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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 > 1,000 ng/mL and 24-hour proteinuria with protein excretion > 3.5 g 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 ± 44.1 mL/min/1.73 m2 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.

Background and objectives Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis. Design, setting, participants, & measurements In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25–10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization. Results At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: −16.3 g/m2; 95% confidence interval, −29.4 to −3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls. Conclusions Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis. Clinical Trial registry name and registration number: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008–003529–17.

Aims: In type 2 diabetic patients with obesity, hyperfiltration is a risk factor for accelerated glomerular filtration rate (GFR) decline and is ameliorated by calorie restriction (CR). We assessed whether CR-induced amelioration of hyperfiltration could translate into slower long-term GFR decline in this population. Methods: In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded endpoint trial, consenting >40-year-old patients with type 2 diabetes, BMI ≥27 kg/m2, creatinine

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 200 mEq [4.8 g] per day) or low-sodium (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 (pInterpretation 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 longterm 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.

Background Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy. Methods and findings VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion. Conclusions Risk/benefit profile of study treatments was similar. Dual renin–angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients. Trial registration EudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152., Piero Ruggenenti and co-workers study prevention of microalbuminuria in patients with type 2 diabetes., Author summary Why was this study done? Renin–angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prevents the onset of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. Some studies found that ACE inhibitor and ARB combination therapy reduced urinary albumin excretion (UAE) more effectively than ACE inhibitor or ARB monotherapy in type 2 diabetic patients with microalbuminuria or macroalbuminuria. Treatment effect was, however, associated with greater blood pressure (BP) reduction. Whether, at comparable BP control, dual RAS inhibition with an ACE inhibitor and an ARB could be more renoprotective than either monotherapy in diabetic patients with no evidence of kidney disease is unknown. What did the researchers do and find? In this prospective, randomized, open-label, blinded endpoint (PROBE) trial, we evaluated whether, at similar BP control, combination therapy with the ACE inhibitor benazepril and the ARB valsartan would reduce the incidence of microalbuminuria more effectively than benazepril or valsartan monotherapy in 612 patients with type 2 diabetes and high-normal albuminuria. Secondarily, we compared the effects of the 2 monotherapies on the primary prevention of microalbuminuria in this population. We found that during a median follow-up of 66 months, combined treatment with half of the standard manufacturer-recommended antihypertensive doses of benazepril and valsartan had no superior effect against progression to microalbuminuria as compared to monotherapy with full recommended doses of either benazepril or valsartan. The protective effects of benazepril and valsartan monotherapies against progression to microalbuminuria were also similar. All treatments were safe and well tolerated, with a slight excess of hyperkalemia and hypotension episodes in the combination therapy group. What do these findings mean? Dual RAS blockade should not be preferred to ACE inhibitor or ARB monotherapy for the primary prevention of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. Recent studies showing that sodium–glucose co-transporter 2 (SGLT2) inhibitors may afford substantial nephro- and cardioprotection to patients with type 2 diabetes and varying degrees of albuminuria might pave the way to novel prevention strategies based upon the integrated use of these novel medications with an ACE inhibitor or an ARB, but not with their combination.

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD. Methods and findings We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15–40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 [−0.63 to 1.75] ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio [HR] [95% CI] adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 [0.127 to 0.742], p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR [95% CI]: 0.121 [0.017 to 0.866], p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size. Conclusions In this study we observed that in later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4. Trial registration ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12., In this double-blind, placebo-controlled, phase 3 randomised trial, Piero Ruggenenti and co-workers assessed the renoprotective effects of Octreotide-LAR in adults with ADPKD at high risk of ESRD, Author summary Why was this study done? Autosomal dominant polycystic kidney disease is the most frequent genetically determined renal disease and affects approximately 10% of patients on chronic dialysis therapy because of end-stage kidney disease. The disease is characterized by relentless growth of renal cysts, with consequent disruption of normal parenchyma and progressive reduction of kidney function up to terminal kidney failure. Previous studies found that octreotide long-acting release (octreotide-LAR), an analog of somatostatin, slowed cyst growth and progressive renal function loss in patients with normal or slightly impaired kidney function. What did the researchers do and find? In this randomized and placebo-controlled trial, we evaluated whether the renoprotective effect of octreotide-LAR could be extended to patients with severe renal disease, that is, with chronic kidney disease stage 3b or 4. One-hundred patients with estimated glomerular filtration rate 15–40 ml/min/1.73 m2 were randomized to receive two 20-mg intramuscular injections of octreotide-LAR (n = 51) or sodium chloride (placebo; n = 49) every 28 days for 3 years. We found that 3-year treatment with octreotide-LAR did not appreciably affect glomerular filtration rate decline compared to placebo, but significantly slowed cyst growth and progression to end-stage kidney failure, in particular in patients with more severe renal insufficiency (stage 4) to start with, and was safe and tolerated well. What do these findings mean? Our present data—combined with previous evidence of a protective effect against kidney and liver volume growth and renal function loss in patients with normal or moderately reduced kidney function—indicate that octreotide-LAR could be a novel disease-modifying therapy that benefits patients with autosomal dominant polycystic kidney disease, including those with later-stage disease. Octreotide-LAR is an expensive medication. The identification of a subgroup of patients with CKD stage 4, accounting for approximately 10% to 15% of patients with autosomal dominant polycystic kidney disease, who are at high risk of kidney failure and at the same time may benefit the most from treatment may help increase the cost-effectiveness of octreotide-LAR for the prevention of end-stage renal disease (and related costs of renal replacement therapy and its complications) in this population.

