The effect of the Kasuya CKD network on prevention of the progression of chronic kidney disease: successful collaboration of a public health service, primary care physicians and nephrologists-community based cohort study.

BACKGROUND: In 2012, we established a CKD network in collaboration with the public health service, primary care physicians, and nephrologists in the Kasuya area. The aim of this study was to clarify if our CKD network was effective in preventing CKD progression. METHODS: 1591 subjects, who had CKD in health checks in 2012 were included in this study. The slope of estimated glomerular filtration rate (eGFR) was compared before and after 2012. Parameters at the first health check visit before 2012, visit in 2012, and the last visit after 2012, were compared. Paired t test, analysis of variance for repeated measurements, and the Friedman test were used for the analysis. RESULTS: Mean age was 65 years. There were 781 men and 810 women. Mean eGFR was 59 ml/min/1.73 m2. The mean slope of eGFR before 2012 was -1.833 ml/min/1.73 m2/year and significantly reduced to - 0.297 after 2012. Low-density lipoprotein cholesterol showed a significant serial lowering. Uric acid was significantly elevated in 2012 compared to the first visit and had decreased by the last. The dipstick urinary protein significantly increased in 2012 compared to the first visit and decreased by the last. The number of current smokers showed a significant reduction over time. On the other hand, systolic blood pressure (SBP) and HbA1c significantly elevated at the last visit. CONCLUSION: The Kasuya CKD network may be effective in preventing CKD progression.

Risk factor for progression to kidney failure with replacement therapy in elderly patients with chronic kidney disease: A retrospective single-centre cohort study.

BACKGROUND: Although the number of elderly patients with chronic kidney disease (CKD) has increased, few studies have examined their prognosis. METHODS: The study design was a retrospective cohort study at a single centre. We evaluated 301 patients aged ≥75 years old with CKD stage G3a to G5. The primary endpoint was kidney failure with replacement therapy (KFRT) and secondary endpoints were all-cause mortality and annual decline rates of estimated glomerular filtration rate (eGFR). The incidence of KFRT was estimated using the cumulative incidence method considering the competing risk of death. To identify the independent risk factors related to KFRT, multivariate Fine-Gray regression model analysis were performed. RESULTS: The median age of the patients was 79 years and the median eGFR was 24.0 mL/min/1.73 m2 at baseline. Urinary protein was positive in 70% of patients. With a median follow-up of 24.5 months, 35% of the patients developed KFRT and 9% died. Kidney survival significantly decreased according to the CKD stage at baseline. In patients without proteinuria, the cumulative incidence of KFRT increased in CKD stage G5 patients, while in patients with proteinuria, the incidence of KFRT increased from patients with CKD stage G3b. Multivariate Fine-Gray regression model revealed that less aged, CKD stage G5, baseline data such as proteinuria, hypoalbuminemia, hyperphosphatemia, and hyperuricemia were independent risk factors for KFRT. CONCLUSION: Elderly CKD patients with proteinuria need to be carefully monitored even at an early CKD stage because of the risk of developing KFRT.

A case of acute kidney injury due to native kidney BK polyomavirus-associated nephropathy in a human T-lymphotropic virus type 1 carrier.

BACKGROUND: BK polyomavirus-associated nephropathy (BKPyVAN) has become a major cause of kidney dysfunction and graft loss in kidney transplant recipients. On rare occasion, polyomavirus has also been known to affect native kidneys of immunocompromised individuals. Only a small number of opportunistic infections have been reported in the carrier phase of human T-lymphotropic virus type 1 (HTLV-1). This is the first reported case of BKPyVAN in native kidneys of an HTLV-1 carrier. CASE PRESENTATION: A 61-year-old man was referred to our hospital from a primary care physician for work-up and treatment of pneumonia. He was diagnosed with Pneumocystis pneumonia and identified as a HTLV-1 carrier who had not yet developed adult T-cell leukemia (ATL). The pneumonia was successfully treated with sulfamethoxazole-trimethoprim. He had never been diagnosed with any kind of kidney dysfunction. Laboratory investigations showed a serum creatinine of 5.3 mg/dL, and urinary sediment showed cells with nuclear enlargement and inclusion bodies suggesting viral infection. The urinary Papanicolaou stain showed inclusions in swollen, ground-glass nuclei, typical of "decoy cells". Renal biopsy showed degeneration of tubules with epithelial enlargement, vacuolar degeneration, nuclear inclusion bodies, and detachment from the tubular basement membrane. Tubular nuclei showed positive staining positive for simian virus 40 large-T antigen. Polymerase chain reaction tests for BK polyomavirus DNA of both urine and plasma were positive. These findings confirmed a diagnosis of BKPyVAN. Intravenous immunoglobulin therapy did not improve renal function, necessitating maintenance hemodialysis therapy. CONCLUSIONS: BKPyVAN should be considered when acute kidney injury occurs with opportunistic infection. HTLV-1 carriers can develop opportunistic infections even before the onset of ATL.

