Surgical treatment of inflammatory bowel disease.

Surgery continues to play an important role in the overall treatment strategy for patients with Crohn's disease and ulcerative colitis. Innovative techniques have greatly facilitated the operative approach in patients with both disorders.

Surgical issues for the elderly patient with hepatobiliary disease.

Hepatobiliary disease is the most common reason for abdominal surgery in the elderly population. Therefore, familiarity with these diseases as they occur in geriatric patients has become increasingly important. This article reviews hepatobiliary disease with a specific emphasis on issues that affect the treatment of the elderly. Although the focus of this review is primarily clinical, pertinent experimental findings have been included.

Role of renal sympathetic nerve activity in renal failure associated with obstructive jaundice in the rat.

The propensity for renal failure associated with obstructive jaundice and liver disease may be related to enhanced vasoconstriction of the renal vascular bed with resultant decreases in renal blood flow. Renal sympathetic nervous activity may be a mediator of this effect. The increased renal production of prostaglandins which has been observed in previous models of bile duct ligation may serve to counterbalance the effects of such vasoconstricting influences. This study was undertaken to assess the effect of bile duct ligation on renal function and prostaglandin production in the rat. Furthermore, this study was designed to determine if renal sympathetic nerve activity contributes to the development of renal failure after bile duct ligation. Sprague-Dawley rats underwent either sham operation (n = 8), bilateral renal denervation (n = 10), bile duct ligation alone (n = 11), or bile duct ligation and bilateral renal denervation (n = 10). Renal function was assessed before and 4 days after operation. Bile duct ligation resulted in a 46% decrease in creatinine clearance (p less than 0.01), a 33% decrease in urinary sodium excretion (p less than 0.01), a twofold increase in urine flow (p less than 0.01), and twofold increases in urinary excretion of PGE2, 6-keto-PGF1 alpha, and thromboxane B2 (p less than 0.01). Renal denervation did not prevent the decreases in creatinine clearance and sodium excretion seen after bile duct ligation and had no effect on the changes in urine flow and prostaglandin excretion. These findings demonstrate that bile duct ligation in the rat results in impaired renal function, accompanied by increases in renal prostaglandin production. In addition, this study indicates that the perturbations in renal function and renal prostaglandin production induced by bile duct ligation are not mediated by renal sympathetic nerve activity.

The relationship of urinary thromboxane excretion to cyclosporine nephrotoxicity.

Alterations in renal prostaglandin production have recently been postulated to modulate the decrease in renal blood flow associated with cyclosporine nephrotoxicity. In particular, increases in renal production of the potent vasoconstrictor thromboxane A2 have been implicated in the pathogenesis of this disorder. The present study was undertaken to explore the relationship between alterations in urinary thromboxane B2 excretion (UTxB2V) and CsA nephrotoxicity in two rat models. Male Sprague-Dawley (SD) rats were treated for 14 days with CsA 50 mg/kg/day (n = 8) or olive oil (C) (n = 9) by gavage. Creatinine clearance (Ccr), urine flow (V), and urinary excretion rates of sodium, N-acetyl-beta-D-glucosaminidase (NAG), glucose, and TxB2 were determined before and after treatment. A similar study was conducted using Fischer rats (CsA: n = 10, C: n = 13). In Fischer rats, CsA caused a 35% decrease in Ccr (P = 0.01), a 33% decrease in sodium excretion (P = 0.02), and a greater than 2-fold increase in NAG excretion (P = 0.03), while V, glucose excretion, and UTxB2V did not change. Although similar changes in sodium and NAG excretion were seen after CsA administration in SD rats, Ccr was not affected. Additional findings in SD rats included a 3-fold increase in V (P less than 0.01), a 24-fold increase in glucose excretion (P = 0.03), and a 5-fold increase in UTxB2V (P = 0.04). Thus, Fischer rats developed CsA nephrotoxicity in the absence of increased UTxB2V. In contrast, SD rats failed to develop nephrotoxicity despite a marked increase in UTxB2V. We conclude that changes in renal TxA2 production are unrelated to the development of CsA nephrotoxicity.

Effects of chronic cyclosporine administration on renal blood flow and intrarenal blood flow distribution.

