Progressive decline of function in renal allografts with normal 1-year biopsies: Gene expression studies fail to identify a classifier.

Histologic findings on 1-year biopsies such as inflammation with fibrosis and transplant glomerulopathy predict renal allograft loss by 5 years. However, almost half of the patients with graft loss have a 1-year biopsy that is either normal or has only interstitial fibrosis. The goal of this study was to determine if there was a gene expression profile in these relatively normal 1-year biopsies that predicted subsequent decline in renal function. Using transcriptome microarrays we measured intragraft mRNA levels in a retrospective Discovery cohort (170 patients with a normal/minimal fibrosis 1-year biopsy, 54 with progressive decline in function/graft loss and 116 with stable function) and developed a nested 10-fold cross-validated gene classifier that predicted progressive decline in renal function (positive predictive value = 38 ± 34%%; negative predictive value = 73 ± 30%, c-statistic = .59). In a prospective, multicenter Validation cohort (270 patients with Normal/Interstitial Fibrosis [IF]), the classifier had a 20% positive predictive value, 85% negative predictive value and .58 c-statistic. Importantly, the majority of patients with graft loss in the prospective study had 1-year biopsies scored as Normal or IF. We conclude predicting graft loss in many renal allograft recipients (i.e., those with a relatively normal 1-year biopsy and eGFR > 40) remains difficult.

Utilization and Cost Analysis of Lung Transplantation and Survival After 10 Years of Adapting the Lung Allocation Score.

BACKGROUND: Lungs are allocated in the United States using the lung allocation score (LAS). We investigated the effect of LAS trends on lung transplant-related costs, healthcare utilization, and mortality. METHODS: Utilization data from Mayo Clinic (Florida and Minnesota) from 2005 to 2015 were obtained from the electronic health records (N = 465). Costs were categorized as 1-year posttransplant or transplant episode and standardized using 2015 Medicare reimbursement and cost-to-charge ratios. Regression analysis was used to assess the relationship of LAS to length of stay (LOS), mortality, and cost of transplant. RESULTS: The mean LAS at transplant increased from 45.7 to 58.3 during the study period, whereas the 1-year survival improved from 88.1% to 92.5% (P < 0.0001). The proportion of patients transplanted with LAS of 60 or greater increased from 16.9% to 33.3%. Posttransplant, overall, and intensive care unit LOS increased with increasing LAS. Patients with higher LAS had substantially higher transplant episode costs. An increase of LAS at transplant by 10 points increased inflation-adjusted costs by 12.0% (95% confidence interval, 9.3%-14.5%). CONCLUSIONS: The mean LAS at transplant has significantly increased over time associated with increases in LOS, resource utilization and cost. Lung allocation score has not jeopardized overall survival, but a high LAS (>60) at transplant is associated with increased mortality.

Feasibility, Safety, and Tolerance of Mesenchymal Stem Cell Therapy for Obstructive Chronic Lung Allograft Dysfunction.

Feasibility, tolerance, and safety of intravenous infusions of allogeneic mesenchymal stem cell (MSC) therapy in lung transplant recipients with bronchiolitis obliterans syndrome (BOS) are not well established. MSCs were manufactured, cryopreserved, transported to our facility, thawed, and infused into nine recipients with moderate BOS (average drop in forced expiratory volume in 1 second was 56.8% ± 3.2% from post-transplant peak) who were refractory to standard therapy and not candidates for retransplant. Cells were viable and sterile prior to infusion. Patients received a single infusion of either 1 (n = 3), 2 (n = 3), or 4 (n = 3) million MSCs per kg. Patients were medically evaluated before; during; and at 24 hours, 1 week, and 1 month after infusion for evidence of infusion-related adverse events and tolerance of therapy. Vital signs, pulmonary function test results, Borg Dyspnea Index, and routine laboratory data were recorded. Vital signs and O2 saturation did not significantly change during or up to 2 hours after MSC infusion. There were no significant changes in gas exchange variables, pulmonary function test results, or laboratory values at 1, 7, and 30 days postinfusion compared with preinfusion values. Infusion of MSCs in patients with BOS was feasible, safe, and well tolerated and did not produce any significant adverse changes in clinical, functional, or laboratory variables during or up to 30 days after infusion. Manufacturing, transport, and administration of intravenous, allogeneic bone marrow-derived MSCs in doses from 1 to 4 million MSCs per kg is safe in lung transplant recipients with BOS. Stem Cells Translational Medicine 2018;7:161-167.

