C5 Convertase Blockade in Membranoproliferative Glomerulonephritis: A Single-Arm Clinical Trial.

RATIONALE & OBJECTIVE: Primary membranoproliferative glomerulonephritis (MPGN) is a rare glomerulopathy characterized by complement dysregulation. MPGN progresses rapidly to kidney failure when it is associated with nephrotic syndrome. We assessed the effects of C5 convertase blockade in patients with MPGN and terminal complement activation. STUDY DESIGN: Prospective off-on-off-on open-label clinical trial. SETTING & PARTICIPANTS: Consenting patients with immune complex-mediated MPGN (n=6) or C3 glomerulonephritis (n=4) with sC5b-9 (serum complement membrane attack complex) plasma levels>1,000ng/mL and 24-hour proteinuria with protein excretion>3.5g identified from the Italian Registry of MPGN and followed up at the Istituto di Ricerche Farmacologiche Mario Negri IRCCS (Bergamo, Italy) between March 4, 2014, and January 7, 2015. INTERVENTION: Anti-C5 monoclonal antibody eculizumab administered during 2 sequential 48-week treatment periods separated by one 12-week washout period. OUTCOMES: Primary outcome was change in 24-hour proteinuria (median of 3 consecutive measurements) at 24 and 48 weeks. RESULTS: Median proteinuria decreased from protein excretion of 6.03 (interquartile range [IQR], 4.8-12.4) g/d at baseline to 3.74 (IQR, 3.2-4.4) g/d at 24 weeks (P=0.01) and to 5.06 (IQR, 3.1-5.8) g/d (P=0.006) at 48 weeks of treatment, recovered toward baseline during the washout period, and did not significantly decrease thereafter. Hypoalbuminemia, dyslipidemia, and glomerular sieving function improved during the first treatment period. 3 patients achieved partial remission of nephrotic syndrome and all had undetectable C3 nephritic factors before treatment. Mean measured glomerular filtration rate was 69.7±35.2 versus 87.4±55.1 and 75.8±42.7 versus 76.6±44.1mL/min/1.73m2 at the start versus the end of the first and second treatment periods, respectively, among all 10 study participants. Unlike C3, sC5b-9 plasma levels normalized during both treatment periods and recovered toward baseline during the washout in all patients. LIMITATIONS: Single-arm design, small sample size. CONCLUSIONS: Eculizumab blunted terminal complement activation in all patients with immune complex-mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in just a subgroup. TRIAL REGISTRATION: Registered in the EU Clinical Trials Register with study no. 2013-003826-10.

Estimation of the 24-h urinary protein excretion based on the estimated urinary creatinine output.

BACKGROUND: The urinary protein/creatinine ratio [Up/Ucr (g/gCr)] has been used in the clinical management of patients with chronic kidney disease (CKD). However, a discrepancy is often noted between the Up/Ucr and 24-h urinary protein excretion [24hUp (g/day)] in patients with extremes of muscle mass. We examined devised a method for precise estimation of the 24-h urinary protein excretion (E-24hUp) based on estimation of 24-h urinary creatinine output (E-24hCr). METHODS: Three parameters, spot Up/Ucr, 24hUP and E-24hUp (=Up/Ucr × E-24hCr), were determined in 116 adult patients with CKD. The correlations among the groups were analyzed. RESULTS: There was a significant correlation between the Up/Ucr and 24hUp (p < 0.001). We divided the patients into three groups according to the 24hUp; the low urinary protein group (<1.0 g/day), the intermediate urinary protein group (1.0-3.5 g/day), and the high urinary protein group (>3.5 g/day). There was a significant correlation between the Up/Ucr and 24hUp in the low (p = 0.04) and high urinary protein (p = 0.01) groups, whereas the correlation coefficient was lower in the intermediate urinary protein (p = 0.07) group. Thus, we found a significant correlation between 24hUp and E-24hUp in the study population overall (p < 0.001), in the low (p = 0.01), in the intermediate (p < 0.001), and in the high urinary protein group (p < 0.001). CONCLUSION: We conclude that a poor correlation exists between the Up/Ucr and 24hUp in patients with intermediate urinary protein excretion levels. The recommended parameter for monitoring proteinuria in such patients may be the E-24hUp, which is calculated using the E-24hCr.

