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Frailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear.Six hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models.Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR], 2.22; 95% confidence interval [CI], 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (PR, 3.22; 95% CI, 1.72-6.06), depressive symptoms (PR, 11.31; 95% CI, 4.02-31.82), less than a high school education (PR, 3.10; 95% CI, 1.30-7.36), and low HRQOL (fair/poor: PR, 3.71; 95% CI, 1.48-9.31). The most common pattern was poor grip strength, low physical activity, and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (hazards ratio = 2.43; 95% CI, 1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (hazard ratio, 2.61; 95% CI, 1.14-5.97) were at increased mortality risk.Age was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely, HRQOL, IADL disability, and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients.

Recent evidence suggests that living kidney donors are at an increased risk of end-stage renal disease. However, predicting which donors will have renal dysfunction remains challenging, particularly among those with no clinical evidence of disease at the time of donation. Although renal biopsies are not routinely performed as part of the donor evaluation process, they may yield valuable information that improves the ability to predict renal function in donors.We used implantation protocol biopsies to evaluate the association between histological abnormalities in the donated kidney and postdonation renal function (estimated glomerular filtration rate, eGFR) of the remaining kidney in living kidney donors. Longitudinal analysis using mixed-effects linear regression was used to account for multiple eGFR measures per donor.Among 310 donors between 1997 and 2012, median (IQR) follow-up was 6.2 (2.5-8.7; maximum 14.0) years. In this cohort, the overall prevalence of histological abnormalities was 65.8% (19.7% abnormal glomerulosclerosis, 23.9% abnormal interstitial fibrosis and tubular atrophy (IFTA), 4.8% abnormal mesangial matrix increase, 32.0% abnormal arteriolar hyalinosis, and 32.9% abnormal vascular intimal thickening). IFTA was associated with a 5-mL/min/1.73 m decrease of postdonation eGFR after adjusting for donor age at donation, sex, race, preoperative systolic blood pressure, preoperative eGFR, and time since donation (P0.01).In this single-center study, among healthy individuals cleared for living donation, IFTA was associated with decreased postdonation eGFR, whereas no other subclinical histological abnormalities provided additional information.

Human leukocyte antigen (HLA) sensitization presents a major obstacle for patients awaiting renal transplantation. HLA antibody reduction and favorable transplantation rates have been reported after treatment with high-dose intravenous immunoglobulin (IVIg).We enrolled 27 patients whose median flow cytometric calculated panel reactive antibody (CPRA) was 100% and mean wait-list time exceeded 4 years in a protocol whereby high-dose IVIg was administered, HLA antibody profiles of sera obtained before and after treatment were characterized, and cross-match tests were performed with all blood group identical kidney offers.Whereas 12.8% of a similarly sensitized historic control cohort underwent transplantation in the course of a year, 41% of the IVIg-treated group underwent transplantation during the study period. Surprisingly, HLA antibody profiles, measured by CPRA, showed no significant change in response to IVIg treatment. In fact, retrospective cross-match testing using pretreatment sera of those receiving deceased-donor allografts showed that all patients would have been eligible for transplantation with their respective donors before IVIg infusions.This study does not corroborate previous reports of CPRA reduction leading to increased deceased-donor transplantation rates in broadly sensitized patients undergoing desensitization with high-dose IVIg. The increased rate of transplantation relative to historic controls is not related to improved cross-match eligibility and likely resulted from frequent crossmatching using a cytotoxic strength threshold, improved medical readiness for transplantation, and newly recognized options for live-donor transplantation, all of which could have been achieved without IVIg treatment.

BACKGROUND Kidney transplants from pediatric donors after cardiac death (PDCD) have quadrupled in the past 9 years, but little data exist on outcomes using these donors. We hypothesized that pediatric organs might be more sensitive to the pathophysiology of cardiac death. METHODS We evaluated outcomes and rates of discard of more than 12,000 pediatric kidneys recovered between 2000 and 2009. We compared short- and long-term graft function among adult and pediatric recipients of PDCD kidneys compared with recipients of pediatric kidneys from donors after brain death (PDBD). RESULTS Overall, 6.3% of pediatric kidneys recovered were PDCD and 93.7% were PDBD. Discard rates were higher for PDCD kidneys (adjusted odds ratio=1.69, 95% confidence interval [CI]=1.31-2.18, P

