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Distinguishing autosomal‐dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture‐based next‐generation sequencing for 69 genes currently known to cause hereditary renal cystic diseases including ADPKD. Through our analysis, 32 patients had PKD1 or PKD2 mutations. Additionally, 3 patients with disease‐causing mutations in NPHP4, PKHD1, and OFD1 were diagnosed with an inherited renal cystic disease other than ADPKD. In patients with PKD1 or PKD2 mutations, the prevalence of polycystic liver disease, defined as more than 20 liver cysts, was significantly higher (71.9% vs 33.3%, P = .006), total kidney volume was significantly increased (median, 1580.7 mL vs 791.0 mL, P = .027) and mean arterial pressure was significantly higher (median, 98 mm Hg vs 91 mm Hg, P = .012). The genetic screening approach and clinical features described here are potentially beneficial for optimal management of adult sporadic polycystic kidney disease patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endoscopic resection of pedunculated polyps with heads 1 cm or greater in diameter presents a risk of bleeding. To minimize this complication, we performed endoscopic resection with hypertonic saline-solution-epinephrine injection plus band ligation and evaluated its safety and effectiveness. METHODS: Seventeen patients with 20 pedunculated or semipedunculated polyps with heads 1 cm or greater in diameter were treated with this technique. Conventional upper-GI endoscope, hypertonic saline-solution and epinephrine, sclerotherapy needle, and endoscopic band ligator device are needed for the procedure. OBSERVATIONS: All lesions were easily and safely resected. During this procedure, a band ligation chamber proved to be satisfactory for accurate recognition of a postpolypectomy ulcer under good visual control. No hemorrhage, perforation, or other complication occurred as a result of the use of this technique. The histologic resection margin was affected by nonneoplastic components in 6 of 20 lesions. Follow-up endoscopy 1 week later revealed a small, shallow ulcer without residual polyp in all lesions. CONCLUSIONS: This preliminary study suggests that endoscopic resection with hypertonic saline-solution-epinephrine injection plus band ligation is a simple and effective method for the prevention of polypectomy-associated bleeding. Prospective trials, including randomized controlled studies, are required to evaluate the suitability of this modality for wide clinical use. [ABSTRACT FROM AUTHOR]

