Initiation of renin-angiotensin system inhibitors and first complete remission in patients with primary nephrotic syndrome: a nationwide cohort study.

BACKGROUND: Evidence on renin-angiotensin system inhibitors (RASis) effect in reducing urinary protein levels in patients with nephrotic syndrome is insufficient. We determined whether RASis can induce complete remission (CR) in patients on immunosuppressive therapy. METHODS: This cohort study included 84 adults (median age, 65 years; males, 57%) with primary nephrotic syndrome (excluding minimal change disease) not receiving RASis during enrollment in the Japanese Nephrotic Syndrome Cohort Study from January 2009 to December 2010, and were followed up for 5 years. Exposure and outcome were RASi initiation and first CR, respectively. Marginal structural models and Poisson regression were used to account for time-varying covariates and estimate causal effects of RASis on CR. RESULTS: Overall, 51 (61%), 73 (87%), and 55 (66%) patients had membranous nephropathy, were prescribed immunosuppressive agents at baseline (1-month post-renal biopsy and/or at start of immunosuppressive therapy), and were prescribed RASis during the study period, respectively. Sixty-five patients experienced first CR (incidence rate, 5.05/100 person-months). RASi use was associated with a higher (adjusted incidence rate ratio [aIRR] 2.27, 95% confidence interval [CI] 1.06-4.84), and lower (aIRR: 0.17, 95% CI 0.04-0.68) first CR in patients with membranous nephropathy and other pathologies, respectively. CONCLUSION: RASis are beneficial as adjuvant therapy for inducing remission in patients with membranous nephropathy.

Tubulointerstitial B-cell infiltration and tertiary lymphoid tissue in adult-onset immunoglobulin A vasculitis with nephritis.

PURPOSE: This study aimed to examine tubulointerstitial B-cell infiltration in patients with adult-onset immunoglobulin A vasculitis (IgAV) and nephritis (IgAV-N), and to evaluate whether B-cell infiltration correlated with clinicopathological variables at kidney biopsy and with short-term renal outcomes. METHODS: Twenty patients with adult-onset IgAV-N and 10 control patients with thin basement membrane nephropathy (TBMN) were retrospectively examined. The lymphatic organization was graded based on B-cell infiltration and was classified into 4 groups: 0-T cells without B cells, 1-scattered B and T cells, 2-clustered B and T cells, and 3-nodular compartmentally arranged B- and T-cell aggregates, equivalent to tertiary lymphoid tissue (TLT). RESULTS: The B-cell infiltration grade was significantly higher in patients with IgAV-N than in patients with TBMN, and no age differences were observed. The B-cell infiltration grade in patients with IgAV-N was significantly correlated with age, serum IgA level, renal dysfunction, and tubulointerstitial injury parameters, but was not correlated with duration after purpura or glomerular injury parameters. Most patients with IgAV-N were treated with corticosteroids. The proteinuria level was significantly decreased, but renal function was not improved in 12 patients after the 24-month follow-up compared with the values at baseline. The B-cell infiltration grade was significantly correlated with renal dysfunction after 24 months of follow-up. CONCLUSIONS: The B-cell infiltration grade in patients with IgAV-N was associated with renal dysfunction and tubulointerstitial injuries but not with glomerular injury parameters. B-cell infiltration and TLT might have a pathologically significant role in irreversible renal dysfunction in patients with early phase adult-onset IgAV-N.

Effects of febuxostat on delaying chronic kidney disease progression: a randomized trial in China.

