Long-Term Outcomes, Including Fetal and Neonatal Prognosis, of Renal Oligohydramnios: A Retrospective Study over 22 Years.

OBJECTIVE: To assess the long-term outcome of renal oligohydramnios and risk factors for fetal, neonatal, and postneonatal death. STUDY DESIGN: This retrospective cohort study included fetuses with prenatally detected renal oligohydramnios between 2002 and 2023. Patients who were lost to follow-up were excluded. Fetal, neonatal, and long-term outcomes were evaluated, and their risk factors were analyzed. RESULTS: Of 131 fetuses with renal oligohydramnios, 46 (35%) underwent a termination of pregnancy, 11 (8%) had an intrauterine fetal death, 26 (20%) had a neonatal death, nine (7%) had a postneonatal death, and 39 (30%) survived. Logistic regression analyses showed that an earlier gestational age at onset (OR 1.16, 95% CI 1.01-1.37) was significantly associated with intrauterine fetal death; anhydramnios (OR 12.7, 95% CI 1.52-106.7) was significantly associated with neonatal death as a prenatal factor. Although neonatal survival rates for bilateral renal agenesis, bilateral multicystic dysplastic kidney (MCDK), and unilateral MCDK with contralateral renal agenesis were lower than for other kidney diseases, 1 case of bilateral renal agenesis and two of bilateral MCDK survived with fetal intervention. Kaplan-Meier overall survival rates were 57%, 55%, and 51% for 1, 3, and 5 years, respectively. In the Cox proportional hazards model, birth weight <2000 g (hazard ratio 7.33, 95% CI 1.48-36.1) and gastrointestinal comorbidity (hazard ratio 4.37, 95% CI 1.03-18.5) were significant risk factors for postneonatal death. CONCLUSION: Long-term survival following renal oligohydramnios is a feasible goal and its appropriate risk assessment is important.

Chronic Tonsillitis and IgA Nephropathy: Findings From a Nationwide Japanese Cohort Study.

RATIONALE & OBJECTIVE: Little is known regarding the association between chronic tonsillitis and the onset of IgA nephropathy (IgAN). In the present study, we examined the potential relationship between chronic tonsillitis and a subsequent risk of developing IgAN. STUDY DESIGN: Observational cohort study. SETTING: & Participants: 4,311,393 individuals without a history of IgAN identified between January 2005 to May 2022 within a Japanese nationwide epidemiological database, the JMDC Claims Database, representing health claims to over 60 insurers. EXPOSURE: Comorbid chronic tonsillitis based on diagnosis codes. OUTCOME: IgAN occurrence. ANALYTICAL APPROACH: Cause-specific Cox proportional hazards analysis adjusting for potential confounding factors were employed to estimate hazard ratios (HRs). RESULTS: Comorbid chronic tonsillitis was identified in 12,842 individuals, constituting 0.3% of the cohort. The cohort had a median age of 44 years (interquartile range: 36-53), and males accounted for 57.9%, with a follow-up of 1,089 days (interquartile range: 532-1,797), during which 2,653 cases of IgAN developed. Cumulative incidence curve showed a higher cumulative incidence of IgAN in individuals with chronic tonsillitis compared to their counterparts without this condition. Multivariable cause-specific analysis further demonstrated that individuals with chronic tonsillitis had an elevated risk of developing IgAN, with a HR of 2.72 (95% confidence interval: 1.79-4.14). LIMITATIONS: Potential residual confounders, and lack of consideration for ethnic distinctions. CONCLUSIONS: Using a largescale epidemiological dataset, these findings suggest a relationship between chronic tonsillitis and an elevated risk of IgAN development in the general Japanese population.