Prognostic factors in kidney transplantation in the septuagenarian: a multicenter analysis.

Kidney transplant (KT) programs have extended recipient eligibility to those who were previously excluded due to advanced age. We aimed to determine the outcomes of the patients ≥70 years undergoing KT and investigate factors predicting survival. Two thousand six hundred and twenty-four KT patients between 2003 and 2013 at two institutions were divided into two groups; those ≥70 years (n=300) and those <70 years (n=2324) at the time of KT. Patient survival at 1, 3, and 5 years was 95%, 86%, and 77% in ≥70 years of age group and 98%, 95%, and 90% in the <70 years group (P<.001). When graft loss due to death was censored, graft survival was not significantly different between the two groups (P=.18). On multivariable analysis, the significant predictors of inferior survival in patients ≥70 years included: body mass index (BMI)>30 kg/m(2) (hazard ratio [HR] 1.07; P=.01), panel reactive antibody (PRA)>20% (HR 2.38; P=.01), previous coronary artery bypass grafting (CABG; HR 1.95; P=.03) and peripheral vascular disease (PVD; HR 2.60; P=.04). Acceptable outcomes can be achieved in KT recipients ≥70 years. Caution should be used when listing these patients if they have BMI>30 kg/m(2) , PRA>20%, CABG or PVD.

Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non-sensitized renal transplant patients treated with rapid steroid withdrawal.

Alemtuzumab and rabbit antithymocyte globulin (rATG) are commonly used for induction therapy in renal transplantation. This retrospective, single-center, cohort study evaluated cumulative incidence of one-yr biopsy-proven acute rejection (BPAR) among 200 consecutive primary non-sensitized kidney transplant recipients who received either alemtuzumab (n = 100) or rATG (n = 100) induction followed by rapid steroid taper, tacrolimus, and mycophenolate mofetil. Protocol biopsies, plasma and urine BK virus PCR, serum creatinine and iothalamate glomerular filtration rate (iGFR), were obtained at 1, 4, and 12 months from transplantation. The one-yr BPAR rates were similar between the alemtuzumab and rATG groups; however, rejection Banff IA and higher was more common in the alemtuzumab arm (18% vs. 5%, p = 0.047). After adjusting for confounding variables, alemtuzumab was still associated with Banff IA and higher rejection (adjusted OR: 3.7, CI: 1.2-10.5, p = 0.02). Despite similar rates of BK viremia, more patients in the alemtuzumab arm developed BK nephropathy (16% vs. 3%, p = 0.046). One-year iGFR (53.4 ± 20.2 vs. 71.9 ± 27.2 mL/min/1.73 m(2), p = 0.002) and three-yr graft survival (89.5% vs. 95%, p = 0.05) were lower in the alemtuzumab group. In low immunological risk kidney transplant recipients on steroid-free immunosuppression, alemtuzumab was associated with more severe rejection and BK nephropathy compared to rATG.

Renal outcomes of liver transplant recipients who had pretransplant kidney biopsy.

