Tatsuru Ota

Targeting Uric Acid and the Inhibition of Progression to End-Stage Renal Disease--A Propensity Score Analysis.

Background The role of uric acid (UA) in the progression of chronic kidney disease (CKD) remains controversial due to the unavoidable cause and result relationship. This study was aimed to clarify the independent impact of UA on the subsequent risk of end-stage renal disease (ESRD) by a propensity score analysis. Methods A retrospective CKD cohort was used (n = 803). Baseline 23 covariates were subjected to a multivariate binary logistic regression with the targeted time-averaged UA of 6.0, 6.5 or 7.0 mg/dL. The participants trimmed 2.5 percentile from the extreme ends of the cohort underwent propensity score analyses consisting of matching, stratification on quintile and covariate adjustment. Covariate balances after 1:1 matching without replacement were tested for by paired analysis and standardized differences. A stratified Cox regression and a Cox regression adjusted for logit of propensity scores were examined. Results After propensity score matching, the higher UA showed elevated hazard ratios (HRs) by Kaplan-Meier analysis (≥6.0 mg/dL, HR 4.53, 95%CI 1.79–11.43; ≥6.5 mg/dL, HR 3.39, 95%CI 1.55–7.42; ≥7.0 mg/dL, HR 2.19, 95%CI 1.28–3.75). The number needed to treat was 8 to 9 over 5 years. A stratified Cox regression likewise showed significant crude HRs (≥6.0 mg/dL, HR 3.63, 95%CI 1.25–10.58; ≥6.5 mg/dL, HR 3.46, 95%CI 1.56–7.68; ≥7.0 mg/dL, HR 2.05, 95%CI 1.21–3.48). Adjusted HR lost its significance at 6.0 mg/dL. The adjustment for the logit of the propensity scores showed the similar results but with worse model fittings than the stratification method. Upon further adjustment for other covariates the significance was attained at 6.5 mg/dL. Conclusions Three different methods of the propensity score analysis showed consistent results that the higher UA accelerates the progression to the subsequent ESRD. A stratified Cox regression outperforms other methods in generalizability and adjusting for residual bias. Serum UA should be targeted less than 6.5 mg/dL.

Predictors and the Subsequent Risk of End-Stage Renal Disease – Usefulness of 30% Decline in Estimated GFR over 2 Years

Background A goal of searching risk factors for chronic kidney disease (CKD) is to halt progressing to end-stage renal disease (ESRD) by potential intervention. To predict the future ESRD, 30% decline in estimated GFR over 2 years was examined in comparison with other time-dependent predictors. Methods CKD patients who had measurement of serum creatinine at baseline and 2 years were enrolled (n = 701) and followed up to 6 years. Time-dependent parameters were calculated as time-averaged values over 2 years by a trapezoidal rule. Risk factors affecting the incidence of ESRD were investigated by the extended Cox proportional hazard model with baseline dataset and 2-year time-averaged dataset. Predictive significance of 30% decline in estimated GFR over 2 years for ESRD was analyzed. Results For predicting ESRD, baseline estimated GFR and proteinuria were the most influential risk factors either with the baseline dataset or the 2-year time-averaged dataset. Using the 2-year time-averaged dataset, 30% decline in estimated GFR over 2 years by itself showed the highest HR of 31.6 for ESRD whereas addition of baseline estimated GFR, proteinuria, serum albumin and hemoglobin yielded a better model by a multivariate Cox regression model. This novel surrogate was mostly associated with time-averaged proteinuria over 2 years with the cut-off of ~1 g/g creatinine. Conclusion These results suggest that decline in estimated GFR and proteinuria are the risk factors while serum albumin and hemoglobin are the protective factors by the time-to-event analysis. Future incidence of ESRD is best predicted by 30% decline in eGFR over 2 years that can be modified by intervention to proteinuria, hemoglobin, uric acid, phosphorus, blood pressure and use of renin-angiotensin system inhibitors in the follow-up of 2 years.