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.

Deep learning analysis of clinical course of primary nephrotic syndrome: Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: Prognosis of nephrotic syndrome has been evaluated based on pathological diagnosis, whereas its clinical course is monitored using objective items and the treatment strategy is largely the same. We examined whether the entire natural history of nephrotic syndrome could be evaluated using objective common clinical items. METHODS: Machine learning clustering was performed on 205 cases from the Japan Nephrotic Syndrome Cohort Study, whose clinical parameters, serum creatinine, serum albumin, dipstick hematuria, and proteinuria were traceable after kidney biopsy at 5 measured points up to 2 years. The clinical patterns of time-series data were learned using long short-term memory (LSTM)-encoder-decoder architecture, an unsupervised machine learning classifier. Clinical clusters were defined as Gaussian mixture distributions in a two-dimensional scatter plot based on the highest log-likelihood. RESULTS: Time-series data of nephrotic syndrome were classified into four clusters. Patients in the fourth cluster showed the increase in serum creatinine in the later part of the follow-up period. Patients in both the third and fourth clusters were initially high in both hematuria and proteinuria, whereas a lack of decline in the urinary protein level preceded the worsening of kidney function in fourth cluster. The original diseases of fourth cluster included all the disease studied in this cohort. CONCLUSIONS: Four kinds of clinical courses were identified in nephrotic syndrome. This classified clinical course may help objectively grasp the actual condition or treatment resistance of individual patients with nephrotic syndrome.

Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy.

BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). RESULTS: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. CONCLUSIONS: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.

Updating the International IgA Nephropathy Prediction Tool for use in children.

Although IgA nephropathy (IgAN) is a common cause of glomerulonephritis in children, the absence of a method to predict disease progression limits personalized risk-based treatment decisions. The adult International IgAN Prediction Tool comprises two validated Cox survival models that predict a 50% decline in estimated glomerular filtration rate (eGFR) or end stage kidney disease (ESKD) using clinical risk factors and Oxford MEST histology scores. Here, we updated the Prediction Tool for use in children using a multiethnic international cohort of 1,060 children with IgAN followed into adulthood. The updated pediatric Prediction Tool had better model fit than the original adult tool with lower Akaike Information Criterion, higher R2D and similar C-statistics. However, calibration showed very poor agreement between predicted and observed risks likely due to the observed disease trajectory in children. Therefore, the Tool was updated using a secondary outcome of a 30% reduction in eGFR or ESKD, resulting in better R2D (30.3%/22.2%) and similar C-statistics (0.74/0.68) compared to the adult tool but with good calibration. The trajectory of eGFR over time in children differed from adults being highly non-linear with an increase until 18 years old followed by a linear decline similar to that of adults. A higher predicted risk was associated with a smaller increase in eGFR followed by a more rapid decline, suggesting that children at risk of a 30% decrease in eGFR will eventually experience a larger 50% decrease in eGFR when followed into adulthood. As such, these two outcomes are analogous between pediatric and adult Prediction Tools. Thus, our pediatric Prediction Tool can accurately predict the risk of a 30% decline in eGFR or ESKD in children with IgAN.

Clinicopathological significance of light chain deposition in IgA nephropathy.

