Infections Following Kidney Transplantation After Exposure to Immunosuppression for Treatment of Glomerulonephritis.

RATIONALE & OBJECTIVE: Kidney transplant patients with glomerulonephritis (GN) as their native disease commonly have received pretransplant immunosuppression (PTI). This may contribute to the immunosuppression burden potentially increasing the risk for infections after transplantation. STUDY DESIGN: Single-center, retrospective cohort study. SETTING & PARTICIPANTS: Recipients of a kidney transplant from January 2005 until May 2020 at a tertiary care university teaching hospital. EXPOSURE: Patients with GN as their native kidney disease who received PTI for treatment of GN (n=184) were compared with nondiabetic recipients of kidney transplants who did not receive PTI (n = 579). OUTCOME: First occurrence after transplantation of an infection outcome, either viral (BK or cytomegalovirus [CMV] infection) or bacterial. ANALYTICAL APPROACH: Cox regression analysis adjusted for age at transplant, sex, race, donor type, year of transplant surgery, dialysis vintage, receipt of T-cell depleting induction, and CMV transplant status. RESULTS: Over a median follow-up period of 5.7 years, patients with GN PTI were not at an increased risk for developing any first viral infection compared with controls (adjusted HR [AHR] 0.69 [95% CI, 0.52-0.91]) nor at increased risk for specific viral infections: BK infection 19.6% vs 26.3% (AHR 0.72 [95% CI, 0.50-1.05]) or CMV infection, 24.5% vs 29.0% (AHR, 0.76 [95% CI, 0.54-1.07]), respectively. There was also no increased risk of developing a first bacterial infection: 54.5% vs 57.5% (AHR, 0.90 [95% CI, 0.71-1.13]). These findings of no increased risk for infection were independent of the type of PTI used (cyclophosphamide, rituximab, mycophenolate mofetil, or calcineurin inhibitor) or the type of T-cell depleting induction therapy (alemtuzumab or antithymocyte globulin) administered. LIMITATIONS: Single-center study, no data on methylprednisone use for PTI, unmeasured confounding. CONCLUSIONS: Use of PTI for the treatment of GN was not associated with an increased risk of viral (BK or CMV) or bacterial infection after transplantation. Additional surveillance for infection after transplantation for patients who received PTI may not be necessary. PLAIN-LANGUAGE SUMMARY: Many kidney transplant patients have glomerular disease as the cause of kidney failure. These patients may be exposed to immunosuppression before transplantation, which could increase the risk for infections after receipt of a transplanted kidney. We identified kidney transplant recipients at a university teaching hospital who received immunosuppression before transplant for the treatment of glomerular kidney disease. We examined their risk for infection after transplantation by comparing it with the risk among transplant patients who were not exposed to immunosuppression before transplant. We observed no increased risk for infection after exposure to prior immunosuppression. Therefore, patients exposed to significant amounts of immunosuppression before transplantation may not require special surveillance or medication adjustment for fear of infection after their receipt of a kidney transplant.

Malignancy risk in kidney transplant recipients exposed to immunosuppression pre-transplant for the treatment of glomerulonephritis.

BACKGROUND: Kidney transplant patients with glomerulonephritis (GN) as their native disease may receive significant amounts of pre-transplant immunosuppression (PTI), which could increase the risk for development of malignancy post-transplant. METHODS: We conducted a single-center, retrospective study of kidney transplant recipients from January 2005 until May 2020. Patients with GN as their native kidney disease who received PTI for treatment of GN (n = 184) were compared with a control cohort (n = 579) of non-diabetic, non-PTI-receiving kidney transplant patients. We calculated hazard ratios (HR) with 95% confidence intervals (95% CI) for outcomes of first occurrence of solid or hematologic malignancy, non-melanoma skin cancer (NMSC) and post-transplant lymphoproliferative disorder (PTLD). RESULTS: Over a median follow-up of 5.7 years, PTI for GN was associated with significantly increased risk for malignancy compared with controls [13.0%  vs 9.7%, respectively; adjusted HR 1.82 (95% CI 1.10-3.00)], but not for NMSC [10.3% vs 11.4%, respectively; adjusted HR 1.09 (95% CI 0.64-1.83)] or PTLD [3.3% vs 3.1%, respectively; adjusted HR 1.02 (95% CI 0.40-2.61)]. The risk for malignancy was significantly increased in those who received cyclophosphamide [HR 2.59 (95% CI 1.48-4.55)] or rituximab [HR 3.82 (95% CI 1.69-8.65)] pre-transplant, and particularly in those who received both cyclophosphamide and rituximab, but not for calcineurin inhibitors or mycophenolate. CONCLUSION: The use of PTI for treatment of GN, especially cyclophosphamide or even with rituximab, is associated with increased risk for development of solid or hematologic malignancy post-transplant. These data highlight potential risks with treatment of GN and underscore the importance of post-transplant malignancy surveillance in this patient population.

