Sirolimus vs mycophenolate mofetil (MMF) in primary combined pancreas and kidney transplantation. Results of a long-term prospective randomized study.

The study was intended to compare pancreas graft survival rates in two groups of pancreas and kidney transplant recipients prospectively randomized to treatment either with sirolimus or MMF. From 2002 to 2013, 238 type 1 diabetic recipients with end-stage kidney disease were randomized 1:1 to sirolimus or MMF treatment. Noncensored pancreas survival at 5 years was 76.4 and 71.6% for sirolimus and MMF groups, respectively (P > .05). Death-censored pancreas survival was better in the sirolimus group (P = .037). After removal of early graft losses pancreas survival did not differ between groups (MMF 83.1% vs sirolimus 91.6%, P = .11). Nonsignificantly more grafts were lost due to rejection in the MMF group (10 vs 5; P = .19). Cumulative patient 5-year survival was 96% in the MMF group and 91% in the sirolimus group (P > .05). Five-year cumulative noncensored kidney graft survival rates did not statistically differ (85.6% in the sirolimus group and 88.8% in MMF group). Recipients treated with MMF had significantly more episodes of gastrointestinal bleeding (7 vs 0, P = .007). More recipients in the sirolimus group required corrective surgery due to incisional hernias (21 vs 12, P = .019). ClinicalTrials No.: NCT03582878.

Early worsening of diabetic retinopathy after simultaneous pancreas and kidney transplantation-Myth or reality?

Early worsening of diabetic retinopathy due to sudden glucose normalization is a feared complication of pancreas transplantation; however, its rate or severity has not been studied prospectively. We followed up 43 pancreas and kidney recipients for a composite endpoint comprising new need for laser therapy, newly diagnosed proliferation, macular edema, visual acuity worsening, and blindness over 12 months. Although 37% of patients met this primary endpoint, its severity was rather low. Mean central retinal thickness and proportion of patients with subclinical macular edema increased significantly, with spontaneous resolution in half of them. Visual acuity did not change. There was no significant difference in the absolute glycated hemoglobin (HbA1c) drop, age, and diabetes duration between the patients who met and those who did not meet the primary endpoint, but a higher proportion of patients with worsening had a recent history of laser treatment. Retinopathy remained stable in 62.8% of patients. In 26%, the visual acuity significantly improved. Although retinopathy worsening was documented in more than one-third of patients, its evolution was not related to the magnitude of metabolic change; rather, it corresponded to the expected natural course of retinopathy. Nonetheless, comprehensive ophthalmologic care should be a substantial component of the recipient management.

Molecular patterns of diffuse and nodular parathyroid hyperplasia in long-term hemodialysis.

Secondary hyperparathyroidism is a well-known complication of end-stage renal disease (ESRD). Both nodular and diffuse parathyroid hyperplasia occur in ESRD patients. However, their distinct molecular mechanisms remain poorly understood. Parathyroid tissue obtained from ESRD patients who had undergone parathyroidectomy was used for Illumina transcriptome screening and subsequently for discriminatory gene analysis, pathway mapping, and gene annotation enrichment analysis. Results were further validated using quantitative RT-PCR on the independent larger cohort. Microarray screening proved homogeneity of gene transcripts in hemodialysis patients compared with the transplant cohort and primary hyperparathyroidism; therefore, further experiments were performed in hemodialysis patients only. Enrichment analysis conducted on 485 differentially expressed genes between nodular and diffuse parathyroid hyperplasia revealed highly significant differences in Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genomes database in ribosome structure (P = 3.70 × 10-18). Next, quantitative RT-PCR validation of the top differently expressed genes from microarray analysis proved higher expression of RAN guanine nucleotide release factor (RANGRF; P < 0.001), calcyclin-binding protein (CACYBP; P < 0.05), and exocyst complex component 8 (EXOC8; P < 0.05) and lower expression of peptidylprolyl cis/trans-isomerase and NIMA-interacting 1 (PIN1; P < 0.01) mRNA in nodular hyperplasia. Multivariate analysis revealed higher RANGRF and lower PIN1 expression along with parathyroid weight to be associated with nodular hyperplasia. In conclusion, our study suggests the RANGRF transcript, which controls RNA metabolism, to be likely involved in pathways associated with the switch to nodular parathyroid growth. This transcript, along with PIN1 transcript, which influences parathyroid hormone secretion, may represent new therapeutical targets to cure secondary hyperparathyroidism.