Cyclosporine-induced decreases in renal blood flow (RBF) and glomerular function are well documented. Glomerular filtration and tubular function may be affected by changes in both total renal blood flow and cortical blood flow distribution (CBFD). The effect of CsA on RBF, CBFD, glomerular filtration rate, and tubular function was studied in conscious ewes receiving a mean CsA dose of 30 mg/kg/day for 28 days with mean CsA trough levels of 344 +/- 45 ng/ml. RBF and CBFD were determined by the injection of 15 microns radioactive microspheres before and after one month of treatment with CsA or its vehicle, olive oil. RBF decreased by 24% from 7.65 +/- 0.87 to 5.79 +/- 0.42 ml/min/g of kidney in CsA-treated ewes (P = 0.014), while no decrease was noted in the control group (7.92 +/- 1.10 vs. 7.62 +/- 0.71). Intracortical blood flow decreased in proportion to the fall in total renal blood flow--thus CsA treatment did not change the cortical distribution of flow. There was a 25% decrease in GFR, as determined by inulin clearance, in the CsA-treated group (80 +/- 6 vs. 62 +/- 3 ml/min; P = 0.027) while there was a nonsignificant increase in control animals (62 +/- 11 vs. 92 +/- 7 ml/min). There was no evidence of tubular dysfunction in either group. There were also no changes in urinary excretion rates of prostaglandins PGE2, 6-keto-PGF1 alpha or thromboxane B2, nor were there changes in plasma renin activity. CsA induced decreases in RBF occur red without redistribution of cortical blood flow, indicating that altered cortical distribution of blood flow is not responsible for the changes in GFR or tubular function that have been reported. The changes in renal blood flow and glomerular filtration rate are independent of changes in renal prostaglandin production, and are likely not associated with altered plasma renin activity.

Obstructive jaundice and renal failure in the rat: the role of renal prostaglandins and the renin-angiotensin system.

We have previously noted that bile duct ligation (BDL) in the rat results in decreased creatinine clearance (Ccr) and decreased urinary sodium excretion (UNaV) as well as increased renal prostaglandin (PG) production. This study was undertaken to assess the role of increased renal PG production in the change in renal function after BDL and to determine if these changes are mediated by the renin-angiotensin system. After baseline measurement of renal function, Sprague-Dawley rats underwent either sham operation (SO) or BDL. Four days later animals received a single intraperitoneal injection of either 0.9% saline, 0.5 ml/kg (SO, n = 10; BDL, n = 10), or indomethacin, 5 mg/kg (SO + Indo, n = 10; BDL + Indo, n = 10), and renal function was reassessed. Plasma renin activity was measured at the end of the second study period. BDL resulted in a 40% decrease in Ccr (p = 0.000), a 38% decrease in UNaV (p = 0.002), a twofold increase in urinary 6-keto-PGF1 alpha excretion (p = 0.005), and fourfold increases in urinary excretion of PGE2 (p = 0.006) and thromboxane B2 (p = 0.000). Indomethacin prevented the increase in urinary PG excretion otherwise seen with BDL and resulted in an additional 41% reduction in UNaV (p = 0.018). Further reductions in Ccr by indomethacin, however, were minimal and nonsignificant. Plasma renin activity did not differ among any of the groups. These findings indicate that the sodium retention associated with BDL is attenuated by the concomitant rise in renal PG production. This elevation in PG production, however, does not protect against the adverse effects of BDL on Ccr. Furthermore, the changes in renal function that occur after BDL do not appear to be mediated by the renin-angiotensin system.

Paraesophageal hernia.

We have reviewed our experience with eight patients with paraesophageal hernias surgically repaired at this institution during an 18-month period. Three of these patients required emergent operation, and although the morbidity was higher in this group than in those undergoing elective surgery, no mortalities occurred in either group. The potential for the development of life threatening complications warrants immediate surgery on patients who are diagnosed to have paraesophageal hernias, even if asymptomatic. We recommend a transabdominal approach for the performance of a crural repair and an antireflux procedure.

Effects of cyclosporine on glucose metabolism.

Cyclosporine may have deleterious effects on glucose metabolism. This study was designed to characterize more precisely cyclosporine-induced alterations in glucose homeostasis in a large animal model with hyperglycemic and euglycemic clamp studies in addition to simple bolus glucose (IVGTT) and insulin (IVITT) tolerance tests. In experiment 1, IVGTTs and hyperglycemic clamp studies were performed in eight ewes before and after 4 weeks of cyclosporine treatment. Studies were repeated 4 weeks after cessation of therapy. In experiment 2, IVITTs and euglycemic clamp studies were performed in seven ewes before and after 4 weeks of cyclosporine treatment. Fasting glucose and insulin levels were not affected by cyclosporine treatment. In experiment 1 cyclosporine did not alter IVGTTs; however, during sustained hyperglycemia, cyclosporine caused a 37% decrease in net glucose disposal (p less than 0.001) and a 39% decrease in plateau plasma insulin levels (p less than 0.05). In experiment 2 cyclosporine had no effect on IVITTs. Plateau insulin values in euglycemic clamp studies were lowered by 27% (p less than 0.05) after cyclosporine treatment. In addition, the metabolic clearance rate of insulin was increased by 25% (p less than 0.05), and the steady-state insulin clearance rate was increased by 16% (p less than 0.003). Measurements of insulin sensitivity were unchanged by cyclosporine. These experiments suggest that cyclosporine treatment results in impairment of sustained synthesis and secretion of insulin, increased insulin clearance, and unaltered insulin sensitivity.

Cyclosporine inhibits endothelial cell prostacyclin production.

