Dean, Patrick G.

Background. Recent studies identified underlying genetic causes in a proportion of patients with various forms of kidney disease. In particular, genetic testing reclassified some focal segmental glomerulosclerosis (FSGS) cases into collagen type 4 (COL4)-related nephropathy. This knowledge has major implications for counseling prospective transplant recipients about recurrence risk and screening biologically related donors. We describe our experience incorporating genetic testing in our kidney transplant multidisciplinary practice. Methods. Patients’ DNA was analyzed using whole exome sequencing for a comprehensive kidney gene panel encompassing 344 genes associated with kidney diseases and candidate genes highly expressed in the kidney. Results were correlated with phenotype by a multidisciplinary committee of nephrologists, renal pathologists, geneticists, and genetic counselors. Between October 2018 and July 2020, 30 recipient and 5 donor candidates completed testing. Results. Among recipient candidates, 24 (80%) carried the diagnosis of FSGS, 2 (6.7%) tubulointerstitial nephritis, and 1 (3.3%) nephrolithiasis, and 3 (10%) had an unknown cause of kidney disease. The yield for pathogenic/likely pathogenic variants was 43.3%, with majority being COL4 variants (53.8%). Among those with FSGS diagnosis, the yield was 10 of 24 (41.6%), with 29% reclassified into a COL4-related nephropathy. Family history of kidney disease was the only clinical characteristic difference between recipients with positive and negative results (76.9 versus 29.4%; P = 0.025). One of 5 donors tested positive for a pathogenic/likely pathogenic variant and was excluded from donation. Conclusions. We conclude that thoughtful use of genetic testing can be valuable for kidney donor selection and transplant recipient management.

Background Obesity is increasingly common in kidney transplant candidates and may limit access to transplantation. Obesity and diabetes are associated with a high risk for post-transplant complications. The best approach to weight loss to facilitate active transplant listing is unknown, but bariatric surgery is rarely considered due to patient- and physician-related apprehension, among other factors. Methods We aimed to determine the magnitude of weight loss, listing, and transplant rates in 28 candidates with a mean BMI of 44.4±4.6 kg/m 2 and diabetes treated conservatively for 1 year post weight-loss consultations (group 1). Additionally, we evaluated 15 patients (group 2) who met the inclusion criteria but received bariatric intervention within the same time frame. All patients completed a multidisciplinary weight management consultation with at least 1 year of follow-up. Results In the conservatively managed group (group 1), the mean weight at the time of initial consultation was 126.5±18.5 kg, and the mean BMI was 44.4±4.6 kg/m 2 . At 1 year post weight-loss consultation, the mean weight decreased by 4.4±8.2 kg to 122.9±17 kg, and the mean BMI was 43±4.8 kg/m 2 , with a total mean body weight decrease of 3% ( P =0.01). Eighteen patients (64%) did not progress to become candidates for active listing/transplantation during the follow-up time of 4±2.9 years, with 15 (54%) subsequently developing renal failure/diabetes-related comorbidities prohibitive for transplantation. In contrast, mean total body weight decreased by 19% at 6 months post bariatric surgery, and the mean BMI was 34.2±4 and 32.5±3.7 kg/m 2 at 6 and 12 months, respectively. Bariatric surgery was strongly associated with subsequent kidney transplantation (HR=8.39 [95% CI 1.71 to 41.19]; P =0.009). Conclusions A conservative weight-loss approach involving multidisciplinary consultation was ineffective in most kidney transplant candidates with diabetes, suggesting that a more proactive approach is needed.

Introduction: Arteriovenous fistulas(AVF) have been associated with high output heart failure but little is known about their effect on patients initiating hemodialysis. We sought to describe echocardiographic changes and identify those with incident heart failure after AVF creation. Methods: This was a retrospective analysis of all patients undergoing AVF creation over a 15 year period from 2000-2014 at the Mayo Clinic in Rochester, MN. Patients undergoing echocardiogram <3 months (median 40 days) before AVF creation and >6 months (median 2.5 years) following surgery were included. Patients with independent modifiers of LV structural changes (such as revascularization or myocardial infarction) were excluded by chart review. Clinical heart failure was defined by Framingham criteria. Results: From 2000-2014, 2236 patients underwent creation of AVFs and 137 patients met inclusion criteria. There was a longitudinal decrease in systolic function as evident by a drop in ejection fraction(-2%, p=0.047) with decrease in s’ tissue Doppler velocity(-0.6 cm/s, p=0.055) and increase in HR(+5 beats/min, p=0.003). There was also an increase in the prevalence of RV dilation(20 to 40%, p=0.002) and RV dysfunction(12 to 29%, p=0.002). With initiation of dialysis and decrease in weight (-7.3kg) and estimated plasma volume (-303ml) (both p<0.0001), there was a decrease in LV end diastolic dimension (-2mm, p=0.006). Despite better volume control, left atrial volume index increased (+5ml/m2, p=0.004). On multivariate Cox regression, worsening RV dilation [HR 1.8 (1.06-3.09),p=0.03] was independently associated with mortality. Incident heart failure developed in 43%(28/65) with no pre-existing HF, of whom 75% had HFPEF and 25% HFrEF. The development of new systolic HF (but not HFPEF) was associated with increased age and sex adjusted mortality [HR 3.0(1.0-7.9), p=0.045]. Conclusions: AVF creation is associated with worsening biventricular function and left atrial and RV dilatation, despite reduction in LV size. These changes are coupled with high incidence of new, unexplained heart failure. Further research is needed to identify the hemodynamic mechanisms underlying heart failure development in patients with ESRD requiring dialysis access.