The number of peritoneal dialysis (PD) catheter-related infections and peritonitis caused by nontuberculous mycobacteria (NTM) has been increasing. Nonetheless, the optimal timing for the relocation of the exit site, removal and reinsertion of the PD catheter, prognosis, and duration of antibiotic treatment remain unclear. This literature review aimed to investigate the epidemiology of patient characteristics and evaluate the most effective diagnostic and treatment strategies for PD catheter-related infections and peritonitis caused by NTM. The systematic literature review was conducted on published cases of PD catheter-related infection and peritonitis caused by NTM in PubMed, Embase, and Ichushi databases up to August 2022. A total of 335 cases (64.1%, male; mean age, 53.4 years; mean dialysis duration, 25.4 months) were analyzed. The most common causative agent of infection was Mycobacterium abscessus (40.1%), followed by Mycobacterium fortuitum (24.8%) and Mycobacterium chelonae (16.6%). With respect to diagnosis, 42.9%, 28.1%, and 29.0% of cases were diagnosed as PD catheter-related infection only, peritonitis only, and both, respectively. The initial cultures were positive for NTM only, positive for any other bacteria, and negative for NTM only in 56.5%, 19.8%, and 23.7% of cases, respectively. Ultimately, more than 80% of cases were treated with multiple antibiotics. PD catheter removal was performed in 55.4% of patients with PD catheter-related infections only and 85.5% of those with PD peritonitis. PD continuation or resumption was possible in 62.2% and 16.0% of patients, respectively. In conclusion, our findings indicate that it is advisable to perform acid-fast bacilli stain and culture in order to promptly identify NTM. PD catheter removal may be an essential management strategy during the early stages of NTM infection., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the local institutional ethical review board (Helsinki committee) of St. Luke’s International Hospital/University. The requirement for informed consent was waived by the ethical review board (Helsinki committee) of St. Luke’s International Hospital/University owing to the retrospective nature of this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Hypothesis: There are limited data on the long-term outcomes and risk factors for non-recovery after development of rituximab (RTX)-associated persistent hypogammaglobulinaemia among children with idiopathic nephrotic syndrome (NS)., Methods: A nationwide Japanese survey was conducted to determine the prognosis of patients with childhood-onset idiopathic NS who developed persistent hypogammaglobulinaemia after RTX administration. Specifically, predictors of IgG level recovery and risk factors for serious infection were examined., Results: The cohort comprised 118 patients (66.1% boys; median age at initial RTX administration, 7.5 years). Among the 121 patients diagnosed with persistent hypogammaglobulinaemia, only 31 (26.3%) recovered within a median observation period of 2.8 years; approximately 70% of patients continued to exhibit persistent hypogammaglobulinaemia. Among the patients who recovered from hypogammaglobulinaemia, the median time to recovery was 14.1 months. Patients with a history of steroid-resistant NS were less likely to recover from persistent hypogammaglobulinaemia (hazard ratio, 0.28; 95% CI, 0.09-0.87). In addition, of the 118 eligible patients, 18 (15.3%) developed serious infections requiring hospitalization, and the main risk factor for infection during hypogammaglobulinaemia was agranulocytosis (a well-known adverse effect of RTX in children)., Conclusions: A significant portion of patients with RTX-associated persistent hypogammaglobulinaemia did not exhibit recovery even after 1 year. Moreover, the data indicate that patients with a history of steroid-resistant NS have a significantly lower probability of recovering from this condition. Agranulocytosis under hypogammaglobulinaemia was significantly associated with an elevated risk of serious infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP)., Methods: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618)., Results: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD., Conclusions: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Introduction: Recently, the monoallelic loss-of-function IFT140 variant was identified as a causative gene for autosomal dominant polycystic kidney disease (ADPKD). In patients with polycystic kidneys who have a positive family history, >90% have pathogenic variants in PKD1 or PKD2 , whereas only 1% have IFT140 . However, approximately 40% of patients with polycystic kidneys without a family history do not have any pathogenic variants in PKD1 and PKD2 ., Methods: We conducted a comprehensive genetic analysis of 157 adult patients with polycystic kidneys whose parents did not have evident polycystic kidneys. We sequenced up to 92 genes associated with inherited cystic kidney disease, including IFT140 ., Results: Of the 157 patients, 7 (4.5%) presented with monoallelic loss-of-function variants in the IFT140 gene, 51 (32.5%) with pathogenic variants in the PKD1 or PKD2 gene, and 7 (4.5%) with pathogenic variants in other genes related to inherited kidney cystic disease. The proportion of monoallelic loss-of-function IFT140 variants in this cohort was higher than that in previously reported cohorts with polycystic kidneys who had a positive family history. None of the patients with monoallelic loss-of-function IFT140 variants had polycystic liver disease (PLD). Furthermore, patients with IFT140 pathogenic variants had a significantly smaller kidney volume and a remarkably higher estimated glomerular filtration rate (eGFR) than those with PKD1 pathogenic variants ( P  = 0.01 and 0.03, respectively)., Conclusion: Because the phenotype of polycystic kidneys caused by the IFT140 gene is mild, parental kidney disease may be overlooked. Therefore, patients without a positive family history are more likely to carry pathogenic variants in IFT140 ., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Autosomal-dominant tubulointerstitial kidney disease caused by UMOD (encoding uromodulin) mutation (ADTKD-UMOD) is a rare hereditary disease. A strong family history of hyperuricemia or gout and inherited kidney disease raises the suspicion of ADTKD-UMOD. Genetic testing can confirm the diagnosis without a kidney biopsy. However, when complicated by other diseases that can cause tubulointerstitial disease, renal biopsy is indispensable for the diagnosis and decisions on treatment strategy. We report the case of a 44-year-old woman referred for evaluation of kidney dysfunction. She had an attack of gout 1 month before referral and a family history of hyperuricemia. She was diagnosed with primary Sjogren's syndrome through an immune workup and ophthalmological examination. However, a kidney biopsy revealed histological features suggesting ADTKD rather than gouty kidney or tubulointerstitial nephritis associated with Sjogren's syndrome, and immunostaining revealed a characteristic staining pattern with UMOD. Comprehensive genetic testing of 93 genes responsible for polycystic kidney disease revealed a novel heterozygous missense variant (c.649 T > A:p. Cys217Ser) in UMOD, and the patient was diagnosed with ADTKD-UMOD. In this case, kidney biopsy contributed to the correct diagnosis of tubulointerstitial kidney disease. This case emphasizes the importance of suspecting ADTKD-UMOD based on family history and careful evaluation of kidney biopsy findings., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Cytomegalovirus (CMV) infection is widespread in immunocompromised people, and several cases of CMV infections of the gastrointestinal (GI) tract have been reported in these individuals. We present a case of an immunocompetent patient on hemodialysis (HD) who developed CMV colitis. We also conducted a review of the literature on CMV GI tract infections among patients with chronic kidney disease undergoing dialysis. A 46-year-old man with a history of end-stage renal disease and undergoing HD developed severe diarrhea and hematochezia. A colonoscopy revealed ulcers, and CMV infection was identified in the biopsy sample. We successfully treated the patient with valganciclovir for 2 months. Our review of the literature yielded 21 articles and 24 cases of CMV GI tract infection in patients undergoing dialysis, including the current case. Hematochezia and diarrhea were purported to serve as indicators of CMV GI tract infection among patients on dialysis. Thus, clinicians should suspect CMV infection of the GI tract in dialysis patients, who experience unexplained bloody diarrhea, and promptly perform a GI endoscopy and biopsy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nakanishi et al.)