Impact of the Triglycerides to High-Density Lipoprotein Cholesterol Ratio on the Incidence and Progression of CKD: A Longitudinal Study in a Large Japanese Population.

BACKGROUND: The impact of the triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) ratio on chronic kidney disease (CKD) is unclear. STUDY DESIGN: Longitudinal cohort study. SETTING & PARTICIPANTS: 124,700 participants aged 39 to 74 years in the Japanese Specific Health Check and Guidance System, including 50,392 men, 74,308 women, 102,900 without CKD, and 21,800 with CKD. PREDICTOR: Quartiles of TG:HDL-C ratio. OUTCOMES & MEASUREMENTS: Changes in estimated glomerular filtration rate (eGFR) and urinary protein excretion during the 2-year study period. Incident CKD in participants without CKD, and progression of CKD in participants with CKD. RESULTS: In the entire study population, higher quartile of TG:HDL-C ratio at baseline was significantly associated with greater decline in eGFR and increase in urinary protein excretion during the 2-year study period, even after adjustment for confounding factors. A higher ratio was associated with higher risk of incident CKD in participants without CKD and higher risk of rapid decline in eGFR and increase in urinary protein excretion in participants with CKD. Higher TG:HDL-C ratio was more strongly associated with decline in eGFR (P for interaction = 0.002) and with incident CKD (P for interaction = 0.05) in participants with diabetes than without diabetes. LIMITATIONS: Short observation period and single measurement of all variables. CONCLUSIONS: A higher TG:HDL-C ratio affects the decline in eGFR and incidence and progression of CKD in the Japanese population.

Factors affecting the progression of renal dysfunction and the importance of salt restriction in patients with type 2 diabetic kidney disease.

BACKGROUND: Type 2 diabetic kidney disease (DKD) is the most common cause of end-stage renal failure, and the prevention of its progression has been a topic of discussion. METHODS: Sixty type 2 DKD patients were retrospectively evaluated for 1 year. Factors independently affecting the annual Ccr decline were examined by multivariable linear regression analysis. Patients were further divided into 2 groups based on their degree of renal function, and between-group differences at study initiation were evaluated. RESULTS: Ccr values were 21.0 ± 11.8 mL/min/1.73 m(2) at study initiation, and 15.7 ± 10.9 mL/min/1.73 m(2) after 1 year of observation. The multivariable linear regression analysis indicated salt intake (standardized coefficient: -0.34, P = 0.010) and urinary protein excretion (standardized coefficient: -0.33, P = 0.011) to be factors independently affecting the annual Ccr decline. Although decliners (-9.8 ± 4.7 mL/min/1.73 m(2)/year) had a significantly higher salt intake than non-decliners (-1.1 ± 3.8 mL/min/1.73 m(2)/year) at study initiation, this difference disappeared at the end of the study as a result of intensive dietary education. In 21 decliners with an additional year of follow-up, the annual Ccr decline significantly improved from -10.1 ± 5.3 to -5.3 ± 7.4 mL/min/1.73 m(2)/year (P = 0.02). CONCLUSION: Salt intake and urinary protein excretion were associated with annual Ccr decline in type 2 DKD patients. Furthermore, dietary education covering salt intake may have positively affected the change in Ccr.

Determinants on urinary excretion of oxalate and other key factors related to urolithiasis among patients with chronic kidney disease: a single center study.