Abstract Introduction: Pancreas Transplantation (PT) improves quality of life in Type 1 Diabetes (T1D) patients but limited longitudinal data are available regarding comprehensive metabolic assessment and lifestyle. Our objective was to comprehensively assess T1D patients who underwent PT (PTA and SPK) ≥ 1 year prior on two separate visits 1 year apart. Methodology: We studied 12 PT recipients ≥1 year post PT. Two assessments 1 year apart included comprehensive assessment of graft function using standard mixed meal tolerance test (MMTT), Continuous Glucose Monitoring (CGM) for 1 week, body composition using DEXA scan, physical activity using ActiGraph for 1 week and dietary assessment by VIOCARE®. Results: PT recipients (9F) were 55.5± 9.7 years old, 91.7 % Caucasian with 34.9 ± 12.3 years of diabetes, 6.7 ± 5.2 years (range-1.3–17.6 years) after PT. Ten participants underwent Pancreas Transplantation alone and two received Simultaneous Pancreas Kidney transplantation. Visit 1(V1) showed HbA1c 5.5 ± 0.7%, Fructosamine 238.4 ± 25.6 mcmol/L, BMI 31.2 ± 6.7 kg/m2, fasting plasma glucose (FPG) 95.2 ± 19.4mg/dL and C-peptide 2.6 ± 1.0 ng/ml and visit 2 (V2) HbA1c 5.5 ± 0.6%, Fructosamine 244.4 ± 41.3 mcmol/L, BMI 29.9 ± 5.1kg/m2, FPG 95.4 ± 27.7mg/dL, and C-peptide 2.5 ± 0.8 ng/ml (p-value not significant). One week CGM (n=9) showed excellent glucose control at both visits with mean glucose 117.8 ± 7.0 vs.112 ± 6.2 mg/dl and 96.3 ± 3.6 vs. 96.9±2.8 % time in target range (70-180mg/dl). Time &gt;180mg/dl and &gt;250mg/dl were 2.7 ± 3.0 vs. 1.3±1.7 % (p=0.0413) and 0.2 ± 0.6 vs. 0.1 ± 0.1 % respectively. Mild CGM hypoglycemia (&lt;70 mg/dl) was observed during both visits (1.0 ± 1.0 vs. 1.7± 2 %). CV was 21.1 ± 5.5 and 20.1 ± 4.8 %. Eight recipients underwent MMTT and showed excellent response to Boost® with no significant difference between visits with exception of insulin concentrations at 60 mins (increased from V1) and 90 mins (decreased from V1) (p=0.0424 and 0.0235). DEXA (n=10) revealed similar total % mean fat, and fat distribution in arms, legs and trunk. ActiGraph (n=10) showed similar physical activity during both visits with 16761 ± 5176 and 14499 ± 4192 average steps/day respectively. Mean MET score was 1.6 ± 0.4 and 1.6 ± 0.2 indicating light intensity activity during both periods. Total mean sedentary bouts increased over 1 year (49.6 ± 39.1 vs. 60.8 ± 43.7, p=0.0038). Dietary assessment in 11 recipients showed no significant difference in dietary intake with calories intake 1.3± 0.4 vs. 1.2±0.5 daily Harris-Benedict and macronutrient intake with fat of 36.7 ± 4.3 % and 36.5 ± 5.7 %, CHO of 45.7 ± 5.5 % and 45.7 ± 5.5 % and Omega-3 of 0.1 ± 0.1 g and 0.05 ± 0.1 g respectively. Conclusion: PT recipients have excellent glucose control and pancreas graft function 1 or more years after PT when assessed over successive 2 years with suboptimal body composition and dietary intake and above average physical activity.

