Health-related Quality of Life in 10 years Long-term Survivors of Chronic Kidney Disease: A From-J Study.

OBJECTIVE: The Chronic Kidney Disease (CKD) practice facilitation program in the Frontier of Renal Outcome Modifications in Japan study reduced cardiovascular disease (CVD) events in patients with CKD. 10-year long-term survivors with CKD lived with serious complications, including end-stage kidney disease and CVD. This study aimed to measure health-related quality of life in 10-year long-term CKD survivors and examine the predictors and determinants of clinical indices for measured quality of life (QOL) scores. METHODS: The EQ-5D-5L, a generic preference-based instrument, was administered to 1,473 CKD survivors enrolled in the Frontier of Renal Outcome Modifications in JapanFrontier of Renal Outcome Modifications in JapanFrontier of Renal Outcome Modifications in Japan study. The 10th-year data collection was performed by either primary care physicians or participants who filled out questionnaires from October 2018 to March 31, 2019. RESULTS: The response rate was 38.2% (423/1,473). The mean QOL score was 0.893 (95% confidence interval (CI), 0.880-0.906), and the median QOL score was 1.000 (interquartile range (IQR), 0.826-1.000). The mean QOL score in participants with renal replacement therapy was 0.824 (95% CI, 0.767-0.881), and the median was 0.828 (IQR, 0.755-1.000). The mean QOL score in participants with CVD was 0.877 (95% CI, 0.811-0.943), and the median was 1.000 (IQR, 0.723-1.000). The mean QOL score in participants with 50% decline in estimated glomerular filtration was 0.893 (95% CI, 0.860-0.926), and the median was 0.889 (IQR, 0.825-1.000). The decrease in QOL scores with baseline CKD stages was significant according to the Jonckheere-Terpstra test for trend (P = .002). Baseline age, systolic blood pressure, and history of hyperuricemia were significant predictors of 10th-year QOL scores. CONCLUSION: We suggest that CKD complications negatively affect the QOL scores in 10-year long-term survivors with CKD. CKD guideline-based practices, prevention of end-stage kidney disease/CVD and management of hypertension, diabetes and hyperuricemia, might contribute to future health-related quality of life in patients with CKD.

Long-term effectiveness of a primary care practice facilitation program for chronic kidney disease management: an extended follow-up of a cluster-randomized FROM-J study.

BACKGROUND: Practice facilitation program by multidisciplinary care for primary care physicians (PCPs) is expected to improve chronic kidney disease (CKD) outcomes, but there is no clear evidence of its long-term effectiveness. We have previously performed a cluster-randomized controlled trial for 3.5 years (the Frontier of Renal Outcome Modifications in Japan (FROM-J) study) with two arms-group A without the program and group B with the program. We aimed to assess the long-term effectiveness of the practice facilitation program on CKD outcomes via an extended 10-year follow-up of the FROM-J study. METHODS: We enrolled patients who were in the FROM-J study. The primary composite endpoint comprised cardiovascular disease (CVD), renal replacement therapy initiation and a 50% decrease in the estimated glomerular filtration rate (eGFR). The secondary endpoints were survival rate, eGFR decline rate and collaboration rate between PCPs and nephrologists. RESULTS: The occurrence of the primary composite endpoint tended to be lower in group B (group A: 27.1% versus group B: 22.1%, P = 0.051). Furthermore, CVD incidence was remarkably lower in group B (group A: 10.5% versus group B: 6.4%, P = 0.001). Although both mortality and the rate of eGFR decline were identical between both groups, the eGFR decline rate was significantly better in group B than in group A only in patients with stage G3a at enrollment (group A: 2.35 ± 3.87 mL/min/1.73 m2/year versus group B: 1.68 ± 2.98 mL/min/1.73 m2/year, P = 0.02). The collaboration rate was higher in group B. CONCLUSIONS: The CKD practice facilitation program for PCPs reliably decreases CVD events and may reduce the progression of cases to end-stage kidney disease.