[Islet transplantation as a treatment for hypoglycemia unawareness syndrome. Evaluation of the pilot program and comparison with pancreas transplantation]. / Transplantace Langerhansových ostruvku v lécbe syndromu poruseného vnímání hypoglykemie. Vyhodnocení pilotního programu a porovnání s transplantací pankreatu.

Islet transplantation (ITx) started in 2005 in IKEM as a potentially safer alternative to pancreas transplantation (PTx), which so far had represented the method of choice in type-1 diabetic patients with conservatively intractable hypoglycemia unawareness syndrome. The aim of the study was to compare these two methods with regard to severe hypoglycemia elimination and to frequency of complications.Up to November 2015 a total number of 48 patients underwent ITx. The results from 22 patients with hypoglycemia unawareness were statistically analyzed. The mean number of transplanted islet equivalents was 12,096 (6,93316,705) IEQ/kg administered percutaneously in local anesthesia under radiological control to the portal vein. 44 patients underwent PTx from 1996. We evaluated glycated hemoglobin(HbA1c), insulin dose, fasting and stimulated C-peptide, frequency of severe hypoglycemia and complications. Medians (interquartile range) were analyzed using the Wilcoxon signed-rank test.One and two years after ITx, HbA1c decreased, C-peptide became significantly positive, insulin dose and frequency of severe hypoglycemia decreased and 18 % of ITx recipients were temporarily insulin-independent. Bleeding was present in 41 % of patients. One year after PTx, 73 % of patients were insulin and hypoglycemia-free, after two years 68 % of patients were insulin and hypoglycemia-free; graftectomy occurred in 20 % of recipients.Both methods led to restoration of insulin secretion and severe hypoglycemia elimination. PTx made more recipients insulin-independent at the cost of serious complications.

[Pancreas transplantation: State of the art and future prospects]. / Transplantace pankreatu: soucasný stav a výhledy do budoucna.

During the past 30 years pancreas transplantation evolved into a routine procedure especially suitable for type 1 diabetic recipients undergoing simultaneously kidney transplantation significantly improving quality of life and life expectancy as compared with kidney only recipients. It provides insulin independence with near-normal glucose control without special dietary restriction, freedom from hypoglycemia and chance for halting or regression of microangiopathic diabetes complications. As a separate procedure, pancreas transplantation is carried out mainly in selected subjects suffering from severe hypoglycemic episodes and impaired hypoglycemia awareness or as a subsequent procedure in type 1 diabetic kidney recipients from both cadaveric or living donors. Five-year insulin independence rate following combined pancreas and kidney, pancreas only and pancreas after kidney procedures currently exceed 75, 50 and 62 %, respectively. Though the outcomes still continue to improve, the rate of pancreas transplants has reached a plateau in several European countries or even declines in the United States. Main reasons for that include fewer referrals from diabetes specialist, decreased donor quality, introduction of islet transplantation as a less invasive procedure but probably most of all probably insufficient information on the latest progress and trends achieved in this area. In the area of transplant therapy of diabetes Czech Republic traditionally ranks to the most active countries providing different transplant options according to individual clinical needs including islet transplantation.

Prevalence and risk factors of polyomavirus BK replication in simultaneous pancreas/kidney transplant recipients from a single transplant center.

