טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAbu-Saleh Niroz
SubjectEffect of Increased Intra-Abdominal Pressure on Kidney
Function in Health and Disease
DepartmentDepartment of Medicine
Supervisors Professor Zaid A. Abassi
Dr. Mogher Khamaisi
Full Thesis textFull thesis text - English Version


Abstract

Introduction: Increased intra-abdominal pressure (IAP) adversely affects kidney function in normal patients with oliguria as the most prominent effect accompanied by hemodynamic dysfunction. It is still not clear whether the renal dysfunction is more exaggerated in patients with background diseases such as chronic heart failure (CHF), myocardial infarction (MI), obstructive jaundice and cirrhosis. Moreover, we explored the cellular mechanisms underlying the adverse impact of elevated IAP on kidney function, and examined potential therapeutic interventions.       

Aims: The present study was designed:  1- To determine the effects of IAP on renal function and kidney injury in sham, CHF, MI and BDL (bile duct ligation) rodent models and 2- To evaluate the involvement of nitric oxide (NO)/cGMP pathways in IAP-induced renal dysfunction.

Methods: Adult male Sprague-Dawley normal rats were subjected to IAP of 0,7,10 and 14 mmHg for 45min each followed by deflation period of 60 min (recovery). Ten additional groups were included in the current study: 1) Sham controls pretreated with L-NAME, NO synthase inhibitor (100 mg/L in drinking water), 2) Sham controls pretreated with Tadalafil, an inhibitor of phosphodiesterase-5 (PDE5-I) (10 mg/kg/day, P.O) for 4 days before IAP, 3) Compensated CHF, 4) Decompensated CHF, 5) Compensated CHF with L-NAME, 6) Decompensated with PDE5-I, 7) Rats with MI, 8) Rats with MI pretreated with PDE5-I, 9) Rats with acute obstructive jaundice, 10) Cirrhotic rats. Mean arterial pressure (MAP), urine flow rate (V), absolute and fractional Na excretion (UNaV, FENa, respectively), glomerular filtration rate (GFR), renal plasma flow (RPF), were determined . NO metabolites, cGMP and NGAL (kidney injury biomarker) were determined in urine samples using Elisa analysis.

 Results: Significant reductions in renal hemodynamics and excretory function were observed when elevated IAP was applied to sham control rats. The adverse effects of pneumoperitoneum (PnP) were aggravated when L-NAME was administered prior to IAP application. While compensated CHF rats behaved like sham controls, decompensated CHF and MI rats displayed exaggerated susceptibility to the deleterious effects of elevated IAP as expressed by profound renal dysfunction compared with sham controls. Pretreatment with L-NAME remarkably aggravated the hypoperfusion/hypofiltration associated with IAP, in compensated CHF rats, suggesting a beneficial role of the NO system in face of the adverse renal effects of IAP. Noteworthy, pretreatment with PDE5-I ameliorated the hypoperfusion/hypofiltration associated with increased IAP in decompensated CHF and MI animals, indicating the significance of cGMP in maintaining vasodilation during PnP.  Rats with acute or chronic BDL didn't develop renal dysfunction when IAP increased, most likely due to the exaggerated activity of the NO system characterizing these conditions. 

Conclusions:  Decreased renal excretory function and hypofiltration induced by increased IAP are more profound in decompensated CHF and MI models than in sham controls, most likely due to perturbations in the NO system. In contrast, rats with acute obstructive jaundice and cirrhosis are protected against the deleterious renal consequences of elevated IAP, due to exaggerated activity of the NO system. The adverse effects of PnP on renal function may be ameliorated by restoration of cGMP levels using PDE5-I, such as Cialis.