Introduction:Approximately 30% of patients with primary membranous nephropathy (MN) and nephrotic syndrome (NS) fail rituximab treatment through mechanisms that could be overcome by the human IgG1 monoclonal anti-CD38 antibody, felzartamab. Methods:In this prospective, single-arm, single-center, open-label trial, 10 consenting Caucasian adult patients with MN, rituximab-resistant NS, and estimated glomerular filtration rate (GFR) > 30 ml/min per 1.73 m2 received a 5-month, 9-dose course of 16 mg/kg felzartamab infusions at the Nephrology Unit of Bergamo Hospital, Italy between November 9, 2021 and February 1, 2023 and were followed up with for 24 months. Clinical and laboratory parameters were evaluated at baseline, 1, 2, 5, 6, 9, 18, and 24 months, whereas GFR as well as albumin and IgG fractional clearances were measured at baseline and at 6, 9, 12, 18, and 24 months posttreatment. The primary outcome was 24-hour proteinuria (median of 3 consecutive measurements) at 12 months. Results:Twelve-month 24-hour proteinuria was similar to baseline. Linear-mixed model analyses showed no significant time-dependent changes in 24-hour proteinuria and albuminuria; serum total-protein, albumin, creatinine and lipid levels, GFR and albumin fractional clearances. Circulating anti-phospholipase A2 receptor (PLA2R) antibodies transiently decreased but were never depleted. All considered Igs transiently decreased up to month 12, and recovered to baseline thereafter. Felzartamab deeply and persistently decreased natural killer (NK), B cells, and antigen-inexperienced transitional B cells; however, it did not affect CD20-expressing memory B cells, plasmablasts, and plasma cells. Treatment was safe and well-tolerated. Conclusion:One course of felzartamab was safe and well-tolerated, but ineffective in patients with MN and rituximab-resistant NS, possibly because of the inability to persistently deplete nephritogenic autoantibody-producing CD38-expressing B cells.

Introduction Approximately 30% of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) fail rituximab therapy through mechanisms that could be overcome by obinutuzumab. Methods In this prospective, single-arm, single-center, open-label trial, twenty consenting adults with MN and rituximab-resistant NS received three 1000 mg obinutuzumab infusions at the Bergamo Nephrology Unit (Italy) between March 2022 and February 2024 and were monitored for at least 12 months. The primary outcome was a composite endpoint of normo-albuminemia and complete (proteinuria <0.3 g/day) or partial (proteinuria <3.5 g/day with ≥50% reduction from baseline) NS remission at 12-month follow-up. Twenty-four-hour proteinuria and GFR were evaluated at baseline and at 3, 6, 9, 12, 18, and 24 months post-treatment. Results At 12 months, 16 patients met the combined endpoint, 4 with complete remission. No patient relapsed after remission. Median [IQR] 24-hour proteinuria decreased from 5.7 [4.7-8.1] to 1.3 [0.5-2.7] g/24-hour. Albumin and IgG fractional clearances also decreased, whereas serum albumin increased from 2.9±0.6 g/dl to 3.9±0.3 g/dl (p<0.0001 for all changes). Dyslipidemia, hypocalcemia and hypo-gammaglobulinemia improved significantly and GFR stabilized. At 12 months, total B-cells and circulating anti-PLA2R antibodies were depleted. Similar findings were observed in the cohort of ten patients who completed 24 months of follow-up. However, total B-cells re-emerged in the circulation without an increase in anti-PLA2R antibodies and proteinuria, or relapses. Treatment was safe and well tolerated. Conclusions Obinutuzumab treatment is extremely effective and safe in patients with MN and rituximab-resistant NS and can achieve persistent remission in this population.