Rationale & 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 & Participants Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy. Intervention After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg 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=49patients). 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/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) 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.

The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 μg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

Summary Background Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. Methods We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m 2 or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. Findings Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. Interpretation These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. Funding Polycystic Kidney Disease Foundation.

Background & Aims Short-term studies have shown that somatostatin analogues are effective in patients with polycystic kidney and liver disease. We evaluated the long-term effects of long-acting release octreotide (octreotide LAR), a somatostatin inhibitor, vs placebo in these patients. Methods We performed a controlled study of adults with polycystic kidney and liver disease (estimated glomerular filtration rate, 40 mL/min/1.73m 2 or more) at a single center in Italy. We analyzed data from 27 patients randomly assigned to groups given octreotide LAR (40 mg, n = 14) or placebo (n = 13) each month for 3 years. The primary outcome was absolute and percentage change in total liver volume (TLV), which was measured by magnetic resonance imaging at baseline, after 3 years of treatment, and then 2 years after treatment ended. Results Baseline characteristics were similar between groups. After 3 years, TLV decreased by 130.2 ± 133.2 mL in patients given octreotide LAR (7.8% ± 7.4%) ( P = .003) but increased by 144.3 ± 316.8 mL (6.1% ± 14.1%) in patients given placebo. Change vs baseline differed significantly between groups ( P = .004). Two years after treatment ended, TLV had decreased 14.4 ± 138.4 mL (0.8% ± 9.7%) from baseline in patients given octreotide LAR but increased by 224.4 ± 331.7 mL (11.0% ± 14.4%) in patients given placebo. Changes vs baseline still differed significantly between groups ( P = .046). Decreases in TLV were similar in each sex; the change in TLV was greatest among subjects with larger baseline TLV. No patient withdrew because of side effects. Conclusions In a placebo-controlled study of patients with polycystic kidney and liver disease, 3 years of treatment with octreotide LAR significantly reduced liver volume; reductions were maintained for 2 years after treatment ended. Octreotide LAR was well-tolerated. ClinicalTrials.gov number: NCT02119052.

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered 2 recurrences over the previous year and were in steroid-induced remission for 1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 μg/min was significantly associated with increased risk compared with albuminuria

Objectives: To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients. Design: The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre, prospective, double-blind, parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria randomized to at least 2-year VeraTran (verapamil/trandolapril 180 mg/2 mg daily) or trandolapril (2 mg daily, identical image) treatment. Main outcome was persistent macroalbuminuria (albuminuria >200 μg/min in two consecutive visits). Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7%. Results: Over a median follow-up of 4.5 years, 18 patients (13%) on VeraTran vs. 15 (10.5%) on trandolapril [unadjusted hazard ratio (95% confidence interval [CI]) 1.07 (0.54-2.12), P = 0.852] progressed to macroalbuminuria, respectively; 62 (44.9%) vs. 71 (49.7%) [0.80 (0.57-1.12), P = 0.198] regressed to normoalbuminuria (urinary albumin excretion

BACKGROUND: The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion. METHODS: We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, ≥20 μg per minute at two consecutive visits). RESULTS: The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups. CONCLUSIONS: In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.