Incidence of Rejection in Renal Transplant Surgery in the LVHN Population Leading to Graft Failure: 6 Year Review

Incidence of Rejection in Renal Transplant Surgery in the LVHN Population Leading to Graft Failure: 6 Year Review Jessica Ludolph1 Lynsey Biondi, MD1,2 and Michael Moritz, MD1,2 1Department of Surgery, Lehigh Valley Health Network 2Research Scholar Program Mentor Abstract To obtain optimal outcomes, it is vital to continually investigate variables potentially effecting rejection and graft failures. 407 renal transplant recipients who were transplanted at The Transplant Center of the Lehigh Valley from January 2009 to December 2014 were analyzed using descriptive statistics. Variables potentially influencing graft survival, including delayed graft function, and cell mediated and antibody mediated rejection, were compared. Demographic information, donor characteristics, and cold ischemic time were also investigated. Rejection of one or more types occurred in 39% of patients. Cellular rejection (35% of total patients) occurred more commonly than antibody mediated rejection (8% of total patients), with borderline cellular rejection the most common (40% of rejections). Antibody mediated rejection negatively impacted graft survival (p=0.0917) whereas cellular rejection did not show a statistically significant effect. Delayed graft function was common (29% of patients), but patients with delayed graft function have similar rejection rates as patients without delayed graft function (29% for both). Delayed graft function was associated with significantly lower graft survival. Background Typical solid organs transplanted are the kidneys, heart, liver, pancreas, and lungs. Kidneys are the most common solid organ transplant performed. The Transplant Center of the Lehigh Valley performs a large volume of kidney transplant surgeries and maintains a large database with the details of these procedures. This project will quantify recent outcomes data related to incidences of the different types of rejection as compared to other variables. These variables include transplant type, cause of renal failure, and time on dialysis prior to transplantation. Currently, there is debate about the impact of acute rejection episodes on graft survival. More recent studies demonstrate a reduction in incidences of rejection over time, but not a similar reduction in renal graft failure.5 Further studies have also seen that graft failures are less dependent on the acute rejection episode itself but rather that an acute rejection can initiate a chronic pathological process that ultimately leads to graft failure.8 Rejection can be broken down into two major types; cell-mediated and antibody mediated rejection. Severity is graded on the Banff ’97 scale. This scale is broken down into seven different categories, in order of increasing severity: Borderline, Grade 1A, Grade 1B, Grade 2A, Grade 2B, Grade 3, and Grade 4, aimed at providing a standard classification system for the varying pathologies seen on histological examination. In addition to the Banff scale, clinical vs. subclinical rejection becomes an important metric for evaluating the ultimate outcome of the allograft. An incidence of subclinical rejection is diagnosed from biopsies performed routinely based on protocol rather than for a change in transplant function. LVHN performs protocol biopsies at 1, 6, and 12 months post-transplant. Additional biopsies are performed when clinically indicated, usually a negative change in transplant function. In some studies, rejection episodes that do not cause a decrease in renal function have a lesser impact on graft survival.5 It can be postulated then, that subclinical rejection episodes do not have as significant of an impact on graft survival as clinical rejection episodes. The occurrence of cell mediated versus antibody mediated rejection can have vastly different effects on outcomes. These two types of rejection should not be thought of as completely separate entities, but rather overlapping, where an episode of unresolved cell-mediated rejection can lead to antibody mediated rejection.8 This study aims to further investigate the relationships between the different types of rejection and the graft failure as well as look at other compounding factors