Outcomes With Belatacept Exposure During Pregnancy in Kidney Transplant Recipients: A Case Series.

BACKGROUND: Posttransplant fertility returns quickly, and female recipients of child-bearing age may conceive while on immunosuppression. However, pregnancy after transplantation confers risks to the recipient, transplant, and fetus, including gestational hypertension, preeclampsia, gestational diabetes, transplant dysfunction, preterm labor, and low birthweight infants. Additionally, mycophenolic acid (MPA) products are teratogenic. Literature evidence regarding belatacept, a selective T-cell costimulation blocker, during pregnancy and while breastfeeding is extremely limited. When female transplant recipients on a belatacept-based regimen are desirous of pregnancy or at the time of conception, transplant providers manage the immunosuppression regimen in 1 of 2 ways: (1) switch both belatacept and MPA to a calcineurin inhibitor-based regimen with or without azathioprine, which is the more common practice but requires several modifications, having potential negative outcomes; or (2) only switch MPA to azathioprine while continuing belatacept. METHODS: This case series includes 16 pregnancies in 12 recipients with exposure to belatacept throughout pregnancy and while breastfeeding. Patient information was obtained from several sources, including Transplant Pregnancy Registry International, providers at Emory University, and Columbia University, as well as literature review. RESULTS: Pregnancy outcomes included 13 live births and 3 miscarriages. No birth defects or fetal deaths were reported in any of the live births. Seven infants were breastfed while their mothers continued belatacept. Outcomes appear comparable to those documented with the administration of calcineurin inhibitors. CONCLUSIONS: This case series provides data supporting the continued administration of belatacept during pregnancy. Additional research will assist in developing better guidelines to counsel female transplant recipients on belatacept desiring to pursue pregnancy.

Belatacept during pregnancy in renal transplant recipients: Two case reports.

Impaired fertility is common among patients with chronic organ failure, including end-stage renal disease (ESRD). Women of childbearing age undergoing transplantation may experience rapid return of fertility. Pregnancy posttransplant presents numerous risks for the patient, fetus, and allograft. Maternal risks include hypertension and preeclampsia. Allograft risks include acute rejection and failure of the organ, and fetal risks include miscarriage, birth defects from immunosuppressants, premature delivery, and low birth weight. Belatacept, a selective T cell costimulation blocker, was approved for use in kidney transplant recipients in the United States in 2011. Little is known about the safety of belatacept during pregnancy in humans. We describe 2 cases of successful pregnancy and delivery with the use of belatacept-based immunosuppression. The Transplant Pregnancy Registry International (TPR) is a voluntary registry for transplant recipients who have had pregnancies or fathered a pregnancy posttransplant. To date, these 2 cases are the only known exposures to belatacept that have been reported to the TPR.

Use of High-Flow Continuous Renal Replacement Therapy with Citrate Anticoagulation to Control Intracranial Pressure by Maintaining Hypernatremia in a Patient with Acute Brain Injury and Renal Failure.

Traumatic brain injury and intracranial hypertension often require treatment to optimize patient outcome. There are a variety of complex medical conditions that can preclude standard approaches to the treatment of intracranial hypertension. We describe a case where a novel approach using continuous dialysis with trisodium citrate was used to optimize the outcome of a young male with acute renal failure and acute respiratory distress syndrome in the setting of acute traumatic brain injury.

Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, double-blinded, randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVES: BK virus reactivation in kidney transplant recipients can lead to progressive allograft injury. Reduction of immunosuppression remains the cornerstone of treatment for active BK infection. Fluoroquinolone antibiotics are known to have in vitro antiviral properties, but the evidence for their use in patients with BK viremia is inconclusive. The objective of the study was to determine the efficacy of levofloxacin in the treatment of BK viremia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Enrollment in this prospective, multicenter, double-blinded, placebo-controlled trial occurred from July 2009 to March 2012. Thirty-nine kidney transplant recipients with BK viremia were randomly assigned to receive levofloxacin, 500 mg daily, or placebo for 30 days. Immunosuppression in all patients was adjusted on the basis of standard clinical practices at each institution. Plasma BK viral load and serum creatinine were measured monthly for 3 months and at 6 months. RESULTS: At the 3-month follow-up, the percentage reductions in BK viral load were 70.3% and 69.1% in the levofloxacin group and the placebo group, respectively (P=0.93). The percentage reductions in BK viral load were also equivalent at 1 month (58% versus and 67.1%; P=0.47) and 6 months (82.1% versus 90.5%; P=0.38). Linear regression analysis of serum creatinine versus time showed no difference in allograft function between the two study groups during the follow-up period. CONCLUSIONS: A 30-day course of levofloxacin does not significantly improve BK viral load reduction or allograft function when used in addition to overall reduction of immunosuppression.

Managing dialysis patients who develop anemia caused by chronic kidney disease: focus on peginesatide.

Anemia in chronic kidney disease is a prevalent and expensive problem in the United States, and it is well documented that anemia worsens as glomerular filtration rates decline. The complications of severe anemia in this patient population contribute significantly to their overall morbidity with increased cardiovascular complications, decreased quality of life, and increased dependence on transfusions to maintain adequate hemoglobin levels. Erythropoietin-stimulating agents (ESAs) have revolutionized the treatment of anemia in this population, but there has been a great deal of controversy surrounding the quest for the ideal hemoglobin target. In addition, there are economic and practice management implications where anemia treatment is concerned, with ongoing refinement of Centers for Medicare and Medicaid Services-bundled payments. One of the newest additions to the arsenal used to fight anemia in end-stage renal disease patients is peginesatide (Omontys), a synthetic, PEGylated, peptide-based ESA that acts by stimulating the erythropoietin receptor. The role of peginesatide in the future treatment of anemia in chronic kidney disease remains uncertain, with new safety concerns being brought to attention as it emerges on the market, prompting a national recall.

Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients.

In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.

Preventing harm during treatment of acute kidney injury: what do we really know?

Acute kidney injury (AKI) affects approximately 5% of all hospitalized patients, and its incidence continues to increase. The treatment of AKI involves tremendous financial costs, estimated to exceed $10 billion in the United States annually. Although our understanding of the pathophysiology of AKI has progressed at a tremendous pace, mortality remains high at 50% to 80%, with no improvement during the past several decades. More questions than answers currently exist regarding the optimal dialysis dose, optimal modality, and optimal timing of the initiation of renal replacement therapy in the setting of AKI, making it particularly difficult for the practicing clinician to both optimize treatment and practice cost-effective medicine. This article will review current evidence and concerns regarding these issues and identify areas of future research.

Alemtuzumab as compared to alternative contemporary induction regimens.

Between 1 January 2002 and 31 December 2007, our center performed 1687 adult renal transplants. A retrospective analysis was performed to compare outcomes between patients receiving alemtuzumab (n = 632) and those receiving either basiliximab (n = 690) or thymoglobulin (n = 125). Patients receiving alemtuzumab were younger (49 vs. 51 years, P = 0.02), had fewer HLA matches (1.7 vs. 2.0, P < 0.0001), were more likely to have a cytomegalovirus (CMV) donor(+)/recipient(-) transplant (22% vs. 17%, P = 0.03) and were less likely to receive a living donor allograft (32% vs. 37%, P = 0.04). Alemtuzumab recipients were less likely to receive tacrolimus (35% vs. 47%, P < 0.0001). The 1-, 3-, and 5-year cumulative incidence of antibody-mediated rejection (AMR) in alemtuzumab-treated patients was 19%, 24%, and 27%, vs. 11%, 15%, and 18% for the other group (P < 0.0001). The 1-, 3-, and 5-year allograft survival in the alemtuzumab group was 88%, 75%, and 67%, vs. 91%, 82%, and 74% for the other group (P < 0.0001). Patient survival was equivalent. Alemtuzumab was an independent risk factor for living donor allograft loss (HR 2.0, P = 0.004), opportunistic infections (HR 1.3, P = 0.01), CMV infections (HR 1.6, P = 0.001), and AMR (HR 1.5, P = 0.002). The significantly worse graft survival in the alemtuzumab cohort may be due to the increased rates of AMR and infectious complications.

