Date Published: April 5, 2019
Publisher: Public Library of Science
Author(s): Norberto Perico, Piero Ruggenenti, Annalisa Perna, Anna Caroli, Matias Trillini, Sandro Sironi, Antonio Pisani, Eleonora Riccio, Massimo Imbriaco, Mauro Dugo, Giovanni Morana, Antonio Granata, Michele Figuera, Flavio Gaspari, Fabiola Carrara, Nadia Rubis, Alessandro Villa, Sara Gamba, Silvia Prandini, Monica Cortinovis, Andrea Remuzzi, Giuseppe Remuzzi, Maarten W. Taal
Abstract: BackgroundAutosomal 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 findingsWe 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.ConclusionsIn 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 registrationClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12.
Partial Text: Every year worldwide, 4.8 to 15.3 per million persons with autosomal dominant polycystic kidney disease (ADPKD) progress to end-stage renal disease (ESRD) . In Europe approximately 10% of all patients undergoing renal replacement therapy have ADPKD . In ADPKD patients, mutations in the genes encoding for either polycystin 1 or polycystin 2 result in polycystin complex dysfunction. This dysfunction results in reduced intracellular calcium concentration, leading to high activity of adenylyl cyclase enzyme and up-regulation of 3′,5′-cyclic adenosine monophosphate (cAMP) levels . In the kidneys, the sustained high intracellular cAMP levels in the proximal and distal nephrons as well as collecting ducts lead to aberrant tubular epithelial cell proliferation and chloride-driven fluid secretion, the 2 key components of the process of cyst formation and growth in ADPKD . Uncontrolled cyst growth results in crowding of adjacent nephrons, destruction of normal renal parenchyma, and, eventually, substantial enlargement of the kidneys and progressive renal failure .
Of 104 assessed patients, 3 withdrew consent and 1 had eGFR < 15 ml/min/1.73 m2. Thus, 100 patients were randomized from October 11, 2011, to March 20, 2014 (51 to octreotide-LAR and 49 to placebo), and followed for a median (IQR) of 36 (24 to 37) months (Fig 1). Forty-eight patients allocated to octreotide-LAR and 47 allocated to placebo had evaluable TKV at baseline. After randomization, 4 patients on octreotide-LAR and 2 on placebo withdrew consent, 2 on octreotide-LAR left the study because of adverse events, and 1 on placebo progressed to ESRD. At 1 year, 45 patients on octreotide-LAR and 46 on placebo were available for GFR slope analyses; 37 on octreotide-LAR and 39 on placebo also had CT scan data evaluable for TKV analyses. After the first year, 3 patients on octreotide-LAR and 7 on placebo progressed to ESRD. All patients in the study at 1 year also had GFR slope data evaluable for analyses at the 3-year evaluation. In each group, 35 patients also had CT scan data for TKV analyses (Fig 1). All patients received all planned doses of octreotide-LAR or placebo from randomization to final visit. Thus, compliance to treatment was 100%. In this study we found that 3-year treatment with octreotide-LAR did not appreciably affect GFR decline compared to placebo in 100 patients with later-stage (CKD stage 3b or 4) ADPKD. Active treatment, however, slowed kidney volume growth and progression to the combined endpoint of doubling of serum creatinine or ESRD, and prevented the urinary protein increase observed in controls randomized to placebo. Octreotide-LAR was well tolerated, and no patient required treatment interruption or even transient dose down-titration during the study. The overall incidence of serious and non-serious adverse events was similar between groups. Our present findings confirm and extend evidence from the ALADIN trial  that octreotide-LAR may slow kidney volume growth and renal function loss in ADPKD patients with normal or moderately reduced kidney function. Moreover, our study provides the novel information that a somatostatin analog may slow the progression to a hard clinical endpoint such as ESRD in patients affected by ADPKD. Only one-sixth of patients on octreotide-LAR progressed to the combined endpoint of ESRD or doubling of serum creatinine compared to two-fifths of those on placebo. This finding may have implications for healthcare providers since postponing or even preventing ESRD, in addition to preserving patient quality of life and physical function, also reduces the direct and indirect costs for chronic renal replacement therapy. Notably, only 4 patients needed to be treated to prevent 1 composite endpoint, and 10 to prevent 1 ESRD event considered as a single endpoint, during the 3-year follow-up. Source: http://doi.org/10.1371/journal.pmed.1002777