In patients undergoing dialysis, increased salt intake is associated with an increased risk of cardiovascular disease (CVD) events, including a higher incidence of congestive heart failure. We calculated the estimated salt intake (eSALT) using a salt intake estimation formula based on the amount of sodium removed by dialysis and investigated its relationship with patients’ prognosis. We included 6,180 patients undergoing dialysis who attended the Zenjinkai Outpatient Clinic. We used Watson’s body water and Ramdeen’s salt estimation equations, utilizing pre- and post-dialysis blood samples collected once a month at the beginning of the week, with a 2-day interval. The eSALT was measured repeatedly in all patients, 36 times in 3 years, starting on April 1, 2016. The observational outcomes included all-cause mortality and CVD events. Statistical analyses were performed using Cox proportional hazard analysis, cubic spline curves, and Generalized Estimating Equations (GEE). Baseline and previous time-dependent repeated-measured eSALT were used in the GEE for exposure factor. The outcomes included normalized protein catabolic rate (nPCR), Geriatric Nutritional Risk Index (GNRI), and body mass index (BMI), as well as percentage change in creatinine clearance rate, blood pressure, creatinine, albumin, and uric acid. Salt intake was 8.15 g/day over 3 years. The eSALT did not predict CVD events in adjusted Cox proportional hazard analysis. Spline curves showed an increased hazard ratio for heart failure with eSALT ≥ 6 g, but not for all-cause mortality. The GEE model indicated that eSALT was associated with nutritional indices, including the GNRI,

Patients undergoing hemodialysis (HD) face severe dietary potassium restrictions, reducing their quality of life (QOL) and potentially worsening their prognosis. Sodium zirconium cyclosilicate (SZC) is a novel selective potassium binder that lowers potassium levels, with minimal effects on other electrolytes. The Y-QOL study will evaluate whether SZC can improve QOL by easing the burden of dietary restrictions. This 8-week, multicenter, randomized, parallel-group, open-label trial will enroll 200 outpatients with hyperkalemia (potassium level 5.5–6.4 mEq/L after a 2-day inter-dialytic interval) on thrice-weekly HD. Participants will be randomized to receive SZC (starting dose 5 g on non-dialysis days, adjustable to 15 g based on serum potassium levels) plus dietary guidance, or dietary guidance alone to maintain serum potassium levels at 4.0–5.4 mEq/L. The primary endpoint is changes in The 7-item QOL Disease-specific Impact Scale (QDIS-7) scores at week 8 from baseline. Secondary endpoints include additional QOL scores, nutritional status, inflammation markers, Bristol Stool Form Scale, serum potassium reduction, and safety. Recruitment began on January 24, 2024, and the study will conclude on March 31, 2026. The Y-QOL study aims to determine the effectiveness of SZC in improving QOL by reducing serum potassium levels in patients with hyperkalemia undergoing HD. Registered Report Identifier: jRCT 031230404. Date of registration; January 15, 2024.

Introduction: Malakoplakia is a rare and chronic granulomatous disease that is pathologically characterized by the presence of Michaelis-Gutmann bodies and large macrophage clusters. Malakoplakia of the renal parenchyma is especially rare. In this report, we describe the long-term prognosis of a patient who was diagnosed with and treated for renal parenchymal malakoplakia in infancy. Case Presentation: Seventeen years after malakoplakia onset, the patient presented to us with worsening proteinuria. Computed tomography revealed structural abnormalities in the kidney, and focal segmental glomerulosclerosis (FSGS) was diagnosed based on renal biopsy findings. No Michaelis-Gutmann bodies were observed in von Kossa-stained biopsy specimens. Regular outpatient monitoring during the next 9 years showed gradual deterioration of renal function and a moderately high protein/creatinine ratio. Conclusion: Our findings suggest that structural changes due to malakoplakia can cause FSGS. Moreover, structural changes indicate the healing of malakoplakia in infancy and the disappearance of its characteristic lesions over time. Owing to its long-term observation period, this unique case provides new insights into the outcomes of patients with renal parenchymal malakoplakia.

