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.

A nationwide survey on clinical practice patterns and bleeding complications of percutaneous native kidney biopsy in Japan.

BACKGROUND: Practice patterns and bleeding complications of percutaneous native kidney biopsy (PNKB) have not recently been investigated and the Japanese Society of Nephrology performed a nationwide questionnaire survey in 2018. METHODS: The survey consisted of nine sections about PNKB: (1) general indications; (2) indications for high-risk patients; (3) informed consent; (4) pre-biopsy evaluation; (5) procedures; (6) sedation; (7) post-biopsy hemostasis, bed rest, and examinations; (8) bleeding complications; and (9) specimen processing. A supplementary survey examined bleeding requiring transcatheter arterial embolization (TAE). RESULTS: Overall, 220 directors of facilities (nephrology facility [NF], 168; pediatric nephrology facility [PF], 52) completed the survey. Indications, procedures, and monitoring protocols varied across facilities. Median lengths of hospital stay were 5 days in NFs and 6 days in PFs. Gauge 14, 16, 18 needles were used in 5%, 56%, 33% in NFs and 0%, 63%, 64% in PFs. Mean limits of needle passes were 5 in NFs and 4 in PFs. The bed rest period was 16-24 h in 60% of NFs and 65% of PFs. Based on 17,342 PNKBs, incidence rates of macroscopic hematuria, erythrocyte transfusion, and TAE were 3.1% (NF, 2.8%; PF, 6.2%), 0.7% (NF, 0.8%; PF, 0%), and 0.2% (NF, 0.2%; PF, 0.06%), respectively. Forty-six percent of facilities processed specimens all for light microscopy, immunofluorescence, and electron microscopy, and 21% processed for light microscopy only. Timing of bleeding requiring TAE varied among PNKB cases. CONCLUSION: Wide variations in practice patterns of PNKB existed among facilities, while PNKBs were performed as safely as previously reported.

Correction to: A nationwide survey on clinical practice patterns and bleeding complications of percutaneous native kidney biopsy in Japan.

In the original publication, some errors have been found in the alignment of Table 9. The corrected table is given below.

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.

The efficacy of exercise training in kidney transplant recipients: a meta-analysis and systematic review.

BACKGROUND: The effectiveness of exercise in kidney transplant recipients is not well established. We, therefore, performed a systematic review of the effects of exercise training in kidney transplantation recipients. METHODS: We searched two electronic databases for articles up to April 2017. Inclusion criteria were as follows: randomized controlled trial and kidney transplant recipients aged 18 years or older. The main outcomes were allograft function (estimated glomerular filtration rate, eGFR), exercise tolerance (VO2 peak), and quality of life (QOL). RESULTS: After screening of 1303 references in PubMed and Ichushi, six randomized control trials were analyzed. For kidney transplant recipients, supervised exercise training was shown to significantly improve VO2 peak [mean difference 2.42; 95% confidence interval (95%CI) 0.22-4.63] and QOL (mean difference 7.23; 95%CI 0.94-13.52). However, exercise training did not improve allograft kidney function (mean difference 6.22; 95%CI - 13.00 to 25.44). No reporting bias was observed in any of the outcomes. There were no reports including patient survival rates and the harm associated with exercise training. CONCLUSIONS: Exercise training for kidney transplant recipients significantly improved exercise tolerability and QOL, but a significant improvement was not obtained with respect to allograft kidney function. Evaluation of patient survival rates and the harm associated with exercise training has not been reported, therefore, future studies are needed to resolve these issues.

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.

Associations of frequency and duration of patient-doctor contact in hemodialysis facilities with mortality.

It is unknown whether regular patient-doctor contact (PDC) contributes to better outcomes for patients undergoing hemodialysis. Here, we analyzed the associations between frequency and duration of PDC during hemodialysis treatments with clinical outcomes among 24,498 patients from 778 facilities in the international Dialysis Outcomes and Practice Patterns Study (DOPPS). The typical facility PDC frequency, estimated by facility personnel, was high (more than once per week) for 55% of facilities, intermediate (once per week) for 24%, and low (less than once per week) for 21%. The mean ± SD estimated duration of a typical interaction between patient and physician was 7.7 ± 5.6 minutes. PDC frequency and duration varied across DOPPS phases and countries; the proportion of facilities with high PDC frequency was 17% in the United States and 73% across the other countries. Compared with high PDC frequency, the adjusted hazard ratio (HR) for all-cause mortality was 1.06 (95% confidence interval [CI], 0.96 to 1.17) for intermediate PDC frequency and 1.11 (95% CI, 1.01 to 1.23) for low PDC frequency (P=0.03 for trend). Furthermore, each 5-minutes-shorter duration of PDC was associated with a 5% higher risk for death, on average (HR, 1.05; 95% CI, 1.01 to 1.09), adjusted for PDC frequency and other covariates. Multivariable analyses also suggested modest inverse associations between both PDC frequency and duration with hospitalization but not with kidney transplantation. Taken together, these results suggest that policies supporting more frequent and longer duration of PDC may improve patient outcomes in hemodialysis.

