Reduced chondroitin sulfate content prevents diabetic neuropathy through transforming growth factor-ß signaling suppression.

Diabetic neuropathy (DN) is a major complication of diabetes mellitus. Chondroitin sulfate (CS) is one of the most important extracellular matrix components and is known to interact with various diffusible factors; however, its role in DN pathology has not been examined. Therefore, we generated CSGalNAc-T1 knockout (T1KO) mice, in which CS levels were reduced. We demonstrated that diabetic T1KO mice were much more resistant to DN than diabetic wild-type (WT) mice. We also found that interactions between pericytes and vascular endothelial cells were more stable in T1KO mice. Among the RNA-seq results, we focused on the transforming growth factor ß signaling pathway and found that the phosphorylation of Smad2/3 was less upregulated in T1KO mice than in WT mice under hyperglycemic conditions. Taken together, a reduction in CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis.

Early diagnosis of tuberculous peritonitis in peritoneal dialysis patients using the T-SPOT test.

A 49-year-old man was admitted with peritonitis nine months after starting continuous ambulatory peritoneal dialysis (CAPD) for kidney failure. Ceftazidime and cefazolin were started. Peritoneal dialysate culture was negative for bacteria, but antibiotic treatment was continued because peritonitis improved. Twenty days later, the patient was discharged with no signs of peritonitis. However, 40-day culture of the original peritoneal dialysate detected Mycobacterium tuberculosis, and peritonitis recurred, leading to readmission. A T-SPOT test was performed and was positive in 4 days. Anti-tuberculosis therapy was started, which cured the peritonitis. The T-SPOT test may enable early diagnosis of tuberculosis.

A case of hypertensive emergency with alveolar hemorrhage and thrombotic microangiopathy.

A 28-year-old woman with a 5-year history of untreated hypertension was admitted for respiratory distress, hemoptysis, and retinopathy. Computed tomography showed diffuse plaques in both lung fields. Acute kidney injury, hemolytic anemia, and thrombocytopenia were noted. Kidney biopsy showed thrombosis with fibrinoid necrosis and edematous intimal thickening and luminal narrowing of the small renal artery, indicating thrombotic microangiopathy; the majority of glomeruli were collapsed. After 8 weeks of treatment with antihypertensive drugs, serum creatinine decreased to 1.0 mg/dL, and the patient recovered. In the absence of any other underlying disease, malignant nephrosclerosis associated with a hypertensive emergency was diagnosed.

Decade-long WT1-specific CTLs induced by WT1 peptide vaccination.

INTRODUCTION: The peptide-based cancer vaccine targeting Wilms' tumor 1 (WT1) is a promising immunotherapeutic strategy for hematological malignancies. It remains unclear how long and to what extent the WT1-specific CD8 + cytotoxic T cell (CTL) persist after WT1 peptide vaccination. METHODS: The WT1 peptide vaccine was administered with written consent to a patient with CML in the chronic phase who did not respond well to imatinib, and the patient was followed for 12 years after vaccination. Immune monitoring was performed by specific amplification of WT1-specific CTLs using a mixed lymphocyte peptide culture. T-cell receptors (TCRs) of amplified WT1-specific CTLs were analyzed using next-generation sequencing. This study was approved by the Institutional Review Board of our institution. RESULT: WT1-specific CTLs, which were initially detected during WT1 peptide vaccination, persisted at a frequency of less than 5 cells per 1,000,000 CD8 + T cells for more than 10 years. TCR repertoire analysis confirmed the diversity of WT1-specific CTLs 11 years after vaccination. CTLs exhibited WT1 peptide-specific cytotoxicity in vitro. CONCLUSION: The WT1 peptide vaccine induced an immune response that persists for more than 10 years, even after cessation of vaccination in the CML patient.

De novo posttransplant membranous nephropathy after COVID-19 vaccination 9 years after renal transplantation in a patient with polycystic kidney disease.