BACKGROUND: A few studies have tested febuxostat for its usefulness in delaying chronic kidney disease (CKD) progression by treating hyperuricemia and results were controversial. Thus, we attempted to conduct a randomized controlled study using the Chinese population with advanced grade of CKD. METHODS: One hundred CKD patients in stages 3 and 4 with asymptomatic hyperuricemia from seven medical centers were included in this prospective randomized controlled study and assigned to the control and febuxostat group, the latter of which received febuxostat to titrate to achieve serum uric acid (SUA) < 6 mg/dL. The observation period was 12 months. The primary outcomes included the event of estimated glomerular filtration rate (eGFR) decline ≥ 30% or 50% from baseline at 12 months, dialysis and death from CKD; secondary outcome was the change in eGFR. Safety analysis was also performed. RESULTS: Forty-seven patients and 45 patients in the febuxostat and control groups, respectively completed the study. Seven of 47 (14.9%) participants reached 30% decline in eGFR in the febuxostat group, while 1 (2.1%) and 2 (4.3%) patients reached 50% decline in eGFR or dialysis. Thirteen (28.9%), 10 (22.2%) and 3 (6.7%) of 45 patients reached primary kidney outcomes separately in the control group. The change in eGFR after 12 months from baseline in the febuxostat group was 0.50 mL/min/1.73 m2, which was significantly higher than that in the control group - 4.46 mL/min/1.73 m2 (p = 0.006). Adverse events did not differ between two groups. CONCLUSIONS: Febuxostat effectively slowed eGFR decline in patients with CKD stages 3 and 4 and asymptomatic hyperuricemia.

Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats.

Nephrotic syndrome, characterized by proteinuria and hypoalbuminemia, results from the dysregulation of glomerular podocytes and is a significant cause of end-stage kidney disease. Patients with idiopathic nephrotic syndrome are generally treated with immunosuppressive agents; however, these agents produce various adverse effects. Previously, we reported the renoprotective effects of a stimulator of the mitochondrial ATP-dependent K+ channel (MitKATP), nicorandil, in a remnant kidney model. Nonetheless, the cellular targets of these effects remain unknown. Here, we examined the effect of nicorandil on puromycin aminonucleoside-induced nephrosis (PAN) rats, a well-established model of podocyte injury and human nephrotic syndrome. PAN was induced using a single intraperitoneal injection. Nicorandil was administered orally at 30 mg/kg/day. We found that proteinuria and hypoalbuminemia in PAN rats were significantly ameliorated following nicorandil treatment. Immunostaining and ultrastructural analysis under electron microscopy demonstrated that podocyte injury in PAN rats showed a significant partial attenuation following nicorandil treatment. Nicorandil ameliorated the increase in the oxidative stress markers nitrotyrosine and 8-hydroxy-2-deoxyguanosine in glomeruli. Conversely, nicorandil prevented the decrease in levels of the antioxidant enzyme manganese superoxide dismutase in PAN rats. We found that mitochondrial Ca2+ uniporter levels in glomeruli were higher in PAN rats than in control rats, and this increase was significantly attenuated by nicorandil. We conclude that stimulation of MitKATP by nicorandil reduces proteinuria by attenuating podocyte injury in PAN nephrosis, which restores mitochondrial antioxidative capacity, possibly through mitochondrial Ca2+ uniporter modulation. These data indicate that MitKATP may represent a novel target for podocyte injury and nephrotic syndrome.NEW & NOTEWORTHY Our findings suggest that the mitochondrial Ca2+ uniporter may be an upstream regulator of manganese superoxide dismutase and indicate a biochemical basis for the interaction between the ATP-sensitive K+ channel and Ca2+ signaling. We believe that our study makes a significant contribution to the literature because our results indicate that the ATP-sensitive K+ channel may be a potential therapeutic target for podocyte injury and nephrotic syndrome.

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.

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Introduction: Impaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients. Methods: In this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index. Results: Of the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (ß = -0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 µg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables. Conclusion: Serum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.

Predictors of early remission of proteinuria in adult patients with minimal change disease: a retrospective cohort study.