that might also show correlation with either the incidence of rejection or the ultimate outcome of the graft. Methods A retrospective study was conducted at the Transplant Center of the Lehigh Valley in Allentown, Pennsylvania. The 407 patients that underwent renal transplantation from January 2009 to December 2014 were included in the study. During this period, a uniform protocol for immunosuppression, post-transplant care, and biopsy by protocol and clinical indication was in place. Patient data was collected from the Organ Transplant Tracking Record (OTTR) database and included transplant date, graft survival time, patient survival time, donor type, types of rejections, treatments received, and demographic information. Those patients who experienced one or more episodes of rejection were then further analyzed to see if there is a correlation between the other factors including, transplant type (living vs. deceased donor, PHS higher risk), demographics (age, sex), delayed graft function (defined as the patient needing dialysis within 7 days of transplant), time on dialysis prior to transplant, cold ischemic time, and the ultimate outcome of the graft. Data from the OTTR was coded so it could be statistically analyzed. Primary disease category was done based on the categories used by the Scientific Registry of Transplant Recipients (SRTR): Glomerular diseases, Tubular and Interstitial diseases, Polycystic Kidneys, congenital/familial/metabolic, Diabetes, Renovascular and Vascular diseases, Neoplasms, and Hypertensive Nephrosclerosis. Most of the data was coded using 0=No and 1=Yes for types or rejection, delayed graft function, and whether or not the patient received a particular treatment. Cell mediated rejection and antibody mediated rejection were compared for history of delayed graft function and graft survival. Descriptive statistics were performed on age, gender, type of donor (living vs. deceased), graft failure, delay of graft function, time on dialysis, cold ischemic time, and incidence of rejection and the proportion of each type of rejection. Patients who died with a functioning graft were excluded in graft survival. Survival analysis was used to analyze cell mediated rejection, antibody mediated rejection, and delayed graft function, versus graft survival time. Results Of 407 total patients included in the study, 159 experienced at least one episode of rejection (39%) and 248 experienced no rejection (61%). (See Table 1) Of those who experienced rejection, the mean age was 57 years old, 32% were female, 19% had a living donor, 23% had graft failure (p=.0254), 29% had delay of graft function. The mean time on dialysis was 1401 days, and the mean cold ischemic time was 712 minutes. Looking at those who experienced no rejection, the mean age was 58 years old, 30% were female, 23% had a living donor, 16% had graft failure, 29% had a delay in graft function, the mean time on dialysis was 925 days, and the mean cold ischemic time was 719 minutes. Only graft failure was statistically significantly different. Regarding all types of rejection, cell mediated borderline rejection was the most common encompassing 40% of all rejections, followed by Acute Cellular Rejection Banff Grade 1B (20%), Acute Cellular Rejection Banff Grade 1A (19%), Antibody mediated rejection (17%), and Grade 2A and 2B (2%). Antibody mediated rejection is associated with a statistically higher incidence (p Delayed graft function was also shown to have an influence on graft survival time (p Discussion In the LVHN population of renal transplant patients, less severe types of cellular rejection are more common (i.e. Borderline, Grade 1B). Overall, there were fewer instances of antibody mediated rejection compared to cell mediated rejection; 31% of the antibody mediated rejections ended in graft failure while only 10% of cell mediated rejections ended in graft failure. While there was a correlation between antibody mediated rejection and graft survival time, the same correlation was not as strong for cell mediated rejection with a p value of (\u3e0.05). Antibody mediated rejection appears to have a greater negative effect on graft survival than cell mediated rejection. In addition to examining the impact of rejection on the outcome of the graft, it is