Measured and Estimated Glomerular Filtration Rate to Evaluate Rapid Progression and Changes over Time in Autosomal Polycystic Kidney Disease: Potential Impact on Therapeutic Decision-Making.

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (-3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.

The error of estimated GFR in predialysis care.

The error of estimated glomerular filtration rate (eGFR) and its consequences in predialysis are unknown. In this prospective multicentre study, 315 predialysis patients underwent measured GFR (mGFR) by the clearance of iohexol and eGFR by 52 formulas. Agreement between eGFR and mGFR was evaluated by concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). In a sub-analysis we assessed the impact of eGFR error on decision-making as (i) initiating dialysis, (ii) preparation for renal replacement therapy (RRT) and (iii) continuing clinical follow-up. For this sub-analysis, patients who started RRT due to clinical indications (uremia, fluid overload, etc.) were excluded. eGFR had scarce precision and accuracy in reflecting mGFR (average CCC 0.6, TDI 70% and cp 22%) both in creatinine- and cystatin-based formulas. Variations -larger than 10 ml/min- between mGFR and eGFR were frequent. The error of formulas would have suggested (a) premature preparation for RTT in 14% of stable patients evaluated by mGFR; (b) to continue clinical follow-up in 59% of subjects with indication for RTT preparation due to low GFRm and (c) to delay dialysis in all asymptomatic patients (n = 6) in whom RRT was indicated based on very low mGFR. The error of formulas in predialysis was frequent and large and may have consequences in clinical care.

Measured GFR in murine animal models: review on methods, techniques, and procedures.

Chronic kidney disease (CKD) is one of the most common chronic diseases worldwide, with increasing rates of morbidity and mortality. Thus, early detection is essential to prevent severe adverse events and the progression of kidney disease to an end stage. Glomerular filtration rate (GFR) is the most appropriate index to evaluate renal function in both clinical practice and basic medical research. Several animal models have been developed to understand renal disease induction and progression. Specifically, murine models are useful to study the pathogenesis of renal damage, so a reliable determination of GFR is essential to evaluate the progression of CKD. However, as in clinical practise, the estimation of GFR in murine by levels of serum/urine creatinine or cystatin-C could not be accurate and needed other more reliable methods. As an alternative, the measurement of GFR by the clearance of exogenous markers like inulin, sinistrin, 51Cr-EDTA, 99mTc-DTPA, 125I-iothalamate, or iohexol could be performed. Nevertheless, both approaches-estimation or measurement of GFR-have their limitations and a standard method for the GFR determination has not been defined. Altogether, in this review, we aim to give an overview of the current methods for GFR assessment in murine models, describing each methodology and focusing on their advantages and limitations.

Early glomerular filtration rate changes in living kidney donors and recipients: an example of renal plasticity.

Background: In living kidney transplantation there are two different individuals, a healthy donor and a renal transplant recipient. This is an excellent human model to study factors that influence kidney function in the context of reduced renal mass and the adaptation of two comparable kidneys to different metabolic demands. Methods: We analyzed the changes in measured glomerular filtration rate (GFR, iohexol) from pretransplantation to 12 months after transplantation in 30 donor-recipient pairs. Each donor was compared with his/her recipient. We defined a priori three different groups based on GFR differences at 12 months: donor > recipient (Group A; 78 ± 8 versus 57 ± 8 mL/min), donor < recipient (Group B; 65 ± 11 versus 79 ± 11 mL/min) and donor ≈ recipient (Group C; 66 ± 7 versus 67 ± 7 mL/min). Other factors like donor/recipient mismatches in body mass index (BMI), surface area and gender were evaluated. Results: In Group A donors were mostly male and recipients were female (75% each). Donors had a higher baseline weight than their recipients. During follow-up, weight remained stable in donors but increased 7% in recipients. In Group B donors were mostly female (60%) and recipients male. At baseline, donors had a lower weight than recipients. At 12 months, weight was stable in donors but increased in recipients. In Group C donors were mostly (75%) female and recipients male. At baseline, donors had a higher BMI than their recipients. At 12 months, BMI was stable in donors but increased 14% in recipients. In multivariable analysis, higher GFR at 12 months was associated with higher baseline weight and GFR in donors and with male gender and higher baseline weight in recipients. Conclusions: Kidneys from living donors are more 'plastic' than originally thought and respond to metabolic demands and weight changes of their new host. These changes should be taken into account when assessing GFR outcomes in this population.

Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1-4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed. METHODS: We evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment. RESULTS: No formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min. CONCLUSIONS: The evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.

Long-term kidney and systemic effects of calorie restriction in overweight or obese type 2 diabetic patients (C.Re.S.O. 2 randomized controlled trial).

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.

