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We report a renal allograft transplant recipient with esophageal tuberculosis ( TB) coinfected with herpes simplex virus ( HSV) and Candida. The patient presented with oropharyngeal candidiasis and was started on fluconazole. Upper gastrointestinal endoscopy showed whitish patches with mucosal ulcers in the esophagus. Histopathological examination confirmed TB and HSV infection. The patient recovered after antiviral, antifungal, and anti-tubercular therapy with reduction in immunosuppression. In a TB-endemic zone, TB can coexist with opportunistic infections in an immunocompromised host. [ABSTRACT FROM AUTHOR]

Aim To monitor B cell subsets in peripheral circulation to find a distinctive phenotypic signature of rejection in our cohort. Methods The study population consisted of 211 consecutive first renal allograft recipients who were followed up for 12 months post-transplant. One ml of EDTA peripheral venous blood was collected pre- transplant, 1 month, 3 months, 6 months, 12 months post-transplant and at the time of graft rejection. A multicolour flowcytometry was performed to monitor the percentage of peripheral Plasma cells (CD20-CD38+CD138+), Total B-cells (CD20+), Naïve B-cells (CD20+CD27-CD38-), Activated B-cells (CD20+CD38+CD138-) and Memory B-cells (CD20+CD138-CD27+). Results Of 211 cases of first kidney allograft recipients, 35 (16.58%) recipients had 38 episodes of acute allograft rejection. Percentage of activated B cells and Memory B-cells were found to be significantly higher in uremic patients ( n = 78) than those of healthy persons ( n = 40) (20.81 ± 0.7616 % vs. 14.37 ± 0.5972%, p < 0.0001 and 10.56 ± 0.5813% vs 7.658 ± 0.6626%, p = 0.0025 respectively). On the contrary, the percentage of naïve B- cells was found to be significantly lower in the patients than normal controls (61.04 ± 1.691% vs 73.62 ± 1.320%, p < 0.0001). Acute rejection episodes ( n = 38) were associated with increase in peripheral percentage of total B-cells (19.02 ± 1.457 vs. 10.80 ± 0.6338, P < 0.0001) and activated B-cells (33.92 ± 1.756 vs. 23.26 ± 1.113, P < 0.0001). On the contrary, the percentage of plasma cells and memory B-cells and naïve B- cells was significantly lower during rejection episodes (0.7447 ± 0.09 vs. 2.363 ± 0.1529, P < 0.0001, 5.871 ± 0.6677 vs. 12.12 ± 0.6584, P < 0.0001 and 44.53 ± 2.504 vs. 52.61 ± 2.488, P = 0.0311 respectively). Conclusion The percentage of activated B-cells and Memory B-cells were persistently high in uremic patients suggesting that these patients are always in a stage of immune activation. Acute rejection episodes were associated with increased percentage of activated B-cells but decrease in the percentage of plasma- and memory-B cells in the peripheral blood. Therefore, post- transplantation, periodic measurements of B-cell subsets may serve as an important marker in the prediction of acute allograft rejection. [ABSTRACT FROM AUTHOR]

We report an 8-year-old child who underwent percutaneous transluminal renal angioplasty (PTRA) and stenting for renal artery stenosis (RAS) and later presented with stent fracture. Ex vivo renal artery repair and renal autotransplantation were successfully done. [ABSTRACT FROM AUTHOR]

Background: Ability to predict the manner in which a recipient’s immune system would respond to a transplanted graft by analyzing cytokine profiles of the “allograft antigen sensitized” recipient lymphocytes in vitro might provide a means to identify patients at risk to adverse clinical endpoints.Methods: Cytokine/chemokine gene expression profiles of peripheral blood mononuclear cells co-cultured with allograft antigen-pulsed macrophages were studied in 49 renal transplant recipients—12 with acute cellular rejection (ACR) with or without antibody-mediated rejection (AMR), 7 with AMR (without ACR), and 30 with stable allografts (SA). An 86-gene inflammatory cytokines and receptors PCR array was used to measure fold changes in gene expression between pulsed and un-pulsed cultures.Results: On linear discriminant analysis and multivariate analysis of variance, a gene set comprising C3, CCL3, IL1B, TOLLIP, IL10, CXCL5, ABCF1, CCR3, IL10RB, CXCL1, and IL1R1 differentiated the ACR-AMR from the SA group. Similarly, a gene set comprising IL10, C3, IL37, IL1B, CCL3, CARD18, and TOLLIP differentiated the AMR from the SA group. No significant difference was found between the ACR-AMR vs AMR groups.Conclusion: Distinct post in vitro stimulation cytokine profiles at the time of transplantation thus correlated with the occurrence of post-transplantation rejection episodes which indicated feasibility of this in vitro model to assess the recipient’s anti-graft response at an early stage. [ABSTRACT FROM AUTHOR]