BACKGROUND: Clinicopathological significance of light chain deposition in IgA nephropathy and the relation of monotypic IgA deposition to bone marrow abnormalities are important issues to be clarified. METHODS: We retrospectively investigated light chain deposition in 526 patients with IgA nephropathy. We divided the patients into 5 groups according to the balance of intensity of both light chain deposition: lambda monotypic, lambda dominant, polytypic, kappa dominant and kappa monotypic. Clinicopathological parameters were compared among the groups. The relation of monotypic IgA deposition to hematological malignancy was also evaluated. RESULTS: The prevalence of monotypic IgA deposition was 6.3%, 33 patients (21 lambda and 12 kappa). Thirty-two (4.0%) and 10 patients (1.9%) were classified into lambda and kappa dominant groups, respectively. Polytypic IgA deposition was observed in 455 patients (85.7%). Age of onset, age at biopsy, urinary protein creatinine ratio, the percentage of global glomerulosclerosis, and the degree of IgA and C3 deposition were different among the groups. However, there was no gradual difference according to the groups. No patient with monotypic IgA deposition showed hematological abnormality at biopsy and during follow-up. CONCLUSIONS: The prevalence of IgA monotypic deposition was extremely low. Clinicopathologically, we could not differentiate patients with monotypic IgA deposition from those with polytypic one and no hematological disorder was documented in patients with monotypic IgA deposition. Whether IgA nephropathy with monotypic IgA deposition and that with polytypic one is the same entity or not, and relation between monotypic IgA deposition and hematological malignancy should be clarified by further investigations.

A cross-sectional study in patients with IgA nephropathy of correlations between clinical data and pathological findings at the time of renal biopsy: a Japanese prospective cohort study.

BACKGROUND: The correlations between clinical data and pathological findings at the time of renal biopsy were investigated in IgA nephropathy patients. METHODS: 771 patients diagnosed with IgA nephropathy by renal biopsy were enrolled. The correlations between clinical variables including eGFR, daily proteinuria, mean arterial pressure (MAP), serum uric acid (UA) values, and pathological parameters were examined. These patients were further divided into three groups: children (< 19 years old), young adults (19-60 years), and elderly patients (> 60 years). RESULTS: Daily proteinuria was moderately correlated with all pathological parameters (Rs = 0.23-0.49). The mesangial score, the percentage of glomeruli that contained endocapillary hypercellularity, cellular/fibrocellular crescents or tuft necrosis, and segmental glomerulosclerosis (GS) affected daily proteinuria most on multiple linear regression analysis (MLRA). eGFR, MAP, and serum UA levels were mainly correlated with the degree of GS and interstitial lesions. In children, the degree of cellular/fibrocellular crescents or tuft necrosis was correlated with not only daily proteinuria, but also decreased eGFR (Rs = 0.51, - 0.24). Endocapillary hypercellularity was the only independent variable related to daily proteinuria on MLRA. CONCLUSION: In all age cohorts of IgA nephropathy patients, daily proteinuria was correlated with all histological parameters, including both acute and chronic glomerular lesions, and the mesangial score. Independent variables for daily proteinuria were the meangial score, acute histological lesions, and segmental GS on MLRA, whereas the remaining independent variable in the pediatric group was endocapillary hypercellurality. The clinical pathological correlation at the time of biopsy varied depending on the age group.

Improving treatment decisions using personalized risk assessment from the International IgA Nephropathy Prediction Tool.

Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria of 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria of 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

Utility of Columbia classification in focal segmental glomerulosclerosis: renal prognosis and treatment response among the pathological variants.

BACKGROUND: The utility of the Columbia classification (Col-class) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven. METHODS: We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class. RESULTS: The patients were classified into the following variants: not otherwise specified [NOS; n = 121 (60.1%)], perihilar [n = 31 (15.4%)], cellular [n = 19 (9.5%)], tip [n = 17 (8.5%)] and collapsing [n = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P = 0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P = 0.539). CONCLUSIONS: The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested.

Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. METHODS: A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. RESULTS: Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. CONCLUSIONS: Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.

Better remission rates in elderly Japanese patients with primary membranous nephropathy in nationwide real-world practice: The Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: The aim of the present study was to clarify the prevalence of immunosuppressive drug use and outcomes in elderly and non-elderly patients with primary membranous nephropathy (MN) in nationwide real-world practice in Japan. PATIENTS AND METHODS: Between 2009 and 2010, 374 patients with primary nephrotic syndrome were enrolled in the cohort study (The Japan Nephrotic Syndrome Cohort Study, JNSCS), including 126 adult patients with MN. Their clinical characteristics were compared with those of nephrotic patients with primary MN registered in a large nationwide registry (The Japan Renal Biopsy Registry, J-RBR). Outcomes and predictors in the elderly (≥ 65 years) and non-elderly groups were identified. RESULTS: Similar clinical characteristics were observed in JNSCS patients and J-RBR patients (n = 1808). At the early stage of 1 month, 84.1% of patients were treated with immunosuppressive therapies. No significant differences were observed in therapies between age groups. However, elderly patients achieved complete remission (CR) more frequently than non-elderly patients, particularly those treated with therapies that included corticosteroids. No significant differences were noted in serum creatinine (sCr) elevations at 50 or 100%, end-stage kidney disease, or all-cause mortality between age groups. Corticosteroids were identified as an independent predictor of CR (HR 2.749, 95%CI 1.593-4.745, p = 0.000) in the multivariate Cox's model. sCr levels, hemoglobin levels, immunosuppressants, clinical remission, and relapse after CR were independent predictors of sCr × 1.5 or × 2.0. CONCLUSION: Early immunosuppressive therapy including corticosteroids for primary MN showed better remission rates in elderly patients in a nationwide cohort study.