Pretransplant immune regulation predicts allograft outcome: bidirectional regulation correlates with excellent renal transplant function in living-related donor-recipient pairs.

BACKGROUND: Tolerance to noninherited maternal antigens has provided clinical advantage when kidney transplants are exchanged between siblings but not when mother herself is the donor. This paradox prompted us to revisit the "two-way" hypothesis of transplant tolerance--that the immune status of both the organ recipient and the organ donor critically influences allograft outcome. METHODS: We obtained peripheral blood monocyte cells from 29 living donor-recipient pairs before transplant and used the trans-vivo-delayed type hypersensitivity assay to measure immune regulation in both the recipient antidonor and donor antirecipient directions. RESULTS: We found preexisting bidirectional regulation in all human leukocyte antigen (HLA)-identical sibling pairs tested (7/7), and one half (9/18) of the HLA haploidentical pairs. No significant regulation was found in four control living unrelated and two HLA haploidentical living-related donor recipient pairs, whereas unidirectional regulation was found in the remaining seven haploidentical pairs. Of the nine HLA haploidentical transplants with unidirectional or no pretransplant regulation, seven had an acute rejection episode and four of these experienced graft loss. In contrast, of the nine HLA haploidentical transplants with bidirectional regulation, only one had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years posttransplant. Significantly (P<0.05) lower mean serum creatinine values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (P<0.005) and 36 months (P<0.0001). CONCLUSIONS: Contrary to the belief that only the recipient's immune status matters, the data indicate that pretransplant immune status of both donor and recipient influence posttransplant outcome.

Review of the mechanism and nutrition recommendations for patients undergoing continuous renal replacement therapy.

Continuous renal replacement therapy (CRRT) is a common treatment modality in the intensive care unit for patients with acute kidney injury requiring renal replacement therapy. It offers hemodynamic stability while maintaining excellent control of solute and extracellular fluid. To those outside of nephrology, continuous dialysis is often a confusing and poorly understood form of renal replacement therapy. This review aims to provide an overview of CRRT as well as address some of the nutrition concerns surrounding this complex group of patients.

Factors affecting employment at initiation of dialysis.

BACKGROUND AND OBJECTIVES: Half the individuals who reach ESRD are working age (< 65 years old) and many are at risk for job loss. Factors that contribute to job retention among working-age patients with chronic kidney disease before ESRD are unknown. The purpose of the study is to understand factors associated with maintaining employment among working-age patients with advanced kidney failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective study we reviewed the United States Renal Data System database (1992 through 2003) and selected all patients (n = 102,104) who were working age and employed 6 months before dialysis initiation. Factors that were examined for an association with maintaining employment status included demographics, comorbid conditions, ESRD cause, insurance, predialysis erythropoietin use, and dialysis modality. RESULTS: Maintaining employment at the same level during the final 6 months before dialysis was more likely among (1) white men ages 30 to 49 years; (2) patients with either glomerulonephritis, cystic, or urologic causes of renal failure; (3) patients choosing peritoneal dialysis for their first treatment; (4) those with employer group or other health plans; and (5) erythropoietin usage before ESRD. Maintaining employment status was less likely among patients with congestive heart failure, cardiovascular disease, cancer, and other chronic illnesses. CONCLUSIONS: The rate of unemployment in working-age patients with chronic kidney disease and ESRD is high compared with that of the general population. Treating anemia with erythropoietin before kidney failure and educating patients about work-friendly home dialysis options might improve job retention.

Post-transplant DSA monitoring may predict antibody-mediated rejection in sensitized kidney transplant recipients.

