Chethan Puttarajappa

Antibody-Mediated Rejection in Kidney Transplantation: A Review

Antibody mediated rejection (AMR) poses a significant and continued challenge for long term graft survival in kidney transplantation. However, in the recent years, there has emerged an increased understanding of the varied manifestations of the antibody mediated processes in kidney transplantation. In this article, we briefly discuss the various histopathological and clinical manifestations of AMRs, along with describing the techniques and methods which have made it easier to define and diagnose these rejections. We also review the emerging issues of C4d negative AMR, its significance in long term allograft survival and provide a brief summary of the current management strategies for managing AMRs in kidney transplantation.

Commercially Available Immunoglobulins Contain Virus Neutralizing Antibodies Against All Major Genotypes of Polyomavirus BK

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype‐specificity, and mechanism of action of anti‐polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co‐transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon‐modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype‐specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti‐viral effects, until effective small molecule inhibitors of BKV replication can be developed.

Cancer risk with alemtuzumab following kidney transplantation.

Alemtuzumab has been employed for induction therapy in kidney transplantation with low rates of acute rejection and excellent graft and patient survival. Antibody induction therapy has been linked to increased vulnerability to cancer. Data regarding malignancy rates with alemtuzumab are limited. We studied 1350 kidney transplant recipients (between 2001 and 2009) at the University of Pittsburgh Starzl Transplant Institute, for post‐transplant de novo and recurrent malignancy, excluding non‐melanoma skin cancer, among patients receiving alemtuzumab, thymoglobulin, and no induction therapies. Of the 1350 patients, 1002 (74.2%) received alemtuzumab, 205 (15.2%) received thymoglobulin, and 122 (9%) received no induction therapy. After excluding cancers occurring within 60 d post‐transplantation, 43 (3.25%) malignancies were observed during a median follow‐up time of 4.0 yr. The incidence of malignancy was 5.4% (1.09 per 100 patient‐years [PY]) with thymoglobulin, 2.8% (0.74 per 100 PY) with alemtuzumab, and 3.3% (0.66 per 100 PY) with no induction (across all groups; p = 0.2342, thymoglobulin vs. alemtuzumab; p = 0.008). Thus, with the exception of non‐melanoma skin cancer which we did not evaluate, alemtuzumab induction was not associated with increased cancer incidence post‐kidney transplantation when compared to no induction therapy and was associated with lower cancer incidence when compared to thymoglobulin.

Mediastinal lipomatosis as a cause of low voltage complexes on electrocardiogram and widened mediastinum: A case report

BackgroundMediastinal widening is a common finding on chest radiograph, and can be caused by numerous conditions. Most of these diseases have grave prognosis if accompanied by chest pain, and require immediate attention. However, mediastinal lipomatosis is a very benign condition caused by deposition of adipose tissue in the mediastinum.Case presentationWe present a case of a morbidly obese female patient who presented to emergency department with a fall. She had mediastinal widening on chest radiograph, and borderline low voltage on electrocardiogram. On computed tomography, mediastinal lipomatosis was evident.ConclusionObesity is a major epidemic in United States, and can lead to deposition of fat in the chest. Mediastinal lipomatosis is very benign condition, which rarely causes grave consequences.

Cytomegalovirus infection in high-risk kidney transplant recipients receiving thymoglobulin induction-a single-center experience.

The burden of cytomegalovirus infection in CMV high‐risk (donor positive to recipient negative) kidney transplant recipients getting thymoglobulin induction and six months of valganciclovir is not well characterized. Additionally, the role of post‐prophylaxis surveillance remains unclear.

Dermatomyositis and supraventricular tachycardia.

Background Dermatomyositis is an idiopathic inflammatory myopathy, often associated with an underlying malignancy. Its prevalence rate is approximately one per 100,000 in the general population, and is even rarer without evidence of a cancer. Dermatomyositis rarely involves myocardial muscle fibers, but has shown to be associated with cardiac arrhythmias. Case Presentation We present a case of a young female patient with known history of dermatomyositis who presented to hospital with a flare up of her disease. She also complained of paroxysms of palpitation. Telemetry monitoring revealed several episodes of paroxysmal supraventricular tachycardia with heart rate reaching up to 220 beats per minute. Conclusion Cardiac involvement in dermatomyositis is a very rare, but well known entity. Dermatomyositis patients with palpitations should be monitored on a Holter monitor, and appropriate therapy initiated if found to have a significant arrhythmia.

Kidney Transplant Outcomes After Primary, Repeat and Kidney After Nonrenal Solid Organ Transplantation: A Single-Center Experience.