Rationale & Objective: Allopurinol and febuxostat, which are xanthine oxidoreductase inhibitors, have been widely used as uric acid-lowering medications. However, evidence regarding their cardiovascular effects in hemodialysis is insufficient. This study compared the effects of allopurinol and febuxostat on mortality and cardiovascular outcomes in patients receiving hemodialysis. Study Design: A retrospective observational cohort study. Setting & Participants: Data of 6,791 patients who had no history of topiroxostat usage and underwent maintenance hemodialysis between March 2016 and March 2019 at Yokohama Daiichi Hospital, Zenjinkai, and its affiliated dialysis clinics in Japan's Kanagawa and Tokyo metropolitan areas were collected. Exposure: Allopurinol, febuxostat, and nontreatment. Outcomes: All-cause mortality, cardiovascular disease (CVD) events, heart failure (H F), acute myocardial infarction (AMI), and stroke. Analytical Approach: For the main analyses, marginal structural Cox proportional hazards models were used to estimate HRs adjusted for time-varying confounding and selection bias because of censoring. Results: Allopurinol and febuxostat showed significantly better survival than nontreatment for all-cause mortality (HR, 0.40; 95% CI, 0.30-0.54 and HR, 0.49; 95% CI, 0.3 8-0.63, respectively), without significant fi cant difference between allopurinol and febuxostat. Allopurinol showed significantly better survival than nontreatment, whereas febuxostat did not for CVD events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 1.01; 95% CI, 0.961.07, respectively), HF (HR, 0.71; 95% CI, 0.560.90 and HR, 1.03; 95% CI, 0.87-1.21, respectively), and AMI (HR, 0.48; 95% CI, 0.250.91 and HR, 0.76; 95% CI, 0.4 9-1.19, respectively). No comparisons showed significant results for stroke. Limitations: The ratio of renal or intestinal excretion of uric acid and uremic toxins could not be elucidated, and we could not investigate gene polymorphism because of the large number of cases. Conclusions: Allopurinol and febuxostat improved survival for all-cause mortality. Allopurinol and not febuxostat reduced the risk of CVD events, HF, and AMI.

OBJECTIVE In subjects with chronic kidney disease (CKD), the effect of low-protein diet (LPD) is expected to alleviate uremic symptoms. However, whether LPD is effective in preventing loss of kidney function is controversial. The aim of this study was to evaluate the association between LPD and renal outcomes. METHODS We conducted a multicenter cohort study of 325 patients who suffered CKD stage 4 and 5 with eGFR ≥ 10ml/min/1.73m2, between January 2008 and December 2014. The primary diseases of the patients were chronic glomerulonephritis (47.7%), nephrosclerosis (16.9%), diabetic nephropathy (26.2%) and others (9.2%). The patients were divided into four groups, based on the mean protein intake (PI) /day, group 1 (n =76): PI < 0.5 g/kg ideal body weight/day, group 2 (n=56): 0.5 ≤ PI < 0.6 g/kg/day, group 3 (n=110): 0.6 ≤ PI < 0.8 g/kg/day, group 4 (n=83): PI ≥ 0.8 g/kg/day. Dietary supplementation with essential amino acids and ketoanalogues was not used. The outcome measure was occurrence of renal replacement therapy (RRT) (hemodialysis, peritoneal dialysis, renal transplantation (excluding preemptive transplantation)) and all-cause mortality until December 2018. Cox regression models were used to examine whether LPD was associated with the risk of outcomes. RESULTS During a mean follow-up of 4.1 ± 2.2 years. 33 patients (10.2%) died of all causes, 163 patients (50.2%) needed to start RRT and 6 patients (1.8%) received a renal transplant. LPD therapy of 0.5 g/kg/day or less was significantly related to a lower risk of RRT and all-cause mortality [Hazard ratio = 0.656; 95% confidence interval, 0.438 to 0.984, p=0.042]. CONCLUSIONS These results suggest that non-supplemented LPD therapy of 0.5 g/kg/day or less may prolong the initiation of RRT in stage 4 and 5 CKD patients.

Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.

Renal tubular epithelial cells are capable of regenerating themselves after severe injury. In cellular regeneration, cell migration plays a crucial role. Previous studies have demonstrated that changes in cellular morphology, including the formation of lamellipodia, are very important in cell migration. However, the ultrastructure of a migrating cell largely remains undescribed. In the present study, we applied scanning electron microscopy techniques to cultured cells, and observed fine ultrastructural changes in cultured renal tubular epithelium during migration. We found that there were small sphere-like structures and/or microvilli on the cell surface of floating epithelia, that leaf-like structures closely resembling lamellipodia developed circumferentially in the early stages of culture, and that long and branched filopodia developed that were much larger in diameter compared to filopodia at earlier stages. To the best of our knowledge, these findings are new, and may contribute to the development of a new therapeutic strategy for severe tubular damage of the kidney.

Many in vivo and in vitro studies have demonstrated vasoprotective effects of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) via direct and indirect actions.A recent clinical trial showed that a GLP-1RA reduced revascularization in diabetic patients.In this study we investigated the mechanisms underlying the vasoprotective effect of a GLP-1RA in vivo and in vitro.Male non-diabetic C57BL6 and diabetic db / db mice (9 weeks old) were implanted subcutaneously with osmotic pumps releasing saline or liraglutide (lira) .On Day 4 after implantation, mice underwent wire injury of the femoral artery.Injured arteries were collected on Day 29.In C57BL6 mice, lira dose-dependently reduced the neointimal area without affecting metabolic parameters, except for active GLP-1 concentration.These effects were abolished by coadministration of a nitric oxide synthase (NOS) inhibitor.In addition, we investigated the optimal treatment regimen.Early treatment (Days 1-14) with the lira was as effective in reducing the neointimal area as treatment for the full study duration (Days 1-29) , whereas delayed treatment (Days 15-29) was ineffective.In db / db mice, lira similarly suppressed neointimal formation.In human umbilical vein endothelial cells, lira dose-dependently stimulated nitric oxide (NO) production, which was dependent on GLP-1 receptor, cAMP, protein kinase A, AMP-activated protein kinase, and NOS.In conclusion, lira directly suppressed restenosis by enhancing endothelial NO production, and this protective effect was maintained under hyperglycemia.Earlier administration of the GLP-1RA led to a better vascular outcome.

Relapsing polychondritis (RP) is a rare systemic autoimmune disorder characterized by the episodic and progressive deterioration of cartilage inflammation. Approximately 30% patients with RP have concurrent disease. However, there have been no previous reports of RP complicated by immunoglobulin G4-related disease (IgG4-RD). Here we report the case of a 67-year-old male who developed IgG4-RD approximately 20 years after RP diagnosis. The association between IgG4-RD and RP remains unclear.

We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS).

Background/Aims: Although microangiopathic hemolysis (MAH) is a well-known complication of malignant phase hypertension (MPH), only less data on whether MAH in MPH predicts renal outcome exist. Therefore, we evaluated whether MAH was associated with the renal outcome in patients with MPH. Methods: We conducted a single-center, retrospective, cohort study. Data from 35 patients diagnosed with MPH between October 1998 and January 2015 were analyzed. MPH was defined as the presence of a diastolic blood pressure of ≥120 mm Hg and grades III/IV hypertensive retinopathy according to the Keith-Wagener-Barker classification. MAH was defined as the presence of a low platelet count (<150 × 109/L) together with either an elevated level of lactate dehydrogenase (LDH; >220 U/L), or the presence of schistocytes, or both and the normalization of platelet and LDH level or schistocyte levels after adequate blood pressure control was achieved. The primary outcome was dialysis induction. Results: Fifteen patients had MAH. Those with MAH had significantly severe renal dysfunction at the onset of MPH. The length of follow-up (median, interquartile range) of patients with MAH and those without MAH were 30 (16-94) and 48 (25-115) months, respectively. Dialysis was induced in 9 of 15 patients with MAH and in 6 of 20 patients without MAH. Renal survival in patients with MAH was worse than that in those without, but this was not statistically significant (p = 0.08). By multivariate Cox regression analysis, MAH was not shown to contribute to dialysis induction. Conclusion: MAH did not predict renal outcome in MPH.

