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. Therefore this dysfunction results in reduced intracellular calcium concentration, leading to the 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. But 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.
ADPKD with a glomerular filtration rate
Therefore they 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. So 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 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.
Therefore the baseline characteristics are 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.
Serum creatinine or ESRD
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 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. In conclusion, they observed that in later-stage ADPKD; octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4.