Background: Conservative kidney management (CKM) is a treatment alternative for patients with end-stage kidney disease (ESKD). Despite the increasing population of elderly dialysis patients in Japan, CKM is not as readily available compared with that in North America and Europe. Therefore, it is important to clarify the barriers to CKM in Japan., Methods: We interviewed 11 experts to explore their beliefs and issues regarding CKM. Based on the interviews, we categorized the CKM barriers into eight categories and created a 24-item questionnaire. A questionnaire survey was conducted among 112 medical professionals involved in ESKD management. To investigate the types of barriers, we conducted an exploratory factor analysis using the questionnaire results., Results: Responses were obtained from 53 (47.3%) of 112 subjects (18 doctors, 29 nurses, 6 clinical engineers), with 94.3% considering CKM as a treatment option for ESKD. Factor analysis categorized the questions into the following: (1) Lack of palliative care experience, (2) Ethics and responsibility, (3) Patient's problem, (4) Dialog with patients and families, and (5) Lack of support system. Regarding barriers to CKM, "lack of experience in palliative care" and "lack of support system" scored the highest, and "ethics and responsibility" scored the lowest., Conclusions: Barriers to CKM may be classified into five factors, with "lack of experience in palliative care" and "lack of support system" being the important barriers to overcome. Additionally, most healthcare professionals consider CKM as the fourth option for renal replacement therapy., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Recent studies have described several children with very early-onset polycystic kidney disease (PKD) that mimicked autosomal recessive polycystic kidney disease because of 2 hypomorphic PKD1 gene variants. However, no reports have described pathological changes in the primary cilia in these cases. We analyzed the primary cilia in the kidney tubules of an early elementary school child who had very early-onset PKD and a history of large, echogenic kidneys in utero. There was no family history of autosomal dominant PKD. The patient developed kidney failure and received a living-donor kidney transplant from his father. Genetic analysis revealed compound heterozygous variants in the PKD1 gene: c.3876C>A (p. Phe1292Leu) and c.5957C>T (p. Thr1986Met). These variants were likely pathogenic based on in silico analysis. The absence of kidney cysts in the parents suggested that these variants were hypomorphic alleles. Pathological examination of the patient's excised kidney showed prominent dilatation of the proximal and distal tubules. Immunofluorescence staining for α-tubulin showed pronounced elongation of the primary cilia. These findings suggest that the hypomorphic PKD1 variants expressed in this patient with very early-onset PKD were pathogenic., (© 2024 The Authors.)