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are nephroprotective in patients with chronic kidney disease (CKD) and mild-to-moderate renal insufficiency. Methods: This prospective, randomized, cross-over, placebo-controlled, double-blind study compared the effects of 6-week dapagliflozin (10 mg/d) with placebo treatment in 31 consenting nondiabetic Caucasian adults with stage 4 CKD and proteinuria > 0.5 g/24 h. Participants were identified at the Nephrology Unit of Papa Giovanni XXIII Hospital and treated at Mario Negri Institute (Bergamo, Italy) between December 2021 and December 2023. Normalized glomerular filtration rate (GFR) (using iohexol plasma clearance) and 24-hour proteinuria (median of 3 urinary measurements) were co–primary outcomes. Analyses were by modified intention-to-treat. Results: At 6 weeks, dapagliflozin significantly decreased GFR by 1.88 ± 5.00 ml/min per 1.73 m2 (P = 0.022) and proteinuria by 0.50 (−0.10 to 0.80) g/24 h (P = 0.026) versus placebo. The dapagliflozin-induced GFR (P < 0.001) and proteinuria (P = 0.003) reduction was already significant at 1 week. At 6 weeks, dapagliflozin reduced absolute GFR (P = 0.026), the CKD-Epidemiology Collaboration (CKD-Epi) equation–based estimated GFR (eGFR) (P = 0.003), the Modification of Diet in Renal Disease (MDRD) equation–based eGFR (P = 0.002), 24-hour albuminuria (P = 0.001), total protein (P = 0.057) and albumin (P = 0.009) fractional clearances, and fasting blood glucose (P < 0.001); and increased serum albumin (P = 0.001), renin activity (P = 0.020), glucosuria (P < 0.001), and glucose fractional clearance (P < 0.001) versus placebo. All changes reversed completely after treatment withdrawal. GFR changes correlated inversely with changes in renal plasma flow (RPF) (P = 0.010) and positively with changes in postglomerular resistance (P < 0.001) but did not correlate with changes in preglomerular resistance. There were no serious adverse events. Conclusion: Dapagliflozin safely ameliorates (compensatory) glomerular hyperfiltration and proteinuria and is glycosuric in nondiabetic patients with preterminal CKD. GFR reduction is likely because of postglomerular vasodilation rather than preglomerular vasoconstriction.

Introduction:Approximately 30% of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) fail rituximab therapy through mechanisms that could be overcome by obinutuzumab. Methods:In this prospective, single-arm, single-center, open-label trial, 20 consenting adults with MN and rituximab-resistant NS received three 1000 mg obinutuzumab infusions at the Bergamo Nephrology Unit (Italy) between March 2022 and February 2024 and were monitored for ≤ 12 months. The primary outcome was a composite end point of normo-albuminemia and complete (proteinuria < 0.3 g/d) or partial (proteinuria < 3.5 g/d with ≥ 50% reduction from baseline) NS remission at 12-month follow-up. Twenty-four-hour proteinuria and glomerular filtration rate (GFR) were evaluated at baseline and at 3, 6, 9, 12, 18, and 24 months posttreatment. Results:At 12 months, 16 patients met the combined end point, 4 with complete remission. No patient relapsed after remission. Median (interquartile range) 24-h proteinuria decreased from 5.7 (4.7-8.1) to 1.3 (0.5-2.7) g/24 h. Albumin and IgG fractional clearances also decreased, whereas serum albumin increased from 2.9 ± 0.6 g/dl to 3.9 ± 0.3 g/dl (P < 0.0001 for all changes). Dyslipidemia, hypocalcemia, and hypo-gammaglobulinemia improved significantly and GFR stabilized. At 12 months, total B cells and circulating anti-phospholipase A2 receptor (PLA2R) antibodies were depleted. Similar findings were observed in the cohort of 10 patients who completed 24 months of follow-up. However, total B cells reemerged in the circulation without an increase in anti-PLA2R antibodies and proteinuria, or relapses. Treatment was safe and well-tolerated. Conclusion:Obinutuzumab treatment is extremely effective and safe in patients with MN and rituximab-resistant NS and can achieve persistent remission in this population.

Large GWAS indicated that genetic factors influence the response to SARS-CoV-2. However, sex, age, concomitant diseases, differences in ancestry, and uneven exposure to the virus impacted the interpretation of data. We aimed to perform a GWAS of COVID-19 outcome in a homogeneous population who experienced a high exposure to the virus and with a known infection status. We recruited inhabitants of Bergamo province-that in spring 2020 was the epicenter of the SARS-Cov-2 pandemic in Europe-via an online questionnaire followed by personal interviews. Cases and controls were matched by age, sex and risk factors. We genotyped 1195 individuals and replicated the association at the 3p21.31 locus with severity, but with a stronger effect size that further increased in gravely ill patients. Transcriptome-wide association study highlighted eQTLs for LZTFL1 and CCR9. We also identified 17 loci not previously reported, suggestive for an association with either COVID-19 severity or susceptibility.