Background. Allograft rejection postkidney transplantation (KTx) is a major clinical challenge despite increased access to a healthcare system and improvement in immunosuppressive (IS) drugs. In recent years, mesenchymal stromal cells (MSCs) have aroused considerable interest in field of transplantation due to their immunomodulatory and regenerative properties. This study was aimed at investigating safety, feasibility, and immunological effects of autologous MSCs (auto-MSCs) and allogeneic MSCs (allo-MSCs) as a complement to IS drug therapy in KTx patients. Methods. 10 patients undergoing KTx with a living-related donor were analysed along with 5 patients in the control group. Patients were given auto-MSCs or allo-MSCs at two time points, i.e., one day before transplant (D-0) and 30 days after transplant (D-30) at the rate of 1.0- 1.5 × 10 6 MSCs per kg body weight in addition to immunosuppressants. Patients were followed up for 2 years, and 29 immunologically relevant lymphocyte subsets and 8 cytokines and important biomarkers were analysed at all time points. Results. Patients displayed no signs of discomfort or dose-related toxicities in response to MSC infusion. Flow cytometric analysis revealed an increase in B regulatory lymphocyte populations and nonconventional T regulatory cells and a decrease in T effector lymphocyte proportions in auto-MSC-infused patients. No such favourable immune responses were observed in all MSC-infused patients. Conclusion. This study provides evidence that auto-MSCs are safe and well tolerated. This is the first ever report to compare autologous and allogeneic MSC infusion in KTx patients. Importantly, our data demonstrated that MSC-induced immune responses in patients did not completely correlate with clinical outcomes. Our findings add to the current perspective of using MSCs in KTx and explore possibilities through which donor/recipient chimerism can be achieved to induce immune tolerance in KTx patients. [ABSTRACT FROM AUTHOR]

Ketoconazole retards metabolic degradation of tacrolimus through its effect on the cytochrome P-450 enzyme system and allows reduction in treatment costs. Enzyme activity is determined by a single nucleotide polymorphism (∗1/∗3) in the CYP3A5 gene.We prospectively investigated the impact of this polymorphism on tacrolimus concentration in a cohort of 79 renal transplant recipients on ketoconazole. Genotyping was carried out by using polymerase chain reaction-restriction fragment length polymorphism technique. Dose-adjusted trough level (C0) was calculated at baseline and at 3, 7, 15, 30, and 60 days.The baseline C0 was significantly lower in those with at least one ∗1 allele [44.95±14.12 vs. 63.43±14.72 (ng/ml)/(mg/kg/day), P<0.0001]. After starting ketoconazole in all genotypes, dose-normalized C0 increased and the cost of therapy decreased. Compared with baseline, the magnitude of increase was 112% and 79% in those without and with ∗1 allele, respectively (P<0.001). The cost savings were 32% and 39% in mycophenolate mofetil-treated and 47% and 61% in azathioprine-treated patients who were with and without one ∗1 allele, respectively.We show that the CYP3A5∗1/∗3 polymorphism is an important determinant of the response to inhibition of tacrolimus metabolism by ketoconazole, with a 30% greater inhibition in those lacking ∗1 allele. This finding will allow better dose adjustment and minimize exposure to subtherapeutic or toxic concentrations. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) reactivation or infection is one of the most important infectious complications in transplant recipient leading to significant morbidity and mortality. Its early detection and prompt treatment is imperative to improve transplant outcome. The present study estimated the frequency of CMV in renal transplant recipients (RTR). Various aspects of pp65Ag assay and quantitative real-time polymerase chain reaction (qRT-PCR) were evaluated in relation to the recent guidelines for CMV detection and treatment. Retrospectively, data of clinically suspected cases of CMV (1610 out of total 2681 renal transplants) were analyzed along with a comparison of pp65Ag assay and qRT-PCR. The overall incidence of CMV syndrome was 14.25%; however, the incidence of CMV viremia in the clinically suspected group was 23.73%. The proportion of positive cases with pp65Ag assay and qRT-PCR were 13.6% (95% CI; 7.9-22.3) and 19.3% (95% CI; 12.4-28.8) with a substantial agreement (Cohen's kappa = 0.632) between the 2 techniques. CMV positive recipients were treated with ganciclovir until their viral count was negative or up to 3 weeks, followed by 3 months of prophylaxis with valganciclovir. No graft failure or mortality was reported secondary to CMV infection until 3 to 5 years of follow-up. CMV infection is quite prevalent in RTR, and early detection and immediate treatment or prophylaxis is of utmost importance. qRT-PCR is the gold standard and preferred over other methods; however pp65Ag assay still holds its importance in low-economic countries and populations where CMV infection is more prevalent and financial constraints are a major limitation. [ABSTRACT FROM AUTHOR]

