Differential Role of TGF-β1/bFGF and ET-1 in Graft Fibrosis in Heart Failure Patients

Collagen overproduction characteristic for dilated cardiomyopathy (DCM) is coregulated by endothelin (ET)-1, transforming growth factor (TGF)-beta1, basic fibroblast growth factor (bFGF) and matrix metalloproteases (MMPs). Whether these molecules affect grafts transplanted to heart failure patients is unknown. In 67 idiopathic DCM patients, 31 patients with ischemic cardiomyopathy (ICM) and 16 controls, the myocardial bFGF, TGF-beta1, pro-collagen (PrCol) type 1 (PrCol1-alpha1, -alpha2) and MMP expressions were examined using real-time RT-PCR or Western blotting. mRNA expression was measured in grafts for 1 year. TGF-beta1/bFGF stimulation or gene silencing was used to examine their effect on collagen synthesis in cardiac tissue cultures. TGF-beta1 and PrCol1 were upregulated in DCM only, while bFGF was upregulated in both groups versus controls. TGF-beta1 downregulated MMP-1 and upregulated collagen 1, whereas bFGF upregulated MMP-13 in DCM tissue. Post-transplant PrCol1-alpha1, -alpha2 and ET-1 mRNA increased over time in grafts of DCM patients only, while other factors returned to control baseline levels in DCM and ICM. These data indicate that cardiac transplantation corrects the dysregulated TGF/bFGF/MMP-1/MMP-13, but not the excess collagen and ET-1 synthesis in cardiac grafts transplanted to DCM patients. ET-1 might be a major pathologic trigger for graft fibrosis in DCM.     

Anti-thrombin Therapy During Warm Ischemia and Cold Preservation Prevents Chronic Kidney Graft Fibrosis in a DCD Model

Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran® (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-β (TGF-β) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.     

Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies: A Multi‐Omics Approach

Progressive fibrosis of the interstitium is the dominant final pathway in renal destruction in native and transplanted kidneys. Over time, the continuum of molecular events following immunological and nonimmunological insults lead to interstitial fibrosis and tubular atrophy and culminate in kidney failure. We hypothesize that these insults trigger changes in DNA methylation (DNAm) patterns, which in turn could exacerbate injury and slow down the regeneration processes, leading to fibrosis development and graft dysfunction. Herein, we analyzed biopsy samples from kidney allografts collected 24 months posttransplantation and used an integrative multi‐omics approach to understand the underlying molecular mechanisms. The role of DNAm and microRNAs on the graft gene expression was evaluated. Enrichment analyses of differentially methylated CpG sites were performed using GenomeRunner. CpGs were strongly enriched in regions that were variably methylated among tissues, implying high tissue specificity in their regulatory impact. Corresponding to this methylation pattern, gene expression data were related to immune response (activated state) and nephrogenesis (inhibited state). Preimplantation biopsies showed similar DNAm patterns to normal allograft biopsies at 2 years posttransplantation. Our findings demonstrate for the first time a relationship among epigenetic modifications and development of interstitial fibrosis, graft function, and inter‐individual variation on long‐term outcomes.     

Fibrosis and angiogenesis

Research during the past few years has contributed vastly to a better understanding of fibrosis and angiogenesis. Although studies to understand the molecular processes associated with fibrosis and angiogenesis were performed independently of each other, some common parallels have emerged. Translation of these observations into potential therapeutic possibilities needs further exploration.     

Risk factors for delayed kidney function and impact of delayed function on patient and graft survival in adult graft recipients

The influence of delayed kidney graft function on allograft outcome is described controversially in the literature. The aim of the study was to evaluate possible risk factors for delayed graft function (DGF) and investigate the impact of DGF on short- and long-term renal allograft function. Two groups were formed: the first one consisted of patients who gained immediate graft function (IGF) (n = 64) after transplantation and the second group included patients with DGF (n = 31; with at least one dialysis needed in first week after transplantation). The DGF group had a statistically significant longer duration on dialyses prior to transplantation (DGF 54 vs. IGF 33 months; p < 0.05), on average more frequently a re-transplantation (DGF 1.7 vs. IGF 1.3; p < 0.01), a longer re-anastomosis time (DGF 52.9 vs. 44.2 min; p < 0.01), a lower systolic (DGF 136 +/-24 mmHg vs. IGF 158 +/- 25; p < 0.001) and diastolic blood pressure (DGF 78 +/- 14 vs. IGF 89 +/- 16 mmHg; p < 0.01) at admission to the hospital and a higher serum (S)-creatinine at discharge (DGF 2.5 +/- 1.6 vs. IGF 1.6 +/- 0.4 mg/dL; p < 0.01). Prior to transplantation the DGF group had more often advanced vascular diseases (DGF 29.0 vs. IGF 12.5%; p < 0.01) and these patients incurred more frequently new ones during the next 3 yr after transplantation (DGF 22.6 vs. IGF 6.3%; p < 0.001). After 3 yr the graft survival tended to be lower in the DGF group (DGF 74.2 vs. IGF 84.4%; NS), but this difference was not statistically significant.     

