310 likes | 474 Views
Prevention of cyst progression in Autosomal dominant polycystic kidney disease (ADPKD) Clinical Study. Dr. Pankaj Shah Prof&HOD Department of nephrolgy &Transplant Medicine. Institute of Kidney Diseases & Research Centre and
E N D
Prevention of cyst progression in Autosomal dominant polycystic kidney disease (ADPKD) Clinical Study Dr. Pankaj Shah Prof&HOD Department of nephrolgy &Transplant Medicine Institute of Kidney Diseases & Research Centre and Institute of Transplantation Sciences, Ahmedabad (India)
ADPKD Incidence 1 : 700 to 1 : 1000 In India : 10,00,000 cases Inheritance : Autosomal Dominant
Modern ADPKD research started when epithelial cell lining the cysts in kidneys of ADPKD patients was successfully isolated and maintained in “ex vivo” cultures.
It is observed that cyst cells continue to proliferate, secrete fluid and destroy the surrounding normal tissue by expansion. Cyst fluid contains many hormonal activities including ADH & EGF (Epidermal Growth Factor)
Mechanism of action (V2RA) Tolveptan has been shown to decrease cyst and kidney volume.
Otsuka Pharmaceutical (basic manufacturer of Tolveptan) is proceeding with multinational, multicentre, phase III clinical trial to examine the efficacy & safety of Tolveptan in ADPKD. Approximately 1500 patients will be randomised to either Tolveptan or Placebo and will be observed for the duration of 5 years.
Diagram : dysregulation & acumulation of mTOR in epithelial lining of cyst, which may be final common pathway in cystogenesis.
Shillingford also observed in a small group of renal transplantation that size of cyst in native ADPKD kidney significally reduced when treated with sirolimus in comparison to CNI. Cincinnati Rapamyein Trial as well as ongoing multicentre trial in UK & US has shown favourable results in cysts of PKD in tuberous sclerosis.
Sirolimus therapy in polycystic kidney disease – A pilot study, Nov. 2009 Transplant proceedings A.R. Soliman, E. Ismail, S. Zamil, Cairo university, Egypt.
Safety and tolerability of Sirolimus treatment in patients with polycystic kidney Andreas L. Serra, Andreas D. Kistler, Daine Poster et al. Nephrol Dia. Trans (2009) 3334-3342
Sirolimus reduces polycystic liver volume in ADPKD patients JASN 19, 631-638, 2008 Qian, Hui Du, Bernal F. King et al.
SOMATOSTATIN • Somatostatin has been shown to reduce chloride and fluid secretion in cyst by inhibition of adenylatecyclase & CAMP in epithelial cells of cysts. Mario Negri Institute of Pharmacological research in Italy will enroll 66 ADPKD patients to test the efficacy of long acting somatostatin octreotide LAR. This study will treat patients with an estimated GFR > 40 ml/min./1.73 m2 and follow the response of therapy by serial MRI over 3 years.
(R) – roscovitine is a (R) – sterioisomer of roscovitine. -- Roscovitine is a low molecular weight compound of 2, 6, 9 – trisubstituted purine family. -- 3 week course has long lasting beneficial effect. -- In clinical trials it is well tolerated. (R) - Roscovitine
(R) – roscovitine is a protein kinase inhibitor with preferenitial selectivity for cyclin dependent kinase (CDKs) Prevents phosphorylation of Rb(retinoblstoma) protein Normalise the level of several cyclins Prevent cell proliferation, transcription and apoptosis Prevents cyst progression.
TRIPTOLIDE • Natural Chinese herbal compound. • Restores intracellular Ca++ regulation in cyst lining cells • Thus inhibits c-AMP dependent cell proliferation and water secretion.
How to monitor the therapeutic efficacy in ADPKD. - Very slowly progressive disease. - Initially GFR remains stable. - Once when S.Creatinine exceeds normal value GFR declines 5 ml/min/yr, leading to ESRD within 10 years. However individual variability is substantial.
Consortium for Radiologic Imaging studies of PKD (CRISP) followed 241 ADPKD patients by sequential MRI measurement of cyst & renal volumes. According to them, Volumetric kidney measurements by MRI is the gold standard to determine disease progression. -- They also observed that Renal & cyst volumes correlated inversly with GFR and directly to hypertension and urinary albumin excertion. Average annual increase in renal volume was 5.3%. Cyst growth was more aggressive in young or who had large renal volume at the time of diagnosis.
Is it time to start clinical trials in ADPKD ? Ofcourse Yes.. ADPKD patients have waited enough & suffered enough to find a cure of their disease so any measure to halt the progression of disease is highly warrented.
Phae I/II study is initiated by the cleveland clinic will enroll a total of 45 patients and monitor the changes in iothalamate GFR and total kidney volume measured by CT over the period of 12 months. The patients will be divided into 3 groups. Control (15) low dose of sirolimus (15) (trough blood level 2-5 ng/ml) and high dose of sirolimus (15) (trough blood level 5-8 ng/ml.).
Other trial will treat 300 ADPKD patients with everolimus. It has been started in Germany and Austria and will follow ADPKD patients with estimated GFR between 30 to 89 ml/min/1.73m2 (CKD stage II & III) for 2 years by repeated MRI. Dose is the same as given in organ transplantation.
I have initiated research study to know the effect of Sirolimus in prevention of cyst progression. • I have enrolled PKD patients with CKD stage I to IV in the study. • The study will continue for 5 years. • I have enrolled 150 cases till now. • I will measure renal volume by CT Scan & GFR by radioneuclear study every year and compare Sirolimus group with control group.
Control : Losartan 50 mg Sirolimus : Losartan 50 mg + Sirolimus 2 mg
Total follow up 5 years Annually : Renal volume GFR 24 hour urinary protein Sirolimus blood level
I have started PKD foundation of India to help the patients suffering from polycystic kidney disease in India. All of you are invited to be part of it.