Time to target uric acid to retard CKD progression.

Uric acid (UA) remains a possible risk factor of chronic kidney disease (CKD) but its potential role should be elucidated given a fact that multidisciplinary treatments assure a sole strategy to inhibit the progression to end-stage renal disease (ESRD). In clinical setting, most observational studies showed that elevation of serum uric acid (SUA) independently predicts the incidence and the development of CKD. The meta-analysis showed that SUA-lowering therapy with allopurinol may retard the progression of CKD but did not reach conclusive results due to small-sized studies. Larger scale, randomized placebo-controlled trials to assess SUA-lowering therapy are needed. Our recent analysis by propensity score methods has shown that the threshold of SUA should be less than 6.5 mg/dL to abrogate ESRD. In animal models an increase in SUA by the administration of oxonic acid, uricase inhibitor, or nephrectomy can induce glomerular hypertension, arteriolosclerosis including afferent arteriolopathy and tubulointerstitial fibrosis. The ever-growing discoveries of urate transporters prompt us to learn UA metabolism in the kidney and intestine. One example is that the intestinal ABCG2 may play a compensatory role at face of decreased renal clearance of UA in nephrectomized rats, the trigger of which is not a uremic toxin but SUA itself. This review will summarize the recent knowledge on the relationship between SUA and the kidney and try to draw a conclusion when and how to treat asymptomatic hyperuricemia accompanied by CKD. Finally we will address a future perspective on UA study including a Mendelian randomization approach.

Unique proximal tubular cell injury and the development of acute kidney injury in adult patients with minimal change nephrotic syndrome.

BACKGROUND: Adult patients with minimal change nephrotic syndrome (MCNS) are often associated with acute kidney injury (AKI). To assess the mechanisms of AKI, we examined whether tubular cell injuries unique to MCNS patients exist. METHODS: We performed a retrospective analysis of clinical data and tubular cell changes using the immunohistochemical expression of vimentin as a marker of tubular injury and dedifferentiation at kidney biopsy in 37 adult MCNS patients. AKI was defined by the criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI. RESULTS: Thirteen patients (35.1%) were designated with AKI at kidney biopsy. No significant differences in age, history of hypertension, chronic kidney disease, diuretics use, proteinuria, and serum albumin were noted between the AKI and non-AKI groups. Urinary N-acetyl-ß-D-glucosaminidase (uNAG) and urinary alpha1-microglobulin (uA1MG) as markers of tubular injury were increased in both groups, but the levels were significantly increased in the AKI group compared with the non-AKI group. The incidence of vimentin-positive tubules was comparable between AKI (84.6%) and non-AKI (58.3%) groups, but vimentin-positive tubular area per interstitial area was significantly increased in the AKI group (19.8%) compared with the non-AKI group (6.8%) (p = 0.011). Vimentin-positive injured tubules with tubular simplification (loss of brush-border of the proximal tubule/dilated tubule with flattening of tubular epithelium) were observed in the vicinity of glomeruli in both groups, suggesting that the proximal convoluted tubules were specifically injured. Two patients exhibited relatively severe tubular injuries with vimentin positivity and required dialysis within 2 weeks after kidney biopsy. The percentage of the vimentin-positive tubular area was positively correlated with uNAG but not with uA1MG in the non-AKI group. CONCLUSIONS: Proximal tubular injuries with increased uNAG exist in MCNS patients without renal dysfunction and were more severe in the AKI group than they were in the non-AKI group. The unique tubular injuries probably due to massive proteinuria might be a predisposing factor for the development of severe AKI in adult MCNS 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 patient's 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.

Time-dependent risk factors associated with the decline of estimated GFR in CKD patients.