PURPOSE: Urolithiasis is a known risk factor for chronic kidney disease (CKD). However, how CKD might affect the risk of incidence of urolithiasis is not widely studied. METHODS: Urinary excretion of oxalate as well as other key factors related to urolithiasis was analyzed in a single center study of 572 patients with biopsy-proven kidney disease. RESULTS: The mean age of the cohort was 44.9 years and 60% were males. The mean eGFR was 65.9 ml/min/1.73 m2. Median urinary excretion of oxalate was 14.7 (10.4-19.1) mg/24-h and associated with current urolithiasis (OR 12.744, 95% CI: 1.564-103.873 per one logarithm transformed unit of urinary oxalate excretion). Oxalate excretion was not associated with eGFR and urinary protein excretion. Oxalate excretion was higher in patients with ischemia nephropathy as compared with patients with glomerular nephropathy and tubulointerstitial nephropathy (16.4 vs 14.8 vs 12.0 mg, p = 0.018). And ischemia nephropathy (p = 0.027) was associated with urinary oxalate excretion on adjusted linear regression analysis. Urinary excretion of calcium and uric acid was correlated with eGFR and urinary protein excretion (all p < 0.001), with ischemia nephropathy and tubulointerstitial nephropathy associated with uric acid excretion (both p < 0.01) as well. Citrate excretion was correlated with eGFR (p < 0.001) on adjusted linear regression. CONCLUSION: Excretion of oxalate and other key factors related to urolithiasis was differentially associated with eGFR, urinary protein, and pathological changes in CKD patients. The influence of these intrinsic traits of the underlining kidney disease should be considered when evaluating urolithiasis risk in patients with CKD.

A case of renal vein thrombosis associated with autoimmune hemolytic anemia and eosinophilic granulomatous polyangiitis.

Only a few cases of renal vein thrombosis (RVT) occurring in patients with vasculitis have been reported. RVT associated with vasculitis and hemolytic anemia has not been reported yet. We describe here a patient with RVT complicated by pulmonary embolism, autoimmune hemolytic anemia, and eosinophilic granulomatous polyangiitis. A 69-year-old Japanese man who had been treated with corticosteroids was referred to our department for severe proteinuria (4.32 g/gCr). Abdominal ultrasonography showed bilateral RVT, and contrast-enhanced computed tomography showed bilateral pulmonary embolism. Therefore, the patient was diagnosed with RVT complicated by pulmonary embolism. Anticoagulation therapy with heparin followed by apixaban was started. Thereafter, the D-dimer concentration decreased from 8.3 to 1.2 µg/mL, and urinary protein excretion improved to 0.62 g/gCr. Renal function was unchanged with an estimated glomerular filtration rate of 68.8 mL/minute/1.73 m2. The thrombi in both renal veins and pulmonary arteries gradually regressed. Clinicians should be aware of this complication when worsening proteinuria is observed during steroid therapy in patients with autoimmune hemolytic anemia and eosinophilic granulomatous polyangiitis.

Effect of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator (SPPARMα), on urinary protein excretion in IgA nephropathy with hypertriglyceridemia.

Lipid abnormalities, including hypertriglyceridemia, are one of the most common comorbidities in patients with chronic kidney disease (CKD) and are independently associated with disease progression. However, it remains uncertain whether treatment for hypertriglyceridemia has favorable effects on the clinical course of IgA nephropathy (IgAN). Pemafibrate is a novel selective peroxisome proliferator-activated receptor-alpha modulator and may be distinct from conventional fibrates in terms of its pharmacological activity and hepatic and renal safety. A recent clinical study demonstrated that pemafibrate was safe and effective for correcting pro-atherogenic lipid abnormalities in CKD patients with a wide range of renal insufficiency. However, the effect of pemafibrate on renal function in patients with IgAN and hypertriglyceridemia has not been verified. This paper is the first to show that 12 months of pemafibrate (0.1 mg daily) administration in three drug-naïve and mild IgAN patients with variable renal dysfunction and histopathology proven IgAN decreased serum triglyceride level and excretion of urinary protein and liver-type fatty acid-binding protein with no change in estimated glomerular filtration rate (eGFR). These findings suggest that pemafibrate is safe and effective for correcting hypertriglyceridemia and decreasing urinary protein excretion without changing eGFR and blood pressure levels in mild IgAN patients with hypertriglyceridemia.

Effect of Lubiprostone on Urinary Protein Excretion: A Report of Two IgA Nephropathy Patients with Chronic Constipation.

