Renal Graft Dysfunction Research Articles

The Oxidative and Inflammatory State in Patients with Acute Renal Graft Dysfunction Treated with Tacrolimus.

Objective. To determine the oxidative stress/inflammation behavior in patients with/without acute graft dysfunction (AGD) with Tacrolimus. Methods. Cross-sectional study, in renal transplant (RT) recipients (1-yr follow-up). Patients with AGD and without AGD were included. Serum IL-6, TNF-α, 8-isoprostanes (8-IP), and Nitric Oxide (NO) were determined by ELISA; C-reactive protein (CRP) was determined by nephelometry; lipid peroxidation products (LPO) and superoxide dismutase (SOD) were determined by colorimetry. Results. The AGD presentation was at 5.09 ± 3.07 versus 8.27 ± 3.78 months (p < 0.001); CRP >3.19 mg/L was found in 21 versus 19 in the N-AGD group (p = 0.83); TNF-α 145.53 ± 18.87 pg/mL versus 125.54 ± 15.92 pg/mL in N-AGD (p = 0.64); IL-6 2110.69 ± 350.97 pg/mL versus 1933.42 ± 235.38 pg/mL in N-AGD (p = 0.13). The LPO were higher in AGD (p = 0.014): 4.10 ± 0.69 µM versus 2.41 ± 0.29 µM; also levels of 8-IP were higher in AGD 27.47 ± 9.28 pg/mL versus 8.64 ± 1.54 pg/mL (p = 0.01). Serum levels of NO in AGD were lower 138.44 ± 19.20 µmol/L versus 190.57 ± 22.04 µmol/L in N-AGD (p = 0.042); antioxidant enzyme SOD activity was significantly diminished in AGD with 9.75 ± 0.52 U/mL versus 11.69 ± 0.55 U/mL in N-AGD (p = 0.012). Discussion. Patients with RT present with a similar state of the proinflammatory cytokines whether or not they have AGD. The patients with AGD showed deregulation of the oxidative state with increased LPO and 8-IP and decreased NO and SOD.

Markers of Endothelial-to-Mesenchymal Transition: Evidence for Antibody-Endothelium Interaction during Antibody-Mediated Rejection in Kidney Recipients.

Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

IgA NEPHROPATHY IN PATIENTS RECEIVING A RENAL TRANSPLANT.

IgA nephropathy (IgAN) is the third most frequent cause of renal graft loss among patients with primary glomerulonephritis. To assess clinical and laboratorial profile of patients with pre and/or post transplant IgAN, in addition to patient and graft survival in both groups. Data from 146 patients who had received a renal transplant were retrospectively collected and were divided in two groups: group 1-patients with biopsy-documented IgAN as the underlying native kidney disease (n = 128); group 2-patients who developed post-transplant IgAN independent of the underlying disease (n = 18). Patients submitted to renal transplantation (1998-2010) with pre and/or post transplant IgAN. Clinical and laboratorial evaluation of renal function of 146 post transplant IgAN patients. Recipients and deceased donors exhibited a higher degree of HLA compatibility (1.0 vs. 2.5 mismatches for groups 1 and 2, respectively). The main post-transplant IgAN presentation was haematuria associated with non-nephrotic proteinuria (44.4%). A histological pattern of focal segmental glomerulosclerosis was observed in 59.2% of biopsy samples. The 10-year patient survival was 93.5% in group 1 and 100% in group 2, and the graft survival rates were 58.5 and 87.2%, respectively. The rate of post-transplant IgA diagnosis in our case series was 11%, and IgAN was diagnosed late in the course of transplantation. In most cases, IgAN manifested as haematuria and non-nephrotic proteinuria, without renal graft dysfunction, and this picture might explain late indication of graft biopsies. The 10-year patient survival rates were excellent.