BACKGROUND: Targeting the modifiable risk factors may help halt the progression of CKD, thus risk factor analysis is better performed using the parameters in the follow-up. This study aimed to examine the time-dependent risk factors for CKD progression using time-averaged values and to investigate the characteristics of rapid progression group. METHODS: This is a retrospective cohort study enrolling 770 patients of CKD stage 3-4. Time-dependent parameters were calculated as time-averaged values by a trapezoidal rule. % decline of estimated GFR (eGFR) per year from entry was divided to three groups: <10% (stable), 10-25% (moderate progression), and ≥25% (rapid progression). Multivariate regression analyses were employed for the baseline and the time-averaged datasets. RESULTS: eGFR decline was 2.83 ± 4.04 mL/min/1.73 m(2)/year (8.8 ± 12.9 %) in male and 1.66 ± 3.23 mL/min/1.73 m(2)/year (5.4 ± 11.0%) in female (p < 0.001). % decline of eGFR was associated with male, proteinuria, phosphorus, and systolic blood pressure as risk factors and with age, albumin, and hemoglobin as protective factors using either dataset. Baseline eGFR and diabetic nephropathy appeared in the baseline dataset, while uric acid appeared in the time-averaged dataset. The rapid progression group was associated with proteinuria, phosphorus, albumin, and hemoglobin in the follow-up. CONCLUSION: These results suggest that time-averaged values provide insightful clinical guide in targeting the risk factors. Rapid decline of eGFR is strongly associated with hyperphosphatemia, proteinuria, and anemia indicating that these risk factors should be intervened in the follow-up of CKD.

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 Sjögren's 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.

A patient presenting with isolated hematuria and renal dysfunction as rare manifestation of cryoglobulinemic glomerulonephritis in the course of autoimmune diseases including Sjögren's syndrome.

Autoimmune diseases are sometimes associated with immune-mediated renal diseases and cryoglobulinemia is one of the causes. Cryoglobulinemia and cryoglobulinemic glomerulonephritis associated with primary Sjögren's syndrome are most frequent condition among non-hepatitis C virus-related condition. Its typical renal manifestation shows high amount of proteinuria with microscopic hematuria and renal insufficiency. We describe a case of 72-year-old woman with Hashimoto disease, autoimmune hepatitis, Sjögren's syndrome, and immune-related pancytopenia complicated by cryoglobulinemic glomerulonephritis. Before kidney biopsy, tubulointerstitial nephritis probably due to Sjögren's syndrome was suspected because of persistent hematuria without significant proteinuria and developing mild renal dysfunction over 6 months. The developing renal dysfunction associated with isolated hematuria is uncommon in glomerular diseases. Kidney biopsy, however, revealed established membranoproliferative glomerulonephritis with subendothelial deposits consisting of tubular structures with IgM, IgG, and C3 staining. Corticosteroids plus mycophenolate mofetil therapy successfully normalized renal function. Physician should not overlook cryoglobulinemic glomerulonephritis, which is potentially poor prognosis, even if urinalysis shows only persistent isolated hematuria in patients with autoimmune diseases.

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

We report a 70-year-old woman with Sjögren's 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 Sjögren's 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.

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.'

Long-term efficacy of vildagliptin in patients with type 2 diabetes undergoing hemodialysis.

BACKGROUND: There are few studies evaluating long-term glycemic control using a dipeptidyl peptidase-4 inhibitor in type 2 diabetes patients with end-stage renal disease (ESRD). The aim of this study was to evaluate the safety and efficacy of vildagliptin therapy over 2 years in type 2 diabetes with ESRD. METHODS: Patients with ESRD resulting from type 2 diabetes requiring dialysis who had ≥20 % glycated albumin (GA) were enrolled. Vildagliptin 50 mg once daily was administered for 2 years. Changes in GA and dry weight were evaluated. RESULTS: In 32 patients (24 men and 8 women) aged 68.3 ± 1.9 years, vildagliptin 50 mg once daily was administered for 2 years, but the dose was increased to 50 mg twice daily in 15 patients. GA was significantly reduced by 2.6 ± 0.6 %, from 22.4 ± 0.6 % at baseline to 19.8 ± 0.4 % at 2 years. After 2 years of vildagliptin therapy, 15 (46.9 %) of 32 patients achieved a GA level of <20 %. Dry weight changed slightly, with an increase of 1.3 ± 0.8 kg at 2 years. No adverse drug reactions related to treatment with vildagliptin were seen. CONCLUSIONS: Vildagliptin is a promising therapeutic option for safe, effective glycemic control in type 2 diabetic patients with ESRD.