We examined whether changes in posttransplant highest intensity donor specific anti-HLA antibody specificity (DSAmax) measured by single antigen bead via Luminex (One Lambda, Inc.) were associated with antibody-mediated rejection (AMR). We conducted a retrospective analysis examining risk factors for AMR in 116 consecutive patients who underwent desensitization between 1/1/2009 and 9/1/2010. All patients had a negative flow cytometry crossmatch. The mean patient age at transplant was 46.4 +/- 4 years. The mean peak PRA (panel reactive antibody) and DSAmax at transplant were 40 +/- 6% and 894 +/- 150 mean fluorescent intensity (MFI), respectively. The mean time to rejection was 1.5 +/- 0.4 months. Cox regression analyses demonstrated that an increase in DSAmax by one week after transplant was significantly associated with AMR (pure or mixed). A rise in DSAmax greater than 500 MFI at 1 week was associated with a 2.6 times greater risk of rejection (HR 2.6, 95% CI 1.1 - 6.3, p = 0.02). We conclude that a rise in DSAmax at one week is an independent risk factor forAMR and that posttransplant DSA monitoring strategies may reduce the risk of AMR in sensitized patients.

One-year serum albumin is an independent predictor of outcomes in kidney transplant recipients.

OBJECTIVE: This research study was conducted to investigate whether serum albumin levels predict allograft/patient outcomes in the new era of transplant medicine and immunology. METHODS: The association of 1-year post-transplant serum albumin, and patient and graft outcomes was retrospectively analyzed in 500 kidney transplant recipients between 1998 and 2005. Albumin was used as a categorical and a continuous variable in univariate and multivariate Cox regression and Kaplan-Meier survival analyses. RESULTS: The average (±SE) age at transplant was 47 ± 12 years. Patients were followed up for 63.4 ± 28 months after transplant. There were 56 graft losses and 38 patient deaths. In univariate analysis, the following variables were associated with the composite endpoint of patient death or allograft loss: 1-year serum albumin (hazard ratio [HR] = 0.52, P = .0009), 1-year serum albumin <4.0 g/dL (HR = 1.81, P = .02), 1-year serum creatinine (HR = 3.55, P < .00001), angiotensin converting enzyme inhibitors or angiotensin receptor blockers use (HR = 1.61, P = .03), a history of previous transplant (HR = 1.54, P = .04), months of dialysis before transplant (HR = 1.01, P = .00003), type of transplant (deceased donor HR = 1.64, P = .02), and acute rejection (HR = 1.52, P = .0000003). Of these, multivariable Cox regression analyses retained 1-year serum albumin (HR = 1.4, P < .0001), serum creatinine (HR = 2.7, P < .0001), and acute rejection (HR = 1.7, P = .02) as significant predictors of patient/graft loss. CONCLUSION: One-year serum albumin is an independent predictor of poor outcomes in the contemporary era of transplant medicine and immunosuppression. Further studies are needed to separate the role of this biomarker in inflammation and nutrition in kidney transplant recipients.

Pretransplant donor-specific antibodies detected by single-antigen bead flow cytometry are associated with inferior kidney transplant outcomes.

BACKGROUND: The clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single-antigen bead flow cytometry (SAB-FC) remains unclear. METHODS: To investigate the impact that pre-Tx DSAs detected by SAB-FC have on early clinical outcomes, we tested pre-Tx sera from all consecutive deceased-donor kidney transplants performed between January 2005 and July 2006 (n=237). RESULTS: In the study population of which 66% had a high-immunologic risk, mean fluorescence intensity (MFI) more than or equal to 100 for class I and more than or equal to 200 for class II were the lowest DSA thresholds associated with inferior antibody-mediated rejection-free graft survival (75% vs. 90%, P=0.004 and 76% vs. 87%, P=0.017, respectively). The hazard ratio for antibody-mediated rejection increased linearly with higher class II DSA from MFI 100 to 800 (1.7[0.8-3.2], P=0.1 for MFI ≥100 vs. 4.7[2.4-8.8], P<0.001 for MFI ≥ 800). Differences in graft function were only evident in patients with class II MFI more than or equal to 500 (estimated glomerular filtration rate: 47.6 vs. 54.3, P=0.02 and proteinuria: 0.6 ± 0.6 vs. 0.4 ± 0.3, P=0.03). A difference in death-censored graft survival was detected in patients with class II MFI more than or equal to 1000 (75% vs. 91.9%, P=0.055). CONCLUSION: High-pre-Tx DSAs detected by SAB-FC are associated with incrementally poor graft outcomes in deceased-donor kidney transplant with high-immunologic risk.