Previous studies reported conflicting results regarding an association between serum albumin concentration and the cumulative incidence of remission of proteinuria in adult patients with minimal change disease (MCD). The present study aimed to clarify the clinical impact of serum albumin concentration and the cumulative incidence of remission and relapse of proteinuria in 108 adult patients with MCD at 40 hospitals in Japan, who were enrolled in a 5-year prospective cohort study of primary nephrotic syndrome, the Japan Nephrotic Syndrome Cohort Study (JNSCS). The association between serum albumin concentration before initiation of immunosuppressive treatment (IST) and the cumulative incidence of remission and relapse were assessed using multivariable-adjusted Cox proportional hazards models. Remission defined as urinary protein < 0.3 g/day (or g/gCr) was observed in 104 (96.3%) patients. Of 97 patients with remission within 6 month of IST, 42 (43.3%) developed relapse defined as ≥ 1.0 g/day (or g/gCr) or dipstick urinary protein of ≥ 2+. Serum albumin concentration was significantly associated with remission (multivariable-adjusted hazard ratio [95% confidence interval] per 1.0 g/dL, 0.57 [0.37, 0.87]), along with eGFR (per 30 mL/min/1.73 m2: 1.43 [1.08, 1.90]), whereas they were not associated with relapse. A multivariable-adjusted model showed that patients with high eGFR level (≥ 60 mL/min/1.73 m2) and low albumin concentration (≤ 1.5 g/dL) achieved significantly early remission, whereas those with low eGFR (< 60 mL/min/1.73 m2) and high albumin concentration (> 1.5 g/dL) showed significantly slow remission. In conclusion, lower serum albumin concentration and higher eGFR were associated with earlier remission in MCD, but not with relapse.

A Patient with Acute Kidney Injury Associated with Massive Proteinuria and Acute Hyperuricemia after Epileptic Seizures.

A 25-year-old man presented with acute kidney injury (AKI), massive proteinuria and hyperuricemia after epileptic seizures. His AKI improved along with the disappearance of proteinuria after corticosteroid treatment. A kidney biopsy revealed no significant glomerular abnormalities, but varying degrees of tubular injury, such as proximal tubular simplification, mild distal tubular proliferation, and Tamm-Horsfall protein-like material accumulation with extravasation into the interstitium, were noted. A further analysis revealed the intratubular depositions of uric acid crystals, indicating the involvement of acute uric acid nephropathy associated with seizures. Our patient's condition is rare, and the clinicopathological aspects of the diagnostic challenges are discussed.

Time to remission of proteinuria and incidence of relapse in patients with steroid-sensitive minimal change disease and focal segmental glomerulosclerosis: the Japan Nephrotic Syndrome Cohort Study.

BACKGROUND: Minimal change disease (MCD) is characterized by a nephrotic syndrome usually steroid-sensitive and a high incidence of relapse of proteinuria. Previous cohort studies have reported conflicting results regarding the association between the time to remission and incidence of relapse. METHODS: This multicenter prospective cohort study included 102 adult patients with steroid-sensitive MCD or focal segmental glomerulosclerosis from a 5-year cohort study of primary nephrotic syndrome, the Japan Nephrotic Syndrome Cohort Study, who achieved remission of proteinuria within 2 months of immunosuppressive therapy (IST). The association between the time to remission of proteinuria after immunosuppressive therapy and incidence of relapse was assessed using Cox proportional hazards models adjusted for clinically relevant factors. RESULTS: Remission was observed at 3-7, 8-14, 15-21, 22-28, and 30-56 days after initiation of immunosuppressive therapy in 17 (16.7%), 37 (36.3%), 21 (20.6%), 13 (12.7%), and 14 (13.7%) patients, respectively. During a median observation period of 2.3 years after the end of the 2nd month after initiation of immunosuppressive therapy, 46 (45.1%) patients relapsed. The time to remission was associated with the incidence of relapse in an inverse U-shaped pattern (multivariable-adjusted hazard ratios [95% confidence intervals] of the time to remission of 3-7, 8-14, 15-21, 22-28, 30-56 days: 1.00 [reference], 1.76 [0.56, 5.51], 6.06 [1.85, 19.80], 5.46 [1.44, 20.64], and 2.19 [0.52, 9.30], respectively). CONCLUSION: The time to remission was identified as a significant predictor of relapse in steroid-sensitive patients.

SLC23A3 is a renal hypoxanthine transporter.

LLC-PK1 renal cells show Na+-dependent and Na+-independent hypoxanthine uptake. While the latter is inhibited by adenine, neither are inhibited by xanthine. In rats, intestinal Na+-dependent hypoxanthine transporter Slc23a4 is not expressed in the kidney, and its action is inhibited by xanthine. This study aimed to clone Slc23a4-paralog SLC23A3 from the human kidney and investigate its hypoxanthine transport activity. We observed Na+-dependent 10 nM [3H]-hypoxanthine uptake in SLC23A3 RNA-injected Xenopus oocytes. Moreover, 100 µM xanthine did not inhibit Na+-independent 300 nM [3H]-hypoxanthine uptake, whereas 100 µM adenine did. These results confirm that SLC23A3 is a hypoxanthine transporter in the human kidney.

Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-Induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice.

BACKGROUND: Hereditary renal hypouricemia type 1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced AKI (EIAKI). However, because there is no useful experimental RHUC1 animal model, the precise pathophysiologic mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI and the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). METHODS: The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. RESULTS: Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine and BUN as renal injury markers, and decreased creatinine clearance observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. CONCLUSIONS: Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1ß via NLRP3 inflammasome signaling and Na+-K+-ATPase dysfunction associated with excessive urinary urate excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2 ), and severely impaired (S) (<30 ml/min/1.73 m2 ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2 .

Hyperkalemia in patients undergoing hemodialysis: Its pathophysiology and management.

Potassium is a major intracellular cation in the body, regulating membrane potential of excitable cells, such as cardiomyocytes and skeletal muscle cells. Because the kidney plays a critical role in controlling potassium balance, the elevation in serum potassium levels is one of the most common complications in patients with maintenance hemodialysis (MHD). In addition to reduced renal potassium excretion, the alteration in body potassium distribution owing to comorbid conditions may also contribute to dyskalemia. Besides potassium elimination through hemodialysis in MHD patients, accumulating data indicate the potential importance of extra-renal elimination involving the gastrointestinal system, which can be affected by the inhibitors of the renin-angiotensin-aldosterone system. In this article, the literature on potassium physiology in MHD patients is reviewed with an emphasis on the changes from individuals with normal kidney function. This article also summarizes the findings of recent studies on dietary control, dialysate prescription, and pharmacological therapy.

A Young Patient with Microscopic Polyangiitis Requiring Hemodialysis with Complications of Repeated Episodes of Posterior Reversible Encephalopathy Syndrome Probably Due to Different Etiologies.

A young woman with microscopic polyangiitis (MPA) requiring hemodialysis showed repeated posterior reversible encephalopathy syndrome (PRES) with spatiotemporal multiple lesions over a period of two months. The first PRES episode with confusion and the second PRES episode with vertigo and nausea were caused by MPA, hypertension and renal failure. These symptoms were improved by the reinforcement of MPA treatment and blood pressure management. The third PRES episode with nausea, headache, seizure and visual changes was induced by rituximab infusion and hypertension. The PRES was improved with blood pressure and convulsant management. These conditions are challenging to diagnose and treat.

A Ruptured Jejunal Arterial Aneurysm in a Young Woman Undergoing Chronic Hemodialysis Due to Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis.

A 21-year-old woman was admitted to our hospital because of massive intestinal bleeding. She started hemodialysis due to myeloperoxidase antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at 18 years of age. Her ANCA titers remained stable; however, her C-reactive protein increased on 5 mg/day prednisolone before admission. Computed tomography angiography revealed a ruptured jejunal arterial aneurysm. Transcatheter arterial embolization, blood transfusion and the reinforcement of steroid therapy resolved her symptoms of AAV. Our case of a young patient with AAV and medium-sized arterial vasculitis is rare and emphasizes that the ANCA titer does not always rise, especially in patients with nonrenal vasculitis flare-ups.