New frontiers in urethral reconstruction: injectables and alternative grafts

Contemporary management of anterior urethral strictures requires both endoscopic as well as complex substitution urethroplasty, depending on the nature of the urethral stricture. Recent clinical and experimental studies have explored the possibility of augmenting traditional endoscopic urethral stricture management with anti-fibrotic injectable medications. Additionally, although buccal mucosa remains the gold standard graft for substitution urethroplasty, alternative grafts are necessary for reconstructing particularly complex urethral strictures in which there is insufficient buccal mucosa or in cases where it may be contraindicated. This review summarizes the data of the most promising injectable adjuncts to endoscopic stricture management and explores the alternative grafts available for reconstructing the most challenging urethral strictures. Further research is needed to define which injectable medications and alternative grafts may be best suited for urethral reconstruction in the future.     

Urolithiasis and Cystic Fibrosis

Purpose

We determined whether cystic fibrosis patients are at increased risk for the development of urolithiasis.

Materials and Methods

Telephone interviews were conducted with 201 cystic fibrosis patients older than 15 years to identify those with a history of urolithiasis. Histories were confirmed by chart review, and only patients with urolithiasis documented by excretory urography, renal ultrasound or spontaneous passage of a stone were included.

Results

A total of 11 patients (5.5 percent) had documented urolithiasis, with 2 or more episodes in 7. Mean age at initial episode was 27.0 years (range 19 to 33).

Conclusions

Cystic fibrosis patients may be at increased risk for urolithiasis compared to age-specific prevalence rates for stone disease in the general population.     

Idiopathic Retroperitoneal Fibrosis Revisited

We have evaluated 21 patients, ranging in age from 44 to 71 years (mean: 55 years), who presented to our department with the radiologic characteristics of retroperitoneal fibrosis.Ureterolysis was performed in all cases. Intraperitoneal placement of the ureter was performed in 9, and placement of the ureter in a lateral extraperitoneal position in 12 cases.We found no difference in the postoperative course and radiological and clinical improvement to favour the first or the second method, and therefore we consider the intraperitoneal approach as an unnecessary manoeuvre.     

Graft intolerance syndrome requiring graft nephrectomy after late kidney graft failure: can it be predicted? A retrospective cohort study

Graft nephrectomy is recommended in case of early graft failure. When the graft fails more than 3–6 months after transplantation, it is current practice to follow a wait‐and‐see policy. A common indication for graft removal is the graft intolerance syndrome. We aimed to create a risk prediction model for the occurrence of graft intolerance resulting in graft nephrectomy. We collected data of kidney transplantations performed in our center between 1980 and 2010 that failed at least 6 months after transplantation. We evaluated the association between baseline characteristics and the occurrence of graft nephrectomy because of graft intolerance using a competing risk regression model. Prognostic factors were included in a multivariate prediction model. In‐ and exclusion criteria were met in 288 cases. In 48 patients, the graft was removed because of graft intolerance. Donor age, the number of rejections, and shorter graft survival were predictive factors for graft nephrectomy because of the graft intolerance syndrome. These factors were included in a prediction rule. Using donor age, graft survival, and the number of rejections, clinicians can predict the need for graft nephrectomy with a reasonable accuracy.     