Concentrated heparin lock is associated with major bleeding complications after tunneled hemodialysis catheter placement.

Vascular access complications, including thrombosis, are associated with significant patient morbidity and mortality. Currently, up to 60% of new patients and 30% of prevalent patients are using a catheter for dialysis. To prevent interdialytic catheter thrombosis, these devices are routinely locked with concentrated heparin solutions. Several recent studies have elucidated the potential for abnormal coagulation markers (aPTT) that may arise from this practice. This abnormal elevation in aPTT may be explained by significant early and late leakage from the catheter that occurs after performing a catheter lock. To date no study has evaluated the impact of this practice, or the elevation in aPTT that may result from it, on bleeding complication rates. We conducted a retrospective analysis comparing bleeding rates in subjects who received concentrated heparin catheter lock (5000 u/cc) [group 1, n = 52] to those who received citrate or dilute heparin catheter lock (1000 u/cc) [group 2, n = 91] immediately after tunneled hemodialysis catheter insertion. Baseline characteristics did not differ between the groups except for the preprocedure INR, which was higher in the postpolicy group compared with the prepolicy group (1.29 vs. 1.21, p = 0.04). Results from logistic regression analyses revealed that the likelihood of a composite bleeding event in group 1 was 11.9 times that of a composite bleeding event in group 2, p = 0.04. Concentrated heparin (5000 u/ml) is associated with increased major bleeding complications posttunneled catheter placement compared with low-dose heparin (1000 u/ml) or citrate catheter lock solution, p = 0.02. Given the findings of this study, a randomized controlled trial comparing the safety and efficacy of common anticoagulation lock solutions is warranted.

Medical care of kidney transplant recipients after the first posttransplant year.

Kidney transplantation is the treatment of choice for patients with ESRD. Despite improvements in short-term patient and graft outcomes, there has been no major improvement in long-term outcomes. The use of kidney allografts from expanded-criteria donors, polyoma virus nephropathy, underimmunosuppression, and incomplete functional recovery after rejection episodes may play a role in the lack of improvement in long-term outcomes. Other factors, including cardiovascular disease, infections, and malignancies, also shorten patient survival and therefore reduce the functional life of an allograft. There is a need for interventions that improve long-term outcomes in kidney transplant recipients. These patients are a unique subset of patients with chronic kidney disease. Therefore, interventions need to address disease progression, comorbid conditions, and patient mortality through a multifaceted approach. The Kidney Disease Outcomes Quality Initiative from the National Kidney Foundation, the European Best Practice Guidelines, and the forthcoming Kidney Disease: Improving Global Outcomes clinical practice guidelines can serve as a cornerstone of this approach. The unique aspects of chronic kidney disease in the transplant recipient require the integration of specific transplant-oriented problems into this care schema and a concrete partnership among transplant centers, community nephrologists, and primary care physicians. This article reviews the contemporary aspects of care for these patients.

Sudden late onset of gross hematuria in a previous renal transplant recipient 3 months after transplant nephrectomy.

Causes of gross hematuria in a patient with end-stage renal disease are limited compared with those in patients with normal renal function. Given the increased likelihood of patients with end-stage renal disease developing renal cell carcinoma, the workup focuses on a careful evaluation of the collecting system. The workup for gross hematuria in a renal transplant recipient is similar; however, the focus shifts toward a more thorough evaluation of the transplanted kidney and bladder because immunosuppression increases the overall risk for malignancy. An immunosuppressed patient also is at risk for infectious processes in the transplanted kidney manifesting as gross hematuria. Concerns for chronic rejection also should be investigated, although microscopic hematuria is more common in this scenario. If this is unrevealing, then close scrutiny of the native kidneys for possible sources of bleeding is warranted. We present an interesting and unusual cause of painless gross hematuria in a patient with end-stage renal disease and transplant nephrectomy 3 months before the onset of bleeding.