A 63-year-old man with polycystic kidney disease underwent kidney transplantation from his wife. Nine years later, after the first and second doses of the COVID-19 vaccination, he developed proteinuria, hematuria, and elevated C-reactive protein. Kidney biopsy 7 months after the initial appearance of proteinuria showed immunoglobulin (Ig)-G granular stain, predominantly IgG1, and spike formation in the glomerular basement membrane. Electron microscopy revealed mainly subepithelial deposits, which corresponds to membranous nephropathy (MN) stage 3 of the Ehrenreich-Churg classification indicating chronic disease, but it also showed electron-dense deposits and endothelial damage. Because a kidney biopsy was performed 1 h after renal transplantation and a biopsy of the patient's native kidney showed intact glomeruli, atypical de novo posttransplant membranous nephropathy (MN) was diagnosed, and a close relationship with COVID-19 vaccination was assumed. Clinicians should consider the involvement of COVID-19 vaccination in de novo posttransplant MN with unclear pathogenesis.

Is Podocytopathy Associated with Gross Hematuria after COVID-19 Vaccination in Patients with Immunoglobulin A Nephropathy?

We experienced three cases of a fever and subsequent severe, prolonged gross hematuria after COVID-19 vaccination. A kidney biopsy revealed immunoglobulin A (IgA) nephropathy, and electron microscopy showed two types of podocytopathy (podocyte damage): loss of foot processes from the glomerular basement membrane and foot process effacement. Mesangial interposition was also present in cases 1 and 3 but not in case 2. Podocytopathy is known to be a cause of proteinuria; however, the reactions to COVID-19 vaccination described here suggest that it may also be related to hematuria in IgA nephropathy.

Gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder after kidney transplantation: A case report.

We report on a 53-year-old Japanese man diagnosed with gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder (B-PTLD) after endoscopy for gastric discomfort 28 months after the patient underwent renal transplantation in Ethiopia. Serum Epstein-Barr virus (EBV) tests were negative before transplantation, but the tumor cells collected from a gastric biopsy showed positive EBV-encoded small RNAs (EBER) at B-PTLD onset. Intensive treatment started with R(rituximab)-CHOP therapy and continued with DA-EPOCH-R therapy has been effective, and relapse has not yet occurred. Burkitt lymphoma has a poor prognosis, but B-PTLD may be effectively treated with high-dose chemotherapy. This is a rare case of gastric B-PTLD in a Japanese patient.

Trajectory of GFR Decline and Fluctuation in Albuminuria Leading to End-Stage Kidney Disease in Patients With Biopsy-Confirmed Diabetic Kidney Disease.

Introduction: Data on longitudinal trajectory of kidney function decline and fluctuation in albuminuria leading to end-stage kidney disease (ESKD) is sparse in patients with type 2 diabetes. Methods: Using data from an observational study of patients with type 2 diabetes and biopsy-confirmed diabetic kidney disease (DKD), generalized additive mixed models (GAMMs) were performed to quantify patterns of longitudinal trajectory of estimated glomerular filtration rate (eGFR) decline to ESKD associated with repeated measures of urine albumin-to-creatinine ratio (ACR). Results: Over a median follow-up period of 3.3 years, 155 of 319 patients progressed to ESKD. Among these patients, 91.6% exhibited a curvilinear pattern in their eGFR trajectory. The median coefficient of variation for ACR, representing the variability in ACR measurements, was 48.9 (interquartile range: 36.9, 68.2). The median compound annual growth rate (CAGR) for ACR, reflecting the variation in ACR progression over time, was 43.6% (interquartile range: 0.0, 102.5); and 84.5% of patients developed nephrotic-range albuminuria, with a majority remaining nephrotic and subsequently progressing to ESKD. There was a positive association between the instantaneous speed of eGFR decline and ACR. Conclusion: The observed curvilinear pattern in eGFR trajectory, high variability in ACR progression over time, and positive correlation between the speed of eGFR decline and ACR highlight the complex dynamics of disease progression and emphasize close monitoring of ACR fluctuation over time in patients with DKD.

Percutaneous Perirenal Mass Biopsy in a Sitting Position Revealed Extramedullary Relapse of Acute Lymphoblastic Leukemia.