Five-year Outcomes of Pulmonary Hypertension With and Without Elevated Left Atrial Pressure in Patients Evaluated for Kidney Transplantation.

BACKGROUND: Pulmonary hypertension (PH) is frequently reported in patients with advanced chronic kidney disease and is associated with early allograft failure and death. However, the causes of PH are heterogeneous, and patient prognosis may vary by etiologic subtype. METHODS: Data from the University of North Carolina Cardiorenal Registry were examined to determine associations between PH, with or without elevated left atrial pressure (eLAP), and mortality in candidates for kidney transplantation. PH and eLAP were determined by Doppler echocardiography and by tissue Doppler imaging, respectively. RESULTS: From 2006 to 2013, 778 registry patients were screened preoperatively by echocardiography. Most patients were black (64%) and men (56%); the mean age was 56 years. PH was identified in 97 (12%) patients; of these, eLAP was prevalent in half. During a median follow-up of 4.4 years, 179 (23%) received a kidney transplant, and 195 (25%) died. After adjustments for demographics, comorbidities, dialysis vintage, and kidney transplantation, PH was associated with twice the 5-year mortality (hazard ratio [HR] = 2.11; 95% confidence interval [CI]: 1.48-3.03), with stronger associations in the absence of eLAP (HR = 2.87; 95% CI: 1.83-4.49) than with eLAP (HR = 1.11; 95% CI: 0.57-2.17), P for interaction = 0.01. CONCLUSIONS: The mortality risk associated with PH among patients with advanced chronic kidney disease appears to differ by etiology. Patients with PH in the absence of eLAP are at high risk of death and in need of focused attention. Future research efforts should investigate potential strategies to improve outcomes for these patients.

Mechanical Anisotropy Assessment in Kidney Cortex Using ARFI Peak Displacement: Preclinical Validation and Pilot In Vivo Clinical Results in Kidney Allografts.

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of mechanical anisotropy in the kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate the clinical feasibility of acoustic radiation force (ARF)-induced peak displacement (PD) measures for both exploiting and obviating mechanical anisotropy in the cortex of human kidney allografts, in vivo. Validation of the imaging methods is provided by preclinical studies in pig kidneys, in which ARF-induced PD values were significantly higher ( , Wilcoxon) when the transducer executing asymmetric ARF was oriented across versus along the nephrons. The ratio of these PD values obtained with the transducer oriented across versus along the nephrons strongly linearly correlated ( R2 = 0.95 ) to the ratio of shear moduli measured by shear wave elasticity imaging. On the contrary, when a symmetric ARF was implemented, no significant difference in PD was observed ( p > 0.01 ). Similar results were demonstrated in vivo in the kidney allografts of 14 patients. The symmetric ARF produced PD measures with no significant difference ( p > 0.01 ) between along versus across alignments, but the asymmetric ARF yielded PD ratios that remained constant over a six-month observation period post-transplantation, consistent with stable serum creatinine level and urine protein-to-creatinine ratio in the same patient population ( p > 0.01 ). The results of this pilot in vivo clinical study suggest the feasibility of 1) implementing symmetrical ARF to obviate mechanical anisotropy in the kidney cortex when anisotropy is a confounding factor and 2) implementing asymmetric ARF to exploit mechanical anisotropy when mechanical anisotropy is a potentially relevant biomarker.

Longitudinal Self-Management and/or Transition Readiness per the TRxANSITION Index among Patients with Chronic Conditions in Pediatric or Adult Care Settings.

OBJECTIVE: To evaluate the roles of key individual, family, and illness characteristics on the levels of and gains in longitudinal healthcare transition (HCT) readiness in the pediatric setting and/or self-management skills (SMS) in the adult-focused setting, we used a large dataset with longitudinal measurements from 2006 to 2015. STUDY DESIGN: This longitudinal observational study followed 566 adolescents and young adults with chronic conditions at University of North Carolina Hospitals. TRxANSITION Index measurements, which represent learning outcomes rather than health outcomes, were collected multiple times per patient and analyzed using a novel application of an education-based approach. RESULTS: Levels of and gains in HCT/SMS scores increased with age (P < .001) with smaller increases at older ages. Mastery of skills varied by age with self-management achieved after 20 years of age. Scores varied positively by father's education and negatively by mother's education and duration of diagnosis. Gains in scores further varied positively with private insurance and negatively with mother's education and duration of diagnosis. CONCLUSIONS: We found diminishing positive increases in HCT/SMS scores as patients become older and smaller levels of and gains in readiness among younger patients with more educated mothers. Risk factors for absolute level of HCT/SMS readiness and inadequate longitudinal gains are not always the same, which motivates a deeper understanding of this dynamic process through additional research. This information can guide providers to focus HCT/SMS preparation efforts on skills mastered at particular ages and to identify patients at risk for inadequate development of HCT/SMS skills.