Validez diagnóstica del índice de resistividad en pacientes trasplantados renales con disfunción del injerto: correlación histológica

ObjectiveTo estimate the diagnostic validity of the resistance index (RI) in renal transplant patients with graft dysfunction, using the histopathological findings as gold standard. Material and methodsA retrospective review was performed on the biopsies of 85 patients with renal graft dysfunction. Patients were grouped according to the histological findings: normal findings, acute rejection, chronic rejection, and other findings. The RI was assessed by Doppler ultrasound, considering values of<.55 and>.75 as pathological, and were analyzed along with the findings in the biopsy. Sensitivity, specificity, positive predictive value and negative predictive value of RI were assessed. The mean RI was compared between patients with normal and abnormal pathological findings. ResultsThe RI was normal in 59 patients, and pathological in 26. The RI showed a specificity of 72.73% and a high positive predictive value of 88.46% in patients with graft dysfunction. There was no statistically significant difference (P=.196) in the RI between patients with normal and pathological histopathology in the biopsy. ConclusionDespite its low sensitivity, the RI is reliable in detecting an abnormal parameter when its value is outside the reference range. However the performing a biopsy is still required to determine the cause of the kidney disease.

Predictive factors for increased aortic pulse wave velocity in renal transplant recipients and its relation to graft outcome.

To evaluate aortic stiffness in renal transplant patients and to determine the correlation of renal insufficiency and estimated glomerular filtration rate (eGFR) with aortic pulse wave velocity (APWV), we studied 96 renal transplant patients followed-up at our center. We measured the APWV using transcutaneous Doppler flow recordings and the foot-to-foot method, and calculated the eGFR using the Modification of Diet in Renal Disease equation. The study included 81 (84.4%) males and 15 (15.6%) females. The mean age of the patients was 37.84 ± 10.10 years. The mean duration of transplant was 47.90 ± 34.40 months. The eGFR of the patients ranged from 1 to 120 mL/min, with a mean GFR of 72.6 ± 23.2 mL/min. Sixty-seven (69.8%) patients had eGFR > 60 mL/min and hence had stages 1 and 2 chronic kidney disease (CKD), 27 (28.1%) patients had eGFR 30-60 mL/min and hence had stage 3 CKD and two (2.1%) patients had eGFR <30 mL/min and hence had stages 4 and 5 CKD. The APWV of the patients ranged from 4 to 14.2 m/s, with a mean of 7.49 ± 2.47 m/s. A significant inverse correlation was found between the APWV and eGFR (Pearson correlation coefficient, -0.427, P = 0.00). The mean APWV was significantly higher among patients with higher CKD stage, P = 0.004. We conclude that the APWV is related to the renal graft dysfunction as measured by eGFR. The poorer the renal function, the higher was the APWV. Determination of the APWV may be helpful in predicting the outcome in renal transplant recipients.

Histoplasmosis in Renal Transplant Patients in an Endemic Area at a Reference Hospital in Medellin, Colombia

BackgroundHistoplasmosis is an uncommon systemic fungal infection, but it is potentially fatal in immunosuppressed populations. In Latin America, which is considered an endemic area for this mycosis, there have been no published reports regarding the incidence, clinical presentation, morbidity, and mortality of histoplasmosis in renal transplant patients. The objective of this study was to describe cases of histoplasmosis in renal transplant patients treated at the Pablo Tobon Uribe Hospital (Medellin, Colombia) between 2006 and 2013. MethodsThis is a descriptive, retrospective study. ResultsThe incidence of histoplasmosis in our renal transplant population was 1.1%. The ages of the 9 patients (4 men and 5 women) ranged between 27 and 59 years. In 2 of these patients, histoplasmosis appeared during the first year after transplantation. At the time of transplantation, 66% of patients received induction with alemtuzumab; 88% had a prior rejection episode and required increased immunosuppressive medication; 88% had renal graft dysfunction with creatinine levels >1.5 mg/dL; and the primary clinical presentation was disseminated histoplasmosis followed by the pulmonary form of the disease. Diagnoses were performed by histology in 6 patients, blood culture in 2 patients, and antigenuria in 1 patient. Three patients required treatment with amphotericin B for the severity of their infection, and 2 of these patients died before receiving the cumulative dose of amphotericin B. The 7 remaining patients received itraconazole for 12 months and had a successful treatment response. Regarding complications, 2 patients had hemophagocytic syndrome. At the 1-year follow-up appointment, renal function remained stable in all patients, and no patients had acute rejection or required renal replacement therapy. Thus, the overall mortality rate observed was 22.2%. ConclusionsIn this series, histoplasmosis in renal transplant patients presented as an aggressive opportunistic infection with a higher incidence than that previously reported in the literature. The following risk factors have been associated with histoplasmosis: renal graft dysfunction, previous acute rejection, immunosuppression with tacrolimus-mycophenolate, and induction with alemtuzumab. The clinical presentation of histoplasmosis was nonspecific, which complicated disease diagnosis, and the treatment regimens were highly toxic and associated with significant morbidity and mortality rates.