Interpersonal psychosocial factors associated with underreported dietary energy intake in hemodialysis patients.

OBJECTIVE: To examine the association between degree of underreporting energy intake and psychosocial (including interpersonal and personal) factors among hemodialysis patients in Japan. DESIGN: We conducted a cross-sectional study. Predictors of difference were identified using multiple linear regression analysis. SETTING: Study was conducted at a public hospital and a dialysis clinic in a single district in northeast Honshu, Japan. SUBJECTS: Participants were hemodialysis outpatients. Patients aged more than 20 years and undergoing treatment for end-stage renal disease for at least 6 months were included. Exclusion criteria were diagnosis of depression, a mental disease, or dementia. MAIN OUTCOME: The outcome measure was the difference in reported energy intake defined by the differences between a brief administered dietary history questionnaire and diet record stratified by standardized weight. RESULTS: Seventy patients undergoing hemodialysis participated (44 men [62.9%] and 26 women [37.1%]). Of these, 54.3% underreported energy intake (by >10%). Sex (male) and employment status (employed) were statistically associated with energy intake underreporting. A lower score of dialysis staff encouragement was associated with greater energy intake underreporting (ß coefficient = 3.89 kcal/standardized weight, 95% confidence interval: 0.89 to 6.90; P = .012). CONCLUSION: Degree of underreporting energy intake is significantly associated with interpersonal psychosocial factors among hemodialysis patients in Japan. The interpersonal relationship with encouragement by the dialysis staff is important in improving the accuracy of reporting energy intake among dialysis patients.

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.

Peculiar renal endarteritis in a patient with acute endocapillary proliferative glomerulonephritis.

Acute glomerulonephritis (AGN) is one of the most common renal diseases. They are often associated with infections and can result in diffuse proliferative glomerulonephritis (GN). This case report reviews an interesting case in which renal endarteritis coexisted in AGN with diffuse endocapillary proliferation. The discussion highlights important pathological findings and clinical aspects in acute endocapillary proliferative GN with renal endarteritis. Coexisting endarteritis should be in the differential diagnosis of AGN in patients with persistent clinical courses.

Predicting the outcome of chronic kidney disease by the estimated nephron number: the rationale and design of PRONEP, a prospective, multicenter, observational cohort study.

BACKGROUND: The nephron number is thought to be associated with the outcome of chronic kidney disease (CKD). If the nephron number can be estimated in the clinical setting, it could become a strong tool to predict renal outcome. This study was designed to estimate the nephron number in CKD patients and to establish a method to predict the outcome by using the estimated nephron number. METHODS/DESIGN: The hypothesis of this study is that the estimated nephron number can predict the outcome of a CKD patient. This will be a multicenter, prospective (minimum 3 and maximum 5 years follow-up) study. The subjects will comprise CKD patients aged over 14 years who have undergone a kidney biopsy. From January 2011 to March 2013, we will recruit 600 CKD patients from 10 hospitals belonging to the National Hospital Organization of Japan. The primary parameter for assessment is the composite of total mortality, renal death, cerebro-cardiovascular events, and a 50% reduction in the eGFR. The secondary parameter is the rate of eGFR decline per year. The nephron number will be estimated by the glomerular density in biopsy specimens and the renal cortex volume. This study includes one sub-cohort study to establish the equation to calculate the renal cortex volume. Enrollment will be performed at the time of the kidney biopsy, and the data will consist of a medical interview, ultrasound for measurement of the kidney size, blood or urine test, and the pathological findings of the kidney biopsy. Patients will continue to have medical consultations and receive examinations and/or treatment as usual. The data from the patients will be collected once a year after the kidney biopsy until March 2016. All data using this study are easily obtained in routine clinical practice. DISCUSSION: This study includes the first trials to estimate the renal cortex volume and nephron number in the general clinical setting. Furthermore, this is the first prospective study to examine whether the nephron number predicts the outcome of CKD patients. The results from this study should provide powerful new tools for nephrologists in routine clinical practice. TRIAL REGISTRATION: UMIN-Clinical Trial Registration, UMIN000004784.