Background Improvements in renal allograft outcomes have permitted kidney transplantation after prior kidney allograft failure as well as after nonrenal solid organ transplantation. This study compares renal allograft outcomes in the 3 groups, that is, primary, repeat, and kidney after nonrenal solid organ transplantation, where transplant group was coded as a time-dependent variable. Methods We retrospectively reviewed registry data for kidney transplant recipients at University of Pittsburgh Medical Center from January 2000 to December 2011. We compared overall graft survival between the 3 groups using Cox regression modeling. We calculated 1-, 3-, and 5-year graft survival and half-lives for each group where feasible. Results The study cohort (N = 2014) consisted of group A (primary kidney transplant, n = 1578, with 7923.2 years of follow-up time), group B (repeat kidney transplant, n = 314, with 1566.7 years of follow-up time) and group C (kidney post-nonrenal solid organ transplant, n = 176, with 844.8 years of follow-up time). Of the 1578 patients in the primary kidney transplant group, 74 later received a repeat transplant and thus also have follow-up counted in the repeat kidney transplant group. The median follow-up was 56, 53, and 55 months, respectively. The 5-year actuarial and death-censored graft survival was 68.69%, 68.79%, and 66.48% and 65.53%, 67.68%, and 62.92%, respectively (P = 0.70). There was no difference in overall graft survival in the Cox-adjusted analysis (group B: odds ratio, 1.02; 95% confidence interval, 0.84-1.26; P = 0.79; group C: odds ratio, 0.96; 95% confidence interval, 0.75-1.23; P = 0.76). Conclusions The adjusted kidney graft survivals in the 3 groups were similar.

Relation of Porphyria to Atrial Fibrillation

Porphyrias are a group of inherited disorders affecting enzymes in the heme biosynthesis pathway, leading to overproduction and/or accumulation of porphyrin or its precursors. Porphyrias have been associated with autonomic dysfunction, which in turn can develop atrial fibrillation (AF). The purpose of this study was to characterize the prevalence of AF and atrial flutter (AFl) in patients with porphyrias. A single-center retrospective cohort study was designed using data from chart reviews of patients who were admitted to the hospital from January 2000 to June 2008. Fifty-six distinct cases were found with a discharge diagnosis of porphyria including all its subtypes. From the same database, age- and gender-matched controls were identified using computer-generated random numbers. We selected 1 age- and gender-matched control for each case. Electrocardiograms and echocardiograms were reviewed by 2 independent reviewers. Only patients with available 12-lead electrocardiograms that showed AF/AFl were labeled with that diagnosis. All patients with a diagnosis of porphyria were included in the study irrespective of their age. Seven of 56 patients with porphyria met inclusion criteria, yielding a prevalence of AF/AFl of 12.5%. This association was significant (p = 0.028, relative risk 7.45, 95% confidence interval 1.01 to 66.14) compared with the age- and gender-matched control group (2%). In conclusion, our observations suggest that porphyria may be significantly associated with AF/AFl.

Short-term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol

The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3‐month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3‐months posttransplant. Among those with stable allograft function at 3 months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n = 71) and Group II: Subclinical Inflammation (SCI, n = 129). We evaluated differences in kidney function at 24‐months and allograft histology score at 12‐month biopsy. SCI patients had a higher serum creatinine (1.6 ± 0.7 vs 1.38 ± 0.45; P = .02) at 24‐months posttransplant, and at last follow‐up at a mean of 42.5 months (1.69 ± 0.9 vs 1.46 ± 0.5 mg/dL; P = .027). The allograft chronicity score (ci + ct + cg + cv) at 12‐months posttransplant was higher in the SCI group (2.4 ± 1.35 vs 1.9 ± 1.2; P = .02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P = .015). De novo donor‐specific antibody within 12 months was more prevalent in the SCI group (12/129 vs 1/71, P = .03). SCI is likely not a benign finding and may have long‐term implications for kidney allograft function.

Atrial fibrillation in renal or liver transplant recipients: A systematic review and meta-analysis

BACKGROUND The prevalence of atrial fibrillation (AF) in patients undergoing renal (RT) or liver transplantation (LT) has increased during the last decades. Yet, there is still uncertainty on the association between AF and patient and graft survival. METHODS Multiple electronic databases were searched using various combinations of keywords and MeSH terms pertinent to the exposure (AF), and outcomes (graft and patient survival). Randomized or quasi-randomized controlled studies, cohort and case-control studies on adults with documented AF undergoing RT or LT were included. The quality of studies was assessed using the Newcastle-Ottawa Assessment Scale. When appropriate, data on the primary and secondary outcomes were pooled in a meta-analysis using the random-effect model. The Odds ratio was used for patients undergoing LT and the hazard ratio was used for patients who underwent renal transplantation. RESULTS A total of 50,362 publications were identified. Six studies, with a total of 136,331 patients, satisfied the inclusion criteria. LT was performed on 2861 patients and RT was performed on 133,470 recipients. Overall, AF affected 6652 (4.8%) transplant recipients. Among them, 153 received a LT and 6499 underwent RT. The OR for mortality after LT was 2.375 (95% CI; 1.532-3.682) (P = 0.000) in AF(+) recipients and the HR was 1.859 (95% CI; 1.031-3.354) (P = 0.039) after RT. The OR for graft loss in AF(+) after LT r was 1.088 (95% CI; 0.311-3.804) (P = 0.894) and the HR for graft loss was 1.632 (95% CI; 1.200-2.218) (P = 0.002) after RT. CONCLUSIONS To the best of our knowledge, this is the first systematic review and meta-analysis to explore the association between AF and patient and graft survival after RT or LT. Our findings suggest that the presence of AF is associated with inferior patient survival. For renal transplant recipients, AF is also associated with inferior graft survival.