Introduction: Kidney disease of unknown etiology accounts for 1 in 10 adult end-stage renal disease (ESRD) cases worldwide. The aim of this study is to clarify the genetic background of patients with chronic kidney disease (CKD) of unknown etiology who initiated renal replacement therapy (RRT) in adulthood., Methods: This is a multicenter cross-sectional cohort study. Of the 1164 patients who attended 4 dialysis clinics in Japan, we first selected patients who started RRT between the ages of 20 and 49 years. After excluding patients with apparent causes of CKD (e.g., diabetic nephropathy, polycystic kidney disease (PKD) with family history, patients who underwent renal biopsy), 90 patients with CKD of unknown cause were included. The 298 genes associated with CKD were analyzed using capture-based targeted next-generation sequencing., Results: Of the 90 patients, 10 (11.1%) had pathogenic variants in CKD-causing genes and 17 (18.9%) had variant of unknown significance (VUS). Three patients had PKD1 pathogenic variants, and 1 patient had PKD1 and COL4A4 pathogenic variants. In addition, 2 patients were diagnosed with atypical hemolytic uremic syndrome (aHUS) due to C3 or CFHR5 . One patient each was diagnosed with Alport syndrome due to COL4A4 and COL4A3 variants , nephronophthisis due to NPHP1 variants, Fabry disease due to GLA variants, and autosomal-dominant tubulointerstitial kidney disease due to UMOD variants. Genetic diagnoses were not concordant with clinical diagnoses, except for patients with PKD1 variant., Conclusion: This largest study on genetic analysis in hemodialysis-dependent adults revealed the presence of undiagnosed inherited kidney diseases., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Metformin-associated lactic acidosis is a well-known metformin treatment complication; however, the development of euglycemic diabetic ketoacidosis (euDKA) has rarely been reported. Here we report a case of lactic acidosis and euDKA after metformin overdose. A 57-year-old female patient was transferred to our hospital with severe metabolic acidosis and acute kidney injury. She had type 2 diabetes mellitus and was on oral antidiabetic therapy of vildagliptin metformin hydrochloride daily. On the admission day, she had committed suicide by overdosing 50 tablets of vildagliptin metformin hydrochloride, which was equivalent to 25,000 mg of metformin and 2500 mg of vildagliptin. She had severe lactic acidosis 5 h after overdosing. However, after 34 h of overdosing, serum lactate levels decreased while serum anion gap levels increased. She received single hemodialysis treatment. Serum total ketone bodies, β-hydroxybutyrate acetoacetic acid, and acetone were increased even after hemodialysis treatment. Her blood glucose levels have never exceeded 250 mg/dL since admission. Therefore, we considered that the cause of metabolic acidosis in this patient was not only lactic acidosis but also euDKA. The causes of euDKA in our patient might be hepatic production of ketone bodies due to metformin overdose in addition to type 2 diabetes mellitus, starvation, infection, and stressful physical conditions such as vomiting and diarrhea. We propose that not only lactic acidosis but also ketoacidosis is one of the important pathological conditions in patients with metformin overdose., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Background: Clinical practice guidelines recommend antihypertensive and tolvaptan therapies for patients with autosomal dominant polycystic kidney disease (ADPKD) in Japan. However, tolvaptan therapy may pose an economic burden. The Japanese Ministry of Health, Labour and Welfare supports patients with intractable diseases. This study aimed to confirm the impact of the intractable disease system in Japan on the clinical treatment of ADPKD., Methods: We analyzed the data of 3768 patients with ADPKD having a medical subsidy certificate from the Japanese Ministry of Health, Labour and Welfare in 2015-2016. The following quality indicators were use: the adherence rate to the 2014 clinical practice guideline for polycystic kidney disease (prescription rates of antihypertensive agents and tolvaptan in this cohort) and the number of Japanese patients with ADPKD nationwide started on renal replacement therapy in 2014 and 2020., Results: Compared with new applications from 2015 to 2016, the prescription rates of antihypertensives and tolvaptan for the indicated patients at the 2017 renewal application increased by 2.0% (odds ratio = 1.41, p = 0.008) and 47.4% (odds ratio = 10.1, p > 0.001), respectively. These quality indicators improved with antihypertensive treatment, especially in patients with chronic kidney disease stages 1-2 (odds ratio = 1.79, p = 0.013) and in those aged < 50 years (odds ratio = 1.70, p = 0.003). The number of patients with ADPKD who were started on renal replacement therapy in Japan decreased from 999 in 2014 to 884 in 2020 in the nationwide database (odds ratio = 0.83, p < 0.001)., Conclusions: The Japanese public intractable disease support system contributes to improvement of ADPKD treatment., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft-Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology's GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.

Siblings with nephronophthisis occasionally show different clinical courses; however, the reasons for this remain unclear. We herein report cases of nephronophthisis in a pair of dizygotic twins with different clinical courses. The brother developed end-stage kidney disease at 17 years old; however, his sister did not show kidney insufficiency. Kidney biopsies revealed severe tubulointerstitial damage at 14 and 22 years old in the brother and sister, respectively. Both had a homozygous NPHP1 deletion with different heterozygous mutations related to hereditary cystic kidney disease. Since the dizygotic twins were exposed to similar environmental factors, genetic factors may have influenced their clinical course more strongly than environmental factors.

A 37-year-old African-British man was referred to our hospital for detailed examination because of persistent fever, swelling and pain in both ankle joints, and blurred vision for two months. Inguinal lymph node biopsy showed a large number of epithelioid granulomas without necrosis. Granulomatous anterior uveitis, nephropathy, high serum angiotensin-converting enzyme activity, and high serum-soluble interleukin-2 receptor were observed, and the diagnosis of systemic sarcoidosis was made. His serum creatinine was 1.4 mg/dL and hematuria, leukocyturia, and urine protein were also seen. The renal biopsy finding was mesangial proliferative glomerulonephritis, with no findings of granuloma formation or tubular interstitial nephritis. Immunofluorescence staining showed deposition of IgG, C3, and C1q in the mesangial region. IgG3 was dominant in subclass staining. There was no monoclonality on kappa and lambda staining. Electron microscopy showed predominant deposition in the mesangial region with some subepithelial and endothelial deposition. His hematuria and leukocyturia disappeared with steroid therapy, suggesting sarcoidosis-related nephropathy. A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region is presented. No cases of such histological findings have been reported so far, and it is necessary to analyze further cases to clarify the pathogenic significance of the renal biopsy findings observed in this case., (© 2021. Japanese Society of Nephrology.)