BACKGROUND: BK virus (BKV) replication is considered as a marker of risk for polyomavirus BK-associated nephropathy (PVAN). We evaluated the occurrence and risk factors for BKV DNA positivity following simultaneous pancreas/kidney transplantation (SPK). METHODS: Point prevalence of BK viruria and viremia was assessed in 183 SPK recipients. Real-time polymerase chain reaction was used with a detection threshold of 10(3) copies/mL. High-level BKV positivity was defined as viruria and/or viremia >10(7) and >10(4) copies/mL, respectively. BKV-positive patients were retested after 4-13 months and underwent an additional six-month clinical follow-up. RESULTS: Urine and serum BKV positivity was detected in 28 (17.3% of available samples) and 7 (3.8%) patients, with high-level viruria and viremia occurring in 6 (3.7%) and 3 (1.6%) patients, respectively. PVAN was biopsy-confirmed in 1 and suspected as a cause of progressive renal failure in another SPK recipient. Patients with single low-level viruria did not progress to high-level positivity or PVAN at follow-up. In multivariate analysis, pre-transplant diabetes duration and delayed graft function were independently associated with BKV positivity. CONCLUSIONS: Point prevalence of high-level BKV positivity and PVAN was low in SPK recipients from a single center. Diabetes duration and delayed graft function were independent risk factors for BKV replication.

[Eversion carotid endarterectomy: evaluation of results after changing the operation technique]. / Everzní endarterektomie arterie carotis interna: hodnocení výsledku po zmene operacní techniky.

BACKGROUND: Stroke is the third most common cause of mortality, and carotid artery stenosis causes up to 30% of all ischemic strokes. Eversion CEA (ECEA) has been proposed as an acceptable alternative to the standard bifurcation endarterectomy in many patients. This study was designed to analyze the long-term durability of ECEA in symptomatic and asymptomatic patients. Data were retrospectively reviewed to determine the incidence of major adverse cardiovascular events (MACEs) within 30 days of surgery, late survival, and the incidence of restenosis. METHODS AND RESULTS: From January 1999 to June 2010, 344 ECEAs were performed on 324 patients (34% female, 38% symptomatic). The mean follow-up period was 30 months. CONCLUSIONS: MACEs occurred in 28 patients (8.6%). The overall incidence of stroke or death after ECEA was 1.7% and 0.9% at discharge. The overall incidence of stoke or death after CEA was 4.3% and 21% (14 strokes, 69 deaths, 8 of which were stroke-related). The overall occurrence of any restenosis (> 50%) after CEA was 4.3% (14 of 324 procedures).

[Islet transplantation for treatment of type-1 diabetes mellitus]. / Lécba diabetu transplantací izolovaných Langerhansových ostruvku.

BACKGROUND: Organ pancreas transplantation represents the only method enabling long-term normalization of glucose metabolism in type-1 diabetic subjects so far. Unfortunately, surgical complications of this kind of therapy are still frequent. As a safer alternative, transplantation of isolated pancreatic islets was introduced at the Institute for Clinical and Experimental Medicine as a clinical experiment in the year 2005. METHODS AND RESULTS: We isolated the islets from pancreases of cadaveric donors which did not fulfil criteria to perform organ pancreas transplantation. Altogether, 36 islet implantations were performed in 28 C-peptide negative subjects suffering from type-1 diabetes by August 2010. In 15 subjects (21 implantations) the main indication was extremely instable course of diabetes due to the hypoglycaemia unawareness syndrome. In 5 and 3 cases, combined islet and kidney and islet and liver transplants were performed, respectively. In addition, islet autotransplantation was performed in 5 subjects undergoing total pancreatectomy. No patient died during the study period. In all but 1 patient with primary islet afunction, islet transplantation led to a complete cure of the hypoglycemia unawareness syndrome. Out of 15 patients, 11 subjects in this group showed a significant C-peptide production (> 0.2 pmol/ml) after 1 year. The mean insulin dose after allotransplantation decreased from 37 to 14 units per day and in 3 subjects, insulin therapy could be withdrawn. Serious technical complications occurred in 6 subjects, which only in 2 cases required surgical revision and did not cause long-term sequels. CONCLUSIONS: In comparison with organ pancreas transplantation, pancreatic islet transplantation represents a substantially safer method for restitution of endogenous insulin production. Though it eliminates serious hypoglycemic episodes in labile diabetes, complete insulin withdrawal is still often not possible. However, due to continuing progress in the laboratory techniques as well as in the transplant procedure itself, the results are steadily improving.