Proton Pump Inhibitors and Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Hemodialysis Patients: Results from the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: Hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is important problem in dialysis patients. While proton pump inhibitors (PPIs) may inhibit iron absorption, few studies have examined associations between PPIs and ESA-resistant anemia in hemodialysis patients. This study examined the associations between PPIs and ESA-resistant anemia in hemodialysis patients. METHODS: The present study was a cross-sectional study using repeated 4-month observations, up to eight observations/patient, from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). The primary outcome was erythropoietin resistance index (ERI). ESA dose, hemoglobin, proportion of erythropoietin-resistant anemia, transferrin saturation (TSAT), and ferritin were also examined. Linear or risk-difference regression models were used with generalized estimating equations to account for repeated measurements. RESULTS: Of 1,644 patients, 867 patients had PPI prescriptions (52.7%). Patients prescribed PPI had higher ERI, higher ESA dose, and lower TSAT levels. Multivariable analysis for 12,048 four-month observations showed significantly greater ERI in PPI users (adjusted difference 0.95 IU/week/kg/[g/dL] [95% CI: 0.40-1.50]). Significant differences were also found in ESA dose (336 IU/week [95% CI: 70-602]) and the prevalence of erythropoietin-resistant anemia (3.9% [2.0-5.8%]) even after adjusted for TSAT and ferritin. Among possible mediators between the association of PPIs and anemia, TSAT was significantly different between PPI users and non-users (adjusted difference, -0.82% [95% CI: -1.56 to -0.07]). CONCLUSIONS: This study showed the associations between PPI and ERI, ESA dose, and TSAT in hemodialysis patients; physicians should consider anemia's associations with PPIs in hemodialysis patients.

Significance of eGFR and proteinuria for cardiovascular disease in individuals beyond 85 years.

BACKGROUND: There are limited data on how advancing age influences prediction of CVD risk based on the estimated glomerular filtration rate (eGFR) and proteinuria, especially in older adults, including those aged ≥ 85 years. This study aimed to clarify the association of eGFR and proteinuria with CVD outcomes and the impact of age on this association. METHODS: The distribution of eGFR and urine protein in Japan was assessed retrospectively using real-world administrative claims and health checkup data collected between April 2014 and November 2022. We investigated the associations of these two parameters with the incidence of CVD, with an emphasis on the impact of aging. RESULTS: We assessed 1 829 020 individuals for distribution of eGFR and proteinuria; after excluding those with known CVD, their association with CVD risk was examined in 1 040 101 individuals aged ≥ 40 years. The prevalence of impaired kidney function (eGFR <60 mL/min/1.73 m2) increased with age, being 0.7%, 9.2%, 21.9%, 40.2%, and 60.2% at the ages of 18-39, 40-64, 65-74, 75-84, and ≥ 85 years (P for trend < 0.001); similarly, the proportion with positive proteinuria increased with age, being 2.7%, 4.3%, 5.6%, 9.2%, and 15.8%, respectively (P for trend < 0.001). Both eGFR and urine protein were identified to be independent risk factors for CVD. Hazard ratios for CVD increased significantly when eGFR was <45 mL/min/1.73 m2 at the ages of 40-64, 65-74, and 75-84 and <30 mL/min/1.73 m2 at ≥ 85 years, while proteinuria remained significantly associated with a high CVD risk regardless of age. These findings were consistent even when analyzed separately by sex. CONCLUSIONS: This study identified eGFR and urine dipstick proteinuria to be independent risk factors for CVD, even among individuals aged ≥ 85 years. However, the contribution of eGFR to the CVD risk was attenuated by aging, whereas proteinuria remained less affected by advancing age.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Long-term effects of denosumab on bone mineral density and turnover markers in patients undergoing hemodialysis.

