alpha-chymotrypsin and Kidney-Failure--Chronic

For many years, the classification of chronic pancreatitis has been oversimplified according to whether the cause is alcoholic (60-70% of cases according to published series) or non-alcoholic (20-40% of the remaining cases). Recognition of smoking as an important risk factor and increasing identification of factors of genetic susceptibility have placed these percentages in doubt and have led to a reconceptualization of the disease as a multifactorial process. Mutations in the PRSS1, SPINK1 and CFTR genes have been confirmed as major risk factors, while mutations in the CTRC and CASR genes are considered lesser risk factors for the development of chronic pancreatitis. These genetic variants are expressed in a much higher percentage of patients with chronic pancreatitis than could be expected by chance. The trans-heterozygous combination multiplies the risk of chronic pancreatitis and demonstrates the degree of complexity of the etiopathogenic mechanisms of the disease. Ductal obstruction and autoimmunity are other important etiologic factors of chronic pancreatitis that need a specific review. The present article reviews the latest studies evaluating the role of alcohol and smoking in chronic pancreatitis and the most significant genetic factors.

Topics: Autoimmune Diseases; Carrier Proteins; Cholestasis; Chymotrypsin; Cystic Fibrosis Transmembrane Conductance Regulator; Duodenal Obstruction; Genetic Predisposition to Disease; Humans; Ischemia; Kidney Failure, Chronic; Mutation; Pancreas; Pancreatitis, Alcoholic; Pancreatitis, Chronic; Radiation Injuries; Receptors, Calcium-Sensing; Risk Factors; Smoking; Trypsin; Trypsin Inhibitor, Kazal Pancreatic

Serum pancreatic enzyme behavior, exocrine function, and morphology of the pancreas were studied in 28 patients with end-stage renal disease undergoing regular hemodialysis, in order to better delineate and assess the clinical relevance of the pancreatic alterations that occur in these patients. Twenty-eight healthy subjects served as controls. Initial studies included serum amylase, isoamylase, and lipase assays; fecal chymotrypsin measurement; and abdominal ultrasonography. The amylase, lipase, and chymotrypsin determinations, as well as ultrasound examination, were repeated four years later. None of the patients had clinical evidence of pancreatic disease at entry into the study, but one had had previous attacks of pancreatitis and another developed mild acute pancreatitis one month after entry. Initial mean serum enzyme levels were significantly higher in patients than in controls (amylase, pancreatic isoamylase, and lipase, P < 0.001; salivary isoamylase P < 0.05). Serum amylase was raised in 16/28 patients; pancreatic isoamylase in 15/28, and lipase in 7/28; these elevations were generally mild. Mean fecal chymotrypsin was significantly lower (P < 0.001) in patients than in controls: abnormally low values were found in 9/28 patients. Amylase, lipase and chymotrypsin measurements repeated after four years showed no significant difference with respect to the first study. Ultrasonographic changes were rare and mild: one patient had a small cyst in the pancreas head, another, an increase in echogenicity of the gland not related to age; these findings were unchanged at repeat examination. The results demonstrate that the frequent elevations of serum pancreatic enzymes and the rare sonographic changes found in patients undergoing hemodialysis do not generally reflect a relevant pancreopathy. However, the finding of significantly decreased fecal chymotrypsin may indicate the presence of pancreatic dysfunction in end-stage renal disease.

Topics: Amylases; Case-Control Studies; Chymotrypsin; Clinical Enzyme Tests; Feces; Female; Follow-Up Studies; Humans; Isoenzymes; Kidney Failure, Chronic; Lipase; Male; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatitis; Renal Dialysis; Time Factors; Ultrasonography