Background Incompatible live donor kidney transplantation is associated with an increased rate of antibody-mediated rejection (AMR) and subsequent transplant glomerulopathy. For patients with severe, oliguric AMR, graft loss is inevitable without timely intervention. Methods We reviewed our experience rescuing kidney allografts with this severe AMR phenotype by using splenectomy alone (n=14), eculizumab alone (n=5), or splenectomy plus eculizumab (n=5), in addition to plasmapheresis. Results The study population was 267 consecutive patients with donor-specific antibody undergoing desensitization. In the first 3 weeks after transplantation (median=6 days), 24 patients developed sudden onset oliguria and rapidly rising serum creatinine with marked rebound of donor-specific antibody, and a biopsy that showed features of AMR. At a median follow-up of 533 days, 4 of 14 splenectomy-alone patients experienced graft loss (median=320 days), compared to four of five eculizumab-alone patients with graft failure (median=95 days). No patients treated with splenectomy plus eculizumab experienced graft loss. There was more chronic glomerulopathy in the splenectomy-alone and eculizumab-alone groups at 1 year, whereas splenectomy plus eculizumab patients had almost no transplant glomerulopathy. Conclusion These data suggest that for patients manifesting early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function.

Live donor kidney transplantation (LDKT) remains underutilized, partly resulting from the challenges many patients face in asking someone to donate. Actual and perceived kidney transplantation (KT) knowledge are potentially modifiable factors that may influence this process. Therefore, we sought to explore the relationships between these constructs and the pursuit of LDKT.We conducted a cross-sectional survey of transplant candidates at our center to assess actual KT knowledge (5-point assessment) and perceived KT knowledge (5-point Likert scale, collapsed empirically to 4 points); we also asked candidates if they had previously asked someone to donate. Associations between participant characteristics and having asked someone to donate were quantified using modified Poisson regression.Of 307 participants, 45.4% were female, 56.4% were non-white race, and 44.6% had previously asked someone to donate. In an adjusted model that included both actual and perceived knowledge, each unit increase in perceived knowledge was associated with 1.21-fold (95% CI: 1.03-1.43, P=0.02) higher likelihood of having asked someone to donate, whereas there was no statistically significant association with actual knowledge (RR=1.08 per unit increase, 95% CI: 0.99-1.18, P=0.10). A conditional forest analysis confirmed the importance of perceived but not actual knowledge in predicting the outcome.Our results suggest that perceived KT knowledge is more important to a patient's pursuit of LDKT than actual knowledge. Educational interventions that seek to increase patient KT knowledge should also focus on increasing confidence about this knowledge.

Background The transplantation of isolated hepatocytes in large animals, including nonhuman primates, must be evaluated before clinical trials are performed. However, in the absence of large transgenic animals and large-animal (as opposed to small-animal) models of genetic deficiencies, it is difficult to evaluate the fate of transplanted hepatocytes, their localization, survival, and function within the parenchyma of the host liver. In this work, we aimed to develop a technique for delivering hepatocytes to the liver of a nonhuman primate and to evaluate their localization and functionality in the short term. Methods A 20% hepatectomy was performed in 34 cynomolgus monkeys (Macaca fascicularis) and hepatocytes were isolated. Hepatocytes were labeled in vitro with a recombinant retrovirus expressing the beta-galactosidase gene and returned to the liver by infusion through a portal catheter left in place. Liver biopsies were performed 4 and 7 d after transplantation. Results Twenty-four monkeys underwent surgery to define the necessary technical adjustments and to optimize conditions. Six monkeys died. The whole protocol, including the transplantation of genetically marked hepatocytes and procurement of liver biopsies, was performed in the remaining 10 monkeys. In eight monkeys, transplanted hepatocytes expressing the beta-galactosidase gene were widely distributed in the portal tracts, sinusoids, and hepatocyte plates of the host liver 4 and 7 d after transplantation. Conclusions We have developed an experimental nonhuman primate model for the evaluation of hepatocyte transplantation. We demonstrated the engraftment and functioning of transplanted hepatocytes in the host liver 4 and 7 d after transplantation.

A patient with end-stage renal disease and known benign monoclonal gammopathy underwent kidney transplantation at Westchester County Medical Center, Valhalla, NY. After surgery, during routine follow-up, the patient had laboratory evidence of frank multiple myeloma. However, she did not show any clinical signs or symptoms of the disease. Four years later, the patient is asymptomatic and continues to have stable renal function. As a result of our experience, and that of others, we support transplantation as a viable option for patients with multiple myeloma.