important to also consider factors that can impact episodes of rejection. In this study, delayed graft function and the presence and type of rejection were examined. For all patients, cell mediated rejection was more common than antibody mediated rejection. The incidence of all types of rejection was similar for delayed graft function and non-delayed graft function patients. Previous studies show delayed graft function after Donation after Cardiac Death (DCD) donors does not have the same negative influence on survival as delayed graft function after brain death. Further investigation into delayed graft function patients and types of donors is warranted. When analyzing graft survival as a continuous variable delayed graft function had a large impact, with the lowest mean graft survival time with a standard error of 53, and cell mediated rejection had the second lowest graft survival time with a similar standard error of 51. Interestingly, antibody mediated rejection had the highest mean graft survival time, but it also had the largest standard error of 114, indicating that its mean is not as well-known as the other two. This can be due to the smaller number of individuals experiencing antibody mediated rejection (36) compared to 118 with delayed graft function and 143 with cell mediated rejection. Late rejections may also influence this data. A survival analysis would have to be run on this data to determine the true relationship between these conditions and graft survival time. Comparing low level (Borderline/1A) with high level cellular rejection may also be useful. This study serves to provide a brief overview of the characteristics of the LVHN Renal transplant population. It is a springboard for future investigation of the rejection process and graft survival. Conclusions Acute cellular rejection (particularly borderline) is more common than antibody mediated rejection. Antibody mediated rejection has a statistically significant (p References Controversial Issues. (n.d.) West\u27s Encyclopedia of American Law, edition 2. (2008). Retrieved February 23 2015 from http://legal-dictionary.thefreedictionary.com/Controversial+Issues Lamb, K.E., Lodhi, S., & Meier-Kriesche, H.U. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011, 11:450-462. Racusen, L.C., Colvin, R.B., Solez, K., et al. Antibody-Mediated Rejection Criteria-an Addition to the Banff ’97 Classification of Renal Allograft Rejection. American Journal of Transplantation 2003, 3: 708-714. Gaber, L.W., Moore, L.W., Alloway, R.R., et al. Correlation between Banff classification, acute renal rejection scores and reversal of rejection. Kidney International 1996, 49: 481-487. Meier-Kriesche, H.U., Schold, J.D., Srinivas, T.R., & Kaplan, B. Lack of Improvement in Renal Allograft Survival Despite a Marked Decrease in Acute Rejection Rates Over the Most Recent Era. American Journal of Transplantation 2004, 4:378-383. El-Zoghby, Z.M., Stegall, M.D., Lager, D.J., et al. Identifying Specific Causes of Kidney Allograft Loss. American Journal of Transplantation 2009, 9:527-535. Wu, K., Budde K., Lu, H., et al. The Severity of Acute Cellular Rejection Defined by Banff Classification Is Associated With Kidney Allograft Outcomes. Transplantation 2014, 97:1146-1154. El Terse, M., Grande, J.P., Keddis, M.T., Rodrigo, E., et al. Kidney Allograft Survival After Acute Rejection, the Value of Follow-Up Biopsies. American Journal of Transplantation 2013, 13:2334-2341. Appendix Table 1: Characteristics of patients with at least one incidence of rejection vs. those with none (n=407) *Influence of rejection as the independent variable. All other variables show incidence of rejection as the dependent variable. Graft failure only includes those who had graft failure unrelated to patient death. Figure 1: Includes types of cell mediated rejections Banff Scale (Grade 1A, 1B, 2A, 2B, 3, 4, Borderline) Figure 2: Delayed graft function is defined as anyone receiving dialysis within 7 days post-transplant. {Mean graft survival time in days} Delayed Graft Function (DGF) Figure 3: Graft failure only included patients who had graft failure unrelated to patient death. Effect of antibody mediated rejection on graft failure p\u3c0.0001 Figure 4: Delayed Graft Function p Cell Mediated Rejection p=.053