Background: In recent years, bioimpedance analysis has come to be widely used in clinical practice for dialysis patients, but there is not sufficient consensus on its significance. We aimed to examine the merits of performing bioimpedance analysis in addition to conventional evaluation methods for dry weight such as measuring human atrial natriuretic peptide (hANP), blood pressure, and cardiothoracic ratio in patients on chronic hemodialysis., Methods: Body composition of 78 hemodialysis patients was performed by using a new and more accurate segmental multifrequency bioimpedance analysis device (Seca ® medical body composition analyzer 525, Seca GmbH & Co. KG, Hamburg, Germany). Laboratory data including hANP at post-dialysis and demographic profile were collected. Statistical analysis was performed with SPSS software., Results: Mean age of the patients was 66.9 ± 12.6 years and 80.8% were males. Mean value of hANP and the ratio of extracellular water to total body water (ECW/TBW) were 61.4 ± 36.4 pg/mL and 46.1 ± 3.9%, respectively. The calculated ECW/TBW cutoff point for hANP > 50 pg/mL was 45.0%, with sensitivity of 74.4% and specificity of 64.7%. Patients with an ECW/TBW of more than 45% and hANP value of > 50 pg/mL had a higher blood pressure and cardiothoracic ratio on chest X-ray examination., Conclusions: Our results suggest that the ratio of extracellular water to total body water of more than 45% and hANP value of ≥ 50 pg/mL were overhydrated in chronic hemodialysis patients. Whether monitoring levels of these parameters has a role in the outcome including patients' survival and cardiovascular events requires further study., (© 2022. Japanese Society of Nephrology.)

Renin-angiotensin-aldosterone system (RAAS) is primarily involved with pathological mechanism of developing hypertensive emergencies. However, none of clinical practice guidelines mention RAAS blockers for the treatment of hypertensive emergencies. A 44 year-old woman presented with severe hypertension, brain stem posterior reversible encephalopathy syndrome and severe acute kidney injury (AKI). We started anti-hypertensive therapy with continuous intravenous nitroglycerin and oral calcium channel blocker (CCB) and spironolactone. Since severe AKI persisted despite this therapy, we administered losartan potassium, which resulted in improvement in her blood pressure and creatinine. Clinical course of our patient suggests that timely initiation of ARB and spironolactone for hypertensive emergencies could be beneficial in terms of blood pressure control and for protection of target organs from this condition., (© 2021. Japanese Society of Nephrology.)

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease and is well known to have extrarenal complications. Cardiovascular complications are of particular clinical relevance because of their morbidity and mortality; however, unclear is why they occur so frequently in patients with ADPKD and whether they are related to the genotypes., Methods: We extracted and retrospectively analyzed clinical data on patients with ADPKD who underwent echocardiography and whose genotype was confirmed by genetic testing between April 2016 and December 2020. We used next-generation sequencing to compare cardiac function, structural data, and the presence of cardiac valvular disease in patients with 1 of 3 genotypes: PKD1 , PKD2 , and non- PKD1 , 2 ., Results: This retrospective study included 65 patients with ADPKD. Patients were divided into 3 groups: PKD1 , n = 32; PKD2 , n = 12; and non- PKD1 , 2 , n = 21. The prevalence of mitral regurgitation (MR) was significantly higher in the PKD1 group than in the PKD2 and non- PKD1 , 2 group (46.9% vs. 8.3% vs. 19.0%, respectively; p = 0.02). In contrast, no significant difference was found for other cardiac valve complications., Conclusion: This study found a significantly higher prevalence of MR in patients with the PKD1 genotype than in those with the PKD2 or non- PKD1 , 2 genotypes. Physicians may need to perform echocardiography earlier and more frequently in patients with ADPKD and the PKD1 genotype and to control fluid volume and blood pressure more strictly in these patients to prevent future cardiac events., Competing Interests: J.H. has received a research Grant from Otsuka Pharmaceutical Co. All other authors have no competing financial interests to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Acidemia is one of the risk factors for end-stage kidney disease and increases the mortality rate of patients with chronic kidney disease (CKD). Although urinary ammonium (U-NH 4 + ) is the crucial component of renal acid excretion, U-NH 4 + concentration is not routinely measured. To estimate U-NH 4 + , urine osmolal gap (UOG = urine osmolality - [2(Na + + K + ) + urea + glucose]) is calculated and the formula (U-NH 4 +  = UOG/2) has traditionally been used. However, the usefulness of this formula is controversial in CKD patients. We assessed the relationship between U-NH 4 + and UOG in patients with CKD. Blood and spot urine samples were collected in 36 patients who had non-dialysis-dependent CKD. The mean ± SD age of patients was 72.0 ± 14.8 years, and the mean ± SD serum creatinine and U-NH 4 + were 2.7 ± 2.3 mg/dl and 9.3 ± 9.2 mmol/L, respectively. A significant relationship was found between UOG/2 and U-NH 4 + (r = .925, p < .0001). U-NH 4 + estimated using the UOG was on average higher by 4.7 mmol/L than the measured one. Our results suggested that UOG could be a useful tool in clinical settings, especially in patients with moderate to severe CKD., (© 2021 Asian Pacific Society of Nephrology.)

