Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Somatostatin in Polycystic Kidney: a Long-term Three Year Follow up Study

Summary: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disease, responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western countries. At comparable levels of blood pressure control and proteinuria, patients with ADPKD have faster decline in glomerular filtration rate than those with other renal diseases and do not seem to benefit to the same extent of ACE inhibitor therapy. A reasonable explanation for the above findings is that in ADPKD progression is largely dependent on the development and growth of cysts and secondary disruption of normal tissue. Thus, renoprotective interventions in ADPKD - in addition to achieve maximal reduction of arterial blood pressure and proteinuria and to limit the effects of additional potential promoters of disease progression such as dyslipidemia, chronic hyperglycemia or smoking - should also be specifically aimed to correct the dysregulation of epithelial cell growth, secretion, and matrix interactions characteristic of the disease.
  Evidence that specific receptors for somatostatin are present in the kidney tissue, arises the possibility that somatostatin treatment in patients with ADPKD might inhibit fluid formation and eventually induce the shrinking of renal cysts.To evaluate the tolerability and the safety of long-acting somatostatin in ADPKD patients, a prospective cross-over controlled study has been recently performed. This pilot study demonstrated the safety of six month treatment of long-acting somatostatin in patients with ADPKD. Moreover, the percent increase of total kidney volume was significantly lower in patients on somatostatin than in placebo. Overall, these findings provide the basis for designing a long-term study in ADPKD patients aimed to document the efficacy of the somatostatin treatment in preventing further increase or even reducing the total kidney volume and the renal volume taken up by small cysts, eventually halting kidney disease progression.

Detailed description: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disease, responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western countries.
  At comparable levels of blood pressure control and proteinuria, patients with ADPKD have faster decline in glomerular filtration rate (GFR) than those with other renal diseases and do not seem to benefit to the same extent of ACE inhibitor therapy. A reasonable explanation for the above findings is that in ADPKD progression is largely dependent on the development and growth of cysts and secondary disruption of normal tissue. Thus, renoprotective interventions in ADPKD - in addition to achieve maximal reduction of arterial blood pressure and proteinuria and to limit the effects of additional potential promoters of disease progression such as dyslipidemia, chronic hyperglycemia or smoking - should also be specifically aimed to correct the dysregulation of epithelial cell growth, secretion, and matrix interactions characteristic of the disease.
  The fluid filling renal cysts in human polycystic kidney is formed mainly by a secretion process of the tubular epithelium lining the cysts. Secretion and re-absorption take place at approximately the same rate, with secretion slightly higher, so that the amount of fluid in the cysts increases slowly over time. The same process, via the secondary active chloride transport, is also involved in the secretion of fluid into the lumen of proximal tubules in teleost and elasmobranch fishes. Of interest, this process of chloride transport can be markedly inhibited by somatostatin, as demonstrated in the shark rectal gland.
  Recently, somatostatin analogues have become available and used with negligible side effects for long-term treatment of tumors (up to 8-12 months). To evaluate the tolerability and the safety of long-acting somatostatin in ADPKD patients, a prospective cross-over controlled study has been recently performed. This pilot study demonstrated the safety of six month treatment of long-acting somatostatin in patients with ADPKD. Moreover, the percent increase of total kidney volume was significantly lower in patients on somatostatin than in placebo. Preliminary data on late stage ADPKD also suggest that loss of renal function in these patients closely correlates with the increase in kidney volume taken by small cysts (<5 mm3), but not total cyst volume.
  Overall, these findings provide the basis for designing a long-term study in ADPKD patients aimed to document the efficacy of the somatostatin treatment in preventing further increase or even reducing the total kidney volume and the renal volume taken up by small cysts, eventually halting kidney disease progression.
  Aims
  The general aim of the study is to compare the effects on disease progression of three year treatment with long-acting somatostatin or placebo in patients with ADPKD and normal renal function or mild to moderate renal insufficiency. Specifically, the following aims will be pursued:
  Primary To compare in somatostatin and placebo ADPKD groups the change over baseline of the total kidney volume at 1 and 3 years follow-up (estimated by gadolinium contrast enhanced and T2-weighted magnetic resonance imaging, MRI).
  Secondary
  1. As secondary efficacy endpoints, the following parameters (absolute and percent change over baseline by MRI analysis) will be compared in the two ADPKD groups at baseline, at 1 and 3 years follow-up:
  -  Renal cyst volume
  -  Total renal parenchymal volume
  -  Residual renal volume
  -  Renal parenchymal volume taken up by small cysts (<5 mm3)
  2. Additional functional parameters will be compared in the two groups at baseline and at 1, 2, 3 years follow-up as follows:
  -  Systolic and diastolic blood pressure
  -  GFR (plasma iohexol clearance)
  -  GFR (over baseline)
  -  RPF (plasma PAH clearance)
  -  Serum creatinine concentration
  -  Diuresis
  -  24 h urinary protein excretion rate
  -  24 h urinary albumin excretion rate
  -  Protein, albumin, creatinine concentrations on spot morning urine samples
  -  Protein /creatinine ratio on spot morning urine samples
  -  Albumin/creatinine ratio on spot morning urine samples
  -  Urinary sodium, urea, glucose, phosphorus concentrations (24 hr samples)
  -  Urine osmolality (calculated)
  3. Correlation analyses between MRI and functional parameters will be also performed
  Patients Patients enrolled in this long-term follow-up study are those with ADPKD and normal renal function or mild to moderate renal insufficiency (estimated GFR >40 ml/min/1.73 m2 by MDRD equation), no evidence of associated systemic, renal parenchymal or urinary tract disease and no specific contraindication to the study drug.

Eligibility: Inclusion Criteria:
  -  Age>18 years
  -  Clinical and ultrasound diagnosis of ADPKD
  -  GFR >40 ml/min/1-73 m2 (estimated by the 4 variable MDRD equation)
  -  Written informed consent
  Exclusion Criteria
  -  Diabetes
  -  Overt proteinuria (urinary protein excretion rate >1g/24 hours) or abnormal urinalysis suggestive of concomitant, clinically significant glomerular disease
  -  Urinary tract lithiasis, infection or obstruction
  -  Cancer
  -  Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study
  -  Pregnancy, lactation or child bearing potential and ineffective contraception (estrogen therapy in post menopausal women should not be stopped)

Relevance to patient case: not relevant