Incidence and factors associated with prescribing renin-angiotensin-system inhibitors in adult idiopathic nephrotic syndrome: A nationwide cohort study.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are prescribed as conservative or adjunctive therapies for adult idiopathic nephrotic syndrome. However, studies on real-world practice patterns are scarce. This study aimed to examine the prevalence and incidence of ACEI/ARB prescription and their associated factors. This nationwide cohort study included adult Japanese patients with idiopathic nephrotic syndrome including minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and others. The outcomes were the prevalence of ACEI/ARB prescription at baseline (date of renal biopsy or date of immunosuppressant initiation) and at 2 months after baseline. Of the 326 eligible patients, 122 (37.4%) had already been prescribed ACEIs/ARBs. Of the remaining 204 patients, 67 (32.7%) were newly prescribed within the 2-month period. MN/FSGS (vs. MCD, adjusted odds ratio [AOR]: 4.96 [95% confidence interval {CI} 2.53-9.72] and 3.95 [95% CI 1.61-9.66], respectively), higher age (per 1-yr increase, AOR: 1.02 [95% CI 1.00-1.04]), other hypertensive agents (AOR: 2.18 [95% CI 1.21-3.92]), antidiabetic drug (AOR: 6.57 [95% CI 1.77-24.4]) were associated with a higher prevalence of ACEI/ARB prescription. MN (vs. MCD, AOR: 6.00 [95% CI 2.57-14.0]) and higher baseline systolic blood pressure (SBP) (per 10-mmHg increase, AOR: 1.36 [95% CI 1.09-1.70]) were associated with a higher incidence of ACEI/ARB prescription. On average, incidence of ACEI/ARB prescription increased from 19.2% to 40.8% as baseline SBP increased from 100 to 140 mmHg. Thus, Japanese nephrologists are likely to prescribe ACEIs/ARBs for nephrotic patients with MN or high baseline SBP, even below the hypertensive range.

Association Between Serum Uric Acid and Depression in Patients with Chronic Kidney Disease not Requiring Kidney Dialysis: Cross-Sectional and Longitudinal Analyses.

BACKGROUND Depression is the main problem of psycho-nephrology. We aimed to investigate clinical risk factors for depression in patients with non-dialysis chronic kidney disease (CKD). MATERIAL AND METHODS A non-dialysis CKD cohort study was conducted with 223 patients. Information on demographic and clinical parameters was collected at baseline. Beck Depression Inventory (BDI) and Pittsburgh Sleep Quality Index (PSQI) questionnaires were used to estimate depression and sleep quality in the patients. The questionnaires were repeated in 158 patients after 6 months. Logistic regression was performed to identify independent factors associated with depression and any longitudinal changes in BDI scores. RESULTS At baseline, 17 patients (7.72%) in the CKD cohort presented with depression. Multivariate logistic regression revealed that being female (odds ratio [OR] 0.319, 95% confidence interval [CI] 0.108 to 0.944, P=0.039) and having lower levels of serum uric acid (SUA) (OR 0.675, 95% CI 0.469 to 0.970, P=0.034) were independent risk factors for depression. A decrease in PSQI score (OR 0.873, 95% CI 0.777 to 0.981, P=0.022) and an increase in SUA level (OR 1.383, 95% CI 1.115 to 1.715, P=0.003) were independently associated with decline in BDI scores in the patients in the 6-month follow-up group. CONCLUSIONS Lower SUA levels and being female were independent risk factors for depression in non-dialysis CKD patients. Improving sleep quality and increasing SUA levels may relieve depression to some extent.

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.

Cardio-renal protective effect of the xanthine oxidase inhibitor febuxostat in the 5/6 nephrectomy model with hyperuricemia.

Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as to whether xanthine oxidase (XO) inhibitors confer organ protection besides lowering serum urate levels. In this study, we addressed the cardio-renal effects of XO inhibition in rodent CKD model with hyperuricemia. Sprague-Dawley rats underwent 5/6 nephrectomy and received a uricase inhibitor oxonic acid for 8 weeks (RK + HUA rats). In some rats, a XO inhibitor febuxostat was administered orally. Compared with control group, RK + HUA group showed a significant increase in albuminuria and renal injury. Febuxostat reduced serum uric acid as well as urinary albumin levels. Histological and immunohistochemical analysis of the kidney revealed that febuxostat alleviated glomerular, tubulointerstitial, and arteriolar injury in RK + HUA rats. Moreover, in the heart, RK + HUA showed individual myofiber hypertrophy and cardiac fibrosis, which was significantly attenuated by febuxostat. We found that renal injury and the indices of cardiac changes were well correlated, confirming the cardio-renal interaction in this model. Finally, NF-E2-related factor 2 (Nrf2) and the downstream target heme oxygenase-1 (HO-1) protein levels were increased both in the heart and in the kidney in RK + HUA rats, and these changes were alleviated by febuxostat, suggesting that tissue oxidative stress burden was attenuated by the treatment. These data demonstrate that febuxostat protects against cardiac and renal injury in RK + HUA rats, and underscore the pathological importance of XO in the cardio-renal interaction.