Initiation of an advanced laparoscopic surgery program requires skill and proper training. Despite description of multiple surgical training modules, an ideal method for training of surgeons for advanced laparoscopic procedures is lacking. We propose an abbreviated self-imposed proctored preceptorship training model as the optimum training method for training skilled laparoscopic surgeons in advanced laparoscopic procedures like laparoscopic donor nephrectomy. The laparoscopic donor nephrectomy program was started at the Institute using preceptorship-proctorship model. One hundred left laparoscopic donor nephrectomies were performed over the course of 2 years. Outcomes in terms of performance related (Surgeon) outcomes in the form of learning curve and patient outcomes in terms of donor outcomes and recipient results and were studied. Learning curve was calculated using the moving average method and calculation of mean operative time of every five consecutive cases. Mean operative time for laparoscopic donor nephrectomy was 108.1 ± 26.5 min, the warm ischemia time averaged at 3.5 ± 1.3 min and the mean blood loss was 130.1 ± 54.9 ml. Moving average analysis revealed that approximately 20 LDN cases were needed to complete the learning phase. According to the mean operative time of every five consecutive cases, learning phase of LDN was completed between 26 and 30 cases. We believe that the abbreviated self-imposed proctored preceptorship model of training is an optimum model for starting a new advanced laparoscopic surgery program and can help surgeons to overcome the initial learning curve. [ABSTRACT FROM AUTHOR]

Background and Aims: Antihypertensive drugs are continued until the day of renal transplant surgery. These are associated with increased incidence of hypotension and bradycardia. Hence, this study was designed to evaluate perioperative haemodynamic and early graft functioning in renal recipients with discontinuation of antihypertensive drugs on the morning of surgery. Methods: This prospective, randomised, double-blind study recruited 120 patients. Group 1 patients received placebo tablet while Group 2 patients received usual antihypertensive drugs on the day of surgery. Perioperative haemodynamics and time for reinstitution of antihypertensives were the primary outcome measures. The secondary outcome measures were need for inotropic support and graft function. Perioperative haemodynamics were analysed using ANOVA and Student's t-tests with Bonferroni correction. Fischer's exact test was used for analysis. Results: Systolic blood pressure (SBP) declined, which was more in Group 2. Forty-one patients developed significant hypotension; a correlation was found between the maximum observed hypotension and number of antihypertensive medications (P = 0.003). Four cases had slow graft function (one in Group 1 and three in Group 2). Twenty-eight patients in Group 2 required mephentermine boluses to maintain their SBP compared to 13 patients in Group 1 (P < 0.001). Two patients in Group 2 required dopamine to maintain SBP above 90 mmHg after the establishment of reperfusion as compared to none in Group 1. Conclusion: Single dose of long-acting antihypertensive drugs can be omitted on the morning of surgery without any haemodynamic fluctuations and graft function in controlled hypertensive end-stage renal disease renal transplant patients receiving a combined epidural and general anaesthesia. [ABSTRACT FROM AUTHOR]