High-risk screening for Fabry disease in hemodialysis patients in Chiba Prefecture, Japan.

BACKGROUND: High-risk screening for Fabry disease in dialysis patients is an effective means for reducing the number of undiagnosed cases. However, such screening has not been conducted in Chiba Prefecture, Japan. Herein, we aimed to estimate the prevalence of Fabry disease among patients undergoing hemodialysis in Chiba Prefecture by high-risk screening using α-galactosidase A (αGal A) activity measurement, and examine the hemodialysis effect on αGal A activity. METHODS: Patients who underwent maintenance hemodialysis at 25 facilities in Chiba Prefecture were recruited. The αGal A activity was measured using the dried blood spot (DBS) test as the first screening. If the enzyme activity was lower than the cut-off, the second screening was performed with the same method before and after dialysis. RESULTS: Overall, 2924 patients (2036 men and 888 women) were included from which 94 cases (45 men and 48 women) showed decreased αGAL activity in the first screening and 3 (two men and one women) in the second screening. Genetic testing was performed in 3 patients, and the c.1078G > A mutation in GLA gene was detected in one male patient (0.03%). There has been a statistically significant decrease in αGal A activity of DBS at post-dialysis compared to that at pre-dialysis (20.5 ± 10.4 pmol/h/disk and 22.7 ± 11.5 pmol/h/disk, p < 0.0001). CONCLUSION: The prevalence of Fabry disease among patients undergoing hemodialysis in Chiba Prefecture was estimated as 0.03%. This is the first time that dialysis has been shown to affect the αGal A activity.

Focal segmental glomerulosclerosis histologic variants and renal outcomes based on nephrotic syndrome, immunosuppression and proteinuria remission.

BACKGROUND: The associations of focal segmental glomerulosclerosis (FSGS) histological variants with renal outcomes have rarely been investigated comprehensively by clinically relevant subgroups in this modern age. METHODS: Data on 304 (173 nephrotic and 131 non-nephrotic) patients with biopsy-confirmed FSGS from 2010 to 2013 were analyzed using the Japanese nationwide renal biopsy registry. The primary outcome was a composite of a 30% decline in estimated glomerular filtration rate or progression to end-stage kidney disease 5 years from the biopsy. We compared outcomes of FSGS variants according to the Columbia classification using survival analyses. Subgroup analyses were performed based on nephrotic syndrome (NS), immunosuppression and proteinuria remission (PR; proteinuria <0.3 g/day) during follow-up. Additionally, associations of NS, immunosuppression and PR with outcomes were examined for each variant. RESULTS: The distribution of variants was 48% (n = 145) FSGS not otherwise specified, 19% (n = 57) tip, 15% (n = 47) perihilar, 13% (n = 40) cellular and 5% (n = 15) collapsing. The outcome event occurred in 87 patients (29%). No significant differences in the outcome were found among the variants. Subgroup analyses yielded similar results. However, there was a trend toward improved outcome in patients with PR irrespective of variants [hazard ratio adjusted for histological variant and potential confounders (adjusted HR) 0.19 (95% confidence interval 0.10-0.34)]. NS was marginally associated with better outcome compared with non-NS [adjusted HR 0.50 (95% confidence interval 0.25-1.01)]. CONCLUSIONS: FSGS variants alone might not have significant impacts on the renal outcome after 5 years, while PR could be predictive of improved renal prognosis for any variant. Specific strategies and interventions to achieve PR for each variant should be implemented for better renal outcomes.

Evaluation of screening with urine dipsticks and renal ultrasonography for 3-year-olds in Chiba City over 30 years.