Evaluating Renal Transplant Status Using Viscoelastic Response (VisR) Ultrasound.

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p <0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics.

Renal Survival in Patients with Collapsing Compared with Not Otherwise Specified FSGS.

BACKGROUND AND OBJECTIVES: Idiopathic collapsing FSGS has historically been associated with poor renal outcomes. Minimal clinical data exist on the efficacy of immunosuppressive therapy. Our study sought to provide a comprehensive description of renal survival in patients with collapsing and not otherwise specified FSGS after controlling for factors affecting renal prognosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective analysis of an inception cohort study of patients diagnosed between 1989 and 2012. All potential patients with collapsing FSGS fulfilling the inclusion criteria were identified and compared with patients with not otherwise specified FSGS (approximately 1:2 ratio) on the basis of biopsy report and record availability. Time to ESRD was analyzed using Cox proportional hazards models. RESULTS: In total, 187 patients were studied (61 collapsing and 126 not otherwise specified), with a mean follow-up of 96 months. At baseline, patients with collapsing FSGS had higher median proteinuria (12.2 [5.6-14.8] versus 4.4 [2.3-8.1] g/d, respectively; P<0.001), lower median albuminemia (2.4 [1.9-3.0] versus 2.9 [1.8-3.7] g/dl, respectively; P=0.12), and lower median eGFR (48 [26-73] versus 60 [42-92] ml/min per 1.73 m2, respectively; P=0.01) than patients with not otherwise specified FSGS. The proportion of patients with remission of proteinuria was similar in patients with collapsing FSGS and patients with not otherwise specified FSGS (65.7% [23 of 35] versus 63.2% [72 of 114], respectively; P=0.84). The overall renal outcome (ESRD defined as eGFR<15 ml/min per 1.73 m2, dialysis, or transplantation) of patients with collapsing FSGS was not poorer than that of patients with not otherwise specified FSGS in multivariate analyses after adjusting for baseline characteristics and immunotherapy (hazard ratio, 1.78; 95% confidence interval, 0.92 to 3.45). CONCLUSIONS: Compared with not otherwise specified FSGS, idiopathic collapsing FSGS presented with more severe nephrotic syndrome and lower eGFR but had a similar renal survival after controlling for exposure to immunosuppressive treatment. These results highlight the importance of early diagnosis and institution of immunosuppressive therapy in patients with collapsing FSGS.

Ecological Factors Predict Transition Readiness/Self-Management in Youth With Chronic Conditions.

PURPOSE: Health care transition readiness or self-management among adolescents and young adults (AYA) with chronic conditions may be influenced by factors related to their surrounding environment. METHODS: Study participants were AYA diagnosed with a chronic condition and evaluated at pediatric- and adult-focused subspecialty clinics at the University of North Carolina Hospital Systems. All participants were administered a provider-administered self-management/transition-readiness tool, the UNC TRxANSITION Scale. Geographic area and associated characteristics (ecological factors) were identified for each participant's ZIP code using the published U.S. Census data. The Level 1 model of the hierarchical linear regression used individual-level predictors of transition readiness/self-management. The Level 2 model incorporated the ecological factors. RESULTS: We enrolled 511 AYA with different chronic conditions aged 12-31 years with the following characteristics: mean age of 20± 4 years, 45% white, 42% black, and 54% female. Participants represented 214 ZIP codes in or around North Carolina, USA. The Level 1 model showed that age, gender, and race were significant predictors of transition readiness/self-management. On adding the ecological factors in the Level 2 model, race was no longer significant. Participants from a geographic area with a greater percentage of females (ß = .114, p = .005) and a higher median income (ß = .126, p = .002) had greater overall transition readiness. Ecological factors also predicted subdomains of transition readiness/self-management. CONCLUSIONS: In this cohort of adolescents and young adults with different chronic conditions, ecological disparities such as sex composition, median income, and language predict self-management/transition readiness. It is important to take ecological risk factors into consideration when preparing patients for health self-management or transition.

Con: Weight loss prior to transplant: no.