In vitro generation of fertile oocytes has been reported in several mammalian species. However, oocyte integrity is compromised by in vitro culture. Here, we aimed to understand the factors affecting oocyte competency by evaluating mitochondrial function and transcriptome as well as lipid metabolism in in vivo-derived oocytes and in vitro grown and matured (IVGM) oocytes under atmospheric (20%) and physiological (7%) O2 concentration. We used single-cell RNA-sequencing as well as Gene Ontology and KEGG analyses to identify the molecular pathways affecting the developmental competence of oocytes. Oocytes grown under 20% O2 conditions showed a significant decrease in mitochondrial membrane potential, upregulation of ceramide synthesis pathway-associated genes, and high ceramide accumulation compared with oocytes grown under 7% O2 conditions and in vivo-grown oocytes. This suggests that excess ceramide level causes mitochondrial dysfunction and poor developmental ability of the oocytes. Mitochondrial DNA copy number was lower in IVGM oocytes irrespective of O2 concentration in culture, although there was no common abnormality in the expression of genes related to mitochondrial biosynthesis. In contrast, some oocytes produced under 7% O2 conditions showed gene expression profiles similar to those of in vivo-grown oocytes. In these oocytes, the expression of transcription factors, including Nobox, was restored. Nobox expression correlated with the expression of genes essential for oocyte development. Thus, Nobox may contribute to the establishment of oocyte competency before and after the growth phase. The comprehensive analysis of IVGM oocytes presented here provides a platform for elucidating the mechanism underlying functional oocyte production in vivo.

Background: Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood., Methods: To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys., Results: In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15 -/- mice. Alox15 -/- CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15 -/- CKD mice. Mediator lipidomics revealed that Alox15 -/- CKD mouse kidneys had significantly higher levels of PGD 2 than the control. To investigate the effects of PGD 2 on renal fibrosis, we administered PGD 2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines., Conclusion: Increased PGD 2 in Alox15 -/- CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD 2 administration may be novel therapeutic targets for CKD.

Introduction: Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH., Methods: We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes., Results: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1 , NPHP3 , NPHP4 , or CEP164 . Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-μm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication., Conclusions: In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Gitelman syndrome (GS), an autosomal recessive kidney disorder, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Generally, diagnosis is made in school-aged children but multiple cases have been diagnosed in adulthood. This study examines the phenotypic differences between genetically confirmed cases and mutation-negative cases in adults. A comprehensive screening of 168 genes, including GS-related genes, was performed for 84 independent individuals who were referred to our institute with a clinical diagnosis of GS. The cases of pseudo-Bartter syndrome (BS)/GS because of diuretic abuse or other causes, which was determined based on patients' medical records, were excluded during registration. Of these 70 eligible cases for analysis, 27 (38.6%) had genetic confirmation of GS, while 37 (52.8%) had no known variants associated with GS and were considered to be unsolved cases. Note that unsolved cases comprised older, mostly female, individuals with decreased kidney function and multiple basic features of GS. The phenotype of unsolved cases is similar to that of pseudo BS/GS cases, although these cases were excluded in advance. However, the genetic and autoimmune profiles of these unsolved cases have not yet been investigated to date. Therefore, these cases may be categorized into new disease groups., (© 2020 Wiley Periodicals LLC.)

We report a case of nail-patella syndrome (NPS) with unusual thinning of the glomerular basement membrane (GBM) associated with a novel heterozygous variant in the LMX1B gene. A 43-year-old female patient with a previous diagnosis of NPS, referred to our hospital for persistent proteinuria, underwent a renal biopsy, which revealed minor glomerular abnormalities. She underwent a second renal biopsy at the age of 56 owing to the presence of persistent proteinuria and decline in serum albumin, meeting the diagnostic criteria for nephrotic syndrome. Light microscopy demonstrated glomerulosclerosis and cystic dilatation of the renal tubules. Notably, electron microscopy revealed unusual thinning of the GBM, which is quite different from typical biopsy findings observed in patients with NPS, characterized by thick GBM with fibrillary material and electron-lucent structures. Comprehensive genetic screening for 168 known genes responsible for inherited kidney diseases using a next-generation sequencing panel identified a novel heterozygous in-frame deletion-insertion (c.723&#95;729delinsCAAC: p.[Ser242&#95;Lys243delinsAsn]) in exon 4 of the LMX1B gene, which may account for the disrupted GBM structure. Further studies are warranted to elucidate the complex genotype-phenotype relationship between LMX1B and proper GBM morphogenesis., (© 2021 S. Karger AG, Basel.)

