Carl Zülke

A Monocyte Chemoattractant Protein-1 (MCP-1) Polymorphism And Outcome After Renal Transplantation

Among the factors modulating transplant rejection and cardiovascular disease, chemokines and their respective receptors deserve special attention. In this respect, increased expression of MCP-1 and the corresponding receptor CCR2 have been demonstrated in renal transplant rejection and coronary artery disease. The impact of the MCP-1-2518G and CCR2-64I genotypes on renal allograft function was investigated in 232 patients who underwent transplantation over an 11-yr period. Genomic DNA was genotyped using PCR with sequence-specific primers followed by restriction fragment length polymorphism analysis. Eighteen (7.8%) patients were homozygous for the MCP-1-2518G mutation. The G/G allele of MCP-1 -2518 behaved as a determinant for long-term allograft survival and resulted in reduction of the mean graft survival, as compared with the heterozygous (A/G) or wild-type (A/A) allele (67 +/- 14 versus 95 +/- 4 mo; Log rank P = 0.0052). The 64I mutation of CCR2 had no effect on kidney graft failure (93 +/- 6 and 91 +/- 5 mo, respectively; P = 0.81). None of the investigated polymorphisms showed a significant shift in gene frequency in acute rejection and rejection-free groups. In conjunction with these findings, peripheral blood mononuclear cells from kidney transplant recipients carrying the G-allele were characterized by a 2.5-fold higher MCP-1 secretion (P < 0.05). In conclusion, recipients of renal transplants homozygous for the -2518 G mutation of the MCP-1 gene are at risk for premature kidney graft failure. This variant of MCP-1 may be a future predictor for long-term kidney graft failure.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ⩽60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Cardiovascular Risk Factors and Estimated Risk for CAD in a Randomized Trial Comparing Calcineurin Inhibitors in Renal Transplantation

Cardiovascular morbidity and mortality is high in patients following renal transplantation. The present analysis assessed major cardiovascular risk factors and estimated the risk of coronary artery disease in the largest present‐day comparative trial of tacrolimus vs. microemulsified cyclosporine A.

Factors Associated With Disease Progression in Patients With Gastrointestinal Stromal Tumors in the Pre-Imatinib Era

The aim of this study was to determine the predictors of survival in 38 patients with curatively resected gastrointestinal stromal tumors (GISTs). The tumor was located in the stomach in 23 cases, the small bowel in 13, and the colon in 2. In 23 patients (61%), a mutation in exon 11 of the kit gene was detected. In 7 cases, all small gastric tumors, a mutation in the platelet-derived growth factor receptor a (PDGFRA) gene was detected. The overall 5-year survival rate was 70%. In 9 patients, GISTs relapsed, leading to an actuarial 5-year disease-free survival of 78%. By multivariate analysis, the presence of distant metastases, the proliferative (MIB-1) index, and deletional mutation in codons 557 and/or 558 of kit exon 11 correlated significantly with poor outcome. None of the PDGFRA mutant GISTs relapsed. These findings suggest a strong relationship between various tyrosine kinase receptor mutations and survival outcome in patients with GISTs.

Liver Transplantation for Hilar Cholangiocarcinoma: A German Survey

BACKGROUND The present study reports a German survey addressing outcomes in nonselected historical series of liver transplantation (OLT) for hilar cholangiocarcinoma (HL). PATIENTS AND METHODS We sent to all 25 German transplant centers performing OLT a survey that addressed (1) the number of OLTs for HL and the period during which they were performed; (2) the incidence of HL diagnosed prior to OLT/rate of incidental HL (for example, in primary sclerosing cholangitis); (3) tumor stages according to Union Internationale Centre le Cancer; (4) patient survival; and (5) tumor recurrence rate. RESULTS Eighty percent of centers responded, reporting 47 patients who were transplanted for HL. Tumors were classified as pT2 (25%), pT3 (73%), or pT4 (2%). HL was diagnosed incidentally in 10% of cases. A primary diagnosis of PSC was observed in 16% of patients. Overall median survival was 35.5 months. When in-hospital mortality (n = 12) was excluded, the median survival was 45.4 months, corresponding to 3- and 5-year survival rates of 42% and 31%, versus 31% and 22% when in-hospital mortality was included. HL recurred in 34% of cases. Three- and 5-year survivals for the 15 patients transplanted since 1998 was 57% and 48%, respectively. Median survival ranged from 20 to 42 months based on the time period (P = .014). CONCLUSIONS The acceptable overall survival, the improved results after careful patient selection since 1998, and the encouraging outcomes from recent studies all suggest that OLT may be a potential treatment for selected cases of HL. Prospective multicenter randomized studies with strict selection criteria and multimodal treatments seem necessary.

Renal transplantation in a patient with end stage renal disease due to cholesterol embolism.