Immunohistochemical analyses on local distributions of serum proteins in living mouse kidneys are usually difficult to examine with conventional preparation methods. By using our "in vivo cryotechnique" combined with freeze-substitution, we have checked immunolocalizations of the serum proteins in nephrons of bovine serum albumin (BSA)-overload mice, and compared them with those obtained by the conventional preparation methods. In two days of daily BSA-injected mice, the immunolocalization of BSA could be observed in Bowman's space and urinary tubules with their overt proteinuria, where another endogenous mouse albumin was similarly immunolocalized. The leakage of BSA and mouse albumin in Bowman's space and their reabsorption into proximal tubules were detected in 55% of nephrons, where no leakage of immunoglobulin G1 (IgG1) was detected. However, the leakage of IgG1, in addition to BSA and mouse albumin, was detected in the other nephrons. By carefully examining immunolocalizations of BSA and IgG1, they were obviously different from those obtained by the conventional preparation methods without normal blood circulation into the kidneys. The immunolocalizations of both BSA and mouse serum proteins could be directly analyzed with the "in vivo cryotechnique", suggesting that functional damage to glomerular filtration barriers are different at early stages of the BSA-overload mouse model, depending on each nephron of living mice.

Aim: Acute kidney injury (AKI) is a common complication of minimal change nephrotic syndrome (MCNS), particularly in adults. We evaluated the prevalence of AKI at the onset of adult MCNS and analyzed the influence of AKI on the duration of achieving complete remission (CR).Methods: A retrospective, single-centre, dynamic cohort study was conducted with biopsy-proven, first-onset, adult MCNS patients treated with corticosteroids. Fifty-three consecutive patients diagnosed with MCNS from January 2000 to April 2014 were enrolled. Age, gender, daily urinary protein excretion, and serum creatinine levels were measured. To evaluate AKI during induction, we used the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI and judged AKI stage according to the fluctuations in serum creatinine levels during the first 4 weeks of starting corticosteroid therapy.Results: Twenty patients (37.7%) met the AKI criteria and all 53 patients achieved CR within 1 year. Kaplan-Meier analysis showed that the median time to CR was significantly longer in patients with AKI than in patients without AKI. Cox proportional hazard analysis showed that the hazard ratio (HR) associated with the presence of AKI for achieving CR within 4 weeks was 0.36 after adjustment for age, gender, serum albumin, daily urinary protein excretion, hypertension, administration of 25% albumin, and methylprednisolone pulse therapy. A graded association was also observed between AKI stage and HR for achieving CR.Conclusions: The prevalence of AKI is high in adult patients with MCNS during induction therapy. AKI is an independent factor that delays the time to CR.

In vivo cryotechnique (IVCT) and cryobiopsy are useful to examine native immunolocalizations of serum proteins in tissues of animal organs, re ecting their living states.We used both methods to examine some immunolocalized proteins in living rat kidneys with nephropathy induced by puromycin aminonucleoside (PAN) administration.At day 3 or 9 after intraperitoneal PAN injection, IVCT was performed on the kidneys of anesthetized rats.Urinary proteins excretions increased at day 3 and exceeded 300 mg/day at day 9.Moreover, blood chemistry analyses indicated hypoalbuminemia and renal dysfunction at day 9.At day 3, minimal morphological changes were detected by hematoxylin-eosin (HE) staining, but albumin and immunoglobulin G1 (IgG1) were immunolocalized along the cytoplasm of podocytes and in the apical parts of proximal convoluted tubule epithelial cell.At day 9, erythrocyte intravascular congestion was observed in almost all of the glomerular basement membranes (GBMs) , with casts in some renal tubules also immunostained for albumin and IgG1.The relative immunoreactivities of albumin and IgG1 were weaker within GBMs, and the deposited renal tubule casts were strongly immunostained, indicating relatively different protein concentrations.Thus, these techniques revealed dynamically changing processes of protein excretion and reabsorption in various nephron segments that enable us to examine the morphofunctional features of animal kidneys in other renal diseases.

