Pathophysiology and treatment of cholemic nephropathy

Renal dysfunction and failure commonly occur in patients with advanced cholestatic liver diseases. Moreover, renal function is a major prognostic factor in patients with end stage liver disease. Therefore serum creatinine and serum bilirubin are included in the model for end stage liver disease score (MELD) for assessment of severity of liver disease and priorization for liver transplantation. Acute kidney injury (AKI) in patients with advanced liver disease is frequently related to (i) hypovolemia and hepatorenal syndrome type I (HRS I), (ii) intrinsic AKI related to acute tubular necrosis, glomerular disease, contrast nephropathy, or (iii) postrenal causes. HRS represents a functional and potentially reversible form of progressive renal failure due to activation of vasoconstrictor systems and related circulatory abnormalities in the absence of alternative identifiable causes. In contrast, there is increasing evidence for structural renal changes at least in a subgroup of patients with end-stage liver diseases. These novel findings question our traditional concepts of predominant functional renal impairment and failure in liver disease, especially in the specific group of patients with advanced cholestatic liver diseases. Therefore our general aim is to explore the mechanisms leading to cholemic nephropathy representing a specific type of kidney injury in cholestatic patients. Our preliminary experimental data strongly argue for urinary excreted bile acids as causative factor for tubular injury in cholemic nephropathy. Consequently we aim on detailed longitudinal and comparative studies in specific mouse models to gain mechanistic insights into this novel concept. Complementary in vitro studies will determine the pathogenetic cellular pathways involved. In addition, we aim to develop novel treatment strategies for cholemic nephropathy by testing the effects of bile acid pool modulation and antioxidative strategies in mouse models and in vitro systems. This complementary set of in vivo and in vitro experiments will help to gain novel mechanistic insights into the pathophysiology of cholemic nephropathy. In addition, this should lead to novel strategies of prevention and treatment in the difficult to manage group of patients with advanced cholestatic liver disease and concomitant renal function impairment.

Acute kidney injury (AKI) and renal failure commonly occur in patients with liver diseases such as cirrhosis and also cholestatic liver diseases (i.e. liver diseases with jaundice). AKI in patients with cirrhosis may be related to prerenal causes such as fluid loss, intrinsic causes, or, although rare, postrenal causes such as obstruction of the urinary tract. The commonly known hepatorenal syndrome-type AKI (HRS-AKI) represents a functional and potentially reversible form of progressive renal failure in the absence of alternative identifiable causes. In contrast, there is increasing evidence for structural renal changes at least in a subgroup of patients with liver diseases. These novel findings question our traditional concepts of predominant functional renal failure in liver disease, especially in the specific group of patients with advanced cholestatic liver diseases with jaundice. Besides bacterial infections, fluid loss, and use of nephrotoxic drugs AKI in liver disease may be triggered by tubular toxicity of cholephiles such as bile acids. Cholemic nephropathy (CN) also known as cholemic nephrosis or bile cast nephropathy supposedly represents a widely underestimated but important cause of renal dysfunction cholestasis or advanced liver disease with jaundice and has almost disappeared from modern medical literature. CN describes impaired renal function along with characteristic histomorphological changes of the kidney. The underlying pathophysiologic mechanisms are not entirely understood and clear diagnostic criteria are still missing. Therefore the general aim of this project was to explore the pathophysiologic mechanisms of CN. Our experimental data generated in animal models for cholestatic liver disease strongly argue for urinary excreted bile acids as causative factor for the characteristic morphological changes that can be found in CN. Moreover, we were able to prevent these morphological changes by experimental modulation of the bile acid pool. Our results may pave the way for novel strategies of prevention and treatment in the difficult to manage group of patients with cholestatic liver diseases and concomitant impairment of renal function.