BACKGROUND: Urinary screening for 3-year-olds cannot adequately detect congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: Urinary screening for 3-year-olds was investigated over 30 years. Dipsticks for proteinuria, hematuria, glycosuria, leukocyturia, and nitrite at first screening, and dipsticks, urinary sediments, and renal ultrasonography at second screening were performed. Screening results were evaluated. RESULTS: The positive rates of proteinuria, hematuria, leukocyturia, and nitrite relative to 218,831 children at the first screening were 1.0%, 4.6%, 2.3%, and 0.88%, respectively. Thirty-seven glomerular disease, 122 CAKUT, and 5 urological disease cases were found. We detected 6 stage 3-4 chronic kidney disease (CKD) and 3 end-stage kidney disease cases, including 3 CAKUT, comprising 2 bilateral renal hypoplasia and 1 vesicoureteral reflux (VUR), and 6 glomerular diseases, comprising 4 focal segmental glomerulosclerosis and 2 Alport syndrome. The positive rates relative to 218,831 children and CKD detection rates for each tentative diagnosis of mild hematuria, severe hematuria, proteinuria and hematuria, proteinuria, and suspected urinary tract infection were 1.4% and 0.67%, 0.11% and 3.7%, 0.01% and 28.6%, 0.02% and 45.0%, and 0.08% and 9.7%, respectively. Among 14 VUR cases with significant bacteriuria, 13 were found by leukocyturia, 12 had grade ≥ IV VUR, and 10 had severe renal scars. CONCLUSIONS: Nine stage 3-5 CKD cases comprising 3 CAKUT and 6 glomerular disease were found by urinary screening of 3-year-olds among 218,831 children. The combination of urine dipsticks including leukocyturia at the first screening and ultrasonography at the second screening appeared useful.

Proteomic Study of Low-Birth-Weight Nephropathy in Rats.

The hyperfiltration theory has been used to explain the mechanism of low birth weight (LBW)-related nephropathy. However, the molecular changes in the kidney proteome have not been defined in this disease, and early biomarkers are lacking. We investigated the molecular pathogenesis of LBW rats obtained by intraperitoneal injection of dexamethasone into pregnant animals. Normal-birth-weight (NBW) rats were used as controls. When the rats were four weeks old, the left kidneys were removed and used for comprehensive label-free proteomic studies. Following uninephrectomy, all rats were fed a high-salt diet until 9 weeks of age. Differences in the molecular composition of the kidney cortex were observed at the early step of LBW nephropathy pathogenesis. Untargeted quantitative proteomics showed that proteins involved in energy metabolism, such as oxidative phosphorylation (OXPHOS), the TCA cycle, and glycolysis, were specifically downregulated in the kidneys of LBW rats at four weeks. No pathological changes were detected at this early stage. Pathway analysis identified NEFL2 (NRF2) and RICTOR as potential upstream regulators. The search for biomarkers identified components of the mitochondrial respiratory chain, namely, ubiquinol-cytochrome c reductase complex subunits (UQCR7/11) and ATP5I/L, two components of mitochondrial F1FO-ATP synthase. These findings were further validated by immunohistology. At later stages of the disease process, the right kidneys revealed an increased frequency of focal segmental glomerulosclerosis lesions, interstitial fibrosis and tubular atrophy. Our findings revealed proteome changes in LBW rat kidneys and revealed a strong downregulation of specific mitochondrial respiratory chain proteins, such as UQCR7.

Correction of serum potassium with sodium zirconium cyclosilicate in Japanese patients with hyperkalemia: a randomized, dose-response, phase 2/3 study.

