Somatostatin In Patients With Autosomal Dominant Polycystic Kidney Disease And Moderate To Severe Renal Insufficiency

Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common hereditary cystic renal disease, has an incidence of 1 in 800 live births and account for 7-10% of patients on dialysis in developed countries. Clinically, ADPKD is characterized by renal and extra renal manifestations. In the kidneys, multiple cysts grow from distal and collecting tubular epithelial cells producing progressive renal enlargement with relatively initial stable renal functions. Thereafter, both tubular and secondary interstitial damage lead to faster renal loss and end-stage renal disease (ESRD) in approximately half of all patients affected in their fifth or sixth decade of life. More than 50% of the patients display hepatic cysts derived from cholangiocyte proliferation and fluid secretion. Pancreatic and intestinal cysts as well as increased risk of aortic aneurysms, heart-valve defects and sudden death due to rupture of intracerebral aneurysms are extra-renal manifestations.

Patients with ADPKD, at similar levels of proteinuria and blood pressure control, do not seem to benefit to the same extent of ACE inhibitor therapy and have faster decline in glomerular filtration rate (GFR) compared with other chronic kidney diseases. Thus, in ADPKD renoprotective interventions - in addition to achieving maximal reduction of arterial blood pressure and proteinuria, and limiting the effects of other potential disease progression promoters (such as dyslipidemia, chronic hyperglycemia, or smoking)- should also be specifically aimed to correct the dysregulation of epithelial cell growth, fluid secretion, and extracellular matrix deposition that is characteristic of this disease. Up to now, no specific therapies for ADPKD are available, but drugs like somatostatin, rapamycin, and tolvaptan targeting to growth and chloride secretion pathways are now being testing worldwide in some clinical trials.

We have performed some years ago a pilot prospective cross-over controlled study with long-acting somatostatin analog in patients with ADPKD and different degree of renal dysfunction. We found that in these patients, 6 month treatment with octreotide was safe, well tolerated, and slowed the time-dependent increase in total kidney volume to a significant extent compared to placebo. The net effect in kidney volume resulted from an action of the drug on cyst volume and on parenchyma volume. Moreover, more recent post-hoc analysis of the concomitant liver disease progression in the same ADPKD patients demonstrated a significant reduction in the total liver volume during octreotide treatment, not appreciably observed during placebo. Moreover, in the untreated ADPKD patients enrolled in our study, computed tomography evaluation of disease progression showed that the ratio of faintly contrast-enhanced parenchyma volume over total parenchyma volume strongly correlated with basal GFR and GFR changes during the observation period.

The good safety profile of octreotide and the slowing of renal growth demonstrated in our short-term clinical study did suggest the feasibility of a randomized trial in larger series of ADPKD patients with normal renal function or mild renal insufficiency to verify whether long-term somatostatin treatment may eventually provide effective renoprotection. This trial - the ALADIN study - is ongoing and the planned ADPKD patients have been enrolled. So far, no particular side effects have been reported. More important, preliminary interim analysis of data from patients who reached 1 year treatment, confirmed the beneficial effect of octreotide in slowing the growth of total kidney volume compared to placebo.

The findings of the safety and potential benefit of octreotide in few patients with severe renal insufficiency observed in our initial pilot study and the encouraging preliminary long-term effect results of octreotide on kidney growth, make worth investigating the efficacy of a long-acting somatostatin (Octreotide LAR) in slowing or even halting the kidney enlargement and renal function decline in ADPKD patients with moderate/severe renal failure.