Pancreatic transplantation is currently the only effective cure for Type 1 diabetes mellitus. It allows long-term glycemic control without exogenous insulin and amelioration of secondary diabetic complications. In India, pancreas transplant has not yet established with only a single successful transplant reported so far in the literature. We report a 24-year-old Type 1 diabetic patient with renal failure who underwent a simultaneous pancreas kidney transplant. On postoperative day 15, he had leak from the graft duodenal stump for which a tube duodenostomy and proximal diversion enterostomy was done. He had a high output pancreatic fistula following the procedure which was managed conservatively. The tube duodenostomy was removed at three and half months and enterostomy closure with restoration of bowel continuity was done at 6 months. After a follow up of 7 months, patient is doing well with a serum creatinine of 0.8 mg/dl and normal blood sugars, not requiring any exogenous insulin or oral hypoglycemic drugs. Managing patients with graft duodenal complications after pancreas transplant is challenging. Tube duodenostomy is a safe option in management of duodenal leak, although can lead to a persistent pancreatic fistula. A proximal diversion enterostomy allows early oral feeding and avoids the cost as well as the long term complications associated with parenteral nutrition. [ABSTRACT FROM AUTHOR]

Background: Surgical construction of an arteriovenous fistula is preferred for end-stage renal failure patients requiring long-term haemodialysis. Methods: Patients were randomised into two groups: brachial plexus group (n = 30) or local infiltration group (n = 30). In all patients, a radiocephalic arteriovenous fistula was created by an experienced surgeon using a standard surgical technique. In both groups 20 ml of 0.375% ropivacaine was used. Doppler assessment of vessels was performed at fixed time intervals. Results: Primary patency rate was 100% in the brachial plexus block group whereas there was 10% fistula failure rate in the local infiltration group (p-value = 0.237). Diameter of the vessels, peak systolic velocity, mean diastolic velocity, and blood flow at 30 minutes, 48 hours, 2 weeks, and 6 weeks after the fistula creation was significantly greater than the preoperative diameter in all patients (p-value < 0.05). Intergroup comparison revealed that vascular parameters were significantly better in the brachial plexus analgesia group versus local infiltration group at all observation points up to and including six weeks post fistula creation (p-value < 0.05). Conclusion: Brachial plexus anaesthesia significantly dilates the vessel diameter and increases blood flow whereas local infiltration has a negligible effect on vessel diameter and blood flow. [ABSTRACT FROM AUTHOR]

Comments on Claudio Ponticelli and Margarita Villa's article about the evaluation of risk factors for late kidney allograft failure. Association between body mass index and risk of graft failure; Effect of nephron dosing on late allograft failure.

Background: The role of neopterin as a marker of cell mediated immunity for immunological monitoring after transplantation is of great potential interest. Neopterin levels among hepatitis C virus (HCV) positive recipients of living-donor renal transplantatio (LDRT) have not been previously described. Methods: Twenty-two HCV-positive (group I) and 10 HCV-negative (group II) recipients of LDRT were serially monitored for serum neopterin levels by enzyme-linked immunosorbent assay (ELISA). Group I patients were monitored thrice, ie, before transplantation, day 10, and 6 months post transplantation, while group II patients were monitored twice (day 10 and 6 months post transplantation). Peripheral blood T lymphocyte subsets (CD3, CD4, CD8, CD4+CD25+, CD16+56) and Th1/Th2 cytokines were monitored concomitantly by flow cytometry. Results: Ten days post transplantation, there was a significant increase in neopterin and neopterin/creatnine levels among group I patients. There was a positive correlation between activated T lymphocyte (CD4+CD25+) and neopterin early post transplantation (day 10). Th2 cytokines IL-10 and IL-5 showed a positive correlation with neopterin levels on day 10 and 6 months post transplantation, respectively. Neopterin levels did not show association with either HCV viral load or allograft rejection among our study cohort. Conclusion: Increased monocyte/macrophage activation with elevated serum neopterin was detected among group I patients on day 10 post transplantation, but it could not predict rejection. It appears that IL-10 either from a regulatory or nonregulatory source helps in the maintenance of stable graft early post transplantation. Further, it would be of interest to assess the role of neopterin in chronic allograft nephropathy and long-term graft outcome. [ABSTRACT FROM AUTHOR]