BACKGROUND: Sodium zirconium cyclosilicate (SZC) is an oral potassium binder approved to treat hyperkalemia in adults in a number of countries, including Japan. METHODS: This phase 2/3, randomized, double-blind, placebo-controlled, dose-response study (ClinicalTrials.gov: NCT03127644) was designed to determine the efficacy and safety of SZC in Japanese adults with hyperkalemia. Patients with serum potassium (sK+) concentrations ≥ 5.1- ≤ 6.5 mmol/L were randomized 1:1:1 to SZC 5 g, SZC 10 g, or placebo three times daily for 48 h (six doses total). The primary efficacy endpoint was the exponential rate of change in sK+ over 48 h. The proportion of patients with normokalemia (sK+ 3.5-5.0 mmol/L) at 48 h and adverse events (AEs) were also evaluated. RESULTS: Overall, 103 patients (mean age, 73.2 years; range 50-89 years) received SZC 5 g (n = 34), SZC 10 g (n = 36), or placebo (n = 33). The exponential rate of sK+ change from 0 to 48 h versus placebo was - 0.00261 (SZC 5 g) and - 0.00496 (SZC 10 g; both P < 0.0001). At 48 h, the proportions of patients with normokalemia were 85.3%, 91.7%, and 15.2% with SZC 5 g, SZC 10 g, and placebo, respectively. No serious AEs were reported. Hypokalemia (sK+ < 3.5 mmol/L) occurred in two patients in the SZC 10 g group; normokalemia was re-established within 6 days and no treatment-related AEs were reported. CONCLUSION: SZC is effective and well tolerated in Japanese patients with hyperkalemia.

A case report of adult-onset COQ8B nephropathy presenting focal segmental glomerulosclerosis with granular swollen podocytes.

BACKGROUND: Primary coenzyme Q10 (CoQ10) deficiency of genetic origin is one of a few treatable focal segmental glomerulosclerosis (FSGS). Renal morphologic evidence for COQ8B mutation and CoQ10 deficiencies of other gene mutations is assessed using electron microscopy with marked increase of abnormal-shaped mitochondria in podocytes. However, light microscopic morphologic features of deficiencies other than FSGS have not been reported. CASE PRESENTATION: A 30-year-old woman was admitted to our hospital because proteinuria was found during four consecutive medical checkups. She had no medical history or family history of proteinuria and severe renal dysfunction. The swollen podocytes were stained to the same extent as mitochondria-rich proximal tubular cells under both Masson's trichrome and hematoxylin-eosin staining, whereas no mitochondrial abnormalities were detected under the first electron microscopic views. As proteinuria and estimated glomerular filtration rate (eGFR) deteriorated after pregnancy, we reevaluated the additional electron microscopic views and detected mitochondrial abnormalities. Genetic testing revealed COQ8B mutation (c.532C > T, p.R178W); therefore, we diagnosed COQ8B nephropathy. CoQ10 supplementation improved proteinuria and stopped eGFR reduction. CONCLUSIONS: This is the first report of granular swollen podocytes due to mitochondrial diseases detected under light microscopy. We propose that this finding can be the clue for the diagnosis of both COQ8B nephropathy and the other CoQ10 deficiencies.

Glomerular basement membrane duplication is a predictor of the prognosis of diabetic nephropathy in patients with type 2 diabetes.

BACKGROUND: Several clinical parameters and pathological findings are known to be predictors of the deterioration of diabetic nephropathy (DN). Glomerular basement membrane duplication (GBM-DP) is a pathological feature representing endothelial injury, which is commonly observed in DN. In the present study, we investigated the association between GBM-DP and the renal prognosis in DN. METHODS: The study enrolled 80 patients with renal biopsy-proven DN who were managed at Chiba-East Hospital from 2005 to 2012. We confirmed the pathological findings according to the Renal Pathology Society classifications, and we further evaluated the GBM-DP, which was defined as double contours of the GBM that expanded more than 10% of capillary loops in the most affected nonsclerotic glomerulus. We used Cox regression models to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), with adjustment for age, sex, systolic blood pressure, HbA1c, estimated glomerular filtration rate (eGFR), and urinary protein excretion (UP) at baseline. RESULTS: Of the 80 patients, 56 were male (70.0%) and the mean age was 59.1 years. The median eGFR and UP were 42 ml/min/1.73 m2 (IQR 30, 59) and 3.1 g/gCr (IQR 1.2, 5.2). Twenty-seven patients progressed to ESRD and one patient died during the median observational period of 2.9 years (IQR 1.5, 4.3). The multivariable analyses showed that GBM-DP was significantly associated with ESRD (HR 3.18 [95% confidence interval (CI): 1.02-9.87], p = 0.045). CONCLUSION: We newly identified GBM-DP as a strong prognostic predictor in DN patients. Further study is needed to clarify the pathogenic mechanism of GBM-DP in DN.

