A 2017 review of epidemiology literature resulted in an estimated prevalence of autosomal dominant polycystic kidney disease (ADPKD) of approximately three to four per 10,000. Patients with ADPKD experience progressive cyst formation in both kidneys and loss of renal function. In the majority of affected patients, end-stage renal disease requiring renal replacement therapy (RRT), dialysis or kidney transplantation, occurs between the fourth and seventh decade of life. Data collected between 1991 and 2010 demonstrate that approximately 10% of patients receiving RRT had ADPKD.
For those in this patient population, there are few treatments to delay the rate of disease progression. Emerging data regarding the pathophysiology of ADPKD has enabled identification of several ADPKD-specific therapeutic targets. In renal tubular cells affected by ADPKD, there is an increase in cyclic adenosine monophosphate, promoting growth of the affected cells and stimulating secretion of transepithelial fluid, two processes involved with formation and growth of cysts.
Somatostatin, a peptide that is secreted by cells in the pancreas, nervous system, gastrointestinal tract, thyroid gland, and other organs, inhibits the enzyme that produces cyclic adenosine monophosphate in renal tubular cells when bound to the somatostatin receptor. Somatostatin analogues have been shown to be renoprotective in models for polycystic kidney disease.
Previous trials in patients with ADPKD have been limited in size and duration. Esther Meijer, PHD, and colleagues in the Netherlands conducted the DIPAK 1 trial to examine the renoprotective efficacy and adverse events of the somatostatin analogue lanreotide in patients with later-stage ADPKD. Results of the open-label randomized trial were reported online in JAMA[doi:10.1001/jama.2018.15870]
The primary outcome of interest was change in kidney function; secondary outcomes were (1) change in estimated glomerular filtration rate (eGFR) between the pretreatment and post-treatment visits; (2) incidence of worsening kidney function; (3) change in the adjusted for height total kidney volume (htTKV) between the baseline and post-treatment visits; and (4) change in health-related quality of life between the baseline and post-treatment visits. Additional secondary outcomes were the patients’ adverse event profile and tolerability of lanreotide.
A total of 377 patients were assessed for eligibility; of those, 309 were enrolled in the study from July 2012 to February 2014. Of the 309 enrollees, 154 were randomly assigned to the lanreotide group and 155 to the control group. Patients in the lanreotide group received standard care plus lanreotide; patients in the control group received standard care only. Following randomization, four patients withdrew without having any efficacy or adverse event data recorded (one in the lanreotide group and three in the control group), resulting in a final cohort of 153 patients in the lanreotide group and 152 in the control group in the primary efficacy and the safety analysis.
The two groups were balanced in demographic and clinical characteristics. Nine patients withdrew from the control group and 35 withdrew from the lanreotide group; there were no differences in baseline characteristics per randomization group between those who completed the study and those who withdrew during the study.
The mean duration of the treatment phase was 104 weeks for the lanreotide group and 117 weeks for the control group. Lanreotide was down-titrated in 26 patients (to 90 mg, subcutaneously [SC], once every 4 weeks in five patients and to 60 mg, SC, once every 4 weeks in five patients). Fourteen patients reached eGFR < 30 mL/min/1.73 m2 and the dose was down-titrated per protocol. Thirty-five patients stopped lanreotide early; 20 of those did so due to adverse events. Of the patients who continued receiving lanreotide, the mean dose at the end of the treatment phase was 112 mg.
There was a slight, statistically significant decline in eGFR of –1.6 mL/min/1.73 m2 in the lanreotide group (95% confidence interval [CI], –2.40 to –0.78) compared with –0.6 mL/min/1.73 m2 in the control group (95% CI, –1.20 to 0.10) during the first 12 weeks of treatment. During the 2.5-year treatment period, the slope of decline in eGFR in the lanreotide group was –3.53 mL/min/1.73 m2 (95% CI, –4.00 to –3.07) compared with –3.46 mL/min/1.73 m2 (95% CI, –3.89 to –3.02) in the control group.
The mean difference in the slope of eGFR decline in the two groups was not statistically significant. Further, there was no evidence in a prespecified sub group analysis that lanreotide improved the primary outcome in any of the subgroups included.
The study included analysis of four secondary outcomes. In the lanreotide group, the change in eGFR between pretreatment and post-treatment visits was –3.58 mL/min/1.73 m2 compared with –3.45 mL/min/1.73 m2 in the control group. There was no statistical difference in the mean difference between the two groups.
There was also no statistically significant difference between the two groups in the incidence of worsening kidney function; 21 patients in the lanreotide group and 29 in the control group reached that outcome, including three in the lanreotide group and two in the control group who initiated RRT, resulting in a hazard ratio of 0.87 (95% CI, 0.49-1.52; P=.87) with lanreotide. There were no significant differences in change in quality of life from the pretreatment and post-treatment visits between the two groups (0.05 vs 0.07; difference, –0.03 units per year).
In the lanreotide group, the rate of change in htTKV between the pretreatment and post-treatment visits was significantly lower than in the control group (4.15% per year vs 5.56% per year; difference, –1.33% per year; 95% CI, –2.41 to –0.24; P=.02). The change corresponded to a 24% reduction in htTKV growth rate. The beneficial effects of lanreotide on the increase in htTKV were seen in all subgroups.
Adverse events in the lanreotide group versus the control group were discomfort at the injection site (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%).
The study had several limitations, including the open-label design, the predominately white study population, and the rate of decline in eGFR in the control group being less than expected in the power analysis.
In conclusion, the researchers said, “Among patients with later-stage ADPKD, 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 to preserve kidney function in later-stage ADPKD.”
- Researchers in the Netherlands conducted an open-label randomized clinical trial to assess the effects of the somatostatin analogue lanreotide on the rate of loss of kidney function in patients with later-stage autosomal dominant polycystic kidney disease (ADPKD).
- The primary outcome of interest was the annual change in estimated glomerular filtration rate during the 2.5-year treatment phase; secondary outcomes included adverse events.
- Treatment with lanreotide did not slow the decline in kidney function compared with standard of care in patients with later-stage ADPKD; adverse events in the lanreotide group were predominantly related to the injection site.