Hybrid Repair Combined with Fresh Arterial Allograft Extra-Anatomical Reconstruction: The Treatment of Infrarenal Abdominal Aneurysm above an Aortobifemoral Bypass Complicated by an Infected Pseudoaneurysm in the Left Groin.

INTRODUCTION: A 72-year-old male patient was admitted into our centre with large infected pseudoaneurysm (PSA) in the left groin. The patient underwent a CT angiography (CTA) that confirmed a large partly thrombosed 6.5 × 5.5 cm PSA in the left groin arising from the distal anastomosis of the aortobifemoral bypass (ABF). Furthermore, the CTA revealed 11 cm juxtarenal abdominal aortic aneurysm (JAAA) from which the proximal anastomosis of the ABF was arising. METHOD: Aorto-uni-iliac stent graft Cook was placed from the right groin trough native severely stenotic right iliac arteries with proximal landing zone below the renal arteries, excluding the JAAA and the ABF. The distal landing zone was in the common iliac artery maintaining patent right internal iliac artery. Afterwards, a femoro-femoral crossover bypass from right to left was performed using a fresh arterial allograft. Postprocedurally, the hospital stay was uneventful. The left groin PSA cultures came positive for Staphylococcus epidermidis and Corynebacterium tuberculostearicum, both sensitive to vancomycin and rifampicin. RESULT: The patient underwent intravenous ATB treatment with vancomycin for two weeks, followed by four weeks of oral rifampicin. The patient was discharged on the 20th postoperative days. CONCLUSION: Hybrid repair combining aortic stent graft and extra-anatomical bypass in the treatment of infected distal parts of an aortofemoral bypass is an acceptable treatment modality.

Successful surgical treatment of multilevel aortic aneurysms combined with renal transplantation.

The concomitant presence of a thoracic aortic aneurysm and an abdominal aortic aneurysm in patients considered for renal transplantation is extremely rare. To our knowledge, this is the first case report of the successful treatment of multilevel aortic aneurysms together with renal transplantation. The treatment modalities in renal transplant patients with concomitant aortic aneurysms are discussed.

Large Hepatic Artery Pseudoaneurysm Resection After Orthotopic Liver Transplantation.

BACKGROUND Hepatic artery (HA) pseudoaneurysm (PSA) after liver transplantation (OLTx) is rare but often fatal complication requiring quick repair. Its prevalence in patients after OLTx is around 0.94%. CASE REPORT A 41-year-old female patient underwent a full-graft orthotopic liver transplantation (OLTx) for alcoholic liver cirrhosis in 2017. During regular postoperative Doppler ultrasonography (DU) check-ups, a large 3-cm pseudoaneurysm (PSA) was detected on the hepatic artery. The patient underwent a computed angiography (CTA) to verify the PSA anatomical localization and relationship with the transplanted liver graft. Selective celiac arteriography showed HA PSA and 90% stenosis of the hepatic artery after PSA. The stent graft placement was unsuccessful as the guiding wire was unable to pass through the post-PSA HA stenosis. The patient was scheduled for an open repair under general anesthesia. Through a right subcostal incision, the HA PSA was resected and the HA was mobilized and re-anastomosed using an end-to-end technique. Three months after the procedure, the patient has a good liver graft perfusion through the HA with no sign of PSA reoccurrence or stenosis. CONCLUSIONS Early detection of the HA PSA after OLTx is a life-threatening complication requiring prompt treatment. If endovascular treatment options fail, open surgical repair, despite its challenges, is the only possible treatment option.

