Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant.

SIGNIFICANCE STATEMENT: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. BACKGROUND: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. METHODS: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. RESULTS: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. CONCLUSIONS: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT04294459 .

Association of Physical Function and Survival in Older-Adult Renal Transplant Recipients.

There is an increase in older-adult renal transplant recipients in United States. The objective of this study was to assess the association between physical function (PF) and patient survival in renal transplant recipients who are aged 65 years or older. Using United Network for Organ Sharing (UNOS) data from 2007 to 2016, renal transplant recipients aged 65 years or older were included. Multivariable Cox regression was used to assess associations between survival and functional status adjusted for age, sex, race, donor quality, diabetes, and dialysis vintage. The study identified 26,721 patients. Patient survival was significantly higher in recipients who needed no assistance and lowest in patients in need of total assistance (P < .0001). In deceased donor (DD) transplants, the relative risk for mortality was 2.06 (1.74-2.43) for total assistance and 1.17 (1.08-1.28) for moderate assistance compared to no assistance (P < .0001). In living donor (LD) transplants, the relative risk of mortality was 1.38 (0.78-2.42) for patients needing total assistance and 1.37 (1.14-1.65) for patients needing moderate assistance compared to patients who did not need assistance (0.003). PF is an independent predictor of post-transplant mortality. Assessment of older potential renal transplant recipients should include assessment and standardization of functional status to counsel about post-transplant survival.

Trends and outcomes in dual kidney transplantation- A narrative review.

Dual kidney transplantation (DKT) is a viable option to increase the donor pool and improve access equity to kidney transplantation. Dual kidneys are procured from carefully selected marginal donors that are not generally acceptable to most transplant centers. This is a narrative review of literature focusing on donor kidney allocation systems and selection of the ideal recipient for DKT. We also discussed surgical approaches for DKTs as well as patient and allograft outcomes. We found that most studies to date showed that DKTs has similar graft survival and delayed graft function rates when compared to single kidney transplants (SKTs). DKT is technically feasible with outcomes that are comparable to expanded criteria donor kidneys (ECD); and has substantial potential in expanding the donor pool. For allograft survival, most studies with strict allocation criteria showed that graft survival was similar in DKT as compared to SKT - ECD transplants.. Our review may encourage transplant centers to review their policies for donor and recipient selection leading to increase in DKT.

Impact of gender and gender disparities in patients with kidney disease.

PURPOSE OF REVIEW: Despite evidence of gender-specific differences in epidemiology and outcomes in all stages of chronic kidney disease (CKD), most studies ignore the issue of gender. This review addresses this knowledge gap by evaluating data on gender disparity in this population. RECENT FINDINGS: Population-based studies indicate a higher prevalence of CKD in women; however, there are fewer women on renal replacement therapy than men. Men may progress to end-stage kidney disease more rapidly. Gender differences in rates of CKD progression may be influenced by potential antifibrotic and antiapoptotic effects of estrogen or proinflammatory deleterious effects of testosterone. Women are referred later for kidney replacement therapy and receive fewer arteriovenous fistulas than men receive, irrespective of race. Women are also less likely to receive kidney transplants as compared with men but are more likely to donate a kidney. SUMMARY: Recommendations for medical management of CKD patients are currently made in a gender-blind manner, despite the fact that women have differing underlying physiology. Addressing gender differences and disparities is an important and overlooked area in the care of patients with kidney disease.

Use of Repository Corticotropin Gel (Acthar) in Progressive Nephrotic Syndrome Secondary to Transplant Glomerulopathy: A Report of Three Cases.

Transplant glomerulopathy is a feared complication of kidney transplantation, often resulting in rapid loss of kidney function and ultimate graft failure. The underlying cause is unclear, with both antibody and cell-mediated immune mechanisms postulated, as well as intrinsic glomerular factors. At the present time, there is no known therapy. We report here 3 cases in which corticotropin gel (Acthar) was used with varying response of proteinuria and stabilization of graft function with continued graft survival as long as 10 years following the diagnosis. Future randomized controlled trials are warranted to examine the efficacy and safety of ACTH gel therapy in nephrotic patients with transplant glomerulopathy.

Complementary and integrative medicine in kidney transplantation.