BACKGROUND: Kidney biopsy has been recommended to guide kidney allocation in selected liver transplant (LT) candidates with renal dysfunction. However, post-LT-alone renal outcomes in recipients who showed evidence of reversible renal injury and limited chronicity on pre-LT kidney biopsy are unclear. METHODS: Renal outcomes of 41 LT recipients who had pre-LT kidney biopsy for unexplained renal dysfunction, proteinuria, and hematuria were retrospectively reviewed. All biopsies showed less than 30% interstitial fibrosis and less than 30% to 40% glomerulosclerosis. Study endpoints were renal replacement therapy (RRT) at 1 month and the need for kidney transplantation at 1 year from LT. RESULTS: Six patients were on RRT at time of biopsy. Median (range) iothalamate glomerular filtration rate and 24-hr urinary protein excretion for the remaining 35 patients were 29 (6-88) mL/min per 1.73 m(2) and 65 (0-4,338) mg/day, respectively. Glomerulonephritis and acute tubular necrosis were present in 28 (68%) and 16 (39%) of the cases. Six patients (15%) did not recover kidney function at 1 month and RRT at time of LT was the only factor associated with this endpoint (P=0.04). Seven of the 31 (22%) patients with 1-year data met criteria for kidney transplantation within the first post-LT year. Surgical re-exploration was the only factor associated with the need for kidney transplantation at 1 year (P=0.05). CONCLUSIONS: The most LT recipients with minimal chronic changes on pre-LT kidney biopsy recovered kidney function within 1 month from LT. A small but significant percentage met criteria for kidney transplantation at 1 year because of the development of unforeseen post-LT complications.

Inferior long-term outcomes of liver-kidney transplantation using donation after cardiac death donors: single-center and organ procurement and transplantation network analyses.

Limited data are available for outcomes of simultaneous liver-kidney (SLK) transplantation using donation after cardiac death (DCD) donors. The outcomes of 12 DCD-SLK transplants and 54 SLK transplants using donation after brain death (DBD) donors were retrospectively compared. The baseline demographics were similar for the DCD-SLK and DBD-SLK groups except for the higher liver donor risk index for the DCD-SLK group (1.8 ± 0.4 versus 1.3 ± 0.4, P = 0.001). The rates of surgical complications and graft rejections within 1 year were comparable for the DCD-SLK and DBD-SLK groups. Delayed renal graft function was twice as common in the DCD-SLK group. At 1 year, the serum creatinine levels and the iothalamate glomerular filtration rates were similar for the groups. The patient, liver graft, and kidney graft survival rates at 1 year were comparable for the groups (83.3%, 75.0%, and 82.5% for the DCD-SLK group and 92.4%, 92.4%, and 92.6% for the DBD-SLK group, P = 0.3 for all). The DCD-SLK group had worse patient, liver graft, and kidney graft survival at 3 years (62.5%, 62.5%, and 58.9% versus 90.5%, 90.5%, and 90.6%, P = 0.03 for all) and at 5 years (62.5%, 62.5%, and 58.9% versus 87.4%, 87.4%, and 87.7%, P < 0.05 for all). An analysis of the Organ Procurement and Transplantation Network database showed inferior 1- and 5-year patient and graft survival rates for DCD-SLK patients versus DBD-SLK patients. In conclusion, despite comparable rates of surgical and medical complications and comparable kidney function at 1 year, DCD-SLK transplantation was associated with inferior long-term survival in comparison with DBD-SLK transplantation.

Validation of a pretransplant risk score for new-onset diabetes after kidney transplantation.

OBJECTIVE: Identification of patients at high risk for new-onset diabetes after kidney transplantation (NODAT) will facilitate clinical trials for its prevention. RESEARCH DESIGN AND METHODS: We previously described a pretransplant predictive risk model for NODAT using seven pretransplant variables (age, planned use of maintenance corticosteroids, prescription for gout medicine, BMI, fasting glucose, fasting triglycerides, and family history of diabetes). We have now applied the initial model to a cohort of 474 transplant recipients from another center for validation. We performed two analyses in the validation cohort. The first was a standard model with variables derived from the original study. The second was a summary score model, in which the sum of dichotomized variables (all the variables dichotomized at clinically relevant cut points) was used to categorize, individuals into low (0-1), intermediate (2, 3), or high (4-7) risk groups. We also conducted a combined database analyses, merging the initial and validation cohorts (n=792) to obtain better estimates for a prediction equation. RESULTS: Although the frequency of several risk factors differed significantly between the two cohorts, the models performed similarly in each cohort. Using the summary score model, incidences of NODAT in low-risk, medium-risk, and high-risk groups in the initial cohort were 12, 29, and 56%, and in the validation cohort incidences were 11, 29, and 51%. CONCLUSIONS: A pretransplant model for NODAT, including many type 2 diabetes risk factors, predicted NODAT in the validation cohort.

Comparison of kidney function between donation after cardiac death and donation after brain death kidney transplantation.