INTRODUCTION: Denosumab, a fully human anti-RANKL monoclonal antibody, is a widely used osteoporosis treatment that is increasingly being used in patients undergoing dialysis; however, its long-term efficacy and safety in these patients remain unknown. MATERIALS AND METHODS: This observational study comprised individuals aged ≥ 20 years undergoing hemodialysis and receiving denosumab. After denosumab administration, we analyzed the long-term changes in bone mineral density (BMD) and levels of bone turnover markers (BTMs) and calcium. RESULTS: The study included 45 patients who have been receiving denosumab for a median duration of 3.8 (interquartile range, 2.5-6.7) years. Tartrate-resistant acid phosphatase 5b (TRACP-5b) levels decreased from a median of 595 (434-778) mU/dL at baseline to 200 (141-430) mU/dL after 6 months of denosumab administration (P < 0.001) and remained low thereafter. Similarly, bone-specific alkaline phosphatase (BAP) levels decreased from a median of 18.2 (15.9-25.8) µg/L at baseline to 12.4 (9.9-15.6) µg/L after 6 months (P < 0.001) and remained low thereafter. Meanwhile, BMD, as assessed with dual energy X-ray absorptiometry and measured at the distal 1/3 of the radius, did not decrease (0.465 ± 0.112 g/cm2 at baseline vs. 0.464 ± 0.112 g/cm2 after administration; P = 0.616). Regarding hypocalcemia, corrected calcium levels reached were the lowest at 7 days after administration and normalized within 30 days. CONCLUSION: The study showed long-term suppression of TRACP-5b and BAP levels and sustaining BMD after denosumab administration over an extended period in patients undergoing hemodialysis.

The relation between proteinuria and the severity of COVID-19.

BACKGROUND: The association between proteinuria, which is also an indicator of chronic kidney disease (CKD), and coronavirus disease 2019 (COVID-19) severity is unclear. METHODS: We selected 342 hospitalized patients with COVID-19 diagnosed via polymerase chain reaction testing between February 2020 and October 2022 and who had at least one urinalysis 14-365 days before admission. RESULTS: Proteinuria before admission was associated neither with oxygen administration nor developing pneumonia in multivariate analysis (odds ratio [OR] 1.03; 95% confidence interval (CI) 0.44-2.40, p = 0.95 and OR 1.01; 95% CI 0.47-2.17, p = 0.98, respectively). Proteinuria on admission was associated both with oxygen administration and developing pneumonia in multivariate analysis (OR 3.29; 95% CI 1.37-7.88, p < 0.01 and OR 3.81; 95% CI 1.68-8.62, p < 0.01, respectively). The percentage of patients with proteinuria on admission was significantly higher than those before admission (37.4% vs. 17.8%; p < 0.01). In the subgroup analysis, proteinuria on admission among patients with eGFR ≥ 60 mL/min/1.73 m2 was associated with both oxygen administration and developing pneumonia (OR 4.86; 95% CI 1.22-19.38, p = 0.03, OR 3.65; 95% CI 1.06-12.58, p = 0.04, respectively). In contrast, proteinuria on admission among patients with eGFR < 60 mL/min/1.73 m2 was associated with developing pneumonia (OR 6.45; 95%CI 1.78-23.35, p = 0.01), not with oxygen administration (OR 3.28; 95% CI 0.92-11.72, p = 0.07). CONCLUSIONS: Although underlying proteinuria before admission was not associated with COVID-19 severity, proteinuria on admission was associated with oxygen demand and developing pneumonia.

Association between serum magnesium levels and cognitive function in patients undergoing hemodialysis.

BACKGROUND: The relationship between chronic kidney disease-mineral and bone disorder (CKD-MBD) and cognitive function remains largely unknown. This cross-sectional study aimed to explore the association between CKD-MBD and cognitive function in patients on hemodialysis. METHODS: Hemodialysis patients aged ≥ 65 years without diagnosed dementia were included. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). CKD-MBD markers, serum magnesium, intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OHD), fibroblast growth factor (FGF)-23, and soluble α-klotho were measured. RESULTS: Overall, 390 patients with a median age of 74 (interquartile range, 70-80) years, mean serum magnesium level of 2.4 ± 0.3 mg/dL, and median MoCA and MMSE scores of 25 (22-26) and 28 (26-29), respectively, were analyzed. MoCA and MMSE scores were significantly higher (preserved cognitive function) in the high-magnesium group than in the low-magnesium group according to the unadjusted linear regression analysis (ß coefficient [95% confidence interval (CI)] 1.05 [0.19, 1.92], P = 0.017 for MoCA; 1.2 [0.46, 1.94], P = 0.002 for MMSE) and adjusted multivariate analysis with risk factors for dementia (ß coefficient [95% CI] 1.12 [0.22, 2.02], P = 0.015 for MoCA; 0.92 [0.19, 1.65], P = 0.014 for MMSE). CONCLUSIONS: Higher serum magnesium levels might be associated with preserved cognitive function in hemodialysis patients. Conversely, significant associations were not observed between cognitive function and intact PTH, 25-OHD, FGF-23, or soluble α-klotho levels.