Introduction: Contemporary dosing strategies for rabbit anti-thymocyte globulin (rATG) in kidney transplantation aim to reduce cumulative exposure, minimizing long-term adverse events. The use of ideal body weight-based dosing has been trialed, however concern for increased rejection post-transplant exists due to lower doses of rATG. Research Questions: The primary aim of this study was to compare rejection rates between rATG dosing protocols using actual body weight and ideal body weight and secondarily to evaluate cost savings following protocol implementation. Design: This was a retrospective study surrounding implementation of an ideal body weight-based dosing protocol for rATG. We compared 75 kidney transplant recipients in whom rATG was dosed based on actual body weight (pre-protocol group) to 64 in whom dosing was based on ideal body weight (post-protocol group), following a nine-month washout. Results: The mean cumulative rATG dose in the pre-protocol group was 6.3 mg/kg of actual body weight. When ideal body weight was used in the post-protocol group, the mean dose was 4.5 mg/kg of actual body weight. The rejection rate was 18.7% pre-protocol and 23.4% postprotocol, which did not represent a statistically significant difference (p = 0.491). The actual annual cost savings after protocol implementation exceeded $162,000, approximately $2,500 per patient. Conclusion: Results suggest ideal body weight-based dosing of rATG may reduce exposure and cost, without significantly impacting the risk of rejection in kidney transplant recipients. More studies are needed to confirm these findings.

Abstract Background Human Immunodeficiency Virus (HIV) outcomes have significantly improved at the expense of other age-related diseases including chronic kidney disease. Early reports of people living with HIV (PLWH) undergoing deceased-donor kidney transplantation (DDKT) showed poor outcomes, but these have notably improved after introduction of antiretrovirals. Despite years of experience, the optimal induction immunosuppression (IIS) in PLWH remains subject of debate. Large-scale studies describing the current ISS practices in PLWH undergoing DDKT are lacking. Here, we describe the U.S. national trends of IIS used in PLWH undergoing DDKT from 2000 to 2018 using the United Network of Organ Sharing (UNOS) database. Methods We analyzed the UNOS database to determine the selection of IIS in PLWH undergoing first-time DDKT between 1/1/2000 and 12/31/2018. Cases with unknown HIV status at the time of transplant were excluded. Age, sex and demographics were analyzed. The regimen used for IIS was compared based on HIV serostatus and the change in induction regimen was trended over time. Results A total of 139,650 cases underwent DDKT during the study period. Among these, 1,384 were identified as HIV-positive. PLWH were significantly younger than HIV-negative (49±10 years vs. 51.6 ± 15.3 years; p&lt; 0.001) (Table 1). A greater proportion of men was seen in the PLWH group compared to HIV-negative persons (76.2% vs. 60.4%; p&lt; 0.0001). In the HIV-negative group, 12.1% undergoing DDKT did not receive IIS compared to 16.4% in PLWH (p&lt; 0.0001). Medications that have significantly increased in use with years in PLWH included rabbit anti-thymocyte globulin (rATG), steroids, and basiliximab (3.54, 3.25, 2.28, respectively; p&lt; 0.001). On our trend analysis (Figure 1), the percentage of PLWH receiving any IIS is increasing by 4.04% each year (p&lt; 0.001). Table 1 Figure 1 Conclusion Our study suggests that IIS is an increasing practice in PLWH undergoing DDKT, predominantly using rATG, steroids, and basiliximab. Understanding the current practices might lead to further studies to determine the long-term outcomes after different induction regimens in PLWH. Disclosures All Authors: No reported disclosures

Background. Experience with sequential hematopoietic stem cell transplant (HSCT) and kidney transplant (KT) is limited. Methods. We conducted a retrospective observational study of adult patients who underwent both HSCT and KT at our center, with a median follow-up of 11 y. Results. In our 54 patients cohort (94% autologous HSCT), 36 (67%) patients received HSCT first followed by KT, while 18 (33%) received KT before HSCT. In both groups, AL amyloidosis represented 50% of hematologic diagnosis. Only 4 patients expired due to hematologic disease relapse (2 patients in each group) and only 3 allografts were lost due to hematologic disease recurrence (HSCT first n = 1 and KT first n = 2). Overall 1, 5, and 10 y death-censored graft survival rates were 94%, 94%, and 94%, respectively, for the HSCT first group and 89%, 89%, and 75%, respectively, for the KT first group. Overall 1, 5, and 10 y patients survival rates were 100%, 97% and 90%, respectively, for the HSCT first group and 100%, 76%, and 63%, respectively, for the KT first group. Conclusions. Our study supports safety of sequential KT and HSCT, with improved overall patient survival compared to recipients of HSCT remaining on dialysis and good long-term kidney allograft outcome.