Michel Carretier

PANCREATIC METASTASIS OF RENAL CELL CARCINOMA: PRESENTATION, TREATMENT AND SURVIVAL

PURPOSE The pancreas is an uncommon site of metastasis from renal cell carcinoma, comprising 2% of pancreatic tumors removed in sizable series of operations. To our knowledge the role of operative resection in the setting of metastatic malignancy to the periampullary region has not yet been defined. We reviewed the records of 6 women and 2 men who underwent pancreatic resection due to malignancy and analyzed various prognostic factors. MATERIALS AND METHODS Between 1985 and 1995, 269 patients underwent pancreatic resection for malignancy at our hospitals, including 150 (56%) for pancreatic duct cancer, 65 (24%) for carcinoma of the ampulla, 27 (10%) for distal bile duct cancer, 19 (7%) for duodenal carcinoma and 8 (3%) for renal cell carcinoma metastasis. We reviewed the records of these latter 8 cases, and analyzed demographics, primary tumor type, disease-free interval, resection type, concomitant other organ resection, histological examination of the specimen, morbidity, adjuvant therapy and survival. RESULTS Pancreatic metastasis of renal cell carcinoma was managed by duodenopancreatectomy in 5 patients and total pancreatectomy in 3. There were no perioperative deaths. Mean tumor size in cases of a solitary pancreatic metastasis was 4 cm. (range 1.5 to 8). In the 3 patients treated with total pancreatectomy there were 2, 5 and 3 pancreatic metastases, respectively. Pathological examination revealed negative lymph nodes in all cases. Mean survival was 48 months. At study end 6 patients were alive at 24, 26, 30, 46, 84 and 88 months, while 2 died at 13 and 70 months, respectively. CONCLUSIONS We advocate aggressive surgical resection when possible. Surgical removal of metastatic lesions prolongs survival but radical lymph node dissection is not mandatory. We also recommend careful long-term followup of patients with a history of renal cell carcinoma.

Trimetazidine prevents renal injury in the isolated perfused pig kidney exposed to prolonged cold ischemia.

BACKGROUND Ischemia caused by cold storage (CS) and reperfusion of the kidney is often responsible for delayed graft function after transplantation. Significant attention has been focused on the cascade of events involved in ischemia-reperfusion injury, with the objective of identifying drugs to ameliorate the functional damage that occurs. METHODS The purpose of this study was to evaluate the renal function of isolated perfused pig kidneys after 48 hr of CS with Euro-Collins (EC) solution plus trimetazidine (EC+TMZ), standard EC solution, or University of Wisconsin (UW) solution. Normothermic isolated perfused pig kidneys were randomized into five experimental groups: (A) control group (cold flush with cold heparinized saline and immediately reperfused; n=6); (B) cold flush with cold heparinized saline with TMZ (10(-6) M), n=6; (C) 48 hr of CS with EC and reperfusion (n=8); (D) 48 hr of CS with EC+TMZ alone and reperfusion (n=8); (E) 48 hr of CS with UW and reperfusion (n=8). Proton nuclear magnetic resonance spectroscopy and biochemical studies were performed for the functional evaluation during reperfusion. Lipid peroxidation was also determined. Histological examination (optical and electron microscopy) was performed after CS and reperfusion. RESULTS Using TMZ, the renal perfusate flow rate as well as the glomerular filtration rate and proximal tubular function were significantly improved. This improvement of renal function during reperfusion was correlated with a less significant cellular and interstitial edema. In addition, tubular injury markers were significantly lower in the group preserved with EC+TMZ, and TMZ reduced lipid peroxidation dramatically during reperfusion. CONCLUSIONS The addition of TMZ to the EC solution increased the preservation quality and renal tubular function, and gave protection from reperfusion injury better than EC alone or UW. These results strongly suggest that TMZ has a cytoprotective effect and may therefore be useful for kidney preservation.