Impaired Kidney Allograft: How Long Can It Function? A Single-Center Study of the Transplantation Population

Impaired renal graft function is a matter of particular concern during post-transplantation care because low estimated glomerular filtration rate (eGFR) is a risk factor for graft loss. The aim of the study was to assess risk factors for inferior outcomes of kidney transplantations with low eGFRs. We identified 72 patients who underwent transplantation between 1999 and 2005 who had chronic renal graft dysfunction after 6 months post-transplantation (eGFR < 40 mL/min/1.73 m2), received a kidney transplant between 1999 and 2005, and were treated in one center through the entire post-transplantation course. Three patients who were lost for follow up after 6.4, 6.7, and 8.5 years are not included in this analysis. A group of 23 patients (33%) had chronic kidney disease stage 4 (eGFR < 30 mL/min/1.73 m2) at 6 months. In 39 patients (56%), delayed graft function was diagnosed. Forty-eight patients (70%) had at least one episode of acute graft rejection. Results were confirmed using biopsy in 39 patients. Eight patients (12%) died and 35 patients (51%) lost their grafts between 1.6 and 14 years (median, 6.3 years). The remaining 26 (38%) patients have still functioning allografts 11 years after transplantation (median). The initial immunosuppression included calcineurin inhibitor (CNI) in all cases. At the end of study, 6 (8.3%) patients received mammalian target of rapamycin inhibitor plus steroids, whereas the remaining were treated with CNIs. Improvement of kidney function by 15% was observed in 23% of the studied population between 6 and 24 months. This satisfactory outcome was a result of the careful follow-up examinations and comprehensive medical care provided by our dedicated staff of nurses and physicians. Improvement of kidney function may reflect a state of immune quiescence in some patients which allows them to sustain a functioning kidney despite injury.

The influence of donor specific antibody on renal function after renal transplantation

Objective To investigate the significance of donor specific antibody (DSA) on acute renal rejection and renal function.Methods DSA was detected with Luminex200 in 459 renal transplant patients who were operated in Yaitai Yuhuangding Hospital from June 2010 to April 2014.Penal reactive antibody ≥10％ was found in 46 patients,including 20 males and 26 females,the average age was 45 years,and DSA was positive in 18 patients.Results There was significant difference in acute renal rejection,delayed renal function and graft dysfunction between DSA-positive group and DSA-negative group,but there was no signaficent difference in patient survival between the two groups.Conclusion DSA played a great role in acute renal rejection and renal function.The detection of DSA in time was the effective method to predict acute rejection after renal transplantation. Key words: Donor specific antibody; Renal function; Renal transplantation

Using Markers of Endothelial to Mesenchymal Transition to Detect Endothelial Activation in Kidney Recipients With Antibody Mediated Rejection.