The Impact of Normal Range of Serum Phosphorus on the Incidence of End-Stage Renal Disease by A Propensity Score Analysis

Background Although hyperphosphatemia is deemed a risk factor of the progression of chronic kidney disease (CKD), it remains unclear whether the normal range of serum phosphorus likewise deteriorates CKD. A propensity score analysis was applied to examine the causal effect of the normal range of serum phosphorus on the incidence of end-stage renal disease (ESRD). Methods A retrospective CKD cohort of 803 participants in a single institution was analyzed. Propensity score was estimated using 22 baseline covariates by multivariate binary logistic regression for the different thresholds of time-averaged phosphorus (TA-P) in the normal range of serum phosphorus incremented by 0.1 mg/dL from 3.3 to 4.5 mg/dL. Results The incidence rate of ESRD was 33.9 per 1,000 person-years over median follow-up of 4.3 years. Total patients showed the mean baseline phosphorus of 3.37 mg/dL and were divided to quartile. The higher quartile was associated with the parameters consistent with the advancement of CKD. A stratified Cox regression showed the highest hazard ratio (HR) at TA-P 3.4 mg/dL (HR 17.60, 95% CI 3.92–78.98) adjusted for baseline covariates such as sex, age, diabetic nephropathy, estimated GFR, serum albumin, Na-Cl, phosphorus, LDL-C and proteinuria. Adjusted HRs remained high up to TA-P 4.2 mg/dL (HR 2.22, 95% CI 1.33–3.71). After propensity score matching conducted at the thresholds of TA-P 3.4, 3.6, 3.8 and 4.0 mg/dL, the higher levels of TA-P showed the higher HRs by Kaplan-Meier analysis (p < 0.05 by stratified log-rank test). The numbers needed to treat were calculated as 3.9 to 5.3 over 5 years. Conclusions The propensity score analysis shows that even the normal range of serum phosphorus clearly accelerates CKD progression to ESRD. Our results encourage clinicians to target serum phosphorus to inhibit CKD progression in the manner of ‘the lower the better.’

Remission of Refractory Ascites and Discontinuation of Hemodialysis after Additional Rituximab to Long-term Glucocorticoid Therapy in a Patient with TAFRO Syndrome

Thrombocytopenia, ascites, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a newly recognized but rare disease, and its treatment has not yet been established. We reported a 50-year-old woman with TAFRO syndrome diagnosed 2 years after the initial symptoms of a fever, fatigue, epigastric pain, edema, ascites, lymphadenopathy, thrombocytopenia and renal insufficiency. The patient showed refractory ascites and required hemodialysis under corticosteroid mono-therapy for suspected immune-mediated disease but was successfully treated with additive rituximab, resulting in improvement in her laboratory data, the withdrawal of hemodialysis and the disappearance of ascites. This case underscores the therapeutic utility of rituximab in patients with corticosteroid-resistant TAFRO syndrome, even long after the onset of the disease.

Emergence of Smoldering ANCA-associated Glomerulonephritis During the Clinical Course of Mixed Connective Tissue Disease and Sjögren's Syndrome

A 67-year-old woman presented with hematuria and proteinuria 16 and 11 months ago, respectively. She had been followed up as mixed connective tissue disease and Sjögrens syndrome for over 19 years. Blood chemistry showed no elevated serum creatinine or C-reactive protein but did reveal myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) of 300 U/dL. A kidney biopsy showed pauci-immune focal necrotizing glomerulonephritis. She was treated with prednisolone and rituximab, resulting in normal urinalysis and decreased MPO-ANCA. The complication of ANCA-associated glomerulonephritis should not be overlooked when abnormal urinalysis findings appear in the course of connective tissue disease, irrespective of the presence of rapidly progressive glomerulonephritis.

Clinical Presentation of Tubulointerstitial Nephritis Caused by Amyloid Light-chain Amyloidosis in a Patient with Sjogren's Syndrome

We report a 70-year-old woman with Sjögrens syndrome who had severe renal dysfunction with mild proteinuria and elevated urinary low-molecular-weight proteins. Based on these clinical presentations, interstitial nephritis due to Sjögrens syndrome was strongly suspected. Unexpectedly, renal pathology revealed amyloid light-chain (AL) lambda-type depositions predominantly in the vasculatures with severe tubulointerstitial damage. Concentrated urine immunofixation was positive for Bence Jones lambda-type monoclonal proteins. Given the involvement in other organs, systemic AL amyloidosis was diagnosed. The patient underwent chemotherapy, but hemodialysis was ultimately instituted. It should be remembered that renal amyloidosis occurs as a clinical presentation of interstitial nephritis.