PURPOSE OF REVIEW: Complementary and integrative medicine (CIM) use is widely prevalent in kidney transplant recipients but studies of efficacy or potential harm are sparse. This review examines prevalence of use of CIM and discusses potential beneficial and harmful aspects of CIM in renal transplant recipients. RECENT FINDINGS: The prevalence of CIM use in kidney transplant patients varies from 12 to 45%. There is a knowledge gap regarding CIM modalities among healthcare professionals that may contribute to reluctance to discuss CIM use with patients. Patients often do not spontaneously disclose its use, and those that use it may be more likely to be nonadherent to allopathic therapies. Herbal supplements may be nephrotoxic or interact with pharmaceutical agents, including calcineurin inhibitors. More data are needed to assess the potential benefits of other modalities of CIM, including yoga, Tai Chi or meditation, as these modalities have been beneficial for people with diabetes or hypertension, both of which are common in the posttransplant period. SUMMARY: Despite a high prevalence of CIM use in kidney transplant recipients, data are limited regarding risks and benefits. Education of healthcare providers who care for kidney transplant recipients should be encouraged. Intervention studies should be designed to investigate the CIM modalities, including yoga, meditation and Tai Chi that have been shown to be beneficial in other chronic diseases.

Mortality in Living Kidney Donors With ESRD: A Propensity Score Analysis Using the United States Renal Data System.

INTRODUCTION: In recent years, data have emerged on the outcomes of living kidney donors who develop end-stage renal disease (ESRD). We aimed to evaluate mortality rates in kidney donors who had initiated dialysis compared with a propensity-matched cohort of dialysis patients without previous kidney donation. METHODS: We used the United States Renal Data System (USRDS) and abstracted 274 previous living kidney donors between 1995 and 2009. There were 609,398 individuals on dialysis without kidney donation. We used propensity score matching to identify 258 donors and 258 nondonors. The time-dependent Cox proportional hazards model was used to compare survival between the 2 matched cohorts. RESULTS: In the propensity score-matched cohort, mortality was lower in donors compared with nondonors (19% vs. 49%; P < 0.0001). The time-dependent Cox proportional hazards model demonstrated that donors had significantly lower mortality compared with nondonors 0 to 5 years since start of dialysis (hazard ratio [HR]: 0.17; 95% confidence interval [CI] 0.11-0.27; P < 0.0001) and with nondonors 5 to 10 years on dialysis (HR: 0.34; 95% CI: 0.19-0.63; P < 0.001). We were unable to estimate the difference between the 2 groups after 10 years on dialysis with any precision (HR: 0.51; 95% CI: 0.18-1.42; P = 0.20) due to the small sample size. CONCLUSION: We observed a lower mortality rate in living kidney donors with ESRD compared with matched nondonors. This data should guide clinicians in the informed consent process with prospective donors.

Gender disparity in fistula use at initiation of hemodialysis varies markedly across ESRD networks-Analysis of USRDS data.

BACKGROUND: Gender disparities had been noted in the care of women with end stage renal disease (ESRD) in the early 2000's, including less frequent initiation of hemodialysis utilizing a fistula but more recent data have not been examined and underlying factors have not been extensively studied. STUDY DESIGN: Data from the United States Renal Data System (USRDS) were examined, including 202,999 hemodialysis patients. Only those who had received prior nephrology care were included. Multiple logistic regression was used, adjusted for possible confounders, including age, race, cause of ESRD, BMI, height, history of alcohol or drug abuse, medical comorbidities, ability to ambulate, time of nephrology care, type of insurance, and ESRD network. RESULTS: The odds of arteriovenous fistula (AVF) use at initiation of hemodialysis were significantly lower in women compared to men (OR = 0.69, 95% CI 0.67-0.71, P < 0.0001). The gender gap in AVF use at initiation was highest in New York and the upper Midwest (networks 2 and12) and smallest for Southern California and the Pacific Northwest and Alaska (18 and 16). Gender disparity was more pronounced for black women, with odds ratios for AVF use at initiation of dialysis (OR = 0.66, 95% CI 0.62-0.69), P < 0.0001 as compared to non-black (OR 0.70, 95% CI 0.68-0.73), P ≤ 0.0001. LIMITATIONS: Limitations include use of USRDS data. Data misclassification or errors in data reporting may exist and certain comorbid conditions may be underreported. Data regarding rate of primary fistula non-function are also not available. CONCLUSION: Adjusted odds ratio for AVF use was significantly lower in women compared to men, independent of time of nephrology care and other predictors. The gender disparity was most pronounced for black women and also varied from 20% to 46% lower odds for AVF use in women for different ESRD networks, after controlling for possible confounding variables, suggesting that practice based factors may be of importance in explaining this important finding.

Association of restless legs syndrome and mortality in end-stage renal disease: an analysis of the United States Renal Data System (USRDS).