Introduction: Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. The efficacy of treatment depends on an accurate diagnosis at an early stage. Sensitive and reliable markers are still lacking. Methods: Using immunohistochemistry, we retrospectively studied the diagnostic value of endothelial-to-mesenchymal transition (EndMT) markers for ABMR in 53 renal transplant biopsies including 20 ABMR, 24 with cell-mediated rejection and 9 normal grafts. We validated our results in a second independent set of 72 non-selective biopsies. Results: The markers of EndMT were very strongly expressed in the endothelial cells of peritubular capillaries in grafts with ABMR, and absent in normal renal grafts. The level of expression of EndMT markers was significantly associated with current ABMR criteria such as capillaritis (rho=0.6, p<0.0001), glomerulitis (rho=0.5, p=0.0002), peritubular capillary c4d deposition (mean of EndMT score=3.44±0.18 vs 1.8±0.24 for c4d+ for c4d- groups respectively, p=0.0019), but not with T cell mediated rejection Banff scores “i” and “t”. In addition, EndMT markers allowed us to identify ABMR at an early stage (i.e. before any clinical or histological features of ABMR), as well as C4d-negative ABMR. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR, predicting late (up to 4 years post biopsy) renal graft dysfunction (rho=-0.66, p<0.0001) and proteinuria (rho=0.414, p=0.023). A prolonged cold ischemia time and a history of delayed graft function were the main risk factors associated with the occurence of EndMT markers. In the second independent set of 72 renal graft biopsies, the diagnostic value of EndMT markers for ABMR was confirmed and showed a sensitivity of 85.7% and a specificity of 96.7%. Conclusion: EndMT markers are a sensitive and reliable diagnostic tool for ABMR, and predict late allograft function loss.

Fibromyalgia and Its Clinical Relevance in Renal Transplant Recipients.

Objective: Fibromyalgia (FM) syndrome was associated with various pathophysiologic mechanisms including oxidative stress, inflammation, coronary heart disease, left ventricular function and endothelial dysfunction. Our aim was to determine the prevalence of FM in renal transplant recipients and to identify possible links between FS and various clinical and laboratory parameters. Methods:Ninety nine kidney transplant recipients with normal graft functions (37.1±10.8 yrs, 67 male, 51.98±16.3 months post-transplantation period) were enrolled. All subjects completed the Fibromyalgia Impact Questionnaire (FIQ) and patients were evaluated with the total FIQ score and their physical impairmant score (PIS:0-10) and stiffness subscales. The biochemical and clinical parameters in the first year of post transplantation period were retrospectively recorded and graft function is evaluated with the yearly decline in eGFR. Cardiovascular parameters including body composition analyses, ambulatory blood pressure monitoring data(ABPM), pulse wave velocity (Pwv) were cross-sectionally analyzed. Results: Mean FIQ score for the whole group was 21.4±14.7. Eight patients had FIQ score >50 and these patients had significantly higher LVMI than patients with lower FIQ score (p:0.048). Patients were divided into two groups;Group 1 PIS ≥5, n:50 and group 2 PIS<5, n:49. Patients with higher PIS had significantly higher serum creatinine (p:0.047) and lower eGFR values (p:0.008) than group 2 patients. In ABPM, group 1 patients had significantly higher overall diastolic (p:0.015) and mean arterial BP (p:0.048) than group 2. Physical impairment score was positively correlated with serum CRP levels (p:0.024, r:.227). Patients were also evaluated with the stiffness score (SS) as group1 patients with (n:41) or group 2 patients without (n:58) stiffness. Patients with stiffness had significantly higher office sistolic (p:0.027) and diastolic BP (p:0.044) levels than patients without stiffness. BMI (p:0.033) and saggittal abdominal diameter (p:0.05) were significantly higher in patients with stiffness. Yearly decline in eGFR levels were significantly higher in patients with higher FIQ (7.6% vs. 9.4%, p:.0001) than other patients. Conclusion: FM in renal transplant recipients was closely related with adverse clinical outcome like hypertension, arterial stiffness, obesity and renal graft dysfunction.