BACKGROUND Renal failure due to cholesterol emboli is mostly irreversible. Therefore chronic renal replacement therapy is necessary. However, to the best of our knowledge no published experience exists with renal transplantation in patients with end-stage renal disease (ESRD) due to cholesterol embolization (CE). METHODS Renal transplantation was performed in a 64-year-old man who suffered from ESRD due to CE after coronary angiography. Because our patient presented with a typical profile of cardiovascular risk factors effective long-term control of these risk factors before and after transplantation was a mandatory prerequisite before considering transplantation. RESULTS After one rejection episode serum creatinine values have been stable and no major complications have occurred during a follow-up of 18 months. No signs of recurrent cholesterol emboli into the donated kidney were seen in renal biopsies performed due to graft rejection. CONCLUSION Cholesterol embolization is an uncommon reason for ESRD and mainly occurs after invasive vascular procedures in patients with hyperlipidemia, arterial hypertension, and smoking. Because ESRD due to CE often is irreversible, chronic renal replacement therapy may be necessary. As demonstrated in our report, renal transplantation should be considered. However, in this setting effective long-term control of the underlying risk factors before and after renal transplantation has to be ensured.

Effects of the combined thromboxane receptor antagonist and synthase inhibitor DTTX-30 on intestinal O2-exchange and energy metabolism during hyperdynamic porcine endotoxemia.

ABSTRACT Sepsis may lead to deranged thromboxane‐prostacyclin ratio with consecutive organ dysfunction. Because of the suggested role of the gut in the pathogenesis of septic shock and multiple organ failure, we investigated the effects of the novel dual thromboxane synthase inhibitor and receptor antagonist DTTX‐30 (TRASI) on intestinal tissue perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic, normotensive porcine endotoxemia. Before, 12, 18, and 24 h after starting continuous i.v. endotoxin (LPS), we measured portal venous (PV) blood flow, intestinal oxygen extraction (iO2ER), intracapillary hemoglobin O2 saturation (HbO2%) of the ileal wall, intramucosal ileal PCO2, PV lactate‐pyruvate (L‐P) ratio, and plasma levels of thromboxane and prostacyclin. Treatment with TRASI (0.12 mg/kg i.v. bolus injection followed by an infusion of 0.29 mg/kg/h) initiated after 12 h of LPS infusion markedly reduced the plasma thromboxane levels and attenuated the LPS‐induced fall in systemic vascular resistance, resulting in hemodynamic stabilization. TRASI did not influence the LPS‐induced increase in PV blood flow nor intracapillary HbO2%, thus reflecting unchanged microcirculatory O2 availability and decreased iO2ER, possibly because of reduced O2 requirements. Nevertheless, TRASI prevented the LPS‐induced increase in the PV L‐P ratio, attenuated the progression of the ileal mucosal‐arterial PCO2 gap, and tended to attenuate the gradual fall of PV pH. Hence, compounds like TRASI may beneficially influence LPS‐related derangements of gut energy metabolism.

Late onset primary oxalosis type I : an uncommon presentation of a rare disease

A 46-year-old woman developed rapidly worsening renal insufficiency. Extensive calcification of the kidneys was found. The patient also suffered from ischaemic neuropathy, myopathy and arthritis. In a muscle biopsy multiple calcium oxalate crystals could be demonstrated surrounded by inflammatory infiltrates. Levels of oxalate in serum were markedly elevated. Diagnosis of primary hyperoxaluria type I was made by measuring alanine/glyoxylate aminotransferase activity in a liver biopsy. The patient underwent kidney transplantation twice, but each of the transplants failed after a very short time owing to hyperacute rejection and rupture of the organ, respectively. Eventually, combined liver/kidney transplantation was successfully performed. Two years after the transplantation, both organs work with good function. This case of primary hyperoxaluria type I is remarkable for the late onset of symptoms and the extensive involvement of other organ systems in addition to the kidneys. This case presentation confirms previous reports discouraging isolated kidney transplantation for patients with primary hyperoxaluria. Only combined liver/kidney transplantation can correct the metabolic defect and may give these patients superior long-term benefit.

Smoking increases the risk of pre- and postoperative complications in patients with pilonidal disease

Smoking has a negative impact on the natural history and on treatment results of many dermatological conditions. However, there are no data demonstrating a similar effect in patients with pilonidal disease.

Validation of portal vein flow measurement by color flow Doppler sonography in a porcine model of septic shock

ObjectiveTo compare portal vein flow values gained by color flow Doppler sonography with simultaneously derived data from an ultrasound transit time flow probe.DesignRepeated, simultaneous flow measurements were performed in a prospective study investigating the effect of various drugs on hepatosplanchnic perfusion and energy balance in a long-term model of stable, hyperdynamic endotoxin shock.SettingInvestigational animal laboratory.SubjectsDomestic pigs.InterventionsAlterations in respirator setting were studied with regard to their effect on the quality of color flow Doppler data in comparison to flow probe data. Additional experiments included variation in PEEP level in conjunction with volume resuscitation.Measurements and resultsRespiratory rates of 14–18/min led to color Doppler flow values consistently 20–40% above simultaneously measured flow probe data. Temporary apnea led to enhanced agreement of data. Reduction in respiratory rate to 8/min with increase in tidal volume consistently led to color Doppler data within 10% of the corresponding flow probe values.ConclusionsA short-term period of respirator-dependent, constant portal vein inflow enables color Doppler sonography to detect correct values in a clinically relevant setting of hyperdynamic endotoxin shock.