BACKGROUND: Kidney graft survival is comparable between donation after cardiac death (DCD) and donation after brain death (DBD) kidney transplantation. However, data concerning kidney function after DCD kidney transplantation are lacking. METHODS: We retrospectively compared kidney function between 64 DCD and 248 DBD kidney transplant recipients. Graft function was assessed using iothalamate glomerular filtration rate at 1, 4, and 12 months, then annually. The primary endpoint was the composite of death-censored graft loss or two consecutive iothalamate glomerular filtration rates less than 50 mL/min/1.73 m² occurring within 5 years from transplantation. Secondary endpoints included death and graft loss or death. RESULTS: Of the 312 patients, 102 (33%) experienced the primary endpoint, 78 (25%) experienced graft loss or death, and 44 (14%) died. In multivariable Cox regression analysis, there was no difference between DCD and DBD recipients regarding the primary endpoint (relative risk [RR], 1.16; P=0.59), death (RR, 0.97; P=0.94), or graft loss or death (RR, 1.09; P=0.79). In the subgroup of 64 DCD recipients, each 10-year increase in donor age was associated with increased risk of the primary endpoint (RR, 1.51; P=0.027) with the highest risk observed for donors older than 45 years (RR, 4.81; P=0.001). Delayed graft function affected 45% of the DCD recipients but had no impact on kidney function, graft survival, or patient survival. CONCLUSIONS: Posttransplantation kidney function is comparable between DCD and DBD kidney transplantations. In the subgroup of DCD recipients, kidneys from donors older than 45 years may be associated with a higher risk of poor kidney function; however, this finding requires validation in a larger patient group.

Hepatorenal syndrome in the intensive care unit.

Hepatorenal syndrome (HRS) is a functional form of acute kidney injury (AKI) associated with advanced liver cirrhosis or fulminant hepatic failure. Various new concepts have emerged since the initial diagnostic criteria and definition of HRS was initially published. These include better understanding of the pathophysiological mechanisms involved in HRS, identification of bacterial infection (especially spontaneous bacterial peritonitis) as the most important HRS-precipitating event, recognition that insufficient cardiac output plays a role in the occurrence of HRS, and evidence that renal failure reverses with pharmacotherapy. Patients with HRS are often critically ill and, by definition, have multiorgan failure. The purpose of this review is to provide an update on novel advances in HRS, with emphasis on the different aspects of management of these patients in the intensive care unit.

Formal quality improvement curriculum and DMAIC method results in interdisciplinary collaboration and process improvement in renal transplant patients.

BACKGROUND: Broad-based formal quality improvement curriculum emphasizing Six Sigma and the DMAIC approach developed by our institution is required for physicians in training. DMAIC methods evaluated the common outcome of postoperative hyponatremia, thus resulting in collaboration to prevent hyponatremia in the renal transplant population. METHODS: To define postoperative hyponatremia in renal transplant recipients, a project charter outlined project aims. To measure postoperative hyponatremia, serum sodium at admission and immediately postoperative were recorded by retrospective review of renal transplant recipient charts from June 29, 2010 to December 31, 2011. An Ishikawa diagram was generated to analyze potential causative factors. Interdisciplinary collaboration and hospital policy assessment determined necessary improvements to prevent hyponatremia. Continuous monitoring in control phase was performed by establishing the goal of <10% of transplant recipients with abnormal serum sodium annually through quarterly reduction of hyponatremia by 30% to reach this goal. RESULTS: Of 54 transplant recipients, postoperative hyponatremia occurred in 92.6% of patients. These potential causes were evaluated: 1) Hemodialysis was more common than peritoneal dialysis. 2) Alemtuzumab induction was more common than antithymocyte globulin. 3) A primary diagnosis of diabetes existed in 16 patients (30%). 4) Strikingly, 51 patients received 0.45% sodium chloride intraoperatively, suggesting this as the most likely cause of postoperative hyponatremia. A hospital policy change to administer 0.9% sodium chloride during renal transplantation resulted in normal serum sodium levels postoperatively in 59 of 64 patients (92.2%). CONCLUSION: The DMAIC approach and formal quality curriculum for trainees addresses core competencies by providing a framework for problem solving, interdisciplinary collaboration, and process improvement.