Hypoglycemia and Glucocorticoid-free Immunosuppression are Related With Low Dehydroepiandrosterone Sulfate Level.

BACKGROUND: Low dehydroepiandrosterone sulfate (DHEAS) levels and a high cortisol/ DHEAS ratio are associated with higher mortality in elderly, dialyzed, and immunocompromised patients. The role of these hormones in patients with hypoglycemia unawareness (hypo) or in pancreas or islet recipients treated by glucocorticoid-free immunosuppressive regimen (IS) has not been studied. OBJECTIVE: The aim of this study was to determine the effects of IS and of recurrent hypoglycemia on DHEAS and adrenocorticotropic hormone (ACTH) levels in patients with type-1 diabetes (T1DM). METHODS: A case control, cross-sectional analysis of patients in a prospective database enrolled 84 patients with T1DM. They were divided into 4 groups of 21 subjects each: 1) islet or pancreas recipients with hypoglycemia who are IS (hypo +, IS +); 2) pancreas and kidney transplant recipients without insulin or hypoglycemia (hypo -, IS +); 3) T1DM patients with hypoglycemia (hypo +, IS -); and 4) T1DM patients without hypoglycemia (hypo -, IS -). RESULTS: DHEAS and ACTH levels were significantly decreased in patients with hypoglycemia (P = 0.0002 and P = 0.0001, respectively) as well as in those with IS (P = 0.0497 and P < 0.001, respectively) compared to those without hypoglycemia or IS. The influence of hypoglycemia unawareness on DHEAS levels was stronger than that of immunosuppression (P < 0.10). CONCLUSION: Low DHEAS and ACTH levels represent an additional component of hypoglycemia unawareness syndrome and they remain low in patients receiving glucocorticoid-free immunosuppression. DHEAS may serve as a marker, the importance of which remains unclear, but deserves attention.

Benefits of Islet Transplantation as an Alternative to Pancreas Transplantation: Retrospective Study of More Than 10 Ten Years of Experience in a Single Center.

BACKGROUND: Pancreas transplantation (PTx) represents the method of choice in type 1 diabetic patients with conservatively intractable hypoglycemia unawareness syndrome. In 2005, the Institute for Clinical and Experimental Medicine (IKEM) launched a program to investigate the safety potential of islet transplantation (ITx) in comparison to PTx. AIM: This study aims to compare the results of PTx and ITx regarding severe hypoglycemia elimination, metabolic control, and complication rate. METHODS: We analyzed the results of 30 patients undergoing ITx and 49 patients treated with PTx. All patients were C-peptide-negative and suffered from hypoglycemia unawareness syndrome. Patients in the ITx group received a mean number of 12,349 (6,387-15,331) IEQ/kg/person administered percutaneously into the portal vein under local anesthesia and radiological control. The islet number was reached by 1-3 applications, as needed. In both groups, we evaluated glycated hemoglobin, insulin dose, fasting and stimulated C-peptide, frequency of severe hypoglycemia, and complications. We used the Mann Whitney test, Wilcoxon signed-rank test, and paired t-test for analysis. We also individually assessed the ITx outcomes for each patient according to recently suggested criteria established at the EPITA meeting in Igls. RESULTS: Most of the recipients showed a significant improvement in metabolic control one and two years after ITx, with a significant decrease in HbA1c, significant elevation of fasting and stimulated C-peptide, and a markedly significant reduction in insulin dose and the frequency of severe hypoglycemia. Seventeen percent of ITx recipients were temporarily insulin-independent. The results in the PTx group were comparable to those in the ITx group, with 73% graft survival and insulin independence in year 1, 68% 2 years and 55% 5 years after transplantation. There was a higher rate of complications related to the procedure in the PTx group. Severe hypoglycemia was eliminated in the majority of both ITx and PTx recipients. CONCLUSION: This report proves the successful initiation of pancreatic islet transplantation in a center with a well-established PTx program. ITx has been shown to be the method of choice for hypoglycemia unawareness syndrome, and may be considered for application in clinical practice if conservative options are exhausted.