Background Tolvaptan and octreotide–long-acting release (LAR) have renoprotective effects in autosomal dominant polycystic kidney disease (ADPKD) that are partially mediated by amelioration of compensatory glomerular hyperfiltration. We compared the effects of tolvaptan and octreotide-LAR combination therapy versus those of tolvaptan monotherapy in patients with ADPKD. Methods This pilot, randomized, placebo-controlled, cross-over trial primarily compared the effects of 1- and 4-week treatments with octreotide-LAR (two 20-mg i.m. injections) or placebo (two i.m. 0.9% saline solution injections) added-on tolvaptan (up to 90 and 30 mg/d) on GFR (iohexol plasma clearance) in 19 consenting patients with ADPKD referred to a clinical research center in Italy. Analyses were intention-to-treat. The local ethical committee approved the study. Results At 4 weeks, GFR significantly decreased by a median (interquartile range) of 3 (−1 to 5) ml/min per 1.73 m 2 with tolvaptan and placebo ( P =0.01) and by 7 (3–14) ml/min per 1.73 m 2 with tolvaptan and octreotide-LAR ( P =0.03). GFR changes during the two treatment periods differed by 2 (−5 to 14) ml/min per 1.73 m 2 ( P =0.28). At 1 week, GFR significantly decreased by 3 (0–7) ml/min per 1.73 m 2 with tolvaptan and placebo ( P =0.006) and by 10 (−6 to 16) ml/min per 1.73 m 2 with tolvaptan and octreotide-LAR add-on therapy ( P <0.001). GFR changes during the two treatment periods significantly differed by 3 (0–12) ml/min per 1.73 m 2 ( P =0.012). Total kidney volume nonsignificantly changed by 4 (−48 to 23) ml with tolvaptan and placebo ( P =0.74), whereas it decreased significantly by 41 (25–77) ml with tolvaptan and octreotide-LAR ( P =0.001). Changes during the two treatment periods differed by 36 (0–65) ml ( P =0.01). Octreotide-LAR also attenuated ( P =0.02) the aquaretic effect of tolvaptan. Treatments were well tolerated. Conclusions In patients with ADPKD, octreotide-LAR added-on tolvaptan reduced GFR more effectively than octreotide-LAR and placebo. Octreotide-LAR also reduced total and cystic kidney volumes and attenuated the acquaretic effect of tolvaptan. Clinical Trial registry name and registration number: Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL), NCT03541447.

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 <1.2 mg/dL and albuminuria ≤300 mg/24 h were randomized (1:1) to two-year 25% CR (n = 53) or standard diet (SD, n = 50). Primary outcome was 6-month measured GFR. Analyses were by modified intention-to-treat. RESULTS:At 6 months GFR decreased by 5.16 ± 10.03 mL/min (P = 0.001) with CR, and by 0.98 ± 9.71 mL/min (P = 0.497) with SD. Between-group difference was significant (P = 0.044). GFR decline from 6 to 24 months was significant with SD (P < 0.01), but not with CR (P = 0.075). Between-group difference, however, was not significant (P = 0.414). Body weight, BMI, waist circumference, systolic blood pressure, HbA1c, blood glucose, serum triglycerides decreased and ApoA-I concentration increased with CR. No changes were observed with SD. Between-group differences were significant. CR was tolerated well. CONCLUSIONS:In obese type 2 diabetic patients, CR ameliorated glomerular hyperfiltration and several cardiovascular risk factors, and blunted long-term GFR decline. TRIAL REGISTRATION:NCT01930136.

BackgroundWe compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.Methods and findingsATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.ConclusionsIn this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.Trial registrationClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.

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.

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.

AimsTo 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 methodsIn 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.ResultsRecruitment 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.ConclusionsIn 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.

In individuals with type 2 diabetes with abdominal obesity, hyperfiltration is a risk factor for accelerated glomerular filtration rate (GFR) decline and nephropathy. In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end point trial, consenting patients with type 2 diabetes aged >18 years, with waist circumference >94 (males) or >80 (females) cm, serum creatinine <1.2 mg/dL, and normoalbuminuria were randomized (1:1) with permuted blocks to 6 months of a 25% calorie restricted (CR) or standard diet (SD). Primary outcome was measured GFR (iohexol plasma clearance). Analyses were by modified intention to treat. At 6 months, GFR significantly decreased in 34 patients on CR and did not change appreciably in 36 on SD. Changes were significantly different between the groups. GFR and body weight reduction were correlated. GFR reduction was larger in hyperfiltering (GFR >120 mL/min) than nonhyperfiltering patients and was associated with BMI, waist circumference, blood pressure, heart rate, HbA(1c), blood glucose, LDL-to-HDL cholesterol ratio, C-reactive protein, angiotensin II, and albuminuria reduction and with increased glucose disposal rate (measured by hyperinsulinemic-euglycemic clamps). Protein and sodium intake and concomitant treatments were similar between the groups. CR was tolerated well. In patients with type 2 diabetes with abdominal obesity, CR ameliorates glomerular hyperfiltration, insulin sensitivity, and other cardiovascular risk factors, effects that might translate into long-term nephro- and cardioprotection.

BACKGROUND AND OBJECTIVES: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.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: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.RESULTS: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) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) 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; P<0.01) 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 (P<0.01 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.CONCLUSIONS: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.

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8-152.0) to 63.3 (52.0-79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.