Is arteriolar vacuolization a predictor of calcineurin inhibitor nephrotoxicity?

Calcineurin inhibitors (CNI) have been commonly used as pivotal immunosuppressive agents to renal transplant recipients and have contributed significantly to improving short-term allograft survival. However, long-term administration of CNI may cause an adverse effect on kidney function, known as chronic nephrotoxicity. Chronic CNI nephrotoxicity (CNI-NT) shows characteristic histopathological findings that involve arteriolar hyalinosis. Recently, the term alternative arteriolar hyalinosis (aah) is used to discriminate CNI-specific arteriolar hyaline deposition from non-specific arteriolar hyalinosis. We studied whether arteriolar vacuolization represents an early lesion of aah as a predictor of CNI-NT. We retrospectively studied the 79 patients under treatment with a CNI immunosuppressant, who underwent living-related renal transplantation (RTx) from January 2007 to March 2009. We examined serial protocol graft biopsies at one h, one, six, and 12 months after RTx. We classified histological findings into two groups on the basis of aah lesion (with or without aah) in serial biopsies for 12 months. Arteriolar vacuolization was more frequently observed in the aah group than in the non-aah group with a significant difference. Arteriolar vacuolization was found even in the one-h biopsy specimens, indicating a non-specific histopathological finding. But in the aah group, arteriolar vacuolization tended to be more frequently observed later on. Aah can be a predictor of CNI-NT.

C-reactive protein and mortality in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: We examined associations of C-reactive protein (CRP) levels with mortality in Japanese hemodialysis patients and trends in prevalence of CRP measurement at hemodialysis facilities internationally. To assess whether measurement of CRP may influence outcomes, we examined associations of facility prevalence of CRP measurement with mortality. METHODS: CRP measurements were from a cross-section of patients in the international Dialysis Outcomes and Practice Patterns Study (n = 610 facilities, 16,355 patients). Cox proportional hazards models assessed associations of mortality with CRP in Japan, and with a facility's frequency of measuring CRP internationally, (except in the USA and Canada). RESULTS: From 2002-2004, CRP was measured in 0-19% of patients in each country, except Japan (55%). From 2005-2007, CRP was measured in ≥ 50% of country patients except in Canada (15%) and the USA (2%). After multivariable adjustment, the hazard ratio (HR) of death was 1.6- to 2.4-fold higher (p < 0.05) for various categories of CRP levels >3 mg/l (vs. <1.0 mg/l). Cardiovascular mortality risk was lower in facilities measuring CRP for ≥ 50% of patients (HR = 0.72, p = 0.01) in multivariable-adjusted analyses. CONCLUSIONS: CRP is informative regarding mortality risk beyond that provided by other inflammatory and nutritional markers, with significantly higher risk seen at CRP >3 mg/l. Greater use of CRP may lead to improved patient care as suggested by the association of greater CRP measurement with lower cardiovascular mortality.

Association of kidney transplantation with mortality on hemodialysis after graft failure.

BACKGROUND: Although a substantial number of patients return to dialysis after kidney transplant failure, it remains controversial whether transplant-failure patients have a higher mortality risk than transplant-naïve patients on dialysis who have never undergone kidney transplantation. We compared outcomes of transplant-failure and transplant-naïve patients on hemodialysis. METHODS: Data from the Japanese National Dialysis Registry (2012-2013) were analyzed, including 220,438 prevalent hemodialysis patients. Multivariable Cox models were used to compare all-cause, cardiovascular, and infection-related mortality during 1-year follow-up between transplant-failure and transplant-naïve patients. Multiple imputation and propensity score matching were utilized as sensitivity analyses. RESULTS: During 209,377 patient-years of follow-up, 18,648 all-cause deaths (8.5% of all patients), 7700 cardiovascular deaths (41% of all-cause deaths), and 3806 infection-related deaths (20% of all-cause deaths) were observed. Adjusted hazard ratios [95% confidence intervals] for all-cause, cardiovascular, and infection-related deaths among transplant-failure patients were 0.81 [0.59-1.11], 0.54 [0.30-0.98], and 1.54 [0.92-2.59], respectively. Sensitivity analyses using multiple imputation and propensity score matching yielded similar results. CONCLUSIONS: This Japanese cohort study suggested that a cardiovascular mortality risk of transplant-failure patients could be significantly lower than that of transplant-naïve patients, while there might be a trend toward a higher infection-related mortality risk in transplant-failure patients. However, this retrospective, single-country study can introduce an immortal time bias in transplant-failure patients, and limit the external validity. Further prospective studies are warranted to improve the comparability of outcomes between transplant-failure and transplant-naïve patients, and to examine worldwide the generalizability of the potential cardiovascular benefit of kidney transplantation even after returning to dialysis.