Late renal recovery after treatment over 1 year post-onset in an atypical hemolytic uremic syndrome: a case report.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease that leads to end-stage kidney disease if only a poor response to plasma exchanges (PEs) or eculizumab therapy is achieved. CASE PRESENTATION: A 58-year-old Japanese man presented with thrombocytopenia, anemia, and kidney failure requiring dialysis without any underlying disease. A kidney biopsy revealed marked mesangiolysis in all glomeruli, compatible with thrombotic microangiopathy (TMA). Based on the positive anti- factor H antibody and negative result for secondary TMA, we diagnosed him as aHUS. Despite eculizumab administration after eight sessions of PE, neither platelet normalization nor kidney recovery was achieved. Eight months later, we discontinued eculizumab therapy due to anaphylactic reaction. At 15 months after the onset of TMA, his platelet count increased gradually from 40 to 150 × 103/µL with a decreased serum creatinine level and increased urine output, eventually allowing the withdrawal of dialysis therapy. A second kidney biopsy showed mesangial widening compatible with the healing of TMA. CONCLUSIONS: This case indicates that aHUS with PEs and eculizumab therapy has the potential for renal recovery even if over 1 year has passed.

Comprehensive evaluation of the significance of immunofluorescent findings on clinicopathological features in IgA nephropathy.

BACKGROUND: The clinicopathological significance of immunofluorescent findings in IgA nephropathy remains controversial. METHODS: The relations of the deposition of IgA, IgG, IgM, C3, C1q and fibrinogen (Fib) with pathological findings, baseline clinical findings, and renal outcome were evaluated in 688 patients with IgA nephropathy. Pathological features included cellular or fibrocellular crescents, endocapillary or mesangial hypercellularity, segmental or global glomerulosclerosis and the Oxford classification. RESULTS: The median age at biopsy was 30 years. There were 289 men. With 74 months median follow-up, 32% of patients received steroids. Twelve percent of patients developed end-stage renal disease (ESRD). The degree of IgA was closely related to the degree of C3, IgG and IgM deposition. The degree of IgA, C3, IgG and Fib deposition was significantly related to the percentage of glomeruli with crescent, endocapillary and mesangial hypercellularity. IgM deposition showed significant association with crescent, mesangial hypercellularity, segmental sclerosis, global glomerulosclerosis and tubular atrophy/interstitial fibrosis. In the patients treated with steroids, the risk for ESRD in patients with 2-3+ IgA deposition was significantly lower with reference of 1+ IgA deposition. CONCLUSION: We found the different roles of glomerular immune reactants' deposition in the inflammatory process from acute to chronic stage. IgA deposition together with IgG, Fib and C3 may produce acute inflammatory injury. IgM deposition might occur in the early stage of inflammation and remains until late sclerotic stage. The prominent deposition of IgA related to low risk for ESRD in patients who received steroids might suggest effectiveness of steroids in such patients.

A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.

Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

Secular trends in the incidence of end-stage renal disease and its risk factors in Japanese patients with immunoglobulin A nephropathy.