Estimated GFR Slope in Kidney Transplant Patients: When the Error Is Random.

BACKGROUND: The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes. METHODS: We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than -3 mL/min/y; stable renal function: -3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y. RESULTS: Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%. CONCLUSIONS: Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.

Glomerular resistances predict long-term GFR decline in type 2 diabetic patients without overt nephropathy: a longitudinal subgroup analysis of the DEMAND trial.

AIMS: Investigating whether and to what extent changes in glomerular hemodynamic parameters, beyond glomerular hyperfiltration, could predict glomerular filtration rate (GFR) decline in hypertensive, non-proteinuric type 2 diabetic patients. MATERIALS AND METHODS: We estimated baseline afferent (Ra) and efferent (Re) arteriolar resistances and glomerular hydrostatic pressure in 60 consecutive patients from DEMAND study, using the Gomez' equations. Baseline renal plasma flow was measured by para-aminohippurate plasma clearance, and GFR was measured by iohexol plasma clearance at baseline and every 6 months for a median of 4.0 years [IQR 3.5-4.0 years]. Patients with a GFR decline > or ≤ 3 mL/min/1.73 m2/year were categorized as "Progressors" and "Non-progressors," respectively. Predictors of GFR decline were studied by univariable and multivariable logistic regression analysis. RESULTS: •The GFR declined by a median [IQR] of 4.06 [5.46-2.00] mL/min/1.73 m2/year in the study group as a whole and by 5.35 [6.60-4.48] mL/min/1.73 m2/year and 1.71 [2.14-1.33] mL/min/1.73 m2/year in Progressors and Non-progressors, considered separately. Progressors had a higher baseline Ra (3487.3 ± 1349.3 dyne•sec•cm-5 vs. 2877.0 ± 668.9 dyne•sec•cm-5, p < 0.05) and higher Ra/Re ratio (1.4 ± 0.5 vs. 1.1 ± 0.3, p < 0.01) than Non-progressors. At multivariable logistic regression analysis, Ra/Re ratio and arterial hypertension duration were independently associated with GFR decline (odds ratio [95% CI] 8.50 [1.56-46.28] and 1.14 [1.01-1.28]), respectively. CONCLUSIONS: Increased Ra/Re ratio and arterial hypertension duration predict early GFR decline in hypertensive non-proteinuric type 2 diabetic patients. These findings could be explained by glomerular hypoperfusion and chronic ischemic injury related to pre-glomerular arteriolar narrowing. CLINICAL TRIAL REGISTRATION: DEMAND, NCT00157586, September 12, 2005.

Estimated glomerular filtration rate by formulas in patients with cirrhosis: An unreliable procedure.

BACKGROUND & AIMS: In cirrhosis, the reliability of formulas that estimate renal function, either those specifically developed in this population or the classic equations, has not been properly quantified. We studied the agreement between estimated (eGFR) and measured glomerular filtration rate (mGFR) in cirrhosis. METHODS: Renal function was estimated with 56 formulas including specific equations: Glomerular Filtration Rate Assessment in Liver Disease (GRAIL), Royal Free Hospital Cirrhosis (RFHC) and Mindikoglu-eGFR, and measured with a gold standard procedure; plasma clearance of iohexol using dried blood spots sampling in a group of cirrhotics. The agreement eGFR-mGFR was evaluated with specific tests: total deviation index (TDI), concordance correlation coefficient (CCC) and coverage probability (CP). We defined acceptable agreement as values: TDI < 10%, CCC ≥ 0.9 and CP > 90%. RESULTS: A total of 146 patients (age 65 ± 9 years, 81% male) were evaluated; 61 (42%) Child A, 67 (46%) Child B and 18 (12%) Child C. Median MELD-Na was 14 (9-15). The agreement between eGFR and mGFR was poor: TDI averaged was of 73% (90% of the estimations ranged from ±73% of mGFR); CCC averaged was 0.7 indicating low concordance and CP averaged 22% indicating that 78% of the estimations have an error > 10%. Specific formulas showed also poor agreement: TDI was 82%, 70% and 37% for the GRAIL, RFHC and Mindikoglu equations, respectively. CONCLUSIONS: Overall, formulas poorly estimated renal function in cirrhotic patients. Specific formulas designed for cirrhosis did not outperform classic equations. eGFR must be considered with caution in cirrhotic patients.

Preventing microalbuminuria with benazepril, valsartan, and benazepril-valsartan combination therapy in diabetic patients with high-normal albuminuria: A prospective, randomized, open-label, blinded endpoint (PROBE) study.

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.

Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial.

BACKGROUND: We 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 FINDINGS: ATHENA, 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. CONCLUSIONS: In 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 REGISTRATION: ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.

Long-Term Outcomes of Kidney Transplants from Older/Marginal Donors: A Cohort Study.