BACKGROUND: Objective of the study is to assess prevalence and survival among end stage renal disease patients with restless legs syndrome (RLS) within a national database (USRDS). METHODS: A case-control, retrospective analysis was performed. Differences in characteristics between the groups, RLS and those with no sleep disorder (NSD), were determined using χ2 tests. Cox proportional hazard regression was used to assess survival between those with RLS and propensity score matched controls. RESULTS: Cases of restless legs syndrome were defined as patients that had received an ICD-9 code of 333.94 at any point during their treatment (n = 372). RLS group demonstrated a significantly higher proportion of patients with major depressive disorder, dysthymic disorder, anxiety, depression, minor depressive disorder, and psychological disorder. The difference between the survival was not statistically significant in those without sleep disorder as compared to those with RLS (HR =1.16±0.14, p = 0.3). CONCLUSIONS: True prevalence of RLS in dialysis patients can only be estimated if knowledge gap for care providers in diagnosis of RLS is addressed. RLS patients also have increased incidence of certain psychological disorders which needs to be addressed.

Dialysis in the Elderly and Impact of Institutionalization in the United States Renal Data System.

BACKGROUND: We hypothesized that in the very elderly dialysis patients in the United States, institutionalization in nursing homes would increase mortality in addition to age alone. METHODS: Incident dialysis patients from 2001 to 2008 above the age of 70 were included. Patients above 70 were categorized into 4 groups according to age as 70-75, 76-80, 81-85, and >85 years and further divided into institutionalized and noninstitutionalized. Kaplan-Meier survival curves were plotted to assess patient survival. RESULTS: A total of 349,440 patients were identified above the age of 70 at the time of initiation of dialysis. For institutionalized patients, the mean survival was significantly lower, 1.71 ± 0.03 years for those in the age range 70-75, 1.44 ± 0.02 years for those in the age range 76-80, 1.25 ± 0.02 years for those in the age range 81-85, and 1.04 ± 0.02 for those in the >85 years age group (p = 0.0001). The hazard ratio for mortality in institutionalized elderly patients on dialysis was 1.80 ([95% CI 1.77-1.83]; p = 0.0001). After adjustment for other variables (multivariate Cox regression), to be institutionalized was still an independent risk factor for mortality (adjusted hazard ratio = 1.57 [95% CI 1.54-1.60]; p = 0.0001). CONCLUSION: There was increased mortality in institutionalized elderly patients as compared to noninstutionalized elderly patients in the same age group. In accordance with the increased frailty and decreased benefits of therapies in the very elderly, especially in those with additional co-morbidities besides age, palliative and end-of-life care should be considered.

Mortality after Renal Allograft Failure and Return to Dialysis.

INTRODUCTION: The outcomes of patients who fail their kidney transplant and return to dialysis (RTD) has not been investigated in a nationally representative sample. We hypothesized that variations in management of transplant chronic kidney disease stage 5 leading to kidney allograft failure (KAF) and RTD, such as access, nutrition, timing of dialysis, and anemia management predict long-term survival. METHODS: We used an incident cohort of patients from the United States Renal Data System who initiated hemodialysis between January 1, 2003 and December 31, 2008, after KAF. We used Cox regression analysis for statistical associations, with mortality as the primary outcome. RESULTS: We identified 5,077 RTD patients and followed them for a mean of 30.9 ± 22.6 months. Adjusting for all possible confounders at the time of RTD, the adjusted hazards ratio (AHR) for death was increased with lack of arteriovenous fistula at initiation of dialysis (AHR 1.22, 95% CI 1.02-1.46, p = 0.03), albumin <3.5 g/dL (AHR 1.33, 95% CI 1.18-1.49, p = 0.0001), and being underweight (AHR 1.30, 95% CI 1.07-1.58, p = 0.006). Hemoglobin <10 g/dL (AHR 0.96, 95% CI 0.86-1.06, p = 0.46), type of insurance, and zip code-based median household income were not associated with higher mortality. Glomerular filtration rate <10 mL/min/1.73 m2 at time of dialysis initiation (AHR 0.83, 95% CI 0.75-0.93, p = 0.001) was associated with reduction in mortality. CONCLUSIONS: Excess mortality risk observed in patients starting dialysis after KAF is multifactorial, including nutritional issues and vascular access. Adequate preparation of patients with failing kidney transplants prior to resuming dialysis may improve outcomes.

Standardised incidence ratios (SIRs) for cancer after renal transplant in systemic lupus erythematosus (SLE) and non-SLE recipients.