High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy.

Podocytes play a key role in diabetic nephropathy pathogenesis, but alteration of their metabolism remains unknown in human kidney. By using a conditionally differentiating human podocyte cell line, we addressed the functional and molecular changes in podocyte energetics during in vitro development or under high glucose conditions. In 5 mM glucose medium, we observed a stepwise activation of oxidative metabolism during cell differentiation that was characterized by peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)-dependent stimulation of mitochondrial biogenesis and function, with concomitant reduction of the glycolytic enzyme content. Conversely, when podocytes were cultured in high glucose (20 mM), stepwise oxidative phosphorylation biogenesis was aborted, and a glycolytic switch occurred, with consecutive lactic acidosis. Expression of the master regulators of oxidative metabolism transcription factor A mitochondrial, PGC-1α, AMPK, and serine-threonine liver kinase B1 was altered by high glucose, as well as their downstream signaling networks. Focused transcriptomics revealed that myocyte-specific enhancer factor 2C (MEF2C) and myogenic factor 5 (MYF5) expression was inhibited by high glucose levels, and endoribonuclease-prepared small interfering RNA-mediated combined inhibition of those transcription factors phenocopied the glycolytic shift that was observed in high glucose conditions. Accordingly, a reduced expression of MEF2C, MYF5, and PGC-1α was found in kidney tissue sections that were obtained from patients with diabetic nephropathy. These findings obtained in human samples demonstrate that MEF2C-MYF5-dependent bioenergetic dedifferentiation occurs in podocytes that are confronted with a high-glucose milieu.-Imasawa, T., Obre, E., Bellance, N., Lavie, J., Imasawa, T., Rigothier, C., Delmas, Y., Combe, C., Lacombe, D., Benard, G., Claverol, S., Bonneu, M., Rossignol, R. High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy.

An equation to estimate the renal cortex volume in chronic kidney disease patients.

BACKGROUND: The renal cortex volume is associated with the kidney function and chronic kidney disease (CKD) risk factors, and it may also be a prognostic factor. We aimed to create an equation to estimate the renal cortex volume of CKD patients in day-to-day clinical practice. METHODS: The subjects included 116 ethnic Japanese CKD patients who were ≥ 18 years of age. The renal size (length, width and thickness) was measured by ultrasound. The body height, weight, year of age, sex, birth weight, gestational age, diabetes status, hypertension status, family history of CKD and dialysis and estimated glomerular filtration rate (eGFR) were collected as expected dependent variables. We made models for the equation regarding the renal cortex volume measured by non-contrast magnetic resonance imaging as a true renal cortex volume. Stepwise multiple linear regression analyses were performed with the log-transformation of dependent and independent variables. The accuracy of the models was compared using the leave one out cross-validation method. RESULTS: The estimated volume of the renal cortex (cm3) = 0.012 × renal length (cm)0.92 × width (cm)0.53 × body weight (kg)0.40 × body height (cm)0.67 × eGFR (ml/min/1.73 m2)0.22 × 1.12 if diabetes. The adjusted R 2 value and the accuracy within 30 and 50% were 0.73, 0.94 and 0.99, respectively. CONCLUSIONS: This study provided a new method for estimating the renal cortex volume in day-to-day clinical practice.

Impact of primary diabetic nephropathy on arteriolar hyalinosis lesions in patients following kidney transplantation.