Efficacy of IVIG for Treatment of De-Novo Donor Specific Antibodies in Renal Transplant Recipients

Abstract Development of Donor Specific Antibodies (DSA) is linked to worsened outcomes in renal transplant recipients. Intravenous immunoglobulin (IVIG) is an immune-modulator utilized in treatment of antibody mediated rejection. A retrospective review of kidney transplant cases at Lehigh Valley Health Network (LVHN) from January 2009 to June 2014 was performed to evaluate the efficacy of IVIG in treatment of new DSAs. All patients undergoing renal transplant at LVHN are cross-match compatible at the time of procedure. Desensitization is not utilized. All highly sensitized patients (PRA\u3e50%) receive prophylactic IVIG monthly x 4 months post-transplant. Study patients that tested positive for DSA post-transplant were treated with additional IVIG (0.5g/kg monthly). 95 patients were treated with IVIG during the study period. Of 55 patients with newly positive DSA, 24 of these cleared the DSA after IVIG treatment. IVIG was more effective in clearance of class I than class II DSA. Highest rates of graft loss occurred in patients that tested positive for both a class I and class II DSA. Conclusion: 1. IVIG can be a useful in eliminating DSA post-renal transplant. 2. IVIG is effective in eliminating Class I DSA. 3. Class II DSA can be difficult to eliminate and requires further investigation. Background Intravenous immunoglobulin (IVIG) is a medication that has emerged as a useful tool in modulating immunity, treatment of antibody mediated rejection (AMR), and in desensitization protocols. IVIG serves as a mediator of the immune system and as a regulator of inflammation. DSAs specifically target the transplant donor organ. The presence of DSAs has been linked to significantly worse graft survival. In patients with AMR, therapy with IVIG paired rituximab and plasmapheresis (PP) can increase graft survival by more than 40% and suppress DSAs. (1) Studies have still not demonstrated optimal regimens for treatment of new DSA. The purpose of this study was to investigate the effectiveness of IVIG in elimination of DSAs. Methodology A retrospective chart review was performed of all kidney transplant patients at Lehigh Valley Health Network who were treated with IVIG post transplantation from January 2009 to June 2014. All patients were cross match compatible (no DSA presence at time of transplant) and had not undergone desensitization protocols. All highly sensitized patients (PRA greater than 50%), were prophylactically treated with 0.5g/kg of IVIG monthly for four doses beginning at the time of transplant per the center’s protocol. These patients had monthly DSA tests for at least one year. Nonsensitized patients (PRA less than 50%) did not receive prophylactic IVIG. These patients were checked for DSAs after 1, 6, and 12 months and when symptoms arose (elevated creatinine, proteinuria). Patients that tested positive for DSA post-transplant were treated monthly with 0.5g/kg of IVIG until clearance of DSA. These patients also underwent renal transplant biopsy at discovery of DSA. Successful treatment was considered elimination of DSA for greater than 1 month. Time to DSA clearance, dates of graft loss, AMR, and development of Class I versus Class II DSA were noted. Results Of the 293 patients who received kidney transplantation at Lehigh Valley Health Network in the study period, 95 were treated with IVIG. 55 patients that were treated with IVIG had a positive DSA (57.8%). 24 (43.6%) of those patients cleared the DSA after treatment with IVIG. Of the remaining 31 patients, 28 did not clear the DSA and 3 patients expired during the study interval. 61 of the 95 (64.2%) patients received prophylactic IVIG. Out of those, 41/61 (67.2%) never developed a DSA while 20/61 (32.8%) did. Out of the 20 that developed a DSA, 9 cleared the DSA. 34 non-sensitized patients (12% total non-sensitized transplants) developed DSAs and then received treatment with IVIG. Outcomes Sensitized versus Non-sensitized Patients Treated with IVIG Outcomes of Class I versus Class II DSAs Treated with IVIG IVIG was more effective in the clearance of class I DSA’s than class II. Following treatment with IVIG, 8/12 (66.7%) of the Class I DSAs cleared and 11/26 (42.3%) of the class II DSAs cleared (p=0.05). Clearance rates were lower in patients starting with both Class I and II antibodies, but Class I cleared more frequently. In only one case, the patient cleared the class II DSA first, however this patient expired only two months later while the class I was still present. Lowest rates of graft loss occurred in patients with a class I DSA, followed by class II, and lastly if a patient had both (p=0.02). P=0.020 P=0.05 Conclusions 1. IVIG can be a useful in eliminating DSA post-renal transplant. 2. IVIG is effective in eliminating Class I DSA. 3. Presence of Class II DSA is associated with higher rates of graft loss. Class II DSA can be difficult to eliminate and requires further investigation, possibly in combination with biologic agents. 4. Limited numbers of patients at this time make statistically significant results difficult to achieve. Further investigation is necessary. References Shehata et al. (2010) The use of immunoglobulin Therapy for Patients Undergoing Solid Organ Transplantation: an Evidence- based practice guideline. Transf Med Rev 2010; 24:7-27. Rocha P et al. (2003) Beneficial Effect of Plasmapheresis and Intravenous Immunoglobulin on Renal Allograft Survival of Patients with Acute Humoral Rejection. Transplantation 75:1490-1495 Lefaucher et al. (2009) Comparison of Combination plasmapheresis/IVIG/Anti-CD20 Versus High Dose IVIG in the Treatment of Antibody-Mediated Rejection. Am J Transplant 9:1099-110

Differentiating Acute Rejection From Preeclampsia After Kidney Transplantation.

OBJECTIVE: To evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses. METHODS: We conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time. RESULTS: There were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P CONCLUSION: In pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients. FUNDING SOURCE: The Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals

Emergent Prelabor Cesarean Birth in Solid Organ Transplant Recipients: Associated Risk Factors and Outcomes.

BACKGROUND: Pregnancies after solid-organ transplant are at a higher risk for antepartum admission and pregnancy complications, including cesarean birth. Emergent prelabor cesarean is associated with increased maternal and neonatal morbidity in other high-risk populations, but its incidence and impact in transplant recipients is not well understood OBJECTIVE: To characterize the risk factors and outcomes of emergency prelabor cesarean birth in kidney and liver transplant recipients STUDY DESIGN: Retrospective cohort study of all kidney and liver transplant recipients \u3e20 weeks\u27 gestation enrolled in the Transplant Pregnancy Registry International between 1976 and 2019. Participants admitted antepartum who required an emergency prelabor cesarean were compared to those admitted antepartum who underwent non-emergent birth. Primary outcomes were composite severe maternal morbidity and neonatal composite morbidity. Multivariable logistic regression was conducted for neonatal composite morbidity RESULTS: Of 1,979 births, 181 pregnancies (188 neonates) with an antepartum admission were included. 51 pregnancies (53 neonates, 28%) were delivered by emergent prelabor cesarean birth compared with 130 pregnancies (135 neonates, 72%) admitted antepartum who subsequently did not require emergent delivery. The most common indication for emergent delivery was non-reassuring fetal heart tracing (44 neonates, 86%). Pregnant people who underwent an emergent prelabor cesarean were less likely to birth at a transplant center (37.3% vs 41.5%, p=0.04) and had increased rates of chronic hypertension (33.3% vs 16.2%, p=0.02). There was no significant difference in severe maternal morbidity (3.9% vs 4.6%, p=0.84), though there was an increase in surgical site infection in the emergent prelabor cesarean cohort (3.9% vs 0%, p=0.02). Among those with an emergent prelabor cesarean, there was a significant increase in neonatal composite morbidity (43.4% vs 19.3%,

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis

New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children

Hyponatremia is the most common electrolyte abnormality encountered in children. In the past decade, new advances have been made in understanding the pathogenesis of hyponatremic encephalopathy and in its prevention and treatment. Recent data have determined that hyponatremia is a more serious condition than previously believed. It is a major comorbidity factor for a variety of illnesses, and subtle neurological findings are common. It has now become apparent that the majority of hospital-acquired hyponatremia in children is iatrogenic and due in large part to the administration of hypotonic fluids to patients with elevated arginine vasopressin levels. Recent prospective studies have demonstrated that administration of 0.9% sodium chloride in maintenance fluids can prevent the development of hyponatremia. Risk factors, such as hypoxia and central nervous system (CNS) involvement, have been identified for the development of hyponatremic encephalopathy, which can lead to neurologic injury at mildly hyponatremic values. It has also become apparent that both children and adult patients are dying from symptomatic hyponatremia due to inadequate therapy. We have proposed the use of intermittent intravenous bolus therapy with 3% sodium chloride, 2 cc/kg with a maximum of 100 cc, to rapidly reverse CNS symptoms and at the same time avoid the possibility of overcorrection of hyponatremia. In this review, we discuss how to recognize patients at risk for inadvertent overcorrection of hyponatremia and what measures should taken to prevent this, including the judicious use of 1-desamino-8d-arginine vasopressin (dDAVP)

Genetic Analyses of Heme Oxygenase 1 (HMOX1) in Different Forms of Pancreatitis

Contains fulltext : 107993.pdf (publisher's version ) (Open Access)BACKGROUND: Heme oxygenase 1 (HMOX1) is the rate limiting enzyme in heme degradation and a key regulator of inflammatory processes. In animal models the course of pancreatitis was ameliorated by up-regulation of HMOX1 expression. Additionally, carbon monoxide released during heme breakdown inhibited proliferation of pancreatic stellate cells and might thereby prevent the development of chronic pancreatitis (CP). Transcription of HMOX1 in humans is influenced by a GT-repeat located in the promoter. As such, HMOX1 variants might be of importance in the pathogenesis of pancreatitis. METHODS: The GT-repeat and SNP rs2071746 were investigated with fluorescence labelled primers and by melting curve analysis in 285 patients with acute pancreatitis, 208 patients with alcoholic CP, 207 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and in 289 controls, respectively. GT-repeat analysis was extended to a total of 446 alcoholic CP patients. In addition, we performed DNA sequencing in 145 patients with alcoholic CP, 138 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and 151 controls. Exon 3 screening was extended to additional patients and controls. RESULTS: S- and L-alleles of the GT-repeat, genotypes and alleles of SNP rs2071746 and non-synonymous variants detected by sequencing were found with similar frequencies in all groups. CONCLUSIONS: Although functional data implicate a potential influence of HMOX1 variants on the pathogenesis of pancreatitis, we did not find any association. As rare non-synonymous HMOX1 variants were found in patients and controls, it is rather unlikely that they will have functional consequences essential for pancreatitis development