Chronic renal failure (CRF) was produced in female Sprague-Dawley rats by 7/8 nephrectomy. Creatinine clearance was depressed significantly (P less than 0.005) and blood urea nitrogen (BUN) increased in CRF rats when compared with the sham-operated (S) controls. CRF caused no apparent change in body weight but significantly increased pancreatic weight as well as increased DNA, RNA, and protein content. Pancreatic protein-to-DNA and RNA-to-DNA ratios were also found to be significantly higher in CRF rats than in the S controls. Trypsin-like activity and immunoreactive cationic trypsinogen levels were both increased in the pancreas of CRF rats, but not in their serum. On the other hand, protease inhibitory activity in the pancreas and serum was significantly decreased by CRF. The ability of the dispersed pancreatic acini isolated from CRF rats to incorporate [3H]-leucine into protein, in the absence and presence of 0.25 nM cholecystokinin octapeptide (CCK-8), was found to be lower than in the controls. Furthermore, discharge of both trypsinogen and chymotrypsinogen induced by CCK-8 was markedly reduced from acini of CRF rats as compared with the S controls. In contrast, lactate dehydrogenase (LDH) was released more readily from pancreatic acini of CRF. It is concluded that mild CRF produces hyperplasia and hypertrophy of the pancreas and lowers the responsiveness of acini to CCK-8 with respect to synthesis and secretion of proteins.

Topics: Animals; Chymotrypsin; Chymotrypsinogen; DNA; Female; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Leucine; Organ Size; Pancreas; Protease Inhibitors; Proteins; Rats; Rats, Inbred Strains; RNA; Trypsin; Trypsinogen

A radioimmunoassay for human pancreatic chymotrypsin II has been developed. Serum immunoreactive chymotrypsin II content in healthy individuals ranged from 14.7 ng/ml to 77.5 ng/ml, the average being 37.5 ng/ml (SD = 19.6). Elevated values were observed in patients with acute pancreatitis and renal failure. After total pancreatectomy, serum immunoreactive chymotrypsin II was not detectable. A significant positive correlation was observed between serum immunoreactive chymotrypsin II and cationic trypsin contents.

Topics: Antibody Specificity; Chymotrypsin; Humans; Kidney Failure, Chronic; Pancreas; Pancreatic Diseases; Radioimmunoassay; Stomach Neoplasms

Topics: Adult; Aged; Amylases; Bicarbonates; Chymotrypsin; Female; Glomerulonephritis; Humans; Kidney Diseases, Cystic; Kidney Failure, Chronic; Male; Middle Aged; Pancreas; Pyelonephritis; Trypsin

An inhibitor of transepithelial sodium transport was found in a low molecular weight fraction obtained from serum of patients with far advanced chronic renal disease. In 18 nondialyzed patients, the mean inhibition of short circuit current (SCC) was 24.9 +/-2.2% (SE). With a comparable fraction from 11 normal subjects. SCC decreased by only 5.3 +/-1.5%. There was significantly greater inhibition with the serum fractions of patients with end stage renal disease being maintained on chronic hemodialysis than in the normal control group; but the degree of inhibition in the dialyzed population was significantly less than that observed in the nondialyzed chronically uremic patients. The inhibition of SCC produced by the serum fractions of a group of seven patients with acute renal failure was not significantly different from the control group despite the presence of high grade uremia in the former. The inhibitory fraction has characteristics identical with the uremic serum fraction which previously has been shown to inhibit p-aminohippurate (PAH) uptake by rabbit kidney cortical slices. With gel filtration through Sephadex G-25, the active fraction appears after the major peaks of substances as small as urea and sodium; hence it may have been retarded on the column. But its ultrafiltration characteristics suggest that its molecular weight may be less than 1000. The inhibitory capability was not destroyed by boiling, freezing, or digestion with chymotrypsin or pronase. Neither methylguanidine nor guanidinosuccinic acid in concentrations well above those present in the serum of uremic patients inhibited sodium transport in the frog skin. The data suggest that there is an inhibitor of sodium transport in the serum of patients with chronic uremia. The role of this material in the regulation of sodium excretion in uremia as well as its possible role as a uremic toxin are subjects of both theoretical and practical interest.

Topics: Acute Kidney Injury; Animals; Anura; Biological Transport; Chemical Phenomena; Chemistry; Chromatography, Gel; Chymotrypsin; Cold Temperature; Guanidines; Hot Temperature; Humans; Kidney Failure, Chronic; Molecular Weight; Peptide Hydrolases; Potentiometry; Renal Dialysis; Skin; Sodium; Succinates; Uremia