Background: Chronic kidney disease (CKD) is known to be associated with cancer mortality. However, no study has considered the well-known cancer prognostic factors, ECOG Performance Status (PS) and cancer treatment, as confounding factors. We assessed the independent relationship between CKD and cancer death in stage IV cancer patients., Methods: In this retrospective observational study, we included stage IV cancer patients diagnosed from 2009 to 2014 in a single center. We collected baseline clinical and laboratory variables, and cancer-specific variables, and assessed the presence of CKD. Our primary outcome was all-cause mortality. The secondary outcome was cancer-specific mortality and site-specific cancer mortality., Results: Among 961 eligible stage IV cancer patients (median age 69 years, 51.8% male), 150 patients had CKD. During follow-up (median 9.8 months), 638 patients died, of whom 526 patients died from cancer. After adjusting for prognostic variables, including ECOG PS and cancer treatment, all-cause mortality and cancer-specific mortality were significantly higher in CKD patients than in non-CKD patients (HR 1.41, 95% CI 1.13-1.77 and HR 1.43, 95% CI 1.12-1.83, respectively). In patients with breast and kidney and urinary tract cancers, CKD was associated with a significantly increased risk of death (HR 7.01, 95% CI 1.47-33.4 and HR 3.33, 95% CI 1.42-7.78, respectively)., Conclusions: CKD at the time of stage IV cancer diagnosis was associated with all-cause mortality and cancer-specific mortality. Moreover, the association between CKD and cancer-specific death was site specific for breast cancer and kidney and urinary tract cancer.

The inappropriate over-activation of the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-sodium chloride cotransporter (NCC) phosphorylation cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK phosphorylation cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. Accordingly, the phosphorylation of both SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress activation of the WNK1-SPAK-NCC phosphorylation cascade in this model, leading to salt-sensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models of CKD. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that tumor necrosis factor (TNF)-α regulates WNK1 protein expression. In fact, TNF-α increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-α inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1-SPAK-NCC phosphorylation cascade in distal convoluted tubules in vivo in the aristolochic acid nephropathy model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK1- SPAK-NCC phosphorylation cascade by TNF-α, reflecting a link with the immune system., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: For continuous renal replacement therapy in small infants, due to the large extracorporeal volume involved, blood priming can be necessary to prevent hypotension and hemodilution. Because packed red blood cells (RBCs) have high levels of potassium and citrate, closed-circuit dialysis is often performed. We assessed the metrics of closed-circuit dialysis and serial citrate concentration changes., Methods: We performed dialysis of closed circuits primed with expired human packed RBC solution and 5% albumin. Blood and dialysate flow rates were 70 and 33.3 mL/min, respectively. The extracorporeal volume was 70 mL. We measured pH, electrolytes, and citrate in the closed circuit every 3 min for 15 min. We also assessed the adequacy of closed-circuit dialysis using the formula: [dialysate flow rate (mL/min) × time of dialysis (min)]/extracorporeal volume (mL) and we assessed the correlation between citrate and ionized calcium concentrations., Results: To reach normal concentrations of sodium, potassium, and chloride, 2.4 times as much dialysate fluid as extracorporeal volume was needed. In contrast, for ionized calcium, bicarbonate, and citrate, 3.8 times as much dialysate fluid as extracorporeal volume was required. By simple linear regression analysis, the concentration of citrate was significantly correlated with that of ionized calcium., Conclusions: For closed-circuit dialysis using an RBC solution, the formula [dialysate flow rate (mL/min) × time of dialysis (min)]/extracorporeal volume (mL) would be a better parameter to estimate efficacy, compared with other metrics. Additionally, the citrate concentration can be readily estimated from the ionized calcium concentration during closed-circuit dialysis.