Background/Aim: Acute lymphoblastic leukemia (ALL) is a blood malignancy characterized by a rapid proliferation of lymphoid progenitor cells. Extramedullary relapse (EMR) is the recurrence of leukemia that occurs outside the bone marrow. The central nervous system is the most prevalent site of EMR in ALL, whereas other organs, particularly the renal organs, are less commonly involved. Case Report: A 49-year-old man diagnosed with Philadelphia chromosome-negative ALL (Ph-negative ALL) received a second umbilical cord blood transplant (uCBT) and was confirmed to be in his third hematological complete remission. However, the perirenal mass lesion emerged after two weeks, and was difficult to detect on echography in the prone position. We successfully performed a percutaneous biopsy of the mass in a sitting position and pathologically identified it as EMR. After the diagnosis, chemotherapy was restarted, and the patient was scheduled to receive a third uCBT. Conclusion: This is the first report of EMR in a perirenal lesion of ALL and shows that this novel biopsy can be performed as a renal biopsy, even in a sitting position. This case is the first to describe a biopsy technique in detail and demonstrates the value of collaboration between hematologists and nephrologists in diagnosing EMR of the kidneys.

Autopsy of a 45-year-old Man with Liver Failure Due to Polycystic Liver Disease.

A 37-year-old man with autosomal polycystic kidney disease (ADPKD) was admitted to our hospital with a liver volume of 8,000 cm3. Hepatic arterial embolization was performed using a microcoil but was ineffective. Eight years later, the hepatomegaly progressed to liver failure and death. At autopsy, the liver weighed 21.5 kg, and the entire liver had been replaced by cysts; in the few remaining areas of liver parenchyma, microscopic, small cysts of various sizes and fibrosis were evident, with only a few normal hepatocytes observed. Hepatic arterial branches developed; however, the portal vein could not be observed.

Immunoglobulin G4-related Dacryoadenitis Successfully Treated with Baricitinib.

A 48-year-old woman visited our hospital because of bilateral lacrimal gland enlargement. Her serum immunoglobulin G4 (IgG4) level was high, and positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal gland. A biopsy revealed a considerable increase in IgG4/CD138, leading to a diagnosis of IgG4-related dacryoadenitis. The disease did not respond to steroid therapy, so treatment was started with baricitinib because of exacerbation of the original atopic dermatitis and dacryoadenitis after the second dose of the coronavirus disease 2019 (COVID-19) vaccine. Baricitinib was effective for resolving both dermatitis and dacryoadenitis, and steroids were able to be discontinued. The IgG4 level also improved.

A Case of Autosomal Dominant Polycystic Kidney Disease With Resolution of Massive Pericardial Effusion After Renal Transcatheter Artery Embolization.

A 68-year-old woman being treated with hemodialysis for autosomal dominant polycystic kidney disease was admitted for progressive dyspnea over 6 months. On chest radiography, her cardiothoracic ratio had increased from 52.2% 6 months prior, to 71%, and echocardiography revealed diffuse pericardial effusion and right ventricular diastolic insufficiency. A resultant pericardial tamponade was thought to be the cause of the patient's dyspnea, and therefore a pericardiocentesis was performed, with a total of 2,000mL of fluid removed. However, 21 days later the same amount of pericardial fluid had reaccumulated. The second pericardiocentesis was performed, followed by transcatheter renal artery embolization (TAE). The kidneys, which were hard on palpation before TAE, softened immediately after TAE. After resolution of the pericardial effusion was confirmed, the patient was discharged after 24 days in hospital. Twelve months later, the patient was asymptomatic, the cardiothoracic ratio decreased to 48% on chest radiography and computed tomography revealed no reaccumulation of pericardial effusion. This case illustrates a potential relationship between enlarged kidneys in autosomal dominant polycystic kidney disease and pericardial effusion.

A case of bullous pemphigoid and renal disease after dipeptidyl peptidase 4 inhibitor administration.

A 62-year-old man with type 2 diabetes was admitted because of a decrease in estimated glomerular filtration rate from 72 to 17.5 mL/min/1.73 m2 in 10 years and development of widespread bullous skin lesions. His hemoglobin A1c level had been maintained at 6.0-7.0% for 10 years with a dipeptidyl peptidase (DPP)-4 inhibitor. Skin biopsy showed typical bullous pemphigoid, and kidney biopsy showed tubulointerstitial nephritis with eosinophilic infiltration and glomerular endothelial cell proliferation. After discontinuing the DPP-4 inhibitor, skin lesions improved, and renal decline slowed. This case indicates that DPP-4 inhibitors can cause not only skin lesions but also renal disease.