Aim This pilot study assesses the safety and feasibility of autologous mesenchymal stromal cell ( MSC) transplantation in four patients that underwent living donor renal transplantation, and the effect on the immunophenotype and functionality of peripheral T lymphocytes following transplantation. Methods All patients received low dose ATG induction followed by calcineurin inhibitor-based triple drug maintenance immunosuppression. Autologous MSCs were administered intravenously pre transplant and day 30 post-transplant. Patients were followed up for 6 months. The frequency of regulatory T cells and T cell proliferation was assessed at different time points. Results None of the four patients developed any immediate or delayed adverse effects following MSC infusion. All had excellent graft function, and none developed graft dysfunction. Protocol biopsies at 1 and 3 months did not reveal any abnormality. Compared to baseline, there was an increase in the CD4 + CD25+ FOXP3+ regulatory T cells and reduction in CD4 T cell proliferation. Conclusion We conclude that autologous MSCs can be used safely in patients undergoing living donor renal transplantation, lead to expansion of regulatory T cells and decrease in T cell proliferation. Larger randomized trials studies are needed to confirm these findings and evaluate whether this will have any impact on immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Deceased donor organ programme is still in infancy in India. Assessing deceased donation potential and identifying barriers to its utilization are required to meet needs of patients with organ failure. Over a 6-month period, we identified and followed all presumed brainstem dead patients secondary to brain damage. All patients requiring mechanical ventilation with no signs of respiratory activity and dilated, fixed and nonreacting pupils were presumed to be brainstem dead. All events from suspicion of brainstem death (BSD) to declaration of BSD, approach for organ donation, recovery and transplants were recorded. Subjects were classified as possible, potential and effective donors, and barriers to donation were identified at each step. We identified 80 presumed brainstem dead patients over the study period. The mean age of this population was 35.9 years, and 67.5% were males. When formally asked for consent for organ donation (n = 49), 41 patients' relatives refused. The conversion rate was only 8.2%. The number of possible, potential and effective donors per million population per year were 127, 115.7 and 9.5, respectively. The poor conversion rate of 8.2% suggests a huge potential for improvement. Family refusal in majority of cases reflects poor knowledge and thus warrants interventions at community level. [ABSTRACT FROM AUTHOR]

Glomerular diseases of the transplanted kidney are the most important cause of poor long- term outcome. The estimation of the magnitude of this problem and an elucidation of pathogenic mechanism is essential for improvement of graft survival. This study from the Indian subcontinent aims (i) to determine the incidence of transplant glomerulopathy ( TG) and thrombotic microangiopathy ( TMA) in a large cohort of indicated renal transplant biopsies, (ii) to evaluate the histological and ultrastructural features of TG and TMA, and (iii) to assess the relationship between the two glomerular lesions. Of a total of 1792 indication renal transplant biopsies received over 5 years (2006-2010), 266 biopsies (of 249 patients) had significant glomerular pathology and were further analyzed along with immunofluorescence, electron microscopy ( EM), and C4d immunohistochemistry. TG is the most common glomerular lesion followed by TMA seen in 5.97% and 5.08% of allograft biopsies, respectively, which constitutes 40.23% and 34.2% of biopsies with significant glomerular lesions. Pathologic antibody-mediated rejection ( AMR) is associated with both TG and TMA in 71% and 46.5%, respectively. A coexistent TG was found in 18.4% of biopsies with TMA. Endothelial swelling with subendothelial widening, a feature of TMA, is also seen in early TG by EM. Our findings support the concept that TG evolves from a smoldering TMA of various causes. [ABSTRACT FROM AUTHOR]