Proteinuria following sirolimus conversion is associated with deterioration of kidney function in liver transplant recipients.

BACKGROUND: The role of sirolimus (SRL) conversion in the preservation of kidney function in liver transplant (LT) recipients with calcineurin inhibitor (CNI) nephrotoxicity is unclear. METHODS: Data on 102 LT recipients with deteriorating kidney function after CNI exposure who were later converted to SRL were retrospectively reviewed. Kidney function was assessed using serum creatinine and estimated glomerular filtration rate (eGFR) at time of conversion and serially thereafter. The primary endpoint was stabilization or improvement of kidney function as assessed by eGFR at last recorded follow-up compared with eGFR at the time of conversion. RESULT: After a median (interquartile range) of 3.1 (1.6-4.5) years of follow-up, serum creatinine decreased from 1.9 ± 0.8 to 1.8 ± 0.7 mg/dL (P=0.25) and eGFR increased from 40.8 ± 16.7 to 44.3 ± 20.0 mL/min (P=0.03). During the same time period, 24-hr urinary protein excretion increased from median (interquartile range) of 72 (0-155) to 382 (169-999) mg/day (P=0.0001). Sixty-five (64%) patients achieved the primary endpoint and 37 (36%) experienced deterioration in kidney function. Independent predictors of deterioration of kidney function after SRL conversion were development of proteinuria ≥ 1000 mg/day (odds ratio [OR]: 3.3, confidence interval [CI]: 1.1-9.5 P=0.03), post-LT diabetes (OR: 4.2, CI: 1.6-11.1, P=0.004), and higher eGFR at time of conversion (OR: 1.6, CI: 1.2-2.2, P=0.003). CONCLUSION: Improvement or stabilization of kidney function occurred in the majority of LT recipients converted to SRL for CNI nephrotoxicity. Proteinuria ≥ 1000 mg/day, post-LT diabetes, and higher baseline eGFR were independent predictors of kidney function loss after SRL conversion.

The challenges of providing renal replacement therapy in decompensated liver cirrhosis.

Development of renal failure requiring renal replacement therapy (RRT) in the cirrhotic patient is a devastating complication. Survival without RRT is less than 10% on average at 6 months. However, it is now appreciated that all renal failure in this group of patients is not due solely to hepatorenal syndrome, and the cause of the renal failure affects the prognosis. This paper reviews the prognosis depending on cause and points out the difficulty in making the correct diagnosis. Provision of RRT is difficult in this group of patients due to hypotension and coagulopathy which is highly prevalent. Survival with RRT is still poor with only 30-60% of patients surviving to liver transplant. Provision of RRT should be offered as a bridge to patients awaiting liver transplant or those undergoing liver transplant evaluation. Provision of long-term RRT is usually not indicated in other cirrhotic patients who develop a need for RRT except as a trial to see if renal function will return. The decision between intermittent hemodialysis or continuous renal replacement therapy (CRRT) is usually based on the clinical characteristics of the patient. Neither has been demonstrated to be superior to the other, although CRRT may be better tolerated in the unstable patient. CRRT is clearly indicated in cases of fulminant hepatic failure as it does not raise intracranial pressure. Provision of intraoperative CRRT during liver transplant may be indicated to help control volume and electrolytes in those patients presenting for liver transplant with renal failure. Newer extracorporeal support systems, such as extracorporeal albumin dialysis (MARS) and fractional plasma separation and adsorption with hemodialysis (Prometheus), have recently been developed to provide both renal and liver support in this group of patients. These are still considered experimental, although the MARS system has been utilized to treat patients with hepatorenal syndrome, and is available outside the United States.

Impact of early conversion from tacrolimus to sirolimus on chronic allograft changes in kidney recipients on rapid steroid withdrawal.