Background: Tolvaptan is the only therapeutic drug for autosomal dominant polycystic kidney disease (ADPKD). The influence of mutations in polycystic kidney disease 1 and 2 genes (PKD1 and PKD2) on the treatment effects of tolvaptan is not well documented in the literature., Methods: We retrospectively evaluated the relationship between genotype and the efficacy of tolvaptan in 18 patients with ADPKD who had been treated at Toranomon Hospital and undergone genetic testing between April 2016 and February 2020., Results: The annual change in estimated glomerular filtration rate (ΔeGFR/y) from before to after tolvaptan was from a median of -5.5 to -2.5 mL/min/1.73 m2 in the PKD1 truncating group, -3.3 to -2.4 mL/min/1.73 m2 in the PKD1 non-truncating group, -3.1 to -1.6 mL/min/1.73 m2 in the PKD2 group, and -1.9 to -2.6 mL/min/1.73 m2 in the group with no PKD1/2 mutation. The median degrees of improvement of ΔeGFR/y were 2.5 (45%), 0.4 (10%), 0.6 (28%), and -0.7 (-37%) mL/min/1.73 m2, respectively. Compared with the group of patients with any PKD1/2 mutation, the group with no PKD1/2 mutation showed significantly less improvement in ΔeGFR/y with tolvaptan (0.6 vs. -0.7 mL/min/1.73 m2, respectively; p = 0.01) and significantly less improvement in the annual rate of increase in total kidney volume (TKV) with tolvaptan (-6.7 vs. -1.1%, respectively; p = 0.02)., Conclusion: Patients with ADPKD and no PKD1/2 mutation showed less improvement in ΔeGFR/y and the annual rate of increase in TKV with tolvaptan. Detecting PKD1/2 mutations may be useful for predicting the effectiveness of tolvaptan., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: There have been still few case reports of pseudohypoaldosteronism type II (PHA2), also known as Gordon's syndrome, genetically diagnosed, and this is the first report of familial PHA2 case in Japan with a novel D564N mutation in WNK4., Methods: A 29-year-old woman was admitted to our hospital due to hyperkalemia (serum potassium: 6.4 mmol/L). She had mild hypertension (135/91 mm Hg), a bicarbonate level at the lower limit of the normal range (HCO 3 : 22 mmol/L) with a normal anion gap, low plasma renin activity (0.2 ng ml -1  hr -1 ), and high urinary calcium excretion (505.4 mg/g Cre). A hereditary condition was suspected because her mother also had the same symptoms. We performed a comprehensive genetic analysis for major inherited kidney diseases with next-generation sequencing including the genes responsible for PHA2 (WNK1, WNK4, KLHL3, and CUL3)., Results: Genetic analysis revealed that the patient and her mother had a novel missense mutation (D564N) in the acidic motif in WNK4, which leads to the diagnosis of PHA2. Administration of trichlormethiazide (1 mg/day) effectively ameliorated her blood pressure (114/69 mm Hg), plasma bicarbonate (25 mmol/L), serum potassium (4.3 mmol/L), and urinary calcium excretion (27.2 mg/g Cre)., Conclusion: We report the first Japanese familial case of PHA2 with WNK4 mutation. D564N mutation in WNK4 is a novel genetic cause of PHA2 with a relatively mild phenotype., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Genetic characteristics of polycystic kidney disease (PKD) patients without apparent family history were reported to be different from those with a positive family history. However, the clinical course of PKD patients with no apparent family history is not well documented in the literature., Methods: We evaluated the relationship between genotype and the clinical course of 62 PKD patients with no apparent family history., Results: The annual decline of renal function was faster in the patients with PKD1/PKD2 mutation (PKD1 truncating [-3.08; 95% CI -5.30 to -0.87, p = 0.007], PKD1 nontruncating [-2.10; -3.82 to -0.38, p = 0.02], and PKD2 [-2.31; -4.40 to -0.23, p = 0.03]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, estimated glomerular filtration rate (eGFR), height-adjusted total kidney volume (TKV), and mean arterial pressure (MAP). There was no significant difference in the annual decline of renal function among the different PKD1/PKD2 groups, but Kaplan-Meier analysis showed that progression to eGFR < 15 mL/min/1.73 m2 was significantly faster in PKD1 truncating group (p = 0.05). The annual rate of TKV increase was larger in the patients with PKD1/PKD2 mutation (PKD1 truncating [4.63; 95% CI 0.62-8.64, p = 0.03], PKD1 nontruncating [3.79; 0.55-7.03, p = 0.02], and PKD2 [2.11; -1.90 to 6.12, p = 0.29]) than in the other patients without PKD1/PKD2 mutation. Similar results were obtained after adjustment for gender, age, eGFR, and MAP., Conclusion: Detection of PKD1/PKD2 mutation, especially PKD1 truncating, is useful for predicting the renal outcome and rate of TKV increase in PKD patients with no apparent family history., (© 2019 S. Karger AG, Basel.)

Objective: Metformin is an antidiabetic drug that is widely used to treat patients with diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys., Methods: Urinary sodium excretion and expression of renal sodium transporters were examined in 8-week-old male C57BL/6 mice with acute and chronic treatment of metformin. In addition, we examined metformin effects using ex vivo preparations of mice kidney slices., Results: In this study, we demonstrated that metformin increased urinary sodium excretion by reducing phosphorylation of the thiazide-sensitive Na-Cl cotransporter (NCC) in acute and chronic metformin administration. We also confirmed reduction of phosphorylated NCC in an ex vivo study. The activity of other renal sodium transporters, such as NKCC2, ENaC, and NHE3 did not show significant changes. WNK-OSR1/SPAK kinase signals were not involved in this inactivation effect of metformin on NCC., Conclusion: Metformin increased urinary sodium excretion by reducing phosphorylation of NCC, suggesting its role in improving hypertension., (Copyright © 2018 Elsevier Inc. All rights reserved.)