Vascular complications post renal transplant – Case report

IntroductionSevere acute graft dysfunction due to vascular complication need prompt decision regarding the type and need of intervention. But many times imaging may not give the definitive diagnosis. Vascular complications continue to account for about 3–15% of the cases of graft dysfunction. Aims and objectivesWe analyzed the clinical features, investigations and intervention done in the cases of possible acute vascular complications post renal transplant. Methods50 patients who have undergone renal transplant at Bombay hospital were studied. Three cases having graft dysfunction in early postoperative period with reported significant vascular pathology on imaging were analyzed.First case had severe renal transplant graft dysfunction on 4th postoperative day (POD) with angiography suggestive of renal artery narrowing requiring re-exploration. Second case had iliac vein thrombosis close to renal vein anastomosis managed conservatively with good outcome. Third case was reported on Doppler ultrasound as compromised renal blood flow. Conclusion3 out of 50 renal transplants at our institute over 15 months follow-up had been reported as early vascular complications. One patient required re-exploration. Appropriate evaluation and management is the key to salvage the graft. Atherosclerosis (donor/recipient), acute rejection, delayed graft function increase this risk.

Cellular Involvement Rather Than Humoral Characteristics Predict Renal Graft Dysfunction 1 Year After Antibody Mediated Rejection.

Antibody-mediated rejection (AMR) after renal transplantation is frequently resistant to conventional anti-rejection therapy and often results in graft dysfunction (Gdys); however, risk factors for Gdys following AMR remain poorly defined. The purpose of this study was to identify predictors of Gdys, defined as graft loss or GFR reduction by ≥50%, at 1 year post-AMR treatment. Kidney transplant recipients treated for biopsy-proven AMR (n=49) were reviewed. Factors approaching significance (p<0.2) in the univariate analysis were included in a multivariate logistic regression backward elimination model to identify independent risk factors for Gdys. Mean time to AMR diagnosis following transplant was 14.5 months. Gdys at 1 year was seen in 22 (45%) patients, with graft loss occurring in 9 patients. Baseline characteristics including age, gender, race, donor type, sensitization, and induction type were similar between groups. The most common anti-humoral therapies administered were IVIG (n=46) and plasma exchange (n=39), with rituximab (n=22) or bortezomib (n=8) given in certain cases; ATG was added to anti-humoral therapies for mixed antibody-cellular rejections. Factors associated with Gdys by univariate analysis were prior cellular rejection, mixed rejection, and plasma cell infiltrates, while bortezomib use was associated with function at 1 year. In contrast, Gdys was not associated with DSA presence, number of antibody specificities, DSA strength, presence of capillaritis or glomerulitis, or other anti-humoral treatments. Multivariate analysis revealed mixed rejection as the only independent predictor of Gdys. Our data suggests that in renal transplantation, concurrent cellular rejection, rather than humoral characteristics, predicts poor graft outcomes at 1 year.Table: No Caption available.Table: No Caption available.

LATE RENAL GRAFT REJECTION: PATHOLOGY AND PROGNOSIS

Rejection has always been one of the most important cause of late renal graft dysfunction. Aim of the study was to analyze the prevalence of different clinico-pathological variants of rejection that cause late graft dysfunction, and evaluate their impact on long-term outcome. Materials and methods. This is a retrospective study that analyzed 294 needle core biopsy specimens from 265 renal transplant recipients with late (48,8 ± 46,1 months after transplantation) allograft dysfunction caused by late acute rejection (LAR, n = 193) or chronic rejection (CR, n = 78) or both (n = 23). C4d staining was performed by immunofl uorescence (IF) on frozen sections using a standard protocol. Results. Peritubular capillary C4d deposition was identifi ed in 36% samples with acute rejection and in 62% cases of chronic rejection (including 67% cases of transplant glomerulopathy, and 50% – of isolated chronic vasculopathy). 5-year graft survival for LAR vs CR vs their combination was 47, 13 and 25%, respectively. The outcome of C4d– LAR was (p &lt; 0,01) better than of C4d+ acute rejection: at 60 months graft survival for diffuse C4d+ vs C4d − was 33% vs 53%, respectively. In cases of chronic rejection C4d+ vs C4d– it was not statistically signifi cant (34% vs 36%). Conclusion. In long-term allograft biopsy C4d positivity is more haracteristic for chronic rejection than for acute rejection. Only diffuse C4d staining affects the outcome. C4d– positivity is associated with worse allograft survival in cases of late acute rejection, but not in cases of chronic rejection.