Disturbance of the normal gut microbiota has been implicated in the pathogenesis of various diseases, including chronic kidney disease (CKD). A common CKD symptom is chronic constipation. Lubiprostone is a safe and efficacious drug for treating chronic constipation. We herein report 2 patients with IgA nephropathy treated with lubiprostone (24 µg 1×/day). The lubiprostone treatment ameliorated their chronic constipation and, unexpectedly, reduced the urinary protein excretion, urinary liver-type fatty acid binding protein and urine occult blood. These results may indicate that lubiprostone is a useful therapeutic intervention against the progression of IgA nephropathy with chronic constipation.

A pilot study to relationship between urinary protein excretion and muscle strengthening in patients with acute onset renal disease.

PURPOSE: The purpose of this study was to investigate urine protein excretion and the effect of muscle strengthening in patients with renal disease. SUBJECTS: Twenty-eight patients (18 to 87 years old) with acute onset renal disease were treated with steroids at the Hospital of Shiga University of Medical Science. Maximum quadriceps force was measured, and 20-minutes sessions in resistance training were started. After 5 weeks, maximum quadriceps force was measured again. RESULTS: Quadriceps force showed no significant difference between before and after intervention. There was negative correlation between mean urinary protein excretion and amount of change in quadriceps force over the 5 weeks (r=-0.40, p=0.038). CONCLUSIONS: We observed the patients with reduced urine protein excretion are tends to easier to obtain muscle strengthening. On the other hand, there is a possibility that the patients with increased urine protein excretion are hard to obtain muscle strengthening, during the intervention.

Effect of Roux-en-Y gastric bypass and diet-induced weight loss on diabetic kidney disease in the Zucker diabetic fatty rat.

BACKGROUND: Reductions in urinary protein excretion after Roux-en-Y gastric bypass (RYGB) surgery in patients with diabetic kidney disease have been reported in multiple studies. OBJECTIVES: To determine the weight loss dependence of the effect of RYGB on urinary protein excretion by comparing renal outcomes in Zucker diabetic fatty rats undergoing either gastric bypass surgery or a sham operation with or without weight matching. SETTING: University laboratories. METHODS: Zucker diabetic fatty rats underwent surgery at 18 weeks of age. A subgroup of sham operated rats were weight matched to RYGB operated rats by restricting food intake. Urinary protein excretion was assessed at baseline and at postoperative weeks 4 and 12. Renal histology and macrophage-associated inflammation were assessed at postoperative week 12. RESULTS: Progressive urinary protein excretion was attenuated by both RYGB and diet-induced weight loss, albeit to a lesser extent by the latter. Both weight loss interventions produced equivalent reductions in glomerulomegaly, glomerulosclerosis, and evidence of renal macrophage infiltration. CONCLUSION: Weight loss per se improves renal structure and attenuates renal inflammatory responses in an experimental animal model of diabetic kidney disease. Better glycemic control post-RYGB may in part explain the greater reductions in urinary protein excretion after gastric bypass surgery.

Low-dose of multi-glycoside of Tripterygium wilfordii Hook. f., a natural regulator of TGF-ß1/Smad signaling activity improves adriamycin-induced glomerulosclerosis in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Transforming growth factor (TGF)-ß1/Smad signaling pathway plays a critical role in the prolonged glomerulosclerosis (GS), which is an important determinant during the progression in chronic kidney disease (CKD). For recent 30 years, multi-glycoside of Tripterygium wilfordii Hook. f. (GTW), an extract from Chinese herbal medicine has been proved clinically effective in improving GS in CKD in China. However, therapeutic mechanisms involved in vivo are still unclear. In this study, we aimed to explain the dose-effects and molecular mechanisms of GTW on GS by regulating TGF-ß1/Smad signaling activity in adriamycin (ADR)-induced nephropathy (ADRN). MATERIALS AND METHODS: Rats with ADRN, created by unilateral nephrectomy and twice adriamycin injections (ADR, 4 mg/kg and 2 mg/kg) within 4 weeks, were divided into four groups, the Sham group, the Vehicle group, the low-dose GTW-treated group, and the high-dose GTW-treated group, and that, sacrificed at the end of the 6th week after administration. Proteinuria, blood biochemical parameters, glomerulosclerotic morphological makers, podocyte shape, and nephrin expression were examined, respectively. Protein expressions of key signaling molecules in TGF-ß1/Smad pathway, such as TGF-ß1, Smad3, phosphorylated-Smad2/3 (p-Smad2/3), and Smad7, were also evaluated individually. RESULTS: The results indicated that the characterizations of ADRN involved the typical prolonged GS, a small amount of abnormal proteinuria, and the failing renal function; TGF-ß1/Smad signaling molecules, especially Smad3, p-Smad2/3, and Smad7 were activated in vivo, accompanied by the exasperation of glomerulosclerotic lesion; GTW at high-dose (100 mg/kg) and low-dose (50 mg/kg) could slightly ameliorate the prolonged GS and nephrin expression, furthermore, the anti-proliferative action of GTW at high-dose was superior to that at low-dose, but caused the significant liver injury; in ADRN model rats, protein expressions of TGF-ß1, p-Smad2/3, and Smad7 in the kidneys could be regulated with the treatment of GTW at low-dose. CONCLUSION: This study farther demonstrated that the low-dose of GTW, as a natural regulator in vivo, could effectively and safely ameliorate the prolonged GS in FSGS model, via the potential molecular mechanisms involving the reduction of ECM components and the suppression of TGF-ß1 over-expression, as well as the bidirectional regulation of TGF-ß1/Smad signaling activity.