Elevated IL-1ß and Comparable IL-1 Receptor Antagonist Levels Are Characteristic Features of L-PRP in Female College Athletes Compared to Male Professional Soccer Players.

Autologous platelet-rich plasma (PRP) therapy has been becoming popular for the treatment of musculotendinous injuries among athletes. However, for individual and practical variations, clinical success is hardly predictable. To overcome this difficulty, we have been exploring possible criterion candidates for monitoring its clinical effectiveness. In this study, we focused on sex-based differences in young elite athletes and compared the biochemical compositions of their PRP. Leukocyte-rich PRP (L-PRP) was manually prepared from blood samples collected from male professional soccer players (mPSPs) (n = 25) and female college athletes (fCAs) (n = 36). Platelet-derived growth factor-BB (PDGF-BB), transforming-growth factor-ß1 (TGFß1), platelet factor-4 (PF4), interleukin-1ß (IL-1ß), and IL-1 receptor antagonist (IL-1RA) were quantified using an enzyme-linked immunosorbent assay. The levels of PDGF-BB, TGFß1, and PF4 in L-PRP were significantly higher in mPSPs than in fCAs. Conversely, IL-1ß and IL-1RA were detected at significantly and slightly higher levels, respectively, in fCAs than in mPSPs. Our findings suggest that, even though L-PRP from fCAs may have lower potential to induce cell growth and differentiation than that of mPSPs, due to the latter's higher capacity to control inflammation, it does not necessarily imply that PRP treatment in fCAs is less effective. Thus, these cytokine levels should be checked before PRP therapy.

A Case of Glomerular Microangiopathy-like Nephropathy Caused by Hyperthyroidism.

A 49-year-old Japanese woman was admitted to our hospital with weight loss of 15 kg, nephrotic-range proteinuria (4.5 g/g.Cre), and hematuria over a 6-month period. She had received two doses of the COVID-19 vaccine one year before the onset of the disease, after which the estimated glomerular filtration rate increased. Laboratory tests and other tests led to a diagnosis of hyperthyroidism, and a kidney biopsy showed thrombotic microangiopathy-like glomerular microangiopathy comprising mainly glomerular endothelial cell damage. Thiamazole (30 mg) was started for the hyperthyroidism. Three months later, the thyroid function normalized, and two months later, the proteinuria and hematuria disappeared, suggesting that COVID-19 vaccination and these events were related.

Syphilis-related Membranous Nephropathy in a 35-year-old Woman.

A 35-year-old woman was admitted for the examination of lower leg edema and proteinuria. A kidney biopsy showed membranous nephropathy (MN) with fine granular deposits of IgG along the glomerular capillary and poor spike formation, differing from primary MN in the presence of positive IgG3 and C1q. Lupus nephritis was excluded because serum complement and anti-dsDNA antibody, anti-Smith antibody, and anti-cardiolipin antibody tests were negative. The serological test for syphilis was positive, as was the Treponema pallidum hemagglutination test. The patient was diagnosed with syphilis, and the proteinuria disappeared with antibiotic treatment. In MN with positive IgG3 and C1q, syphilis nephropathy may be a differential diagnosis.