Background: Measures to prevent chronic calcineurin inhibitor (CNI) toxicity have included limiting exposure by switching to sirolimus (SIR). SIR may favorably influence T regulator cell (Treg) population. This randomized controlled trial compares the effect of switching from CNI to SIR on glomerular filtration rate (GFR) and Treg frequency. Methods: In this prospective open label randomized trial, primary living donor kidney transplant recipients on CNI-based immunosuppression were randomized to continue CNI or switched to sirolimus 2 months after surgery; 29 were randomized to receive CNI and 31 to SIR. All patients received mycophenolate mofetil and steroids. The main outcome parameter was estimated GFR (eGFR) at 180 days. Treg population was estimated by flowcytometry. Results: Baseline characteristics in the two groups were similar. Forty-eight patients completed the trial. At six months, patients in the SIR group had significantly higher eGFR as compared to those in the CNI group (88.94±11.78 vs 80.59±16.51 mL/min, p = 0.038). Patients on SIR had a 12 mL/min gain of eGFR of at the end of six months. Patients in the SIR group showed significant increase in Treg population at 30 days, which persisted till day 180. There was no difference in the adverse events in terms of number of acute rejection episodes, death, infections, proteinuria, lipid profile, blood pressure control and hematological parameters between the two groups. Four patients taking SIR developed enthesitis. No patient left the study or switched treatment because of adverse event. Conclusions: A deferred pre-emptive switch over from CNI to SIR safely improves renal function and Treg population at 6 months in living donor kidney transplant recipients. Registered in Clinical Trials Registry of India (CTRI/2011/091/000034) [ABSTRACT FROM AUTHOR]

Whether or not completing the hepatitis B vaccination in patients who have undergone kidney transplantation in the middle of incomplete vaccination schedule leads to development of protective antibody titres is not known. This study was designed to determine whether the strategy of completing hepatitis B virus (HBV) vaccination after transplantation is efficacious. Sixty-four end-stage renal disease (ESRD) patients were screened for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B surface antigen (anti-HBs), hepatitis B e-antigen (HBeAg) and HBV DNA. HBsAg negative patients received four doses of 40 µg recombinant HBV vaccine. Schedule was continued in after transplantation period if it was incomplete before transplant. Anti-Hbs titres were evaluated at 1, 3, 6, 9 and 12 months. Past HBV infection was noted in 12 patients: 10 by serology plus viraemia and two by viraemia alone. Of the 46 patients without current or past HBV infection who had received at least two doses of the vaccine before transplant, 17 each had received two and three doses and 12 had completed the schedule. Seventeen (37%) exhibited protective titres. Patients who had completed vaccination were more likely to have protective titres than those incompletely vaccinated ( P = 0.02). Five patients responded to post-transplant vaccination. Partially vaccinated patients do not mount an adequate antibody response despite continued vaccination in the post-transplant period, whereas complete vaccination provides protection in 60%. The present study data highlights the need of administration of a full schedule of HBV vaccination before kidney transplantation. Nucleic acid-based tests can identify occult HBV infection. Patients partially vaccinated against HBV do not mount an adequate antibody response despite continued vaccination in the post-transplant period. The data presented here highlights the need for administration of a full schedule of vaccination before kidney transplantation for maximal protection against HBV infection. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about mycophenolic acid used for the prevention of graft rejection after renal allograft transplantation.

Presents a letter to the editor on early allograft failure in an unrecognized case of primary hyperoxalosis.

Identification of pathological events in the renal allograft using protocol biopsies at predetermined time intervals may yield useful information and improve outcomes. We examined the influence of decisions taken on the basis of 1 and 3-month protocol biopsies findings on 1-year renal allograft function in a prospective randomized study. Out of 102 living-donor allograft recipients, 52 were randomized to undergo protocol biopsies and 50 controls had only indicated biopsies. All acute rejection episodes (clinical and subclinical) were treated. CNI dose adjustments were made on clinical judgement. Baseline recipient and donor characteristics, immunosuppressive drug usage, HLA matches, and 2-hour cyclosporine levels were similar in both groups. At 1 and 3 months, protocol biopsies revealed borderline changes in 11.5% and 14% patients, acute rejection in 17.3% and 12%, and chronic allograft nephropathy in 3.8% and 10%. The incidence of clinically evident acute rejection episodes was similar in the two groups, but biopsy group had lower serum creatinine at 6-months (P=0.0003) and 1-year (P< 0.0001). The creatinine values were similar in those with normal histology and borderline changes. Protocol biopsies are helpful in detecting subclinical histological changes in the graft; and management decisions based on this information improve short-term renal allograft function. [ABSTRACT FROM AUTHOR]