Clinical manifestations of focal segmental glomerulosclerosis in Japan from the Japan Renal Biopsy Registry: age stratification and comparison with minimal change disease.

Focal segmental glomerulosclerosis (FSGS) is a serious condition leading to kidney failure. We aimed to investigate the clinical characteristics of FSGS and its differences compared with minimal change disease (MCD) using cross-sectional data from the Japan Renal Biopsy Registry. In Analysis 1, primary FSGS (n = 996) were stratified by age into three groups: pediatric (< 18 years), adult (18-64 years), and elderly (≥ 65 years), and clinical characteristics were compared. Clinical diagnosis of nephrotic syndrome (NS) was given to 73.5% (97/132) of the pediatric, 41.2% (256/622) of the adult, and 65.7% (159/242) of the elderly group. In Analysis 2, primary FSGS (n = 306) and MCD (n = 1303) whose clinical diagnosis was nephrotic syndrome (NS) and laboratory data were consistent with NS, were enrolled. Logistic regression analysis was conducted to elucidate the variables which can distinguish FSGS from MCD. On multivariable analysis, higher systolic blood pressure, higher serum albumin, lower eGFR, and presence of hematuria associated with FSGS. In Japanese nationwide registry, primary FSGS patients aged 18-64 years showed lower rate of NS than those in other ages. Among primary nephrotic cases, FSGS showed distinct clinical features from MCD.

A case report of recurrence of mixed cryoglobulinemic glomerulonephritis in a renal transplant recipient.

Recurrence of glomerulonephritis (GN) is one of the major risk factors of long-surviving renal graft dysfunction. Cryoglobulinemic glomerulonephritis of hepatitis-C virus (HCV)-negative patient is a rare cause of end-stage renal disease. There is little case report of recurrent cryoglobulinemic glomerulonephritis in negative HCV recipients after renal transplantation. We represent a renal allograft recipient of an interesting recurrent cryoglobulinemic glomerulonephritis. The patient was diagnosed with mixed cryoglobulinemic glomerulonephritis by kidney biopsy at the age of 32 . He had no HCV, HBV nor liver dysfunction. He received immunosuppressive therapy, however, was introduced to hemodialysis treatment after 13 yr. He received a cadaveric renal transplantation at the age of 50, and immunosuppressive treatment was started with ciclosporin, prednisolone and mycophenolate mofetil (MMF). Four yr after transplantation, he developed fever and purpura of lower limbs. His serum creatinine level did not increase, however, proteinuria, hematuria, hypocomplementemia, positive rheumatoid factor and mixed cryoglobulinemia were noted. Detailed analysis failed to reveal the composition of mixed cryoglobulinemia. The renal allograft biopsy showed membranoproliferative-type GN with monocyte and polynuclear leukocyte accumulation of capillary loops and small cellular crescent. Immunofluorescent study showed C3, IgG and IgM deposition of mesangial and capillary pattern. Regardless of steroid pulse therapy, hypocomplementemia and positive rheumatoid factor did not improve. Ten yr after transplantation, he was affected by cellulitis and sepsis. Afterward, rising of serum creatinine and nephrotic range proteinuria developed. The allograft biopsy revealed advanced cryoglobulinemic glomerulonephritis with characteristic vascular lesions. Electron microscopy showed organized subendothelial deposits compatible with cryoglobulinemic glomerulonephritis and proteinaceous thrombus in arteriole.

Clinical effectiveness of steroid pulse therapy combined with tonsillectomy in patients with immunoglobulin A nephropathy presenting glomerular haematuria and minimal proteinuria.

AIM: The effectiveness of steroid pulse therapy combined with tonsillectomy (ST) has been shown in immunoglobulin A nephropathy (IgAN) patients with moderate or severe urinary abnormalities. The present study aimed to clarify whether the effectiveness may be extrapolated to IgAN with minor urinary abnormalities, and whether the effectiveness may depend on the histological severity with minor urinary abnormalities. METHODS: Data on 388 IgAN patients diagnosed by renal biopsies between 1987 and 2000 in Sendai Shakaihoken Hospital, who presented glomerular haematuria and minimal proteinuria (