term allograft survival. Despite decades of laboratory and clinical investigations, and the advent of renal replacement therapy, the overall mortality rate due to acute tubular injury has changed little. I/R-induced DNA damage results in p53 activation in proximal tubule cells (PTC), leading to their apoptosis. Therefore, we examined the therapeutic effect of temporary p53 inhibition in two rat renal transplantation models on structural and functional aspects of injury using intravital two-photon microscopy. Nephrectomized Sprague-Dawley rats received syngeneic left kidney transplantation either after 40 min of intentional warm ischemia or after combined 5-h cold and 30-min warm ischemia of the graft. Intravenously administrated siRNA for p53 (siP53) has previously been shown to be filtered and reabsorbed by proximal tubular epithelial cells following the warm ischemia/reperfusion injury in a renal clamp model. Here, we showed that it was also taken up by PTC following 5 h of cold ischemia. Compared to saline-treated recipients, treatment with siP53 resulted in conservation of renal function and significantly suppressed the I/R-induced increase in serum creatinine in both kidney transplantation models. Intravital two-photon microscopy revealed that siP53 significantly ameliorated structural and functional damage to the kidney assessed by quantification of tubular cast formation and the number of apoptotic and necrotic tubular cells and by evaluation of blood flow rate. In conclusion, systemic administration of siRNA for p53 is a promising new approach to protect kidneys from I/R injury in renal transplantation.

Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here, we identify the transcription factor, MondoA, as a regulator of cellular senescence, autophagy, and mitochondrial homeostasis. MondoA protects against cellular senescence by activating autophagy partly through the suppression of an autophagy-negative regulator, Rubicon. In addition, we identify peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 work independently to regulate senescence. Furthermore, we find that MondoA knockout mice have exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus is correlated with human aging and ischemic AKI. Our results suggest that decline of MondoA worsens senescence and age-associated disease.

Anionic constituents in the peritubular capillary basement membranes and the glomerular endothelial cells have been demonstrated to function as a size- and charge-selective barrier. Cationic colloidal iron staining of human biopsy specimens revealed a glycocalyx on the surface of the glomerular basement membrane (GBM), peritubular capillary (PTC) endothelial cells, and brush border of the tubular epithelial cells of normal kidney. However, the glycocalyx was abolished in the PTC wall of C4d-positive acute humoral rejected kidney, and in the GBM as well as the PTC wall of a chronic, allograft, nephropathy kidney. In addition, cyclosporine eliminated the glycocalyx in the PTC wall, while treatment with heparin inhibited the elimination of the PTC glycocalyx. In conclusion, the glycocalyx on the surface of the GBM and PTC is an important component in the endothelial cell barrier.

Several studies have shown that erythropoietin (EPO) can protect the kidneys from ischemia-reperfusion injury and can raise the hemoglobin (Hb) concentration. Recently, the EPO molecule modified by carbamylation (CEPO) has been identified and was demonstrated to be able to protect several organs without increasing the Hb concentration. We hypothesized that treatment with CEPO would protect the kidneys, partly due to the increased peritubular capillaries. The therapeutic effect of CEPO was evaluated using an endothelial tube formation assay in vitro, and a rat ischemia-reperfusion injury model in vivo. EPO treatment showed the tendency of increased tube formation, while CEPO treatment induced more capillary-like formation than EPO. Ischemia-reperfusion-induced kidneys exhibited characteristic nuclei of apoptosis in tubular epithelial cells with decreased peritubular capillaries, while EPO treatment inhibited tubular apoptosis with preserved endothelial cells. Moreover, CEPO-treated kidneys showed minimal tubular apoptosis with increased peritubular capillary endothelial cells. In conclusion, we identified a new therapeutic approach using CEPO to protect kidneys from ischemia-reperfusion injury by promoting angiogenesis.

The analysis of mycophenolic acid (MPA) has proved a valuable adjunct to the clinical care of organ transplant recipients. The analytic validation of the enzyme multiplied immunoassay technique (EMIT) for the determination of MPA in plasma is described. The EMIT MPA standard curve was 0 to 15.0 g/mL, and curve storage was maintained for 4 weeks. The MPA EMIT assay proved reliable and reproducible, as shown by the intra-assay and interassay coefficients of variation (1.58–3.68 and 1.23–7.57, respectively). Excellent linear correlation (r0.999) was observed for dilution linearity. The sensitivity of the assay was 0.01 g/mL. Recoveries of 99.4 to 104.2 were obtained by spiking aliquots of three controls of known MPA concentrations with MPA. No interference was observed for endogenous substances and coadministered immunosuppressant drugs, and no cross-reactivity from the major metabolite MPA glucuronide was found. The high-performance liquid chromatography (HPLC) assay used protein precipitation and C18 ion-pair chromatography with ultraviolet detection at 304 nm. Plasma concentrations of MPA were measured using EMIT and HPLC. A linear relationship was observed between EMIT and HPLC (EMIT 1.091 × HPLC - 0.089;r20.990, n 129). These results indicate that EMIT is a simple, rapid, and sensitive assay method for the measurement of MPA in plasma.