Medication Compliance in Renal Transplant Patients During the Great East Japan Earthquake

IntroductionOral immunosuppressant suspension induces renal graft dysfunction in renal transplant patients. After the Great East Japan Earthquake, not only were drugs lost in the tsunami, but visiting hospitals became difficult owing to information and transportation network disruption. We investigated medication compliance in renal transplant patients and actions taken immediately after the earthquake. Materials and MethodsWe included 315 patients who were visiting our outpatient department as of March 11, 2011, from June to August 2011. Information was collected from questionnaires, medical records, and outpatient diaries. ResultsThe questionnaire collection rate was 93%, with valid replies from 296 patients. One hundred eighty-five patients (62%) had stockpiled oral medications before the earthquake; of these, 131 (44%) always carried medications with them. Forty-five patients (16%) had difficulties with continuing oral immunosuppressants after the earthquake (supply delay, 29 patients; drugs lost in tsunami, 9; others, 10). Of these 48, oral medication was suspended in 18 for 3 days at maximum. As to outpatient prescriptions, out-of-hospital prescriptions were sent by fax to 17 patients, prescription drugs were sent from our hospital by mail or home delivery services to 11, and prescriptions were given to 13 who visited other hospitals. Because of the difficulty in requesting prescriptions from disaster base hospitals, drugs prescribed at our hospital were delivered to 3 severely damaged institutions for patients living in surrounding areas. After the earthquake, our usual self-management guidance proved effective. ConclusionFurther examination of the infrastructure for communicating with patients and supplying drugs is needed.

Posttransplant Metabolic Complications in Living-Related Renal Allograft Recipients of Kashmir Valley

Renal transplant offers a definitive therapeutic modality for patients with end-stage renal disease; however, 50% to 70% of these patients have graft dysfunction after the transplant. Proactive prevention management of metabolic complications may reduce posttransplant morbidity and mortality in these patients. A retrospective and prospective review of 120 kidney transplant recipients during 5 years' follow-up was performed to analyze the incidence and status of the various metabolic complications after a renal transplant. In our study, postrenal transplant diabetes mellitus was seen in 9 of 120 patients (7.5%). The incidence of posttransplant diabetes mellitus was 5% in tacrolimus-treated patients (n=6) compared with 2.5% in cyclosporine-treated patients (n=3). Dyslipidemia, as hypercholesterolemia and hyper-triglyceridemia, was seen in 31 recipients (25.83%). Significant posttransplant hyperlipidemia was documented (P < .05). Further, it was noted that 25 patients who developed hyperlipidemia (20.83%) were taking cyclosporine-based therapy, while 6 were treated with tacrolimus-based therapy (5%; P < .05). However, most subjects with hyperlipidemia had renal graft dysfunction. Posttransplant erythrocytosis affected 9 renal transplant recipients (7.5%) with a mean (±SD) hematocrit of 41.3%±6.7%. A statistically significant correlation was seen between prerenal and postrenal transplant hematocrit by 12 months. Hyperparathyroidism was observed in 1 renal transplant patient (1.25%). On the basis of this study, we conclude that posttransplant diabetes mellitus occurred in 7.5% patients, hypercholesteremia and hyper-triglyceridemia occurred in 25.83% patients, posttransplant erythrocytosis affected 7.5% patients, and hyperparathyroidism occurred in 1 renal transplant patient (1.25%). Moreover, dyslipidemia, contributed to progressive graft dysfunction.