Calcium-based phosphate binders and bone mineral density in patients undergoing hemodialysis: a retrospective cohort study.

BACKGROUND: Calcium supplements are commonly prescribed to prevent fractures in patients with osteoporosis. Nonetheless, they are generally eschewed in hemodialysis patients because they increase vascular calcification and induce cardiovascular disease. This retrospective cohort study aimed to investigate the effect of calcium-based phosphate binders (CBPB) on bone mineral density (BMD) in hemodialysis patients. METHODS: Outpatients on dialysis who underwent BMD measurement from January to December 2017, whose data on BMD trends and CBPB administration were recorded over the next 4 years, were enrolled. Patients receiving anti-osteoporotic medications were excluded. The association between the presence and duration of CBPB administration and changes in BMD was evaluated. RESULTS: The femoral neck's BMD decreased from 0.836 g/cm2 (0.702-0.952) to 0.764 g/cm2 (0.636-0.896) (P < 0.001) in the non-CBPB group (patients who never received CBPB over 4 years, n = 32). The CBPB group (n = 56) exhibited only a minute decrease from 0.833 g/cm2 (0.736-0.965) to 0.824 g/cm2 (0.706-0.939) (P = 0.004). Multivariate linear regression analysis revealed better BMD maintenance in the CBPB group [ß-coefficient (95% CI): 0.033 (0.001-0.065); P = 0.046] than in the non-CBPB group. Additionally, the prolonged-CBPB administration group showed superior BMD preservation [ß-coefficient (95% CI): 0.038 (0.001-0.076); P = 0.042]. CONCLUSION: CBPB administration may be associated with BMD maintenance.

Association between the serum zinc level and nutritional status represented by the geriatric nutritional Rrisk index.

BACKGROUND: Although it is widely known that patients with chronic kidney disease (CKD) can develop zinc deficiency, in our previous analysis, the estimated glomerular filtration rate (eGFR) was not independently associated with the serum zinc level. Thus, a post hoc analysis was conducted to investigate the involvement of nutritional status. METHODS: A total of 655 subjects not on dialysis (402 males; mean age, 57 ± 18 years) who underwent serum zinc level measurements at Jikei University Hospital between April 2018 and March 2019 were selected using the Standardized Structured Medical Information eXchange2 (SS-MIX2) system. In addition, anthropometric data and the Geriatric Nutritional Risk Index (GNRI) representing nutritional status were obtained, and the relationship between the serum zinc level and nutritional status was investigated by multiple regression analysis. RESULTS: The serum albumin level and the GNRI were lower in the zinc-deficiency group, and both were positively associated with the serum zinc level (rho = 0.44, P < 0.01 and rho = 0.44, P < 0.01, respectively). On multiple regression analysis, the GNRI (t = 3.09, P < 0.01) and serum albumin level (t = 4.75, P < 0.01) were independently associated with the serum zinc level. Although a higher eGFR was associated with a higher serum zinc level, this association disappeared on multivariate analysis. CONCLUSION: In this post hoc analysis, the GNRI, as well as the serum albumin level, were correlated with the serum zinc level, indicating that nutritional status is an important determinant of the zinc level. Further investigations are needed to clarify the effects of nutritional status and kidney function on zinc deficiency.

Estimating baseline creatinine levels based on the kidney parenchymal volume.