BACKGROUND: Calcineurin-inhibitor therapy is a contributing factor to the origin of interstitial fibrosis and tubular atrophy (IFTA). METHODS: We conducted a prospective randomized trial of conversion of tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal. We compared the chronic changes (IFTA and sum of Banff chronic scores--Total Score) on protocol biopsies at 1 month, 1 year, and 2 years in all randomized patients. We compared the outcomes between treatment groups and analyzed the impact of previous rejection on the chronic changes. RESULTS: We randomized 122 patients, 62 to sirolimus and 60 to tacrolimus. The 1-year biopsy was performed in 54 patients (90%) of the tacrolimus group and 56 patients (90%) of the sirolimus group. The proportion of biopsies with IFTA more than or equal to 2 and the Total Score more than 2 increased over the 2 years but were not different between the study groups at any time point. On the 1-year biopsy, there was more IFTA, and the fraction with Total Score more than 2 was higher in the tacrolimus group with previous rejection. In the cohort without rejection, there was a significant progression of the IFTA and Total Score between 1 and 2 years in both the sirolimus and tacrolimus groups. CONCLUSION: Conversion from tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal does not decrease the progression of chronic changes on protocol biopsies during the first 2 years even in those patients without previous acute rejection.

Results of a prospective randomized trial of sirolimus conversion in kidney transplant recipients on early corticosteroid withdrawal.

BACKGROUND: The use of calcineurin inhibitors is associated with chronic nephrotoxicity and lower glomerular filtration rate (GFR). As a result, one strategy of transplant immunosuppression is calcineurin inhibitor elimination. METHODS: The aim of this study was to determine the outcome of a prospective randomized trial of kidney transplant recipients receiving rapid corticosteroid withdrawal, tacrolimus and mycophenolate mofetil (MMF) for 1 month followed by randomization to switch to sirolimus-MMF or to stay on tacrolimus-MMF. The primary outcome was the difference in measured GFR at 1 year using intention-to-treat analysis. RESULTS: Sixty patients were randomized to stay on tacrolimus-MMF and 62 to sirolimus-MMF. Actual graft survival (including death) at 2 years was 98.4% in the sirolimus group, 96.7% in the tacrolimus group. Sixty-three percentage of the patients in the sirolimus group withdrew during the 2-year period of the study compared with 18% of the tacrolimus group (P<0.0001), primarily related to rejection or medication side effects. Rejection during the first year occurred in 5% of the tacrolimus group and 13% of the sirolimus group (P=0.15). Measured GFR at 1 year (mean±SD) was 57.4±20.7 mL/min/1.73 m in the sirolimus group and 62.7±26.5 mL/min/1.73 m in the tacrolimus group (95% CI of difference -3.7-14.4). CONCLUSIONS: We conclude that conversion from tacrolimus-MMF to sirolimus-MMF at 1 month posttransplant in kidney recipients on rapid steroid withdrawal is poorly tolerated and does not improve GFR at 1 year.

Kidney transplantation after previous liver transplantation: analysis of the organ procurement transplant network database.

BACKGROUND: Patients after liver transplant have a high incidence of chronic kidney disease and end-stage renal disease (ESRD). We investigated kidney transplantation after liver transplantation using the Organ Procurement Transplant Network database. METHODS: The Organ Procurement Transplant Network database was queried for patients who received kidney transplantation after previous liver transplantation. These patients were compared with patients who received primary kidney transplantation alone during the same time period. RESULTS: Between 1997 and 2008, 157,086 primary kidney transplants were performed. Of these, 680 deceased donor kidney transplants and 410 living donor kidney transplants were performed in previous recipients of liver transplants. The number of kidney after liver transplants performed each year has increased from 37 per year to 124 per year in 2008. The time from liver transplant to kidney transplant increased from 8.2 to 9.0 years for living donor transplants and from 5.4 to 9.6 years for deceased donor. The 1, 3, and 5 year actuarial graft survival in both living donor kidney after liver transplant and deceased donor kidney after liver transplant are less than the kidney transplant alone patients. However, the death-censored graft survivals are equal. The patient survival is also less but is similar to what would be expected in liver transplant recipients who did not have ESRD. In 2008, kidney after liver transplantation represented 0.9% of the total kidney alone transplants performed in the United States. CONCLUSION: Kidney transplantation is an appropriate therapy for selected patients who develop ESRD after liver transplantation.