Dipeptidyl peptidase-4 inhibitor-related renal disease.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used to treat type 2 diabetes (T2D). Lowering blood glucose is expected also to reduce the progression of diabetic nephropathy. We experienced a patient with T2D who achieved good glycemic control with a DPP-4 inhibitor but experienced rapid deterioration of renal function. Therefore, we performed a retrospective study of similar patients treated at our hospital. METHODS: Out of 56 patients with biopsy-proven diabetic nephropathy who underwent native kidney biopsy at Toranomon Hospital from January 2018 through December 2022, we selected 22 patients who had been receiving DPP-4 inhibitors for at least 9 months at the time of kidney biopsy. Of these patients, we evaluated 16 diagnosed with class IIa diabetic nephropathy according to Tervaert's pathologic classification. The yearly estimated glomerular filtration rate (eGFR) slope in the 16 patients was arranged from the highest to the lowest slope. Ten patients with a large eGFR slope had thrombotic microangiopathy (TMA)-like lesions characterized by glomerular endothelial cell proliferation and GBM duplication on kidney biopsy (group A), whereas the remaining 6 patients did not have TMA-like lesions (group B). RESULTS: Group A had a median (interquartile range [IQR]) eGFR of 18.2 (16.2, 26.2) and a yearly median (IQR) eGFR slope of -11.2 (-17.6, -9.2) mL/min/1.73 m2 after of DPP-4 administration, whereas group B had a median (IQR) eGFR of 31.5 (21.9, 34.8) mL/min/1.73 m2 and a yearly median (IQR) eGFR slope of -1.6 (-3.1, -0.3). Renal function declined significantly more rapidly in group A than in group B, and proteinuria was higher in group A than in group B (median [IQR], 3.4 [2.6, 4.4] g/day vs 0.8 [0.4, 1.3] g/day, respectively). Five patients in group A progressed to dialysis during follow-up, but none of the patients in group B did. Median (IQR) hemoglobin A1c was 6.2 % (6.0 %, 6.6 %) in group A and 5.8 % (5.7 %, 6.6 %) in group B. CONCLUSION: DPP-4 inhibitors promote vascular endothelial regeneration, but when this effect occurs in the glomerulus, glomerular endothelial cell proliferation leads to TMA-like lesions, which may cause an increase in proteinuria and rapid decline in renal function.

Characterization of Leukocyte- and Platelet-Rich Plasma Derived from Female Collage Athletes: A Cross-Sectional Cohort Study Focusing on Growth Factor, Inflammatory Cytokines, and Anti-Inflammatory Cytokine Levels.

Platelet-rich plasma (PRP) has been increasingly used in sports medicine owing to its various advantages. The purpose of our project was to standardize the parameters before performing large-scale clinical trials in the near future to precisely evaluate individual PRP quality. To examine the effects of regular exercise on PRP quality, this study focused on young female athletes, who have been relatively less studied. Blood samples were obtained from female college athletes (n = 35) and ordinary healthy adults (n = 30), which were considered as controls, and leukocyte-rich PRP (L-PRP) was prepared manually. Body composition indices were determined using a bathroom weight scale equipped with an impedance meter. Growth factors and cytokines were quantified using ELISA kits. Platelet-derived growth factor-BB (PDGF-BB) and Transforming-growth factors ß1 (TGFß1) levels (per platelet) in L-PRP were significantly lower in female athletes than in controls. In contrast, Interleukin-1ß and Interleukin 1 receptor antagonist (IL-1RA) levels (per platelet and L-PRP) in L-PRP were significantly higher in athletes, and this difference was more prominent in IL-1RA. These findings suggest that L-PRP from athletes may facilitate the inflammatory phase of the healing process by regulating the pro-inflammatory and anti-inflammatory balance. These chemical compositions can be adopted as "must-check" parameters to characterize individual PRP preparations prior to clinical trials.

Strategic analysis of body composition indices and resting platelet ATP levels in professional soccer players for better platelet-rich plasma therapy.

Background: Autologous platelet-rich plasma (PRP) therapy is ambiguously thought to be more effective in elite athletes than in sedentary patients, although the possible importance of recipient responsiveness remains poorly understood. To address this issue, along with the well-known PRP quality, in this initial study, we evaluated two candidate biomarkers: body composition indices (BCIs), which reflect systemic physical conditions, and resting platelet ATP levels, which reflect platelet energy expenditure and the mass of energy generation units. Methods: In this cross-sectional cohort study, blood samples were collected from male professional soccer players (PSPs) on a local professional team during the off-season and platelet ATP levels were quantified using an ATP luminescence assay kit. BCIs were measured using the body mass impedance method. Age-matched male sedentary participants were used as the controls. Results: Among the BCIs, the body mass index, basal metabolic rate (BMR), and skeletal muscle weight levels were higher in the PSPs than in the controls. The platelet ATP levels in the PSPs group were significantly lower than those in the control group. The correlation between BMR and platelet ATP levels was moderately negative in the control group, but weakly positive in the PSPs group. Conclusion: Owing to regular physical exercise, PSPs had higher BMR levels and lower platelet ATP levels without a significant mutual correlation compared to sedentary controls. This study did not indicate the influence of these biomarkers on the success of PRP therapy but provided evidence for a better understanding of PRP therapy, particularly for elite athletes.