INTRODUCTION: To safely expand the donor pool, we introduced a strategy of biopsy-guided selection and allocation to single or dual transplantation of kidneys from donors >60 years old or with hypertension, diabetes, and/or proteinuria (older/marginal donors). Here, we evaluated the long-term performance of this approach in everyday clinical practice. METHODS: In this single-center cohort study, we compared outcomes of 98 patients who received one or two biopsy-evaluated grafts from older/marginal donors ("recipients") and 198 patients who received nonhistologically assessed single graft from ideal donors ("reference-recipients") from October 2004 to December 2015 at the Bergamo Transplant Center (Italy). RESULTS: Older/marginal donors and their recipients were 27.9 and 19.3 years older than ideal donors and their reference-recipients, respectively. KDPI/KDRI and donor serum creatinine were higher and cold ischemia time longer in the recipient group. During a median follow-up of 51.9 (interquartile range 23.1-88.6) months, 11.2% of recipients died, 7.1% lost their graft, and 16.3% had biopsy-proven acute rejection (BPAR) versus 3.5, 7.6, and 17.7%, respectively, of reference-recipients. Overall death-censored graft failure (rate ratio 0.78 [95% CI 0.33-2.08]), 5-year death-censored graft survival (94.3% [87.8-100.0] vs. 94.2% [90.5-98.0]), BPAR incidence (rate ratio 0.87 [0.49-1.62]), and yearly measured glomerular filtration rate decline (1.18 ± 3.27 vs. 0.68 ± 2.42 mL/min/1.73 m2, p = 0.37) were similar between recipients and reference-recipients, respectively. CONCLUSIONS: Biopsy-guided selection and allocation of kidneys from older/marginal donors can safely increase transplant activity in clinical practice without affecting long-term outcomes. This may help manage the growing gap between organ demand and supply without affecting long-term recipient and graft outcomes.

Iohexol plasma clearance simplified by Dried Blood Spot (DBS) sampling to measure renal function in conscious mice.

There is no simple method to measure glomerular filtration rate (GFR) in mice, which limits the use of mice in models of renal diseases. We aimed at simplifying the plasma clearance of iohexol in mice, using dried blood spot (DBS) sampling in order to reduce the amount of blood taken for analysis. GFR was measured simultaneously by a reference method in total blood-as described before-and tested method using DBS in fifteen male and six female C57BL/6J mice. Total blood extraction was 50 µL for the reference methods and 25µL for the tested methods, distributed in 5 samples. The agreement of GFR values between both methods was analyzed with the concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). The agreement between both methods was excellent, showing a TDI = 8.1%, which indicates that 90% of the GFR values obtained with DBS showed an error ranging from - 8 to + 8% of the reference method; a CCC of 0.996 (CI: 0.992), reflecting high precision and accuracy and a CP of 94 (CI: 83), indicating that 6% of the GFR values obtained with DBS had an error greater than 10% of the method in blood. So, both methods are interchangeable. DBS represent a major simplification of GFR measurement in mice. Also, DBS improves animal welfare by reducing the total blood required and refining the procedure.

A Simplified Iohexol-Based Method to Measure Renal Function in Sheep Models of Renal Disease.

Sheep are highly adequate models for human renal diseases because of their many similarities in the histology and physiology of kidney and pathogenesis of kidney diseases. However, the lack of a simple method to measure glomerular filtration rate (GFR) limits its use as a model of renal diseases. Hence, we aimed to develop a simple method to measure GFR based on the plasma clearance of iohexol by assessing different pharmacokinetic models: (a) CL2: two-compartment (samples from 15 to 420 min; reference method); (b) CL1: one-compartment (samples from 60 to 420 min); (c) CLlf: CL1 adjusted by a correction formula and (d) SM: simplified CL2 (15 to 300 min). Specific statistics of agreement were used to test the models against CL2. The agreement between CL1 and CL2 was low, but both CL1f and SM showed excellent agreement with CL2, as indicated by a total deviation index of ~5-6%, a concordance correlation of 0.98-0.99% and a coverage probability of 99-100%, respectively. Hence, the SM approach is preferable due to a reduced number of samples and shorter duration of the procedure; two points that improve animal management and welfare.

Kidney transplant tolerance associated with remote autologous mesenchymal stromal cell administration.

Here we report the case of successful immune tolerance induction in a living-donor kidney transplant recipient remotely treated with autologous bone marrow-derived mesenchymal stromal cells (MSC). This case report, which to the best of our knowledge is the first in the world in this setting, provides evidence that the modulation of the host immune system with MSC can enable the safe withdrawal of maintenance immunosuppressive drugs while preserving optimal long-term kidney allograft function.

Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial.

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.

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

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

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.