Measuring and Estimating GFR and Treatment Effect in ADPKD Patients: Results and Implications of a Longitudinal Cohort Study

Trials failed to demonstrate protective effects of investigational treatments on glomerular filtration rate (GFR) reduction in Autosomal Dominant Polycystic Kidney Disease (ADPKD). To assess whether above findings were explained by unreliable GFR estimates, in this academic study we compared GFR values centrally measured by iohexol plasma clearance with corresponding values estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas in ADPKD patients retrieved from four clinical trials run by a Clinical Research Center and five Nephrology Units in Italy. Measured baseline GFRs and one-year GFR changes averaged 78.6±26.7 and 8.4±10.3 mL/min/1.73 m2 in 111 and 71 ADPKD patients, respectively. CKD-Epi significantly overestimated and aMDRD underestimated baseline GFRs. Less than half estimates deviated by <10% from measured values. One-year estimated GFR changes did not detect measured changes. Both formulas underestimated GFR changes by 50%. Less than 9% of estimates deviated <10% from measured changes. Extent of deviations even exceeded that of measured one-year GFR changes. In ADPKD, prediction formulas unreliably estimate actual GFR values and fail to detect their changes over time. Direct kidney function measurements by appropriate techniques are needed to adequately evaluate treatment effects in clinics and research

Moderate salt restriction with or without paricalcitol in type 2 diabetes and losartan-resistant macroalbuminuria (PROCEED) : a randomised, double-blind, placebo-controlled, crossover trial

Background Macroalbuminuria predicts renal and cardiovascular events in patients with type 2 diabetes. We aimed to assess the albuminuria-lowering effects of salt restriction, paricalcitol therapy, or both, in this population. Methods In this randomised, double-blind, placebo-controlled, crossover trial, we recruited adult patients with type 2 diabetes from six diabetology outpatient clinics in northern Italy, with 24 h albuminuria of more than 300 mg despite 100 mg per day losartan therapy, blood pressure of less than 140/90 mm Hg, serum creatinine concentration of less than 2 mg/dL, stable renal function on stable renin-angiotensin system inhibitor therapy with a fixed dose of losartan, parathyroid hormone concentration of 20 pg/mL to &lt;110 pg/mL, serum calcium concentration of less than 9·5 mg/dL, and serum phosphate concentration of less than 5 mg/dL, who had been more than 80% compliant with placebo treatment during a 1 month placebo run-in. We allocated patients 1:1 with computer-generated randomisation to an open-label 3 month high-sodium (&gt;200 mEq [4·8 g] per day) or low-sodium (&lt;100 mEq [2·4 g] per day) diet and, within each diet group, to a 1 month double-blind treatment period of oral paricalcitol (2 μg per day) or placebo, followed by 1 month of placebo washout and then a further 1 month double-blind treatment period of paricalcitol or placebo in which patients crossed over to the opposite treatment period. The primary outcome was 24 h albuminuria (median of three consecutive measurements). Analyses were modified intention-to-treat (including all randomly allocated patients who took at least one dose of study drug and had an efficacy measurement after the first treatment period). Patients and investigators were masked to paricalcitol and placebo assignment. Those assessing outcomes were masked to both study drug and diet assignment. This study is registered with ClinicalTrials.gov, number NCT01393808, and the European Union Clinical Trials Register, number 2011-001713-14. Findings Between Dec 13, 2011, and Feb 17, 2015, we randomly allocated 57 (50%) patients to a low-sodium diet (28 [49%] to paricalcitol then placebo and 29 [51%] to placebo then paricalcitol) and 58 (50%) to a high-sodium diet (29 [50%] to paricalcitol then placebo and 29 [50%] to placebo then paricalcitol). In the low-sodium group (30 mEq of daily sodium intake reduction, equivalent to approximately 1·7–1·8 g per day), 24 h albuminuria was reduced by 36·6% (95% CI 28·5–44·9) from 724 mg (441–1233) at baseline to 481 mg (289–837) at month 3 (p&lt;0·0001), but no significant change occurred in the high-sodium group (from 730 mg [416–1227] to 801 mg [441–1365]; 2·9% [–16·8 to 16·4] increase; p=0·50). Changes between diet groups differed by 32·4% (17·2–48·8; p&lt;0·0001) and correlated with changes in natriuresis (r=0·43; p&lt;0·0001). On the high-sodium diet, paricalcitol reduced the salt-induced albuminuria increase by 17·8% (3·9–32·3) over the month of treatment compared with placebo (p=0·02), whereas on the low-sodium diet, paricalcitol did not have a significant effect versus placebo (increase of 4·1% [–9·3 to 21·6]; p=0·59). During placebo treatment, albuminuria decreased with the low-sodium diet (p=0·0002) and did not significantly change with the high-sodium diet, but changes were significantly different between diet groups (p=0·0004). Treatment was well tolerated and no patients withdrew from the study because of treatment-related effects. 67 adverse events occurred in 52 (45%) patients during paricalcitol treatment and 44 events occurred in 36 (31%) patients during placebo treatment. During paricalcitol therapy, 14 cases of hypercalciuria, six cases of hypercalcaemia, and five cases of hyperphosphataemia were reported in one patient each, all of which were possibly treatment related. One case of hypercalciuria was reported in one patient during the placebo treatment period. One stroke and one coronary event occurred during paricalcitol therapy. No patients died during the study. Interpretation In patients with macroalbuminuria and type 2 diabetes, moderate salt restriction enhances the antialbuminuric effect of losartan, an effect that could be nephroprotective and cardioprotective in the long term. The finding that paricalcitol prevents a sodium-induced increase in albuminuria provides support for trials to test the long-term risk-benefit profile of paricalcitol add-on therapy in patients with type 2 diabetes and macroalbuminuria refractory to dietary salt restriction, including patients refractory to even moderate salt restriction. Funding AbbVie

Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.

To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26

Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.

To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26

Effects of valsartan, benazepril and their combination in overt nephropathy of type 2 diabetes: A prospective, randomized, controlled trial

Aims: To evaluate whether angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) combination therapy is more nephroprotective than ACE inhibitor or ARB monotherapy in people with type 2 diabetes and overt nephropathy. Materials and methods: In this prospective, randomized, open, blind-endpoint phase III trial sponsored by the Italian Drug Agency, 103 consenting patients with type 2 diabetes, aged >40 years, with serum creatinine levels 159 to 309 μmol/L, spot morning urinary albumin–creatinine ratio > 1000 mg/g (or > 500 mg/g in those on ACE inhibitor or ARB therapy at inclusion) were stratified by centre and randomized to 4.5-year treatment with valsartan 320 mg/d (n = 36), benazepril 20 mg/d (n = 34) or halved doses of both medications (n = 33). The primary endpoint was end-stage renal disease (ESRD). Modified intention-to-treat analyses were performed. Results: Recruitment took place between June 2007 and February 2013 at 10 centres in Italy and one in Slovenia. A total of 77 participants completed the study and 26 were prematurely withdrawn. During a median (interquartile range) of 41 (18–54) months, 12 participants on benazepril (35.3%) and nine on combination therapy (27.3%) progressed to ESRD, versus five on valsartan (13.9%). Differences between benazepril (hazard ratio [HR] 3.59, 95% confidence interval [CI] 1.25–10.30; P = 0.018) or combination therapy (HR 3.28, 95% CI 1.07–10.0; P = 0.038) and valsartan were significant, even after adjustment for age, gender and baseline serum creatinine, systolic blood pressure and 24-hour proteinuria (HR 5.16, 95% CI 1.50–17.75, P = 0.009 and HR 4.75, 95% CI 1.01–22.39, P = 0.049, respectively). Adverse events were distributed similarly among the groups. Conclusions: In people with type 2 diabetes with nephropathy, valsartan (320 mg/d) safely postponed ESRD more effectively than benazepril (20 mg/d) or than halved doses of both medications

Effects of sevelamer carbonate in patients with ckd and proteinuria. the answer randomized trial

Rationale &amp; Objective: Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD. Study Design: Phase 2, randomized, controlled, open-label, crossover trial. Setting &amp; Participants: Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs) &gt; 15 mL/min/1.73 m2 and residual proteinuria with protein excretion ≥ 0.5 g/24 h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy. Intervention: After stratification by serum phosphate level, ≤4 or &gt;4 mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600 mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period. Outcomes: The primary outcome was 24-hour proteinuria (n = 49 patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness. Results: Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24 h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24 h) sevelamer were similar (P = 0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer. Limitations: Short treatment duration, lower pretreatment proteinuria than expected. Conclusions: 3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria. Funding: Sanofi (Milan, Italy). Trial Registration: Registered at ClinicalTrials.gov with study number NCT01968759