Background: There are limited data on secular trends in the incidence of end-stage renal disease (ESRD) and frequencies of its risk factors or treatment modalities in patients with immunoglobulin A nephropathy (IgAN). Methods: This study divided 1255 patients with IgAN into three groups according to the timing of renal biopsy: 1979-89 (n = 232), 1990-99 (n = 574) and 2000-10 (n = 449). The age-adjusted incidence rates, incidence rate ratios and 95% confidence intervals (CIs) for ESRD were calculated by the person-year method and compared using Poisson regression analysis. Results: A total of 63 patients (5.0%) developed ESRD. The age-adjusted incidence of ESRD decreased significantly over time, i.e. 11.5 per 1000 person-years (95% CI 5.4-24.6) in 1979-89, 6.5 per 1000 person-years (95% CI 1.0-25.2) in 1990-99 and 4.2 per 1000 person-years (95% CI 1.0-17.7) in 2000-10. The proportions of patients with preserved renal function and acute-stage inflammatory histologic changes (i.e. endocapillary hypercellularity and extracapillary proliferation) at the timing of biopsy increased over time, as did the rates of prescriptions of renin-angiotensin system blockers and corticosteroids (all P for trend <0.05). The effect of acute inflammatory histologic lesions on renal prognosis was drastically reduced over time. Conclusions: These findings suggest that early diagnosis in the acute inflammatory phase and subsequent aggressive treatment may have contributed to the significant downward trend in the incidence of ESRD in patients with IgAN over three decades.

Regional variations in immunosuppressive therapy in patients with primary nephrotic syndrome: the Japan nephrotic syndrome cohort study.

BACKGROUND: The lack of high-quality clinical evidences hindered broad consensus on optimal therapies for primary nephrotic syndromes. The aim of the present study was to compare prevalence of immunosuppressive drug use in patients with primary nephrotic syndrome across 6 regions in Japan. METHODS: Between 2009 and 2010, 380 patients with primary nephrotic syndrome in 56 hospitals were enrolled in a prospective cohort study [Japan Nephrotic Syndrome Cohort Study (JNSCS)], including 141, 151, and 38 adult patients with minimal change disease (MCD), membranous nephropathy (MN), and focal segmental glomerulosclerosis (FSGS), respectively. Their clinical characteristics were compared with those of patients registered in a large nationwide registry of kidney biopsies [Japan Renal Biopsy Registry (J-RBR)]. The regional prevalence of use of each immunosuppressive drug was assessed among adult MCD, MN, and FSGS patients who underwent immunosuppressive therapy in the JNSCS (n = 139, 127, and 34, respectively). Predictors of its use were identified using multivariable-adjusted logistic regression models. RESULTS: The clinical characteristics of JNSCS patients were comparable to those of J-RBR patients, suggesting that the JNSCS included the representatives in the J-RBR. The secondary major immunosuppressive drugs were intravenous methylprednisolone [n = 33 (24.6%), 24 (19.7%), and 9 (28.1%) in MCD, MN, and FSGS, respectively] and cyclosporine [n = 25 (18.7%), 62 (50.8%), and 16 (50.0%), respectively]. The region was identified as a significant predictor of use of intravenous methylprednisolone in MCD and MN patients. CONCLUSION: Use of intravenous methylprednisolone for MCD and MN differed geographically in Japan. Its efficacy should be further evaluated in a well-designed trial.

A Multicenter Study of the Predictive Value of Crescents in IgA Nephropathy.

The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean±SD eGFR of 78±29 ml/min per 1.73 m2 and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in one fourth or more of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.

Reproducibility for pathological prognostic parameters of the Oxford classification of IgA nephropathy: a Japanese cohort study of the Ministry of Health, Labor and Welfare.

BACKGROUND/AIMS: The Oxford classification of IgA nephropathy (IgAN) was proposed by international working group in 2009. Interobserver reproducibility of each pathological definition was already evaluated, but that of four pathological prognostic parameters score has not yet been assessed. We first assess the reproducibility of each pathological definition in Japanese patients. Our study is aimed to assess that of four pathological prognostic parameters score among the five Japanese pathologists. METHODS: The renal specimens from 411 Japanese patients, aged 3-85 years, with biopsied proven primary IgAN were collected from 50 facilities between 2006 and 2012. The reproducibility of pathological definitions was assessed by the intraclass correlation coefficient (ICC) and that of four pathological prognostic parameters score (mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T)) was assessed by kappa statistics. RESULTS: The ICC of M, E, S, T, global sclerosis and cellular crescents and/or fibrocellular crescents were good or moderate agreement among the five pathologists and were well agreed with results of the Oxford study. Kappa statistics was moderate agreement for M and T score assessed with the semi-quantitative method by the Oxford group, but that was poor agreement for S and E score based on a simple "present" or "absent" assessment. CONCLUSION: This is the first report to assess the reproducibility of pathological prognostic parameters score in the Oxford classification. Our study supports the utilization of the pathological lesions in routine diagnosis. The methodological assessment of pathological prognostic parameters score should be reconsidered.