BACKGROUND: Acute kidney injury (AKI) diagnosis often lacks a baseline serum creatinine (Cr) value. Our study aimed to create a regression equation linking kidney morphology to function in kidney donors and chronic kidney disease patients. We also sought to estimate baseline Cr in minimal change disease (MCD) patients, a common AKI-predisposing condition. METHODS: We analyzed 119 participants (mean age 60 years, 50% male, 40% donors) with CT scans, dividing them into derivation and validation groups. An equation based on kidney parenchymal volume (PV) was developed in the derivation group and validated in the validation group. We estimated baseline Cr in 43 MCD patients (mean age 45 years, 61% male) using the PV-based equation and compared with their 6 month post-MCD onset Cr values. RESULTS: In the derivation group, the equation for the estimated glomerular filtration rate (eGFR) was: eGFR (mL/min/1.73m2) = 0.375 × PV (cm3) + (- 0.395) × age (years) + (- 2.93) × male sex + (- 13.3) × hypertension + (- 14.0) × diabetes + (- 0.210) × height (cm) + 82.0 (intercept). In the validation group, the eGFR and estimated Cr values correlated well with the measured values (r = 0.46, p = 0.01; r = 0.51, p = 0.004, respectively). In the MCD group, the baseline Cr values were significantly correlated with the estimated baseline Cr values (r = 0.52, p < 0.001), effectively diagnosing AKI (kappa = 0.76, p < 0.001). CONCLUSIONS: The PV-based regression equation established in this study holds promise for estimating baseline Cr values and diagnosing AKI in patients with MCD. Further validation in diverse AKI populations is warranted.

Analysis of the impact of obesity on the prognosis of IgA nephropathy according to renal function and sex.

BACKGROUND: Few studies have observed the direct effect of obesity on renal prognoses in immunoglobulin A nephropathy (IgAN) or separately evaluated its effects according to sex. We aimed to evaluate the direct and indirect effects of obesity on the renal outcomes of IgAN and observe these effects separately according to renal function and sex. METHODS: We extracted patients with body mass index (BMI) descriptions from a multicenter retrospective cohort analysis in Japan, and excluded those with < 30 days of follow-up, diabetes mellitus, and steroid treatment. Patients were divided into normal (n = 720; 18.5 ≤ BMI < 25) and obese (n = 212; BMI ≥ 25) groups, which were then compared. The endpoints were a 1.5-fold increase in serum creatinine levels and the initiation of renal replacement therapy. RESULTS: The obese group was older, included more males, and was more likely have hypertension, dyslipidemia, proteinuria, tubular atrophy, and lower renal function than the normal group. Patients with an eGFR < 60 mL/min/1.73 m2 had well-matched characteristics between the groups; however, hypertension, low high-density lipoprotein cholesterol, and hypertriglyceridemia were more common in the obese group. Obesity contributed to tubular atrophy, even when adjusted for renal function. In addition, it contributed to proteinuria only in females. However, obesity itself was not a significant prognostic factor. CONCLUSIONS: Although no independent effect on renal prognosis was observed during the study period, the obese group had more risk factors for IgAN progression and obesity contributed to tubular atrophy and female proteinuria. Our results suggest that separately analyzing the prognostic effect of obesity according to sex is important.

Effect of tonsillectomy combined with steroid pulse therapy upon IgA nephropathy depending on proteinuria status at diagnosis: a nationwide multicenter cohort study in Japan.

BACKGROUND: The effects of tonsillectomy combined with steroid pulse (TSP) therapy for IgA nephropathy (IgAN) are little known. Therefore, we examined the effects of TSP therapy on the kidney outcomes of IgAN in a large, nationwide cohort study in Japan. METHODS: Between 2002 and 2004, 632 IgAN patients with ≥ 0.5 g/day proteinuria at diagnosis were divided into three groups with mild (0.50-0.99 g/day; n = 264), moderate (1.00-1.99 g/day, n = 216), or severe (≥ 2.00 g/day; n = 153). Decline in kidney function and urinary remission were compared among the three groups after TSP therapy, corticosteroid (ST) therapy, or conservative therapy during a mean follow-up of 6.2 ± 3.3 years. 10.6% and 5.9% of patients in the ST and conservative therapy group underwent tonsillectomy. RESULTS: The rate of urinary remission at the final observation was significantly higher in the TSP therapy group than in the ST or conservative therapy groups (mild proteinuria: 64%, 43%, and 41%; moderate proteinuria: 51%, 45%, and 28%; severe proteinuria: 48%, 30%, and 22%, respectively). In contrast, the rate of a 50% increase in serum creatinine was lower in groups TSP therapy, than ST or conservative therapy (mild proteinuria: 2.1%, 10.1% and 16.7%; moderate proteinuria: 4.8%, 8.8% and 27.7%; severe proteinuria: 12.0%, 28.9% and 43.1%, respectively). In multivariate analysis, TSP therapy significantly prevented a 50% increase in serum creatinine levels compared with conservative therapy in groups with moderate and severe proteinuria (hazard ratio, 0.12 and 0.22, respectively). CONCLUSION: TSP significantly increased the rate of proteinuria disappearance and urinary remission in IgAN patients with mild-to-moderate urinary protein levels. It may also reduce the decline in kidney function in patients with moderate-to-severe urinary protein levels.

