Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease

Abstract

IMPORTANCE Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options. OBJECTIVE To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD. DESIGN, SETTING, AND PARTICIPANTS An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m 2. Follow-up of the 2.5-year trial ended in August 2017. INTERVENTIONS Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152). MAIN OUTCOMES AND MEASURES Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]). RESULTS Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was −3.53 vs −3.46 mL/min/1.73 m 2 per year (difference, −0.08 [95% CI, −0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (−3.58 vs −3.45; difference, −0.13 mL/min/1.73 m 2 per year [95% CI, −1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, −0.03 units per year [95% CI, −0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, −1.33% per year [95% CI, −2.41% to −0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%). CONCLUSIONS AND RELEVANCE Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease.

Pannexin‐1 mediates fluid shear stress‐sensitive purinergic signaling and cyst growth in polycystic kidney disease

“…Also, cystic PKD cell cultures display increased ATP release at basal conditions . Furthermore, previous studies have related purinergic receptors P2Y2 and P2X7 to cyst growth in an in vitro cystic model, and in vivo, in zebrafish and mouse PKD models …”

“…Conversely, approaches that did reach clinical research stages for PKD involve vasopressin antagonists, mTOR inhibitors, and somatostatin analogues. However, these approaches are not a definitive curative treatment option . An improved understanding of the molecular mechanisms behind ATP signaling in PKD may promote the development of novel therapeutic strategies for this disease.…”

International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people

“…Use of somatostatin analogues to delay disease progression in ADPKD has been studied only in adults. RCTs indicate that these agents are beneficial in patients with severe liver disease but do not have a sustained beneficial effect on renal function [131][132][133][134][135] . No severe cases of ADPKDrelated liver disease in children have been reported in the literature, and paediatric experience with these drugs…”

Novel Treatments for Polycystic Kidney Disease

“…follow-up [46]. Jinarc ® (Tolvaptan) has been approved in Europe, Japan, Canada and Australia for treatment of ADPKD in adults.…”