IgA nephropathy (IgAN) is characterized by mesangial deposition of IgA, C3, and often IgM. We examined the relationship among IgM deposition, clinical features, and renal outcome in IgAN patients who underwent combined treatment of tonsillectomy with steroid pulse therapy (Tx-SP). We retrospectively reviewed 73 IgAN patients treated with Tx-SP from March 2006 to March 2014. The patients were divided into those with moderate (2+) to severe (3+) mesangial IgM deposition (Prominent IgM-positive patients, P-Group) and those with negative (−) to faint (1+) deposition (the "Other" patients, O-Group). Using propensity scores to minimize confounding factors, 11 propensity score-matched patients with O-Group (mO-Group) were compared to 11 P-Group patients. The study outcome was defined as urinary protein grade by urine test strip before Tx-SP and one year after Tx-SP. P-Group patients exhibited an increased severity of proteinuria compared to O-Group (p=0.018) and mO-Group patients (p=0.009) before Tx-SP. After Tx-SP, proteinuria was significantly ameliorated in the P-Group, reaching the same severity recorded in the O-Group (p=0.007) and mO-Group (p=0.021). No significant differences were noted between P-Group and mO-Group in microhematuria, serum creatinine level, and histological severity. Prominent IgM deposition is associated with severe proteinuria in IgAN. However, Tx-SP induces a sufficient reduction in the severity of proteinuria in IgM-positive IgAN.

Introduction and Aims: Deposition of C1q occurs in 0 to 45% of patients with IgAN. In order to identify whether mesangial C1q deposition in IgAN is a novel marker for the response to tonsillectomy plus steroid pulse therapy (TSP), we studied the association between mesangial C1q deposition in IgAN and the remission rate after TSP therapy for IgAN. Methods: We conducted a retrospective cohort study at a single Japanese center. We analyzed data on 110 patients diagnosed with IgA nephropathy who received TSP between January 2003 and December 2012. Positive C1q findings were defined as diffuse mesangial C1q deposition. The study outcome was the resolution of abnormal urinary findings and was defined as negative proteinuria and negative occult blood 1 year after steroid pulse therapy. Results: In all enrolled cases, 69 patients (62.7%) went into remission. Ten out of 24 (41.7%) C1q-positive patients experienced remission, and 59 out of 86 (68.6%) C1q-negative patients experienced remission. Multiple logistic regression model analysis showed that the absence of C1q deposition increased the odds ratio for remission (odds ratio 4.41; 95% confidence interval 1.33-15.75, p = 0.017). Conclusions: These results suggest that the absence of diffuse C1q deposition in the mesangial area of the glomerulus in patients with IgA nephropathy is a positive predictive sign for a response to TSP and is associated with the resolution of urinary abnormalities 1 year after TSP.

We report a 68-year-old Japanese female patient with subepidermal blistering disease with autoantibodies to multiple laminins, who subsequently developed membranous glomerulonephropathy. At skin disease stage, immunofluorescence demonstrated IgG anti-basement membrane zone antibodies reactive with dermal side of NaCl-split skin. Immunoblotting of human dermal extract, purified laminin-332, hemidesmosome-rich fraction and laminin-521 trimer recombinant protein (RP) detected laminin γ-1 and α-3 and γ-2 subunits of laminin-332. Three years after skin lesions disappeared, nephrotic symptoms developed. Antibodies to α-3 chain of type IV collagen (COL4A3) were negative, thus excluding the diagnosis of Goodpasture syndrome. All anti-laminin antibodies disappeared. Additional IB and ELISA studies of RPs of various COL4 chains revealed reactivity with COL4A5, but not with COL4A6 or COL4A3. Although diagnosis of anti-laminin γ-1 (p200) pemphigoid or anti-laminin-332-type mucous membrane pemphigoid could not be made, this case was similar to previous cases with autoantibodies to COL4A5 and/or COL4A6.