Upward-directed exit-site of the swan-neck catheter and "Easy-to-disinfect the backside area of exit-site" may prevent PD complications.

BACKGROUND: Upward-directed exit-site has been believed to be the worst for frequent ESI by an old retrospective study using straight catheters. No comparison study of 3 exit-site directions using swan-neck catheter has been performed regarding which direction is the best for our endpoints, Easy-to-see the backside area of exit-site: ESBE, Easy-to-disinfect the backside area of exit-site: EDBE, reduction of both exit-site infection (ESI), symptomatic catheter dislocation and peritonitis. METHODS: We assessed the relationship of exit-site direction with our endpoints in a quantitative cross-sectional, multicentered questionnaire survey. Patients who received either non-surgical catheter implantation or exit-site surgery were excluded. RESULTS: The numbers (percentage) of exit-site directions in included 291 patients were upward 79 (26.0), lateralward 108 (37.5) and downward 105 (36.5). Cochran-Armitage analysis showed a significant step-ladder increase in the prevalence of ESI as the direction changed from upward to lateralward to downward (0.15 ± 0.41, 0.25 ± 0.54, 0.38 ± 0.69 episodes/patient-year, p = 0.03). Multivariable regression analysis revealed the upward exit-site independently associates with both higher frequency of ESBE (OR 5.55, 95% CI 2.23-16.45, p < 0.01) and reduction of prevalence of ESI (OR 0.55, 95%CI 0.27-0.98, p = 0.04). Positive association between the prevalence of symptomatic catheter dislocation and ESI (OR 2.84, 95% CI 1.27-7.82, p = 0.01), and inverse association between EDBE and either prevalence of symptomatic catheter dislocation (OR 0.27, 95% CI 0.11-0.72) or peritonitis (OR 0.48, 95% CI 0.23-0.99) observed. CONCLUSION: Upward-directed swan-neck catheter exit-site may be the best for both ESBE and prevention of ESI. EDBE may reduce catheter dislocation and peritonitis. Symptomatic catheter dislocation may predict ESI.

Association of serum magnesium levels with renal prognosis in patients with chronic kidney disease.

BACKGROUND: Magnesium deficiency is associated with various health conditions, but its impact on the progression of chronic kidney disease (CKD) remains unclear. This study aimed to investigate the association between serum magnesium levels and prognosis of renal function in CKD patients. METHODS: This is an analysis of the Japan Chronic Kidney Disease Database Ex　(J-CKD-DB-Ex), which is a multicenter prospective cohort including CKD patients enrolled from January 1, 2014 to December 31, 2020. We included adult outpatients with CKD stage G3 and G4 at the time of initial magnesium measurement. Patients were classified by magnesium levels as low (<1.7 mg/dl), normal (1.7-2.6 mg/dl), or high (>2.6 mg/dl). The primary outcomes were the composite of an eGFR < 15 ml/min/1.73 m2 or a ≥30% reduction in eGFR from the initial measurement, which was defined as CKD progression. We applied the Kaplan-Meier analysis and Cox regression hazard model to examine the association between magnesium levels and CKD progression. RESULTS: The analysis included 9868 outpatients during the follow-up period. The low magnesium group was significantly more likely to reach CKD progression. Cox regression, adjusting for covariates and using the normal magnesium group as the reference, showed that the hazard ratio for the low magnesium group was 1.20 (1.08-1.34). High magnesium was not significantly associated with poor renal outcomes compared with normal magnesium. CONCLUSION: Based on large real-world data, this study demonstrated that low magnesium levels are associated with poorer renal outcomes.

Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness. CASE PRESENTATION: A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels. CONCLUSION: Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Fetal Kidney Grafts and Organoids from Microminiature Pigs: Establishing a Protocol for Production and Long-Term Cryopreservation.

Fetal organs and organoids are important tools for studying organ development. Recently, porcine organs have garnered attention as potential organs for xenotransplantation because of their high degree of similarity to human organs. However, to meet the prompt demand for porcine fetal organs by patients and researchers, effective methods for producing, retrieving, and cryopreserving pig fetuses are indispensable. Therefore, in this study, to collect fetuses for kidney extraction, we employed cesarean sections to preserve the survival and fertility of the mother pig and a method for storing fetal kidneys by long-term cryopreservation. Subsequently, we evaluated the utility of these two methods. We confirmed that the kidneys of pig fetuses retrieved by cesarean section that were cryopreserved for an extended period could resume renal growth when grafted into mice and were capable of forming renal organoids. These results demonstrate the usefulness of long-term cryopreserved fetal pig organs and strongly suggest the effectiveness of our comprehensive system of pig fetus retrieval and fetal organ preservation, thereby highlighting its potential as an accelerator of xenotransplantation research and clinical innovation.

Evaluation of the ability of human induced nephron progenitor cells to form chimeric renal organoids using mouse embryonic renal progenitor cells.

The number of patients with end-stage renal failure is increasing annually worldwide and the problem is compounded by a shortage of renal transplantation donors. In our previous research, we have shown that transplantation of renal progenitor cells into the nephrogenic region of heterologous fetuses can induce the development of nephrons. We have also developed transgenic mice in which specific renal progenitor cells can be removed by drugs. By combining these two technologies, we have succeeded in generating human-mouse chimeric kidneys in fetal mice. We hope to apply these technologies to regenerative medicine. The quality of nephron progenitor cells (NPCs) derived from human pluripotent stem cells is important for the generation of chimeric kidneys, but there is currently no simple evaluation system for the chimerogenic potential of human NPCs. In this study, we focused on the fact that the re-aggregation of mouse renal progenitor cells can be used for nephron formation, even when merged into single cells. First, we examined the conditions under which nephron formation is likely to occur in mice during re-aggregation. Next, to improve the differentiation potential of human NPCs derived from pluripotent stem cells, NPCs were sorted using Integrin subunit alpha 8 (ITGA8). Finally, we demonstrated chimera formation between different species by mixing mouse cells with purified, selectively-induced human NPCs under optimum conditions. We observed these chimeric organoids at different time points to learn about these human-mouse chimeric structures at various stages of renal development. We found that the rate of chimera formation was affected by the purity of the human NPCs and the cell ratios used. We demonstrated that chimeric nephrons can be generated using a simple model, even between distant species. We believe that this admixture of human and mouse renal progenitor cells is a promising technology with potential application for the evaluation of the chimera formation abilities of NPCs.

Urate Transporter ABCG2 Function and Asymptomatic Hyperuricemia: A Retrospective Cohort Study of CKD Progression.