OBJECTIVE: We investigated malignancy risk after renal transplantation in patients with and without systemic lupus erythematosus (SLE). METHODS: Using the United States Renal Data System from 2001 to 2009, 143 652 renal transplant recipients with and without SLE contributed 585 420 patient-years of follow-up to determine incident cancers using Medicare claims codes. We calculated standardised incidence ratios (SIRs) of cancer by group using age, sex, race/ethnicity-specific and calendar year-specific cancer rates compared with the US population. RESULTS: 10 160 cancers occurred at least 3 months after renal transplant. Overall cancer risk was increased in both SLE and non-SLE groups compared with the US general population, SIR 3.5 (95% CI 2.1 to 5.7) and SIR 3.7 (95% CI 2.4 to 5.7), respectively. Lip/oropharyngeal, Kaposi, neuroendocrine, thyroid, renal, cervical, lymphoma, liver, colorectal and breast cancers were increased in both groups, whereas only melanoma was increased in SLE and lung cancer was increased in non-SLE. In Cox regression analysis, SLE status (HR 1.1, 95% CI 0.9 to 1.3) was not associated with increased risk of developing cancer, adjusted for other independent risk factors for developing cancer in renal transplant recipients. We found that smoking (HR 2.2, 95% CI 1.2 to 4.0), cytomegalovirus positivity at time of transplant (HR 1.3, 95% CI 1.2 to 1.4), white race (HR 1.2, 95% CI 1.2 to 1.3) and older recipient age at time of transplantation (HR 1.0 95% CI 1.0 to 1.2) were associated with an increased risk for development of cancer, whereas shorter time on dialysis, Epstein-Barr virus or HIV were associated with a lower risk for development of cancer. CONCLUSIONS: Cancer risk in renal transplant recipients appeared similar in SLE and non-SLE subjects, aside from melanoma. Renal transplant recipients may need targeted counselling regarding surveillance and modifiable risk factors.

Intravenous immunoglobulin in kidney transplantation.

PURPOSE OF REVIEW: Antibody-mediated injury of renal allografts has assumed increasing importance with the availability of potent immunosuppressants directed against T-lymphocytes. Intravenous immunoglobulin (IVIG) has been used for prevention and treatment of antibody-mediated rejection. The review summarizes recent advances that shed light on mechanisms of action of IVIG and outlines current roles of IVIG in kidney transplantation. RECENT FINDINGS: Observational studies support the use of IVIG for desensitization and treatment of acute rejection. Most studies are small and uncontrolled, but a matched case-control study reported a better survival with incompatible live-donor kidney transplant after desensitization using IVIG-containing regimens compared with dialysis or waiting for compatible transplant. Recent data indicate that variations in glycosylation and amino acid sequence cause the crystallizable fragment of immunoglobulin G to assume specific conformations that have high affinity for canonical crystallizable fragment receptors (FcR) or a newly discovered class of FcRs, labelled type II FcRs. Signaling through type II FcRs appears to trigger anti-inflammatory pathways. SUMMARY: Recent discoveries expand our understanding of the mechanism of action of IVIG. Future research is expected to clarify the relevance of these findings to humans and could lead to the development of novel immunomodulatory agents.

Poor kidney allograft survival associated with positive B cell - Only flow cytometry cross matches: a ten year single center study.

The presence of donor specific antibody (DSA) to class 1 or class 2 HLA as detected respectively in T cell or B cell - only flow cytometry cross matches (FCXMs) are risk factors for renal allograft survival, though the comparative risk of these XMs has not been definitively established. Allograft survival and FCXM data in 624 microcytotoxicity (CDC) XM negative kidney transplants were evaluated. Short and long term allograft survival was significantly less in recipients with T(-) B(+) FCXMs (1 year, 74%, 10 year, 58%) compared to T(+) B(+) FCXMs (1 year, 84%, 10 year, 68%) and to T(-) B(-) FCXM (1 year, 90%, 10 year, 85%). Risk factors were positive FCXM, deceased donor (DD) transplantation and donor age, but not race, gender, recipient age or previous transplant. Recipients with T(-) B(+) and T(+) B(+) FCXMs were at 4.5 and 2.5 fold greater risk, respectively, of DD allograft failure compared to patients with T(-) B(-) FCXMs. The quantitative value of FCXM did not correlate with the duration of graft survival. We conclude that patients with DSA to class 2 HLA have a greater risk of early and late allograft failure compared to patients with DSA to class 1 HLA.

Impact of renal posttransplantation amputation on allograft outcomes: a study of United States renal data system.

