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To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria 2 (IQR: 0.16–0.50 mL/min per 1.73 m 2 ) on combined therapy, 0.36 mL/min per 1.73 m 2 (IQR: 0.18–0.53 mL/min per 1.73 m 2 ) on delapril, and 0.30 mL/min per 1.73 m 2 (IQR: 0.12–0.50 mL/min per 1.73 m 2 ) on placebo ( P =0.87 and P =0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04–0.78; P =0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07–0.99; P =0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24–0.87; P =0.017) and 0.52 (0.27–0.99; P =0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo ( P =0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

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.

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

Context Acetyl-l-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk. Objective To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy. Design After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin. Setting Five diabetology units and one clinical research center in Italy. Patients Two hundred twenty-nine patients with hypertension and dyslipidemic T2D >40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine, In a prospective randomized controlled trial in 229 patients with hypertension and T2D, 6-month oral acetyl-L-carnitine (1000 mg twice daily) or placebo treatment had similar effects on blood pressure, metabolic control, lipids, and GFR.

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.

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.