Discontinuation of Hemodialysis in a Patient with Anti-GBM Disease by the Treatment with Corticosteroids and Plasmapheresis despite Several Predictors for Dialysis-Dependence

A 26-year-old man highly suspected of having antiglomerular basement membrane (GBM) disease was treated with corticosteroid pulse therapy 9 days after initial infection-like symptoms with high procalcitonin value. The patient required hemodialysis the next day of the treatment due to oliguria. In addition to corticosteroid therapy, plasmapheresis was introduced and the patient could discontinue hemodialysis 43 days after the treatment. Kidney biopsy after initiation of hemodialysis confirmed anti-GBM disease with 86.3% crescent formation. Physician should keep in mind that active anti-GBM disease shows even high procalcitonin value in the absence of infection. To pursue recovery of renal function, the challenge of the immediate and persistent treatment with high-dose corticosteroids plus plasmapheresis for highly suspected anti-GBM disease is vitally important despite the presence of reported predictors for dialysis-dependence including oliguria and requiring hemodialysis at presentation.

Proteomics Approach Identifies Factors Associated With the Response to Low-Density Lipoprotein Apheresis Therapy in Patients With Steroid-Resistant Nephrotic Syndrome.

Low‐density lipoprotein apheresis (LDL‐A) has been shown to reduce proteinuria in a subgroup of nephrotic syndrome patients refractory to immunosuppressive therapy. Factors influencing the efficacy of LDL‐A in nephrotic syndrome are completely unknown. Using a proteomics approach, we aimed to identify biological markers that predict the response to LDL‐A in patients with steroid‐resistant nephrotic syndrome (SRNS). Identification of plasma proteins bound to the dextran‐sulfate column at the first session of LDL‐A was determined by mass spectrometry. To investigate biological factors associated with the response to LDL‐A, we compared profiles of column‐bound proteins between responders (defined by more than 50% reduction of proteinuria after the treatment) and non‐responders by 2‐dimensional gel electrophoresis (2‐DE) coupled to mass spectrometry in seven patients with SRNS. Evaluation of proteins adsorbed to LDL‐A column in patients with SRNS revealed the identity of 62 proteins, which included apolipoproteins, complement components, and serum amyloid P‐component (SAP). Comparative analysis of the column‐bound proteins between responders and non‐responders by 2‐DE demonstrated that apolipoprotein E (APOE) and SAP levels were increased in non‐responders as compared with responders. These results were confirmed by western blotting. Moreover, serum levels of APOE and SAP were significantly higher in the non‐responder group than in the responder group by ELISA. Our data provide comprehensive analysis of proteins adsorbed by LDL‐A in SRNS, and demonstrate that the serum levels of APOE and SAP may be used to predict the response to LDL‐A in these patients.

Pathological implications of linear immunoglobulin G staining on the glomerular capillary walls in a case of infection-related glomerulonephritis

We report a 32‐year‐old man with nephrotic syndrome and preceding symptom of infection. He had renal insufficiency, hypocomplementemia, and elevated titer of anti‐streptolysin O. Renal biopsy showed mesangial hypercellularity and focal segmental endocapillary hypercellularity with double contour of the glomerular basement membrane (GBM). Immunofluorescence study showed granular C3 staining on the mesangial areas and glomerular capillary walls (GCWs) and linear immunoglobulin G (IgG) staining on GCWs. Electron microscopy revealed sporadic subepithelial humps, discontinuous small and thin deposits in the endothelial side of the GBM and mesangial deposits. He was diagnosed with infection‐related glomerulonephritis (IRGN) with the striking finding of linear IgG staining, which is unusual in IRGN. The patient did not have diabetes mellitus or anti‐GBM disease. The patients serum seemed not to contain IgG, which can bind to GCW. He showed normalization of complement within two months after relief from infection symptoms and a trend toward improvement in proteinuria, hematuria and renal function over 14 months. We discuss the possible mechanisms of linear IgG staining in our case based on clinical and experimental studies on IRGN with cationic bacterial protein as antigen.