BACKGROUND: The prevalence of renal posttransplantation amputation and its impact on allograft and patient survival have not been widely reported. METHODS: We used an incident cohort of patients who underwent renal transplantation between June 2004 and September 2009. Amputation data were obtained using Medicare institutional claim forms. Baseline demographics and comorbidities, such as peripheral vascular disease (PVD), diabetes, ischemic heart disease, cerebrovascular disease, hypertension, and smoking, were captured. The chi-square and t tests were used for statistical associations. Kaplan-Meier survival curves were plotted for renal allograft and patient survival. Independent associations between patient factors and amputation were examined using multivariable Cox regression analysis. RESULTS: Of the 85,873 renal transplant recipients, 1062 patients had amputation. The prevalence of amputation was higher in those with PVD versus those without PVD at listing (5.6% vs. 1%; P=0.0001). Mean allograft survival was 55.5±0.55 months in patients with amputation versus 60.6±0.06 months in patients without amputation (P=0.0001). All-cause mortality was higher in patients with amputation versus those without amputation (19.9% vs. 7.3%; P=0.0001). Mean allograft survival was 60.97±0.67 months in non-African Americans without amputation versus 55.7±0.65 months in non-African Americans with amputation. Allograft survival was 59.73±0.13 months in African Americans without amputation versus 54.9±1.06 months in African Americans with amputation. In patients with amputation, race did not have any impact. Infectious complications were noted in 39 patients leading to death. CONCLUSIONS: Amputation is associated with decreased allograft and patient survival. Early detection and preventive strategies for PVD may decrease amputation rate and improve survival.

Effect of peripheral vascular disease on kidney allograft outcomes: a study of U.S. Renal data system.

BACKGROUND: The U.S. Renal Data System was used to analyze renal allograft outcomes in patients with peripheral vascular disease (PVD) at the time of transplant listing. METHODS: We used an incident cohort of patients who underwent renal transplantation between June 2004 and September 2009. We defined PVD as symptomatic PVD at wait-listing. Comorbid conditions were diabetes mellitus, ischemic heart disease, cerebrovascular disease, hypertension, and smoking. Chi-square test, Student's t test, and Cox regression were used for statistical associations. RESULTS: The mean graft survival was 55.3±0.40 months in patients with PVD versus 60.8±0.06 months in patients without PVD. There was an increased risk of graft failure with PVD (hazard ratio, 2.01; 95% confidence interval, 1.83-2.21; P=0.0001). After adjusting for other variables, PVD remained an independent risk factor for graft failure. Patients with PVD had lower death-censored graft survival versus patients without PVD at 1 year (93.3% vs. 96.6%), 2 years (89.7% vs. 95%), and 3 years (87.2% vs. 93.7%). All-cause mortality was higher in PVD versus without PVD (6.2% vs. 3.0%). In African Americans, the mean allograft survival was 54.8±0.98, months with PVD versus 59.7±0.135 months without PVD (P=0.0001). In non-African Americans, the mean allograft survival was 55.4±0.44 months with PVD versus 61.1±0.069 months without PVD (P=0.0001). There were no differences in survival between African Americans with PVD and non-African Americans with PVD. CONCLUSIONS: Patients with PVD have inferior allograft and patient survival versus those without PVD. Caution should be exercised when placing patients with symptomatic PVD or amputation on the wait-list.

Practice patterns in evaluation of living kidney donors in United Network for Organ Sharing-approved kidney transplant centers.

INTRODUCTION: The current pattern of evaluation for living kidney donors was investigated. METHODS: We designed a 37-question electronic survey to collect information about living kidney donor evaluation. Of the 181 United Network for Organ Sharing (UNOS)-approved centers, 72 responded. Survey responses were coded and downloaded into SPSS. Data was expressed as means and standard deviations or the percentage of centers with specific responses. RESULTS: 66% of the centers used a cut-off of <80 ml/min for exclusion of living kidney donors. 24-hour urine measuring creatinine clearance (CrCl) was the most common screening method for glomerular filtration rate (GFR) assessment in potential living donors. 56% of the centers excluded donors with blood pressure (BP) >140/90, whereas 22.7 and 7.1% excluded patients with pre-hypertension with a cut-off BP of 130/85 and 120/80, respectively. 66% of the centers used 24-hour urine creatinine to assess for proteinuria. 20% of the centers accepted living kidney donors with microalbuminuria and 84% accepted patients with a history of nephrolithiasis. 24% of the centers reported use of formal cognitive testing of potential living donors. DISCUSSION: There were significant variations in exclusion criteria based on GFR, history of kidney stones, body mass index, BP and donors with urinary abnormalities. The definitions for hematuria and proteinuria were variable. There is a need for uniformity in selection and for a living donor registry. We also recommend raising the cut-off for estimated GFR to 90 ml/min to account for 10-15% overestimation when CrCl is used.