Polyethylene Glycol Reduces Early and Long-Term Cold Ischemia-Reperfusion and Renal Medulla Injury

Ischemia-reperfusion injury (IRI) after transplantation is a major cause of delayed graft function, which has a negative impact on early and late graft function and improve acute rejection. We have previously shown that polyethylene glycol (PEG) and particularly PEG 20M has a protective effect against cold ischemia and reperfusion injury in an isolated perfused pig and rat kidney model. We extended those observations to investigate the role of PEG using different doses (30g or 50g/l) added (ICPEG30 or ICPEG50) or not (IC) to a simplified preservation solution to reduce IRI after prolonged cold storage (48-h) of pig kidneys when compared with Euro-Collins and University of Wisconsin solutions. The study of renal function and medulla injury was performed with biochemical methods and proton NMR spectroscopy. Histological and inflammatory cell studies were performed after reperfusion (30–40 min) and on days 7 and 14 and weeks 4, 8, and 12. Peripheral-type benzodiazepine receptor (PBR), a mitochondrial protein involved in cholesterol homeostasis, was also studied. The results demonstrated that ICPEG30 improved renal function and reduced medulla injury. ICPEG30 also improved tubular function and strongly protect mitochondrial integrity. Post-IRI inflammation was strongly reduced in this group, particularly lymphocytes TCD4+, PBR expression was influenced by IRI in the early period and during the development of chronic dysfunction. This study clearly shows that PEG has a beneficial effect in renal preservation and suggests a role of PBR as a marker IRI and repair processes.

Long-term outcome of severe radiation enteritis treated by total parenteral nutrition.

The outcome of 31 patients with severe radiation enteritis treated by total parenteral nutrition (TPN) was analyzed. Before initiation of parenteral nutrition, 18 of the patients had not had abdominal surgery, while 13 had either a resection or an intestinal bypass for radiation enteritis. Median follow-up was 21/2 years (range: 1 month to 12 years) from the time of initiation of parenteral nutrition. Surgery was required in 15 cases because parenteral alimentation could not be continued. Only eight of these 15 were able to resume a normal oral intake. Total parenteral nutrition allowed oral feeding to be resumed in 11 (36%) after a median follow-up of 40 months (range: 6–142 months). In general, total parenteral nutrition was well tolerated and was associated with low morbidity. Eighteen patients died, 13 of complications due to radiation therapy, four of cancer recurrence, and one of an unrelated cause. Survival probability was 58% at one year and 36% at five years. When possible, prognostic factors present either before or at initiation of total parenteral nutrition were analyzed. Age, predisposing vascular factors (hypertension, diabetés mellitus, or vascular disease), and enteric fistula and/or perforation were found to have prognostic value. The probability of clinical radiation enteritis recurrence was 34% at one year and 47% at two years. A clinical recurrence of symptoms was more frequent but not significantly so after parenteral nutrition as compared to surgical therapy of radiation enteritis. Although TPN corrected denutrition and allowed deferred surgery in some patients, severe radiation enteritis remains a poorly predictable progressive disease with numerous relapses.

A modified University of Wisconsin preservation solution with high-NA+ low-K+ content reduces reperfusion injury of the pig kidney graft.