Cyclosporine (CsA)-induced alterations in endothelial production of prostacyclin (PGI2) may be a contributing factor to the decreased renal blood flow and glomerular thromboses associated with CsA nephrotoxicity. This study was performed to determine the effects of clinically relevant doses of CsA on arachidonic acid-stimulated production of PGI2 by cultured human vein endothelial cells (HUVEC). Confluent monolayers of HUVEC were incubated at 37 degrees C under 5% CO2/95% air for 15 min in Hanks'/Hepes buffer containing 0.01-5.0 microM CsA in 0.01% absolute alcohol. PGI2 production was then stimulated by the addition of 20 microM arachidonic acid and further incubation for 15 min. Supernatants were assayed for 6-keto-PGF1 alpha by radioimmunoassay. The results of this experiment indicate that CsA had a dose-dependent effect on arachidonic acid-stimulated PGI2 production by HUVEC which varied linearly with the log of the dose (r = -0.48, P = 0.003). Concentrations of 0.01, 0.05, and 0.1 microM were stimulatory and 0.5, 1.0, and 5.0 microM were inhibitory. Separate experiments demonstrated that 0.1-5.0 microM CsA had no effect on cell viability (trypan blue exclusion) or growth. These results indicate that CsA inhibits arachidonic acid-stimulated production of PGI2 by HUVEC in a dose-dependent fashion beginning at concentrations comparable to the high end of the therapeutic range. This suggests that CsA-induced decreases in endothelial production of PGI2 may contribute to the development of CsA nephrotoxicity.

Renal failure complicating obstructive jaundice.

Postoperative acute renal failure in patients with obstructive jaundice remains a clinically significant complication. Acute renal failure occurs in approximately 9 percent of patients requiring surgery for relief of obstructive jaundice, and contributes to eventual mortality in 76 percent of those who develop it. The overall mortality rate for patients undergoing surgery for obstructive jaundice is 16 percent. Despite advances in perioperative care, these figures have changed very little over the past 25 years. This article describes the clinical association between jaundice and renal failure and reviews the studies that have contributed to the delineation of the possible underlying pathophysiologic mechanisms, as well as possible preventive measures which have been developed as a result of these investigations. With increased awareness of the potential risk of developing postoperative acute renal failure, the institution of prophylactic measures may result in an improvement in the mortality rate seen after surgery for obstructive jaundice.

Renal vascular reactivity in the bile duct-ligated rat.

The renal dysfunction associated with liver disease appears to be caused by decreased renal perfusion. Altered renal vascular reactivity (RVR) may contribute to the development of decreased renal blood flow. This study was undertaken to assess the effect of bile duct ligation (BDL) on RVR to norepinephrine and angiotensin II in the rat and to evaluate the role of prostaglandins in the modulation of altered RVR. Male Sprague-Dawley rats underwent either sham operation (SO) or BDL. Four days later, isolated kidney perfusions were established. Dose-response curves to norepinephrine (SO, n = 9; BDL, n = 10) and angiotensin II (SO, n = 7; BDL, n = 9) were obtained. The perfusate was modified to contain indomethacin, 10(-6) mol/L, and dose-response curves to norepinephrine (SO, n = 10; BDL, n = 8) and angiotensin II (SO, n = 4; BDL, n = 8) were obtained as well. Baseline resistances did not differ between any of the groups. RVR to norepinephrine did not appear to be altered by BDL; however, increased RVR to norepinephrine was unmasked by inhibition of prostaglandin synthesis. BDL did not affect the RVR to angiotensin II with or without indomethacin. BDL is associated with an increase in renal vascular sensitivity to norepinephrine, which is balanced by a compensatory increase in renal prostaglandin activity in response to norepinephrine stimulation. These findings are consistent with theories that decreased renal perfusion associated with liver disease may be mediated by catecholamines.

Renal vascular reactivity in jaundice.

Obstructive jaundice is associated with a predisposition to hypotension and acute renal failure that may be related to changes in renovascular responsiveness, particularly to norepinephrine (NE). This study was undertaken to investigate changes in vascular response to NE and to determine how these changes are related to prostaglandins. Kidneys from bile duct-ligated (BDL) rabbits (n = 5) were perfused with Krebs' solution at 7.65 ml/min, and the response to varying boluses of NE (0.78 to 6.24 micrograms) was measured as changes in perfusion pressure. When compared with sham-operated control kidneys (n = 8), a significantly blunted response was seen at all doses tested. The NE response was further assessed by measuring force development in mounted segments of main renal arteries (MRAs) (n = 8) and interlobar arteries (ILAs) (n = 6) from BDL rabbits and sham-operated controls (MRA, n = 8; ILA, n = 6). The dose-response curves were significantly depressed in both MRAs and ILAs from BDL animals. In addition, MRAs from sham-operated control animals exhibited decreased response to NE after incubation for 1 hour in jaundiced serum. This attenuated response of MRAs to NE was prevented when indomethacin (5 mg/kg) was given to BDL rabbits before death (n = 9) or when 10(-6)mol/L of indomethacin was added to jaundiced serum during incubation (n = 6). These results indicate that obstructive jaundice induces a decreased vascular contractile response in rabbits to NE and that this effect is mediated by prostaglandins.