AIM: Arteriolar hyalinosis (AH) is a common lesion in allograft biopsies taken following kidney transplantation. Recent studies have shown that severe AH may predict transplant outcomes and provide information about previous exposure to certain drugs, such as calcineurin inhibitors (CNI). However, the incidence of AH as a direct result of diabetic nephropathy (DN) after kidney transplantation has not been fully evaluated. This study aimed to assess the impact of primary DN on the development of AH lesions in patients who underwent kidney transplantation. METHODS: Eighty-three patients who underwent living-donor kidney transplantation between April 2005 and June 2015 were enrolled in this study. A total of 33 patients had DN prior to transplantation. Allograft biopsies were scored according to the Banff classification, and the relationship between the individual histological lesions and clinical baseline data was assessed. RESULTS: At early biopsy (3-12 months), there were no differences in the rates of AH lesions between the DN group and the non-DN group (ah ≥ 1: 37% vs. 41.3%, P = 0.719; aah ≥ 1: 14.8% vs. 6.5%; P = 0.453). However, there were significant differences between the groups in biopsies taken more than 3 years after the transplant (ah ≥ 2: 83.3% vs. 36.8%, P = 0.013; aah ≥ 2: 66.7% vs. 21.1%, P = 0.011). Multivariable analysis showed that both the length of time after transplantation and the presence of DN were independent risk factors for ah ≥ 2 (odds ratio [OR]: 2.55, 95% confidence interval [CI]: 1.47-19.54, P = 0.011) and aah ≥ 2 (OR: 7.55, 95% CI: 1.49-38.33, P = 0.015). CONCLUSION: This is the first report showing that the presence of primary DN disease contributes to the development of severe AH late in the course after kidney allografts.

Determinants of renal shape in chronic kidney disease patients.

BACKGROUND: The determinants of renal shape are not well established. The purpose of this study was to investigate the relationship between the renal shape, as measured by ultrasound, and the clinical characteristics in chronic kidney disease (CKD) patients. METHODS: The study included 121 CKD patients who had undergone kidney biopsy. The renal shape was defined by: (1) the renal shape index: renal length/(renal width + renal thickness) and (2) the renal width/length. IgA nephritis patients (excluding patients with diabetes), comprised the largest subgroup (n = 49) and were analyzed separately. RESULTS: The correlation analyses and two-sample Student's t test results showed that age, eGFR, BMI, cortex volume fraction measured by MRI (cortex volume/renal volume), percentage of global sclerosis, weight, sex, hypertension and diabetes were significantly correlated with the renal shape in both kidneys. In a stepwise multiple linear regression analysis, old age and high BMI were independently associated with plump kidney. As for the left renal shape index, low cortex volume fraction was also independently associated with plump kidney. In the IgA nephritis patient subgroup, the cortex volume fraction was the most significant factor contributing to the left renal shape index (r = 0.50, p < 0.01) and the width/length (r = -0.47, p < 0.01). CONCLUSION: Age and BMI were stronger determinants of renal shape than renal function in CKD patients. The left renal cortex volume fraction was also an independent determinant and a more important factor in IgA nephritis patients.

Advanced stage of chronic kidney disease is risk of poor treatment outcome for smear-positive pulmonary tuberculosis.