Ácido úrico como indicador pronóstico de severidad de la excreción urinaria de proteínas en 24 horas

Establecer el papel de las concentraciones de ácido úrico como indicador pronóstico de la severidad de la excreción urinaria de proteínas en 24 horas. Se seleccionaron pacientes con diagnóstico de preeclampsia en las que se pudo determinar las concentraciones de ácido úrico y la excreción urinaria de proteínas en 24 horas. Las muestras de sangre se recolectaron en todas las pacientes antes del parto e inmediatamente después del diagnóstico. Hospital Central “Dr. Urquinaona”. Maracaibo, Estado Zulia. El valor promedio de excreción urinaria de proteínas fue de 4,1 ± 2,0 gramos en 24 horas y de ácido úrico de 7,2 ± 1,6 mg/dL. Los valores de excreción urinaria de proteínas y ácido úrico mostraron una correlación moderada, positiva y significativa (r = 0,518; P < 0,001). Utilizando un valor de 7 mg/dL para dividir a las pacientes en dos grupos, se observó una diferencia estadísticamente significativa en las concentraciones de excreción urinaria de proteínas en 24 horas (P < 0,05). También se observaron diferencias estadísticamente significativas en la edad gestacional al momento del parto, índice de masa corporal, presión arterial sistólica y diastólica (P < 0,05). Usándolo como valor de corte, la sensibilidad para detectar una excreción urinaria de proteínas de 3 gramos fue de 83,3 por ciento, la especificidad fue de 75 por ciento, el valor predictivo positivo de 62,5 por ciento y el valor predictivo negativo de 90,0 por ciento con una exactitud de 79,2 por ciento. Las concentraciones de ácido úrico se correlacionan estadísticamente con la excreción urinaria de proteínas en 24 horas

To establish the role of uric acid concentration as prognostic indicator of 24-hours urinary protein excretion severity. Patients with diagnosis of preeclampsia which uric acid and urinary protein excretion could be determined were selected. Blood samples were recollected in all patients before delivery and immediately after diagnosis. Hospital Central “Dr. Urquinaona”. Maracaibo, Estado Zulia. Mean value of urinary protein excretion was 4,1 ± 2.0 grams in 24 hours and uric acid of 7.2 ± 1.6 mg/dL, showing a moderate, positive and significant correlation (r=0.518; P < 0.001). Using a value of 7 m g/dL to divide patients in two groups, there were statically significant difference in 24-hour urinary protein excretion (P < 0.05). There was also statitiscally significant differences in gestational age at the moment of delivery, body mass index, systolic and diastolic blood pressure (P < 0.05). Using it as a cutoff value, sensibility to detect a 24 -hour urinary protein excretion of 3 gram was 83.3 percent, specificity of 75 percent, positive predictive value of 62.5 percent and negative predictive value of 90.0 percent with and accuracy of 79.2 percent. Uric acid concentrations statitiscally correlates with 24-hour urinary protein excretion