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.

Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells.

Transforming growth factor-beta (TGF-beta) plays a crucial role in vascular development and homeostasis by regulating many transcriptional targets. Activin receptor-like kinase 5 (ALK-5) is a TGF-beta type I receptor expressed in various TGF-beta-responsive cells. In contrast, ALK-1 functions as a TGF-beta type I receptor in endothelial cells, and is responsible for human hereditary hemorrhagic telangiectasia (HHT) type II. ALK-5 and ALK-1 mediate TGF-beta signals through distinct Smad proteins, i.e., Smad2/Smad3 and Smad1/Smad5, respectively. To identify target genes of ALK-1 and ALK-5 in endothelial cells, we conducted oligonucleotide microarray analysis. Human umbilical vein endothelial cells (HUVEC) were infected with recombinant adenoviruses carrying a constitutively active form of ALK-1 or ALK-5. ALK-5 inhibited the proliferation, network formation, and tube formation of HUVEC and induced their apoptosis, whereas ALK-1 did not exhibit significant effects on HUVEC in vitro. mRNAs were extracted from HUVEC and used for hybridization of oligonucleotide arrays representing approximately 7,000 human genes. Northern blot and quantitative real-time polymerase chain reaction (PCR) analyses were also performed for some of these genes, confirming the validity of this microarray analysis. We found that ALK-1 specifically upregulated Smad6, Smad7, Id1, Id2, endoglin, STAT1, and interleukin 1 receptor-like 1. ALK-5, in contrast, upregulated PlGF, SM22alpha, connexin 37, betaIG-H3, and LTBP1. ALK-1 downregulated Smad1, CXCR4, Ephrin-A1, and plakoglobin, whereas ALK-5 downregulated claudin 5 and integrin beta(5). These results revealed some new targets of TGF-beta in endothelial cells, and differences in transcriptional regulation patterns between ALK-1 and ALK-5.

Modulation of interferon-induced genes by lipoxin analogue in anti-glomerular basement membrane nephritis.

Immune complex deposition is associated with the accumulation of neutrophils, which play an important role in the various immune-mediated diseases. A novel anti-inflammatory agent, the lipoxin A (LXA) analogue (15-epi-16-(FPhO)-LXA-Me)), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A4 (ATLa), was used in experimental anti-glomerular basement membrane (GBM) antibody nephritis in mice. ATLa was administered before the induction of the disease, and 2 h later, the animals were killed. ATLa reduced the infiltrating neutrophils and nitrotyrosine staining in glomeruli. Subsequent changes of gene expression in the early phase were evaluated, and 5674 genes were present under the basal conditions in kidneys from normal mice; 54 upregulated genes and 25 downregulated genes were detected in anti-GBM nephritis. Eighteen of these upregulated genes were those induced by IFN-gamma. Real-time quantitative PCR analysis confirmed the results of the microarrays. To investigate a role of IFN-gamma in neutrophil infiltration, anti-GBM nephritis was induced in IFN-gamma knockout mice. The number of infiltrating neutrophils in these mice did not differ from those in wild-type mice. Also examined were CD11b expression on neutrophils from mice treated with ATLa by flow cytometry, but suppression of this adhesion molecule was not observed. Neutrophil infiltration was successfully inhibited by ATLa in the early phase of murine anti-GBM nephritis. Microarray analysis detected the change of mRNA expression in anti-GBM nephritis and demonstrated amelioration of various genes by ATLa, which may provide a clue to the development of novel therapeutic approaches in immune renal injury.