Chronic kidney disease (CKD) is an increased risk for the development of active tuberculosis, but few studies have analyzed the treatment outcome of pulmonary tuberculosis among CKD patients. A retrospective cohort study was conducted at Chiba-East Hospital in Chiba, Japan. Our study estimated the treatment outcomes in smear-positive pulmonary tuberculosis in relation to CKD and its stages. Total subjects were 759 patients (12-99 years) hospitalized between 2007 and 2012. Patients suffering from multi-drug-resistant tuberculosis were excluded. Patients with CKD were 19.3% aged <65 years (n = 384), and 49.6% aged ≥ 65 years, respectively (P < 0.001). Successful treatment was 52.7% in CKD (n = 260) and 67.3% in non-CKD (n = 499) (P < 0.001). Death was 25.4% in CKD and 12.4% in non-CKD (P < 0.001). Treatment outcome was especially poor in patients with low estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m(2), as successful treatment was 20.0%, and death was 50.0%, significantly lower than in other CKD and non-CKD patients. After multivariate logistic regression analysis, eGFR<30 ml/min/1.73 m(2) was an independent factor affecting successful treatment and death, and its adjusted odds ratios (aOR) were 0.20 (95% confidence interval (CI) 0.07-0.50) and 2.99 (95%CI 1.20-7.51), respectively. Other factors affecting successful treatment were serum albumin <3.0 mg/dl, steroid therapy for underlying disease and cardiovascular disease, with aOR (95%CI) of 0.28 (0.20-0.39), 0.32 (0.16-0.63) and 0.49 (0.28-0.86), respectively. Several factors were associated with poor treatment outcome of smear-positive pulmonary tuberculosis. Advanced stage of CKD with eGFR of <30 ml/min/1.73 m(2) was a risk factor for poor treatment outcome.

A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy.

BACKGROUND: The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). METHODS: Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. RESULTS: During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01-8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. CONCLUSIONS: The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

7501 T > A mitochondrial DNA variant in a patient with glomerulosclerosis.

The presence of granular swollen epithelial cells (GSECs) in tubular cells was recently reported to be a specific change associated with mitochondrial cytopathy. However, at present, GSEC is not routinely evaluated. We, in this study, present a case of glomerulosclerosis, in which the presence of GSECs should provide us one clue to understand the pathogenesis of its progressive decline of renal function. A 54-year-old Japanese female, who had been diagnosed with Graves' disease, was referred for the examination and treatment of her proteinuria (5.4 g/gCre at the first visit to our hospital). A kidney biopsy showed 28.6% of the glomeruli to be globally sclerosed and 10.7% of the glomeruli to have completely collapsed. However, according to a light microscopic analysis, all other glomeruli showed an almost normal appearance, except for some slight enlargement. Almost 30% of the interstitium was damaged by fibrosis. Characteristically, GSECs were observed in the medulla collecting ducts. Although she had no symptoms of either myopathy or encephalopathy, no history of stroke-like episodes or difficulty in hearing, her serum concentrations of lactate and pyruvate were both elevated. Therefore, mitochondrial DNA sequencing was performed to assess the etiopathogenesis of her nephropathy. Consequently, a homoplasmic 7501 T > A replacement, which has not been previously reported in patients with renal diseases, was detected. This case suggests that the routine evaluation of GSECs can provide important clues to assess the etiopathogenesis of cryptogenic glomerulosclerosis.

Changes in histopathology and heteroplasmy rates over 8 years and effectiveness of taurine supplementation in a patient with mitochondrial nephropathy caused by MT-TL1 mutation: A case report.

The m.3243A > G mutation in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene is known to cause mitochondrial nephropathy. However, its long-term effects of the m.3243A > G mutation on renal histopathology or heteroplasmy rates remain unknown. Here we present the case of a female patient who underwent renal biopsy at 34 years of age to investigate the reason for a low estimated glomerular filtration rate (eGFR) of 47.9 mL/min/1.73 m2. Light microscopy revealed nephrosclerosis with granular swollen epithelial cells (GSECs) in the renal tubules. Genetic testing revealed the m.3243A > G mutation in the MT-TL1 gene. Over a follow-up period of 8 years, the eGFR declined at a rate of 1.50 mL/min/1.73 m2/year. A second renal biopsy was performed at the age of 42 years; the patient's glomerular sclerosis rate had increased from 45.5% to 63.2%, and the frequency of GSECs in the collecting ducts had increased from 5.8% to 20.8%. Furthermore, the heteroplasmy rate in blood cells and urinary sediment cells increased from 9% to 20% and 20% to 53%, respectively. Taurine therapy was initiated just after the second kidney biopsy. To date, after approximately 3 years of taurine administration, the rate of eGFR decline has markedly decreased to 0.26 mL/min/1.73 m2/year. This experience suggests that an increased heteroplasmy rate may be associated with the progression of mitochondrial nephropathy caused by MT-TL1 mutation. Furthermore, our case is the first to suggest the effectiveness of taurine for mitochondrial nephropathy caused by the m.3243A > G mutation in the MT-TL1 gene.