Evaluation of serum interleukin 6 and tumour necrosis factor alpha levels, and their association with various non-immunological parameters in renal transplant recipients

Renal transplant rejection involves both immunological and non-immunological factors. The objective of the present study was to investigate the association between immunological factors, such as serum interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α), and non-immunological parameters, such as age, serum creatinine (SCr), creatinine clearance (CrCl) and dyslipidaemia, in renal transplant recipients (RTRs). This study included 90 RTRs and 90 healthy controls. Biochemical parameters, including serum IL-6 and TNF-α, were estimated using standard protocols. CrCl was calculated using the Cockroft-Gault equation, and the type of rejection was confirmed on biopsy. Student's t-test and univariate and multivariate analyses were performed using the Statistical Package for the Social Sciences for Windows version 15. The mean levels of serum IL-6 and TNF-αwere significantly higher in RTRs than in the control group (p < 0.001). These parameters were also found to be significantly different between the transplant rejection (TR) and transplant stable (TS) groups (p < 0.001). CrCl was significantly decreased in the TR group when compared to the TS group (p < 0.001). The two cytokines, IL-6 and TNF-α, correlated significantly with all metabolic parameters, such as SCr, CrCl and dyslipidaemia. Multiple regression analysis showed that TNF-α and CrCl were the strongest predictors of IL-6. We conclude that immunological factors, as well as non-immunological factors such as CrCl, SCr and dyslipidaemia, play important roles in the pathogenesis of graft rejection and renal graft dysfunction.

Combined Intestine and Kidney Transplantation in a Patient with Encapsulating Peritoneal Sclerosis: Case Report

Introduction: Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis (PD) characterized by fibrosis and calcification of small bowel. Clinical manifestations include abdominal pain, persistent small bowel obstructions, malnutrition and in severe cases total parenteral nutrition (TPN) dependency and chronic intestinal failure. Medical and surgical interventions carry a poor prognosis in these patients. Case Presentation: A 22-year-old female was started on PD for idiopathic end stage renal disease that was discontinued 8 years later for new onset of EPS of obstructing physiology. At age of 31, she underwent living donor kidney transplantation. She was referred to our institution for further evaluation at the age of 34 for worsening intestinal failure and a physiology of severe bowel obstruction requiring TPN (see CT scan). Dehydration from recurrent vomiting caused suboptimal renal perfusion and graft dysfunction. Conservative management (adhesiolysis and stricturoplasty) was not considered appropriate as overall health deteriorated. The decision was made to perform a combined intestine and kidney transplantation. At a two year follow-up, the patient maintains appropriate renal and intestinal graft function and is tolerating normal oral diet. This represents the first case to our knowledge in which EPS is treated with combined intestine and kidney transplantation. Summary: Although the number of intestinal transplantations worldwide remains small (approximately 200 per year), advances in the immunosuppressive field and in patient management over the last decade have transformed intestinal transplantation into a viable treatment option for patients with intestinal failure. At specialized centers, combined intestine and kidney transplantation may offer the only therapeutic option for EPS patients who have failed medical and surgical treatment.Figure: No Caption available.

BAFF and BAFF-R Levels Are Associated With Risk of Long-Term Kidney Graft Dysfunction and Development of Donor-Specific Antibodies

There are lines of evidence that B cells may play a role in transplantation. B cell activating factor, BAFF, is a homotrimer that has been shown to play a role in B cell survival, maturation and activation. To date, little is known of the role of BAFF and its receptors in transplantation. We analyzed the level of BAFF mRNA and its soluble protein, as well as transcripts coding for its receptors, BAFF-R, TACI and BCMA, in the blood of 143 patients with stable kidney transplant function 5 years or more posttransplantation. Three endpoints were analyzed: the time to renal dysfunction, the time to appearance of anti-HLA antibodies and the time to development of donor-specific antibodies. We established threshold values for BAFF and BAFF-R and showed that (1) stable patients with high BAFF-R levels had a higher risk of developing graft dysfunction, (2) patients with lower levels of BAFF transcripts or a higher level of soluble BAFF had a significantly higher risk of developing donor-specific antibodies. These data suggest that BAFF constitutes a risk factor for renal graft dysfunction and development of donor-specific antibodies. They also suggest that agents targeting BAFF-R interactions may offer new therapeutic opportunities in transplantation.