Combining Donor Characteristics with Immunohistological Data Improves the Prediction of Islet Isolation Success.

Variability of pancreatic donors may significantly impact the success of islet isolation. The aim of this study was to evaluate donor factors associated with isolation failure and to investigate whether immunohistology could contribute to organ selection. Donor characteristics were evaluated for both successful (n = 61) and failed (n = 98) islet isolations. Samples of donor pancreatic tissue (n = 78) were taken for immunohistochemical examination. Islet isolations with 250000 islet equivalents were considered successful. We confirmed that BMI of less than 25 kg/m2 (P < 0.001), cold ischemia time more than 8 hours (P < 0.01), hospitalization longer than 96 hours (P < 0.05), higher catecholamine doses (P < 0.05), and edematous pancreases (P < 0.01) all unfavorably affected isolation outcome. Subsequent immunohistochemical examination of donor pancreases confirmed significant differences in insulin-positive areas (P < 0.001). ROC analyses then established that the insulin-positive area in the pancreas could be used to predict the likely success of islet isolation (P < 0.001). At the optimal cutoff point (>1.02%), sensitivity and specificity were 89% and 76%, respectively. To conclude, while the insulin-positive area, determined preislet isolation, as a single variable, is sufficient to predict isolation outcome and helps to improve the success of this procedure, its combination with the established donor scoring system might further improve organ selection.

Epidermal innervation in type 1 diabetic patients: a 2.5-year prospective study after simultaneous pancreas/kidney transplantation.

OBJECTIVE: To assess the effect of normoglycemia following simultaneous pancreas/kidney transplantation (SPK) on neurological function and intraepidermal nerve fiber density (IENFD) in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed vibration perception threshold (VPT) testing and autonomic function testing (AFT) and assessed IENFD in skin biopsies from the lower thigh and upper calf in 14 healthy control subjects and 18 patients with type 1 diabetes at the time of and at 21-40 (median 29) months post SPK. RESULTS: At baseline, significantly increased VPTs, pathological AFT results, and severe reduction in IENFD were present in SPK recipients. After SPK, an increase of IENFD in the thigh of more than one epidermal nerve fiber per millimeter was noted in three patients (median 4.1, range 1.9-10.2), but changes were not significant for the group as a whole. CONCLUSIONS: We conclude that either irreversible nerve damage might be present in some SPK recipients or that longer periods of normoglycemia might be needed to allow nerve regeneration.

Kidney retransplantation following graft loss to polyoma virus-associated nephropathy: an effective treatment option in simultaneous pancreas and kidney transplant recipients.

Polyomavirus-associated nephropathy (PVAN) has emerged as an important cause of graft loss following kidney transplantation. Experience with kidney retransplantation (reKT) in PVAN is very limited, especially in the setting of uninterrupted immunosuppression protecting the still functioning pancreatic graft after simultaneous pancreas/kidney transplantation (SPK). We present a review of five cases of reKT in four SPK recipients with Type 1 diabetes mellitus from a single centre (a second reKT was performed in one patient following first reKT failure due PVAN recurrence). Pre-emptive nephrectomy of the failed graft was performed in three of the cases and all kidney grafts for reKT were harvested from cadaveric donors. All patients are dialysis- and insulin-independent at 30 (9-55), median (range), months following last reKT with maintenance immunosuppression consisting of tacrolimus/sirolimus in three and cyclosporine A/mycophenolate mofetil in one patient. In conclusion, reKT represents an effective treatment option in SPK patients with kidney failure on account of PVAN. Use of interventions designed to reduce active viral replication, including pre-emptive nephrectomy of the failed graft, should be considered before reKT.