International audience; BACKGROUND: Hepatocyte transplantation could be an alternative to whole liver transplantation for the treatment of metabolic liver diseases. However, the results of clinical investigations suggest that the number of engrafted hepatocytes was insufficient to correct metabolic disorders. This may partly result from a lack of proliferation of transplanted hepatocytes. In rodents, portal ligation enhances hepatocyte engraftment after transplantation. We investigated the effects of partial portal ligation and embolization on engraftment and proliferation of transplanted hepatocytes in primates. METHODS: Hepatocyte autotransplantation was performed in Macaca monkeys. The left lateral lobe was resected for hepatocyte isolation. The first group of monkeys underwent surgical ligation of the left and right anterior portal branches; in the second group, the same portal territories were obstructed by embolization with biological glue. To evaluate the proportion of cell engraftment hepatocytes were Hoechst-labeled and transplanted via the portal vein. Cell proliferation was measured by BrdU incorporation. RESULTS: Hepatocyte proliferation was induced by both procedures but it was significantly higher after partial portal embolization (23.5% and 11.2% of dividing hepatocytes on days 3 and 7) than after ligation (3% and 0.8%). Hepatocytes engrafted more efficiently after embolization than after ligation. They proliferated and participated to liver regeneration representing 10% of the liver mass on day seven and their number remained constant on day 15. CONCLUSIONS: These data suggest that partial portal embolization of the recipient liver improves engraftment of transplanted hepatocytes in a primate preclinical model providing a new strategy for hepatocyte transplantation.

Background. Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described. Methods. In 45 patients with serum creatinine more than 120 μmol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1–49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus ≤5 ng/mL, cyclosporin A ≤50 ng/mL) in 29 patients (18 patients without [group II] and 11 patients with [group III] previous refractory rejection [rejection after two episodes of treated rejection]). Results. In group I (median interval receiving MMF, 33 months), only one patient (6%) experienced cellular rejection, and serum creatinine normalized in five of eight patients long term. In group II (median follow-up 26.5 months), none of 18 experienced rejection, and serum creatinine normalized in 6 of 10 long term. In group III (median follow-up 34 months), 5 of 11 patients (45%) experienced further rejection, one was not steroid responsive, and serum creatinine normalized in four of eight patients long term. There was no graft loss or death as a result of rejection. Conclusions. Our cohort with prolonged follow-up showed significant improvement in renal function with both MMF monotherapy and in combination with low-dose CNI with minimal rejection (five of six steroid responsive) and no graft loss. MMF substitution is a therapeutic strategy that deserves more extensive use in liver transplantation.

The transplantation of isolated hepatocytes in large animals, including nonhuman primates, must be evaluated before clinical trials are performed. However, in the absence of large transgenic animals and large-animal (as opposed to small-animal) models of genetic deficiencies, it is difficult to evaluate the fate of transplanted hepatocytes, their localization, survival, and function within the parenchyma of the host liver. In this work, we aimed to develop a technique for delivering hepatocytes to the liver of a nonhuman primate and to evaluate their localization and functionality in the short term.A 20% hepatectomy was performed in 34 cynomolgus monkeys (Macaca fascicularis) and hepatocytes were isolated. Hepatocytes were labeled in vitro with a recombinant retrovirus expressing the beta-galactosidase gene and returned to the liver by infusion through a portal catheter left in place. Liver biopsies were performed 4 and 7 d after transplantation.Twenty-four monkeys underwent surgery to define the necessary technical adjustments and to optimize conditions. Six monkeys died. The whole protocol, including the transplantation of genetically marked hepatocytes and procurement of liver biopsies, was performed in the remaining 10 monkeys. In eight monkeys, transplanted hepatocytes expressing the beta-galactosidase gene were widely distributed in the portal tracts, sinusoids, and hepatocyte plates of the host liver 4 and 7 d after transplantation.We have developed an experimental nonhuman primate model for the evaluation of hepatocyte transplantation. We demonstrated the engraftment and functioning of transplanted hepatocytes in the host liver 4 and 7 d after transplantation.

A mouse monoclonal antibody, specific for binding with the epithelial surface antigen in human renal proximal tubules, was produced by hybridoma culture. Using this antibody, an enzyme-linked immunosorbent assay was developed to measure the human renal tubular epithelial antigen (HRTE) concentrations in serum samples from 25 normal subjects and 66 consecutive renal allograft recipients. In 46 patients treated with azathioprine and prednisone, serum HRTE was elevated more than two-fold in 56 of 62 rejection episodes 2-5 days before the clinical diagnosis was made. Of the 56 rejection episodes, the antigen level fell to baseline after treatment in 44 steroid-responsive episodes, but it remained elevated in 8 steroid-resistant rejections, and it became undetectable 3-4 days after the initial elevation in 4 episodes in which allografts were lost to rejection. In 20 patients treated with cyclosporine and prednisone, all 25 rejection episodes demonstrated a greater than two-fold increase of serum HRTE 1-6 days prior to the diagnosis of rejection. The antigen level fell to baseline in 23 reversible rejection episodes, however serum HRTE remained elevated in 2 steroid-resistant patients whose grafts were lost to rejection. Cyclosporine nephrotoxicity without rejection was confirmed in 6 episodes, each of which demonstrated a more than two-fold increase in HRTE 2-4 days before toxicity was diagnosed. When the cyclosporine dose was reduced, the antigen level decreased as the serum creatinine declined. Serial determinations of serum HRTE in renal transplant recipients can provide valuable information for the early diagnosis and management of allograft rejection and cyclosporine nephrotoxicity.