Spectrum of Cytomegalovirus-Induced Renal Pathology in Renal Allograft Recipients

Viral infections in renal allograft recipients constitute an important cause of renal graft dysfunction. They have shown an increasing incidence coinciding with more potent immunosuppression regimens. Cytomegalovirus (CMV) is well-known cause of a tubulointerstitial nephritis rich in plasma cells with cytopathic changes in tubular epithelial and endothelial cells. However, involvement of glomeruli and larger arteries in the absence of tubulointerstitial disease is rare. In this study, we demonstrated the spectrum of renal disease caused by CMV among renal allograft recipients. Retrospective analysis of 2900 renal allograft biopsies performed over a 10-year period revealed 10 cases of CMV infection, with half of them (5/10) detected in 2010–2011. Although tubulointerstitial nephritis due to CMV was the most common lesion (7/10), we noted an increased incidence of CMV glomerulopathy with (1/10) or without (3/10) coexisting tubulointerstitial CMV disease. Isolated glomerular involvement was characterized by a relative lack of inflammation in any of the compartments along with the presence of cytopathic changes in the glomerular endothelial cells and podocytes. Another patient had CMV-induced thrombotic microangiopathy. The coexistent diseases were calcineurin inhibitor toxicity (n = 1), antibody-mediated rejection (n = 1), cellular rejection (n = 2), and invasive fungal infection (n = 1). In conclusion, there is a wide spectrum of CMV-induced lesions. CMV glomerulopathy is characterized by cytopathic changes in glomerular endothelial cells and podocytes with a lack of significant inflammation. In contrast, CMV-induced arteriopathy can present as thrombotic microangiopathy. Coinfection with other pathogens like invasive fungi can lead to graft failure.

Both Darbepoetin Alfa and Carbamylated Erythropoietin Prevent Kidney Graft Dysfunction Due to Ischemia/Reperfusion in Rats

Ischemia/reperfusion (I/R) injury is an important cause of renal graft dysfunction. Increases in cold and warm ischemia times lead to a higher risk of early posttransplant complications including delayed graft function and acute rejection. Moreover, prolonged cold ischemia is a predictor of long-term graft loss in kidney transplant patients. Darbepoetin alfa (DA) and carbamylated nonerythropoietic derivative of erythropoietin (CEPO) protective effects were evaluated in a model of I/R injury after kidney transplantation in both syngeneic and allogeneic combinations. The effects of wortmannin (phosphorylated Akt [p-Akt] inhibitor) administration were also investigated. Serum creatinine was evaluated at 16, 24, 48 hr and at 4 and 7 days posttransplant. Animals were killed 24 hr or 7 days after transplant and kidneys were processed for histological analysis, immunohistochemistry assessment of erythropoietin receptor (EPOR) and β-common chain receptor expression, granulocyte infiltration, nitrotyrosine staining, p-Akt expression, peritubular capillary (PTC) density, apoptosis, antioxidant, and antiapoptotic gene expression. DA and CEPO significantly reduced serum creatinine, tubular injury, tubular nitrotyrosine staining, and prevented I/R-induced tubular apoptosis, but only when given both to the donor and to the recipient. DA and CEPO cytoprotection was associated with prevention of I/R-induced drop of p-Akt expression in tubuli, and almost complete preservation of capillary density in the tubulointerstitium of the graft. CEPO was more effective than DA in reducing tubular oxidative stress and preserving PTCs. DA and CEPO when given both to the donor and to the recipient, prevented renal graft dysfunction, tubular oxidative stress, and apoptosis after I/R injury in kidney transplantation. Their cytoprotection was mediated by tubular p-Akt activation and PTC density preservation.