In large registries of hemodialysis patients, higher body mass index (BMI) is known to be associated with lower mortality rates, while weight loss associates with reduced survival. This so-called 'obesity paradox' includes patients categorized as overweight and obese. Transplantation in the obese patient population has been shown to improve quality of life and reduce mortality when compared with obese recipient candidates remaining on dialysis. Most transplant centers, however, restrict access to transplant based upon predetermined BMI cutoffs. This policy effectively mandates weight loss for many obese transplant candidates. However, BMI, though easily measured, is an inadequate assessment of nutritional status and lean muscle mass in obese patients. Regimens designed to prevent protein-energy wasting may include dietary recommendations and exercise programs that result in favorable changes in body composition without significantly impacting weight. The goal of weight loss is not achievable for many if not most obese dialysis patients. The consequence to the patient is reduced access to life improving transplantation. Patients are forced to pursue dietary, behavioral and possibly surgical interventions to accomplish weight loss despite limited evidence regarding the safety and utility of these interventions. The delay in transplantation also hinders the achievement of improved exercise capacity after successful transplant, a time when weight loss regimens may be safer and more effective.

Pretransplantation erythropoiesis-stimulating agent hyporesponsiveness is associated with increased kidney allograft failure and mortality.

BACKGROUND: Poor response to erythropoiesis-stimulating agents (ESA) is associated with morbidity and mortality among dialysis patients. It is unclear whether the risk associated with poor ESA response during dialysis extends beyond kidney transplantation. We examined pretransplantation ESA response and its effect on allograft failure and mortality. METHODS: The cohort included all adult Medicare recipients from the U.S. Renal Data System who had received a kidney transplant during years 2000 to 2007 and had at least 6 months of hemodialysis immediately before transplantation. ESA hyporesponsiveness was primarily defined as a monthly ESA dose of 75,000 units or higher and hematocrit 33% or less for at least 3 consecutive months in the pretransplantation period. Crude and adjusted Cox proportional hazards models and Kaplan-Meier methods were used to estimate the effect of ESA hyporesponsiveness on allograft failure and all-cause mortality. RESULTS: The study group consisted of 36,450 patients; 1004 exhibited hyporesponsiveness. The adjusted hazard ratios (95% confidence interval) for allograft failure and mortality after transplantation were 1.23 (1.10-1.42) and 1.61 (1.43-1.81), respectively, supporting that poor ESA response during hemodialysis is associated with adverse posttransplantation outcomes. CONCLUSIONS: ESA hyporesponsiveness may be useful in identifying potential allograft recipients who are at high risk for subsequent morbidity and mortality and may benefit from more intensive pretransplantation and posttransplantation monitoring.

High prevalence of unlabeled chronic kidney disease among inpatients at a tertiary-care hospital.

BACKGROUND: Although awareness of chronic kidney disease (CKD) is low in outpatient settings, the prevalence of unrecognized CKD in the inpatient setting is unknown. METHODS: We examined the extent of unlabeled CKD among adults admitted to a tertiary-care hospital in North Carolina, based upon a combination of web-based medical record review, chart review, ICD-9 codes and laboratory information from 2000 to 2005. RESULTS: A total of 9772 patients had 2 or more serum creatinine measures at least 6 months apart and demographic variables for race and sex; 431 met criteria for stage 5 CKD (estimated glomerular filtration rate<15 mL/min/1.73 m2) and 6851 patients had stage 2 to 4 CKD (estimated glomerular filtration rate between 15 and 89 mL/min/1.73 m2). Within the latter groups, 3002 had stage 3 to 4 CKD, and 3849 had stage 2 CKD. Forty-three percent were male, 37% had a minority race/ethnicity. The number of patients not labeled as having CKD by ICD-9 code was 2176 (72.5%). Women and whites were less likely than men and minorities to be labeled as having CKD by ICD-9 codes. Medical record review of 600 randomly selected patients identified 399 patients with stage 3 or 4 CKD diagnosis. ICD-9 codes had a sensitivity of 0.50, specificity of 0.88, and positive predictive value of 0.39. CONCLUSIONS: A large proportion of individuals with CKD are going unrecognized in the hospital setting. Automatic laboratory reporting of GFR and education about CKD may help increase awareness in both the inpatient settings.

Bone morphogenetic protein 7 (BMP7): a critical role in kidney development and a putative modulator of kidney injury.

Bone morphogenetic protein 7 (BMP7), a member of the tumor growth factor beta superfamily, appears to have a role in both kidney development and response to kidney injury. Signals through its pathways permit both epithelial differentiation during embryogenesis and preservation of normal kidney architecture after stress, leading to the hypothesis that BMP7 may exert its kidney-protective effects in adult animals by preventing or reversing epithelial-to-mesenchymal transformation. This review attempts to synthesize the data supporting those conclusions and suggest some future areas of research.