Background. Ischemia‐reperfusion injury has been associated with both early and late effects on allografts in the form of delayed graft function and decreased graft survival. Recent studies demonstrated that functional parameters were influenced by cold storage conditions and particularly the ratio of Na+:K+ of the preservation solution. Methods. We have extended this study to examine whether the high‐Na+ low‐K+ formulation of Belzers solution (HEH) was efficient in an autotransplanted pig kidney model when compared with the classical low‐Na+ high‐K+ University of Wisconsin solution and the new high‐Na+ low‐K+ Celsior solution. Kidneys were harvested, cold flushed, and preserved for 24, 48, or 72 hr with HEH, Celsior solution, or University of Wisconsin solution and autotransplanted. Renal function was determined on days 1, 3, 7, and 14, and at 4 to 16 weeks after autotransplantation. Histologic changes and cell infiltration were assessed on kidney biopsy specimens taken after reperfusion (30‐40 min), at days 5 and 14, and at 4 to 5 and 10 to 12 weeks after surgery. Peripheral benzodiazepine receptor (PBR), a structural mitochondrial protein, was also studied. Results. Cold storage in HEH resulted in reduction of delayed graft function and renal damage, with a decrease in interstitial inflammation. HEH reduced interstitial fibrosis, tubular atrophy, and improved PBR expression. Conclusion. This study suggests that cold preservation in HEH has a beneficial action in in vivo renal preservation and reduces tubular necrosis, interstitial inflammation, and fibrosis in these groups. In addition, PBR detection was correlated to the level of preservation integrity.

Comparison of conventional and laparoscopic Hartmann's procedure reversal.

Purpose This study compares open Hartmanns procedure reversal (OHPR) and laparoscopic Hartmanns procedure reversal (LHPR) in patients first treated for peritonitis (Henchey III or IV). Methods Fourteen patients who underwent LHPR during a 2-year period were compared with 20 patients who had previously undergone an open procedure at the same institution. Results Conversion rate was 14.28%. Operating time was shorter for the laparoscopic group [143 (90 to 240) vs. 180 (90 to 350) min, P<0.05]. Hospital length of stay was shorter for the laparoscopic group [9.5 (4 to 18) vs. 11 (6 to 39)]. Use of patient-controlled analgesia was not significantly shorter in the laparoscopic group [3 (0 to 4) vs. 3.5 (0 to 8)]. Morbidities observed in the LHPR group include a parietal abscess and an anastomotic stenosis without surgical treatment. The OHPR group had 6 complications: 1 anastomotic leak and 5 incisional hernias. Conclusions LHPR with a conversion rate of 14.28% seems to be a method with shorter operating time and less morbidity compared with OHPR.

Endotoxin tolerance enhances interleukin-10 renal expression and decreases ischemia-reperfusion renal injury in rats.

ABSTRACT The potential implication of interleukin (IL) 6, tumor necrosis factor &agr; (TNF-&agr;), and IL-10 in the protective effect of low-dose lipopolysaccharide (LPS) administration against renal ischemia-reperfusion injury was evaluated in a rat model. Eighteen male Sprague-Dawley rats were injected intravenously with either 0.5 mg/kg of LPS (tolerant group) or saline (control group) 2 days before surgery. Ischemic renal injury was induced by clamping the left renal artery for 60 min on rats immediately after right-side nephrectomy. Reperfusion was obtained by clamp removal and was studied at R0 (no reperfusion), 2H (R2), and 24H (R24) by renal tubular disorder characterization and by plasma creatinine as well as renal cytokine (IL-6, IL-10, and TNF-&agr;) studies. No differences were observed between the two groups as concerns the period immediately after renal ischemia (R0). The endotoxin-tolerant group was associated with a significantly lower creatinine level at R24 (231 ± 28 vs 315 ± 36 &mgr;mol/L; P = 0.007). Pretreatment with LPS significantly reduced the degree of proximal tubule necrosis and outer medulla congestion. In such tolerant animals, renal IL-6 production was decreased, whereas IL-10 production was significantly increased at R2 and R24. There were no differences in TNF-&agr; renal production. In this study, we demonstrated that administration of low doses of LPS to rats had a protective effect from renal reperfusion injury, and our data suggest that IL-10 might play a role in this phenomenon.