Focal segmental glomerulosclerosis with a mutation in the mitochondrially encoded NADH dehydrogenase 5 gene: A case report.

NADH dehydrogenase 5 (ND5) is one of 44 subunits composed of Complex I in mitochondrial respiratory chain. Therefore, a mitochondrially encoded ND5 (MT-ND5) gene mutation causes mitochondrial oxidative phosphorylation (OXPHOS) disorder, resulting in the development of mitochondrial diseases. Focal segmental glomerulosclerosis (FSGS) which had podocytes filled with abnormal mitochondria is induced by mitochondrial diseases. An MT-ND5 mutation also causes FSGS. We herein report a Japanese woman who was found to have proteinuria and renal dysfunction in an annual health check-up at 29 years old. Because her proteinuria and renal dysfunction were persistent, she had a kidney biopsy at 33 years of age. The renal histology showed FSGS with podocytes filled with abnormal mitochondria. The podocytes also had foot process effacement and cytoplasmic vacuolization. In addition, the renal pathological findings showed granular swollen epithelial cells (GSECs) in tubular cells, age-inappropriately disarranged and irregularly sized vascular smooth muscle cells (AiDIVs), and red-coloured podocytes (ReCPos) by acidic dye. A genetic analysis using peripheral mononuclear blood cells and urine sediment cells detected the m.13513 G > A variant in the MT-ND5 gene. Therefore, this patient was diagnosed with FSGS due to an MT-ND5 gene mutation. Although this is not the first case report to show that an MT-ND5 gene mutation causes FSGS, this is the first to demonstrate podocyte injuries accompanied with accumulation of abnormal mitochondria in the cytoplasm.

Independent risk factors of rapid glomerular filtration rate decline in patients with type 2 diabetes with preserved kidney function and normoalbuminuria: A multicenter cohort study.

AIMS/INTRODUCTION: Research on the incidence and underlying mechanisms of rapid renal function decline in patients with type 2 diabetes mellitus with preserved renal function and normoalbuminuria is limited. This study aimed to investigate the involvement of hemoglobin level as a risk factor for rapid decliners among patients with type 2 diabetes with preserved renal function and normoalbuminuria. MATERIALS AND METHODS: This was a retrospective observational study of 242 patients with type 2 diabetes with a baseline estimated glomerular filtration rate of ≥60 mL/min/1.73 m2 and normoalbuminuria (<30 mg/gCr), followed up for >1 year. The annual rate of estimated glomerular filtration rate decline during the follow-up period was calculated using least square regression analysis; rapid decliners defined at ≥3.3%/year. Risk factors associated with rapid decliners were identified using a logistic regression analysis of variables previously identified as risk factors of rapid decliners. RESULTS: The median follow-up period was 6.7 years, and 34 patients showed rapid decliners. On multivariate analysis, lower baseline hemoglobin level was a risk factor of rapid decliners (odds ratio 0.69, 95% confidence interval 0.47-0.99; P = 0.045). Furthermore, the baseline hemoglobin levels were correlated positively with iron and ferritin levels, implying that an impaired iron metabolism might cause lower hemoglobin levels in rapid decliners. CONCLUSIONS: In patients with type 2 diabetes with preserved renal function and normoalbuminuria, lower hemoglobin levels were a risk factor for rapid decliners, where disturbed iron metabolism might precede the development of diabetic kidney disease.

Corrigendum to "Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease"Kidney International Reports, Volume 7, Issue 4, April 2022, Pages 857-866.

[This corrects the article DOI: 10.1016/j.ekir.2021.12.037.].