RATIONALE & OBJECTIVE: Treatment of asymptomatic hyperuricemia is not commonly implemented. However, it is unclear whether urate deposition that begins during asymptomatic hyperuricemia can induce nephropathy. Dysfunction of ATP-binding cassette subfamily G member 2 (ABCG2), a urate efflux transporter, leads to elevated serum uric acid concentration (SUA). We investigated the association between asymptomatic hyperuricemia and decreased estimated glomerular filtration rate (eGFR), and the impact of ABCG2 on this relationship. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 1,885 Japanese adults undergoing routine health care follow-up between 2007 and 2017 who had eGFR ≥60 mL/min/1.73 m2, of which 311 had asymptomatic hyperuricemia (SUA >7.0 mg/dL). Study participants were classified into 3 categories of estimated ABCG2 function (full, 75%, and ≤50% function). PREDICTORS: Baseline SUA and estimated ABCG2 function. OUTCOME: Change in eGFR over time. ANALYTICAL APPROACH: Linear mixed-effect models were used to analyze the relationship between asymptomatic hyperuricemia, ABCG2 function, and eGFR decline. RESULTS: Asymptomatic hyperuricemia was negligibly associated with eGFR decline overall. However, among those with eGFR 60-89 mL/min/1.73 m2 and ≤50% ABCG2 function, eGFR decline was associated with asymptomatic hyperuricemia (P = 0.03). ABCG2 was not associated with eGFR reductions when the SUA was <6.0 mg/dL. Among participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, ≤50% ABCG2 function was associated with approximately 1.2-fold faster eGFR decline compared with fully functional ABCG2 (P = 0.02). Among the participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, the adjusted eGFR slopes (given as mean ± standard error of the mean, in mL/min/1.73 m2 per year) were -0.946 ± 0.049, -1.040 ± 0.046, and -1.148 ± 0.069 for full, 75%, and ≤50% ABCG2 function, respectively. LIMITATIONS: Lack of measurement of urinary urate and uremic toxins that are known to be transported by ABCG2, and no independent validation cohort. CONCLUSIONS: Asymptomatic hyperuricemia was not associated with eGFR decline, except when in the presence of ≤50% ABCG2 function. PLAIN-LANGUAGE SUMMARY: The urate transporter ABCG2 is a protein that regulates serum urate concentrations; when dysfunctional, it can lead to elevated serum concentrations of this compound (ie, hyperuricemia). Although persistent hyperuricemia induces gout and kidney injury, the effects on organs during the asymptomatic phase have yet to be established. Therefore, to clarify the relationship between ABCG2, asymptomatic hyperuricemia, and kidney function, we conducted a retrospective cohort study of 1,885 healthy participants, including 311 participants with asymptomatic hyperuricemia. We found that the coexistence of asymptomatic hyperuricemia and severe ABCG2 dysfunction was associated with the age-dependent decline in kidney function. We concluded that asymptomatic hyperuricemia represents a risk factor for chronic kidney disease, at least in individuals with highly dysfunctional ABCG2. This new finding highlights the potential importance of ABCG2 in the pathogenesis of hyperuricemia-induced kidney injury.

Urinary Immunoglobulin G Is Associated with Deep and Infratentorial Cerebral Microbleeds in Stroke Patients.

BACKGROUND: Cerebral microbleeds (CMBs) detected on susceptibility-weighted imaging (SWI) are associated with cerebral small vessel disease. Chronic kidney disease and microalbuminuria have been associated with the presence of CMBs in stroke patients. Urinary immunoglobulin G (IgG) is measured to document glomerular injury; however, the relationship between urinary IgG and CMBs is unknown. METHODS: We retrospectively enrolled consecutive patients who had been admitted with transient ischemic attack (TIA) or ischemic stroke and identified those who had undergone SWI and a spot urine test. The location of CMBs was classified on magnetic resonance imaging as strictly lobar, deep/infratentorial (D/I), or mixed areas. We analyzed the association between urinary IgG and the presence and location of CMBs. RESULTS: We included 298 patients (86 female, median age 70 years, median eGFR 65.8 mL/min/1.73 m2). Positive urinary IgG and CMB results were found in 58 (19%) and 160 patients (54%), respectively. Urinary IgG positivity was significantly associated with CMBs compared with non-CMBs (28% vs. 9%, p < 0.001), and with D/I or mixed CMBs compared with non-D/I or mixed CMBs (34% vs. 10%, p < 0.001). Multivariate analysis revealed that urinary IgG and hypertension positivity were strongly associated with D/I or mixed CMBs (OR 3.479, 95% CI: 1.776-6.818, p < 0.001; OR 3.415, 95% CI: 1.863-6.258, p < 0.001). CONCLUSIONS: Urinary IgG was associated with the prevalence of D/I or mixed location CMBs in TIA or ischemic stroke patients. Our findings provide new insights into the association between urinary IgG and the distribution of CMBs.