The development of erythrocytosis following renal transplantation has been reported to be caused by a number of factors. These include acute and chronic rejection, hydronephrosis and renal artery stenosis. In this study, seven patients were noted to have erythrocytosis with hematocrits ranging between 53.5 and 66%. Serum erythropoietin levels were elevated and ranged between 11 and 60 mU/ml with a mean of 31.9 mU/ml in six of seven patients. Selective catheterization of veins of native and transplanted kidneys in three patients revealed mean serum levels of 40.9 and 13.0 mU/ml, respectively. This suggests that excess erythropoietin is being produced from the diseased native kidneys. Bilateral nephrectomy in one patient cured erythrocytosis and dropped systemic levels of erythropoietin (EP) to 6.1 mU/ml. In four of the remaining five patients, hematocrits came down spontaneously to within normal over a 1- to 3-year period. Consequently, it appears that in a number of transplant patients the retained diseased kidneys, having lost all excretory and concentrating function, may remain capable of functioning as endocrine erythropoietin-producing organs.

A case report of marked peripheral blood eosinophilia and eosinophilic infiltration of a rejected renal allograft in a transplant recipient stimulated our review of the clinical course of 132 consecutive renal transplant recipients. A total of 187 acute rejections occurred in 112 patients. Diagnosis was made by renal biopsy in 124 cases. The percentage of eosinophils in the leukocyte differential of patients with irreversible rejection was 5.2 +/- 5.7 (mean +/- SD) versus that seen in patients with reversible rejection, 2.9 +/- 3.5 (P less than .05). The difference in the total eosinophil counts in each group was not statistically significant. Patients with peripheral blood eosinophil percentages greater than or equal to 4% had a 37.9% irreversible rejection rate, whereas those who had less than 4%, had a 22.4% loss rate (P less than .01). Six of seven patients with greater than or equal to 2% eosinophils in the inflammatory infiltrate of their renal allograft lost their kidney, whereas grafts with less than 2% eosinophils had a 36.8% loss rate (P less than .02). We conclude that the increased presence of eosinophils in the peripheral blood and/or renal allograft biopsy specimen is an adverse prognostic factor for acute rejection outcome.

The predictive value of peripheral blood T cell subset monitoring in renal allograft recipients has been questionable, and there has been no information concerning the correlation of T cell subset changes with the clinical event related to cyclosporine nephrotoxicity. This study was conducted to investigate the clinical usefulness of serial T cell subset monitoring in 34 consecutive renal transplant patients treated with cyclosporine by determining the total peripheral lymphocyte count and T cell subset counts using Leu-4, Leu-3ab, and Leu-2a monoclonal antibodies and flow cytometry up to 6 months after transplantation. The absolute counts of all cells were lower in transplanted patients than those of normal controls, but were not different from those of hemodialysis patients. During infection, the helper/suppressor (H/S) ratio and the cell counts, except for suppressor cells, decreased significantly. Within one week prior to rejection, all cell counts also decreased significantly. Furthermore, cell counts before steroid-resistant rejection were significantly lower than those before steroid-responsive rejection. In contrast, lymphocyte and T cell counts were increased significantly within one week prior to cyclosporine nephrotoxicity being diagnosed; the H/S ratio was not correlated with rejection or toxicity. These results indicate that H/S ratio is not associated with clinical events of renal allograft recipients, but serial lymphocyte and T cell subset counts can provide valuable information for the differentiation of rejection from cyclosporine nephrotoxicity, and also for predicting the outcome of the allograft rejection.

The development of erythrocytosis following renal transplantation has been reported to be caused by a number of factors. These include acute and chronic rejection, hydronephrosis and renal artery stenosis. In this study, seven patients were noted to have erythrocytosis with hematocrits ranging between 53.5 and 66%. Serum erythropoietin levels were elevated and ranged between 11 and 60 mU/ml with a mean of 31.9 mU/ml in six of seven patients. Selective catheterization of veins of native and transplanted kidneys in three patients revealed mean serum levels of 40.9 and 13.0 mU/ml, respectively. This suggests that excess erythropoietin is being produced from the diseased native kidneys. Bilateral nephrectomy in one patient cured erythrocytosis and dropped systemic levels of erythropoietin (EP) to 6.1 mU/ml. In four of the remaining five patients, hematocrits came down spontaneously to within normal over a 1- to 3-year period. Consequently, it appears that in a number of transplant patients the retained diseased kidneys, having lost all excretory and concentrating function, may remain capable of functioning as endocrine erythropoietin-producing organs.