Assessment of acute renal transplant rejection with blood oxygen level-dependent MR imaging: initial experience.

PURPOSE: To prospectively assess the oxygenation state of renal transplants and determine the feasibility of using blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging to differentiate between acute tubular necrosis (ATN), acute rejection, and normal function. MATERIALS AND METHODS: This HIPAA-compliant study had institutional human subjects review committee approval, and written informed consent was obtained from all patients. BOLD MR imaging was performed in 20 patients (age range, 21-70 years) who had recently received renal transplants. Six patients had clinically normal functioning transplants, eight had biopsy-proved rejection, and six had biopsy-proved ATN. R2* (1/sec) measurements were obtained in the medulla and cortex of transplanted kidneys. R2* is a measure of the rate of signal loss in a specific region and is related to the amount of deoxyhemoglobin present. Statistical analysis was performed by using a two-sample t test. Threshold R2* values were identified to discriminate between transplanted kidneys with ATN, those with acute rejection, and those with normal function. RESULTS: R2* values for the medulla were significantly lower in the acute rejection group (R2* = 15.8/sec +/- 1.5) than in normally functioning transplants (R2* = 23.9/sec +/- 3.2) and transplants with ATN (R2* = 21.3/sec +/- 1.9). The differences between the acute rejection and normal function groups (P = .001), as well as between the acute rejection and ATN groups (P < .001), were significant. Acute rejection could be differentiated from normal function and ATN in all cases by using a threshold R2* value of 18/sec. R2* values for the cortex were higher in ATN (R2* = 14.2/sec +/- 1.4) than for normally functioning transplants (R2* = 12.7/sec +/- 1.6) and transplants with rejection (R2* = 12.4/sec +/- 1.2). The difference in R2* values in the cortex between ATN and rejection was statistically significant (P = .034), although there was no threshold value that enabled differentiation of all cases of ATN from cases of normal function or acute rejection. CONCLUSION: R2* measurements in the medullary regions of transplanted kidneys with acute rejection were significantly lower than those in normally functioning transplants or transplants with ATN. These results suggest that marked changes in intrarenal oxygenation occur during acute transplant rejection.

Epithelial cell polarity and improved early outcomes in delayed graft function: a pilot study of polyclonal vs monoclonal antibodies.

BACKGROUND: Polyclonal antibody preparations contain antibodies that bind not only to molecules on circulating lymphocytes but also to other sites that bear similar antigens. We hypothesized that this extra-antibody effect would increase the number of intact tubular epithelial cells in organs at high risk for delayed graft function (DGF). METHODS: We used immunohistochemistry to examine serial biopsy samples (time 0 and 7-10 days after transplantation) in 18 kidney transplant recipients with DGF. These individuals received either polyclonal rabbit antithymocyte sera or a monoclonal humanized anti-CD25 antibody as induction immunosuppression. We also examined their early clinical course over 6 months. RESULTS: Individuals treated with the polyclonal preparation demonstrated greater preservation of kidney epithelial cell polarity manifested by more intense and more localized basolateral distribution of E-cadherin (P = 0.016), beta-catenin (P = 0.008) and Na-K ATPase (P = 0.02). These individuals were also more likely to maintain greater estimated glomerular filtration rates (eGFRs) at follow-up than patients treated with an anti-CD25 monoclonal antibody (6 month eGFR polyclonal: 55.5+/-7.12 ml/min vs monoclonal: 43.33+/-6.48 ml/min; P = 0.002). CONCLUSION: Though a pilot study, these data suggest that a purified polyclonal antibody preparation may help conserve functional kidney mass during DGF with potential benefits on transplant function overall.