Evaluation of Injury Preservation in Pig Kidney Cold Storage by Proton Nuclear Magnetic Resonance Spectroscopy of Urine

The isolated perfused kidney (IPK) model from pig was used to assess initial renal functions after cold flush and a 24- and 48-hour cold storage preservation (CSP) with Euro-Collins (EC) and to determine ischemia reperfusion (IR) impairment by biochemical, histological and proton nuclear magnetic resonance (NMR) spectroscopy of urine analysis. Eighteen pig kidneys were used. There were three experimental groups: Group 1--control kidneys flushed with cold heparinized saline, Group 2--cold flush followed by 24-hour CSP and reperfusion, Group 3--cold flush followed by 48-hour CSP and reperfusion. Kidneys were perfused for 2-hour at 37.5C for the determination of exogenous creatinine clearance (CCr), perfusion flow rate (PFR) and tubular function. Functional parameters and histological data are very poor after prolonged cold ischemia. Levels of tubular injury markers determined by proton NMR spectroscopy analysis were significantly higher with a longer ischemic time correlating well with the increased degree of renal functional and anatomic impairment. A new peak detected only in the 48-hour ischemic group was identified. In this model, proton NMR spectroscopy may be a useful technique in the evaluation of both new preservation solutions or methods.

Protection of autotransplanted pig kidneys from ischemia-reperfusion injury by polyethylene glycol

Background. Ischemia-reperfusion injury (IRI) is often responsible for graft rejection and leads to delayed graft function of cadaveric kidneys. We have shown that adding polyethylene glycol (PEG 20M) to the preservation solutions helps protect isolated perfused pig kidneys against cold ischemia and reperfusion injury. Methods. We compared the effects of adding PEG to a simplified high-K+ perfusion solution of cold-stored kidneys to Euro-Collins or University of Wisconsin solutions on the function of reperfused autotransplanted pig kidneys. The left kidney was cold-flushed with the preservation solutions and stored for 48 hr at 4°C before reimplantation. Creatinine clearance and fractional excretion of sodium were analyzed 2 days before surgery and over 7 days after transplantation. Histological sections were obtained 40 min after reperfusion and on day 7 after surgery. Results. Adding PEG to the perfusate significantly reduced IRI from autotransplanted pig kidneys. Creatinine clearance was significantly higher and fractional excretion of sodium was significantly lower in pigs transplanted with kidneys cold-flushed with PEG-supplemented perfusate than in those flushed with Euro-Collins or University of Wisconsin solutions. PEG supplementation also better preserved the integrity of kidney cells and markedly reduced interstitial cell infiltrates. Conclusion. PEG protects against IRI and reduces early cellular inflammation. PEG may impair the recruitment and migration of leukocytes into retransplanted pig kidneys. Cold preservation of donor organs with PEG-supplemented solutions may therefore help limit IRI in human renal transplantation.

Citrate, acetate and renal medullary osmolyte excretion in urine as predictor of renal changes after cold ischaemia and transplantation.

Abstract In organ transplantation, the determination of reliable parameters to assess ischaemic damage is essential to predict renal injury after preservation. The aim of this study was to assess renal medullary injury by 1H NMR (proton nuclear magnetic resonance) spectroscopy after preservation and reperfusion. Three experimental groups of pigs were examined during a 2-week period: control group (n = 4), Euro-Collins group (EC) (cold flushed and 48 h cold storage of kidney in EC and autotransplantation, n = 7), and University of Wisconsin (UW) group (cold flushed and 48 h cold storage of kidney in UW and autotransplantation, n = 7). Creatinine and urea were improved in the two cold stored groups. The most relevant resonances determined by 1H NMR spectroscopy after transplantation were those arising from citrate and acetate in urine and trimethylamine-N-oxide (TMAO) in urine and plasma. We demonstrate that graft dysfunction is associated with damage to the renal medulla as determined by TMAO release in urine and plasma. Conversely, citrate excretion can discriminate kidneys with favourable outcome. This study outlines the specific and beneficial impact of UW solution on renal preservation and suggests that 1H NMR spectroscopy is efficient both to detect ischaemic damage of preserved kidneys and to discriminate the preservation quality between different preservation solutions.