Lung Transplantation for Cystic Fibrosis and Non-cystic Fibrosis Bronchiectasis: A Single-Center Experience

ObjectivesLung transplantation is a well-established treatment for selected patients with advanced cystic fibrosis (CF)- and non-cystic fibrosis (non-CF)--related bronchiectasis. Because the number of lung transplants performed for patients with non-CF bronchiectasis is much smaller than for patients with CF, little data is available regarding patient selection, choice of procedure, and outcomes.MethodsBetween November 1997 and December 2013, 42 patients with CF and 33 patients with non-CF bronchiectasis underwent lung transplantation at the Rabin Medical Center, Israel. We analyzed and compared pretransplant evaluation data and short- and long-term results in both groups.ResultsMedian survival for the CF group in our study was 8.4 years, compared with 7.1 years for the non-CF group (P = .098), similarly to that reported by the International Society for Heart and Lung Transplantation Registry data. The main survival difference between groups was in the early postoperative period. Both groups achieved similar peak forced expiratory volume in 1 second values and had stable lung function at the 3-year follow-up. Biopsy-proven rates of acute cellular rejection were low for both groups. Rates of chronic lung allograft dysfunction development did not differ between CF and non-CF recipients.ConclusionOur institutional experience confirms that lung transplantation is feasible for non-CF bronchiectasis, and results are comparable to our CF cohort. The increased early mortality in this study occurred from 1999 to 2008 and was probably related to surgical techniques used at the time. Overall, 3-year and 5-year survival were comparable with the International Society for Heart and Lung Transplantation Registry data. Non-CF bronchiectasis patients achieved and maintained satisfactory lung function.     

Renal graft intolerance syndrome in late graft failure patients: efficacy and safety of embolization as first‐line treatment compared to surgical removal

Although renal graft percutaneous embolization was introduced to avoid the risk associated with graft nephrectomy, there is no universal consensus about its indications and results. In order to evaluate the efficacy of graft embolization in the treatment of graft intolerance syndrome as well as its safety compared to surgical removal with respect to complications and other morbidity measures, We performed a retrospective observational study comparing two groups of patients treated for graft intolerance syndrome: Group 1: patients who had embolization as first‐line treatment and Group 2: patients directly treated by surgical removal. 72 patients were included, (32 in Group 1 and 40 in Group 2); the postintervention follow‐up continued for 12 months. Patients in Group 1 are older than those in Group 2. Otherwise, the two groups are similar concerning sex, manifestations of graft intolerance syndrome, diabetes and nutritional and functional status. The overall success rate of embolization in complete resolution of graft intolerance syndrome and ultimately avoidance of surgical removal was 84.37%. The surgical removal group had more serious complications, a longer hospital stay and needed more blood transfusions. We conclude that embolization of symptomatic renal grafts has considerable efficacy with less morbidity, and no serious complications compared to the standard surgical graft removal.     

Detailed evaluation of 2959 allogeneic and xenogeneic dense connective tissue grafts (fascia lata, pericardium, and dura mater) used in the course of 20 years for duraplasty in neurosurgery

Summary Surgical experience with 2959 allogeneic and xenogeneic dense connective tissue grafts (1767 of fascia lata, 909 of pericardium, and 283 of dura mater), used in 2665 neurosurgical operations performed in the course of 20 years (1976 to 1995) is reported.Duraplasty using either allogeneic or xenogeneic grafts has had a similar, and favourable clinical outcome. Nevertheless, the pliable deep frozen fascia lata grafts, which could be used in any location, have been reserved for sella turcica plugging, anterior cranial base plasty, aneurysmal wrapping, and surgery of lipomyelomeningocele. Pericardium and dura mater grafts were in the majority of cases used over the brain convexity and posterior cranial fossa. Ovine pericardium proved to be superior to bovine and allogeneic pericardia because of its workability, flexibility, reduced thickness, and better transparency.Postsurgical complications occurred in 7.3%, and they were: 1) cerebrospinal fluid fistulas in 2.8%; 2) meningites in 2.3% (aseptic 1.4%, bacterial 0.8%, and tumoural 0.1% meningites); 3) pseudomeningoceles in 2.2%; 4) wound infections in 0.6%; 5) malresorptive hydrocephalus in 0.5%; and 6) adhesions to nerve tissue in 0.5%. The majority of complications healed without surgery. Forty-eight grafts (1.6%) failed to fulfil the requirements of the surgeon, and 46 of them were re-operated upon. Though another thirty-nine grafts healed successfully, 39 shunts (1.5%) had to be performed for malresorptive hydrocephalus (0.9%), and/or for a big pseudomeningocele (0.6%). So, the pure complication rate in 2665 duraplasties was 3.1%.The complex evaluation of the allogeneic and xenogeneic grafts (fascia, pericardium, and dura mater), used for duraplasty in neuro-surgery during the last 20 years proved them, as remarkably good, with a success rates of 96.9%.     

European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre

A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognized that outcomes for patients cared for in specialist CF Centres are better than for those who are not. Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease. This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries.