Renal outcome after simultaneous heart and kidney transplantation

Simultaneous heart‐kidney transplant (HKTx) is a valid treatment for patients with coexisting heart and renal failure. The aim of this study was to assess renal outcome in HKTx and to identify predictive factors for renal loss. A retrospective study was conducted among 73 HKTx recipients: Donors’ and recipients' records were reviewed to evaluate patients’ and renal transplants’ survival and their prognostic factors. The mean follow‐up was 5.36 years. Renal primary non‐function occurred in 2.7%, and complications Clavien IIIb or higher were observed in 67.1% including 16 (22%) postoperative deaths. Five‐year overall survival and renal survival were 74.5% and 69.4%. Among survivors, seven returned to dialysis during follow‐up. The postoperative use of ECMO (HR = 6.04, P = 0.006), dialysis (HR = 1.04/day, P = 0.022), and occurrence of complications (HR = 31.79, P = 0.022) were independent predictors of postoperative mortality but not the history of previous HTx or KTx nor renal function prior to transplantation. History of KTx (HR = 2.52, P = 0.026) and increased delay between the two transplantations (HR = 1.25/hour, P = 0.018) were associated with renal transplant failure. HKTx provides good renal transplant survival and function, among survivors. Early mortality rate of 22% underlines the need to identify perioperative risk factors that would lead to more judicious and responsible allocation of a scarce resource.     

End-stage renal failure and cardiac mortality after heart transplantation

BACKGROUND: Coronary artery disease (CAD) is the leading cause of mortality after the first year of heart transplantation. End-stage renal failure (ESRF) is more frequent because of long-term survival. Impact of ESRF on cardiac mortality in heart transplant patients is unappreciated. The hypothesis of accelerated CAD in uremic patients has been suggested. METHODS: In Pitié La Salpêtrière hospital, 1211 heart transplants have been performed between 1982 and 2001. Thirty-three patients have reached ESRF. A case-control study was performed to identify risk factors responsible for ESRF and to appreciate the impact of ESRF on cardiac mortality. RESULTS: In cases at 6 months, serum creatinine tended to be higher (159 +/- 31 micromol/L vs. 141 +/- 44 micromol/L, p = 0.06) and cyclosporine (CSA) dosage (mg/kg) was significantly lower (5.4 +/- 1.8 mg/kg vs. 7.7 +/- 2.7 mg/ kg, p = 0.002). Mean triglyceride level after transplantation until dialysis was significantly lower in cases (2.18 +/- 0.82 mmol/L vs. 1.48 +/- 0.62 mmol/L, p = 0.002). In cases and controls, cardiac mortality was responsible for 67% (10 of 15) and 38% (three of eight) of all deaths, respectively. High triglyceride level (> or = 2 mmol/L) was associated with cardiac mortality [p < 0.03, hazard ratio (HR) = 3.89]. Kaplan Meier cardiac free survival rates were significantly lower in cases than in controls (p < 0.03). CONCLUSION: These data suggest that CSA nephrotoxicity could result from individually determined susceptibility and that hypertriglyceridemia may have a negative impact on renal function and cardiac mortality. The risk of cardiac mortality is increased in heart transplant patients with ESRF. The hypothesis of accelerated atherosclerosis in ESRF patients after heart transplantation leading to higher cardiac mortality incidence needs further study.     

Severe right heart failure after heart transplantation. A single-center experience

We reviewed our heart transplantation recipient population, using hard criteria defining severe right heart failure (RHF), and analyzed possible risk factors for outcome after RHF. Between 1983 and 1998 621 cardiac transplantations were performed at our institution. RHF was defined by the necessity to implant an assist device or echocardiographically confirmed right ventricular ballooning with concomitant end organ failure. RHF patients were compared with a matched control group. Thirty-five patients (5.9%) with severe RHF after transplantation fulfilled inclusion criteria. Of these, 32 patients died, while none of the control patients died (P < 0.001). Increased preoperative pulmonary capillary wedge (P = 0.005) and mean pulmonary artery pressure (P = 0.006) were identified as significant risk factors for severe RHF. Severe RHF as defined in our study is irreversible in almost every case without differences among therapeutical concepts. Hence, improvement of postoperative outcome necessitates avoidance or aggressive therapy of possible risk factors.     

Carvedilol improves functional class in patients with severe left ventricular dysfunction referred for heart transplantation

PURPOSE: Limited options are available to improve the functional class of patients awaiting cardiac transplantation. We assessed the effect of carvedilol on New York Heart Association (NYHA) class, heart rate (HR), blood pressure (BP), jugular venous pressure (JVP), electrolytes and renal function in patients with markedly decreased left ventricular (LV) function referred for cardiac transplantation assessment. METHODS: Sixty-one patients (age = 52 +/- 12 yr, EF = 23 +/- 7%, VO2 max = 16 +/- 5 mL/kg/min) referred to the cardiac transplant clinic were reviewed before and after the addition of carvedilol (starting dose 3.125 mg twice daily to target dose of 25 mg twice daily) to usual heart-failure therapy. Over a 1-yr period, at each visit prior to initiation, at baseline initiation visit and at each follow-up visit, NYHA class, BP, HR, JVP, electrolytes, and renal function were obtained. Statistical analysis was performed using random effects regression approach. A multiple logistic regression analysis was performed on 52/61 patients to determine possible associations between NYHA improvement and the following patient characteristics: sex, etiology of cardiomyopathy, initial NYHA class, and dose of carvedilol. RESULTS: Three patients died (2 after stopping carvedilol) and 3 were transplanted. Median follow-up was 100 d. Sixteen patients reached the target dose after a mean of 137 d (2.75 visits). Estimated time-to-target dose is 8 months (5.6 visits). BP tended to increase (p = 0.07 for change in trend) with no change in JVP, electrolytes or renal function. HR decreased 6 +/- 3 b.p.m. (p = 0.03). Of 14 patients NYHA class I/II at baseline, none were class III/IV at last follow-up visit. Of 47 patients NYHA class III/IV at baseline, 25 were class I/II, and 22 were class III/IV at last follow-up (p < 0.001). Multiple logistic regression analysis did not demonstrate any factor predictive of subsequent NYHA class improvement. CONCLUSIONS: Despite less than target doses in most patients, a favorable effect of carvedilol on functional class in patients with severe congestive heart failure (CHF) referred for transplant was observed. Those with good functional status remained stable and those with poor functional status improved or remained stable. No baseline patient characteristic predicted improvement. The shortage of donor organ requires optimal use of medical regimens which may improve functional class while awaiting transplantation and which may delay the necessity for heart transplantation. Therefore, addition of carvedilol to usual medical therapy may be beneficial even in patients with severe LV dysfunction and poor NYHA classification.     

Single‐center outcomes of combined heart and liver transplantation in the failing Fontan

Long‐term outcomes of the Fontan operation include Fontan failure and liver disease. Combined heart‐liver transplantation (CHLT) is an option for select patients although limited data exist on this strategy. A retrospective review of Fontan patients 18 years or older referred for cardiac transplant evaluation between 2000 and 2013 at the Hospital of the University of Pennsylvania was performed. All patients were considered for potential CHLT. Clinical variables such as demographics, perioperative factors, and short‐term outcomes were reviewed. Of 17 referrals for cardiac transplantation, seven Fontan patients underwent CHLT. All patients who underwent CHLT had either advanced fibrosis or cirrhosis on liver biopsy. There were no perioperative deaths. The most common postoperative morbidity was acute kidney injury. Short‐term complications include one episode of acute liver rejection but no cardiac rejection greater than 1R. CHLT is an acceptable therapeutic option for patients with failing Fontan physiology who exhibit concomitant advanced liver fibrosis. However, optimal patient selection is currently undefined, and long‐term outcomes are not known.     

Alterations in plasma L-arginine and methylarginines in heart failure and after heart transplantation

Objective. Endothelial function, including the nitric oxide (NO)-pathway, has previously been extensively investigated in heart failure (HF). In contrast, studies are lacking on the NO pathway after heart transplantation (HT). We therefore investigated substances in the NO pathway prior to and after HT in relation to hemodynamic parameters. Design. 12 patients (median age 50.0 yrs, 2 females), heart transplanted between June 2012 and February 2014, evaluated at our hemodynamic lab, at rest, prior to HT, as well as four weeks and six months after HT were included. All patients had normal left ventricular function post-operatively and none had post-operative pulmonary hypertension or acute cellular rejection requiring therapy at the evaluations. Plasma concentrations of ADMA, SDMA, L-Arginine, L-Ornithine and L-Citrulline were analyzed at each evaluation. Results. In comparison to controls, the plasma L-Arginine concentration was low and ADMA high in HF patients, resulting in low L-Arginine/ADMA-ratio pre-HT. Already four weeks after HT L-Arginine was normalized whereas ADMA remained high. Consequently the L-Arginine/ADMA-ratio improved, but did not normalize. The biomarkers remained unchanged at the six-month evaluation and the L-Arginine/ADMA-ratio correlated inversely to pulmonary vascular resistance (PVR) six months post-HT. Conclusions. Plasma L-Arginine concentrations normalize after HT. However, as ADMA is unchanged, the L-Arginine/ADMA-ratio remained low and correlated inversely to PVR. Together these findings suggest that (i) the L-Arginine/ADMA-ratio may be an indicator of pulmonary vascular tone after HT, and that (ii) NO-dependent endothelial function is partly restored after HT. Considering the good postoperative outcome, the biomarker levels may be considered “normal” after HT.     

Induction immunosuppression strategies and long-term outcomes after heart transplantation

Although the use of induction therapy has reduced the risk of acute rejection after heart transplantation, its use may be associated with other adverse outcomes. We aimed to examine the effect of no induction (NoInd), induction with basiliximab (BAS), or induction with antithymocyte globulin (ATG) on outcome after heart transplantation. We analyzed data from the International Society for Heart and Lung Transplantation (ISHLT) registry for adult heart transplants performed between 2000 and 2013. The primary outcome was cumulative all-cause mortality, and the secondary outcome was cause-specific death. We identified 27 369 transplants whose recipients received NoInd (n = 15 688), ATG (n = 6830), or BAS (n = 4851). Over a median follow-up of 1497 days, overall 30-day mortality was 5% and 1-year mortality was 11%. Survival after transplant was similar in patients treated with NoInd compared with ATG. The survival was improved using NoInd compared with BAS (log-rank P = .040), adjustment HR = 1.11 (95% CI, 1.04-1.19). Compared to NoInd, BAS was associated with higher risk of graft failure-related deaths, HR = 1.27 (95% CI, 1.02-1.58), and ATG was associated with higher risk of malignancy-related deaths, HR = 1.18 (95% CI, 1.01-1.39). Survival of patients who received NoInd was similar to ATG and better compared with BAS. Further, the use of ATG may be associated with increased malignancy-related mortality, compared with NoInd.     

Preoperative pulmonary hypertension and its impact on survival after heart transplantation

Objectives. Pulmonary hypertension (PH) due to left heart disease may impair outcome after heart transplantation (HT). To evaluate to what extent previous, and present, haemodynamic criteria discriminate the impact of pre-operative-PH on survival, we characterized the PH in our HT-patients according to ESC's guidelines, ISHLT's summary statement and ISHLT's relative contraindications and criteria for early risk of death after HT. Design. Records from the 215 HT-patients in Lund during 1988–2010 were reviewed. Subsequent analysis included adults (n = 94) evaluated with right-heart-catheterization at our lab, at rest before HT. End of follow-up was 30th of June 2012. Results. Survival (mean, n) did not differ (p = ns) for the 94 HT-patients; without (13.0 years, n = 28) or with (13.9 years, n = 66) PH, passive (13.8 years, n = 50) or reactive (12.2 years, n = 13) post-capillary-PH, “modified” passive (13.1 years, n = 40), mixed (16.6 years, n = 23), “modified” reactive (12.6 years, n = 7) or non-reactive (12.2 years, n = 8) post-capillary-PH; or for ISHLT's relative contraindications (12.0 years, n = 22) or increased risk of right-heart-failure and early death (16.5 years, n = 23) after HT. Conclusions. As previous and present haemodynamic criteria did not sufficiently discriminate the impact of pre-operative-PH for survival after HT at our centre, larger multi-centre studies are encouraged to redefine criteria that may influence outcome.     

Outcomes after heart transplantation in patients with and without pretransplant renal dysfunction

Abstract

Objective. To compare long-term survival and incidence of ESRD between patients with and without preoperative renal dysfunction following heart transplantation. Design. Fifty consecutive patients with preoperative estimated GFR ≤ than 50 ml/min were compared with 50 age-matched patients with estimated GFR ≥ than 80 ml/min who underwent heart transplantation between 1994 and 1998. We investigated two primary outcomes: death and development of ESRD. We also analyzed risk factors. Results. Eight patients (16%) developed ESRD and 19 (38%) died in the control group whereas 10 patients (20%) developed ESRD and 26 (52%) died in the renal failure group during a mean follow-up period of 6.74 ± 3.31 years. Survival and time to ESRD were not significantly different. In univariate and multivariate analysis, waiting time was the only risk factor found to predict mortality but not ESRD. High cyclosporine levels were only found to be associated with lower estimated GFR (p < 0.009). Among the control group, mortality was significantly higher in the subgroup of patients that developed ≥ 50% reduction of estimated GFR at the end of the first post transplant year (p < 0.05). Conclusions. This study suggests that low pre-transplant estimated GFR may not accurately predict long-term development of ESRD.     

Age and heart transplantation: results from a heart failure management unit

Abstract: Background: More evidence is needed to assess the pros and cons of maintaining age‐limit policies in heart transplantation (HT). Methods: We analyzed clinical data from a heart failure management unit to investigate the impact of age on prognosis of two distinct cohorts: (i) 309 patients (median age, 57 yr; 62% male) with severe chronic heart failure (CHF) consecutively screened for HT; (ii) 336 HT recipients (median age 56 yr, 82% male). Results: In CHF patients (screened for HT), prognosis was conditioned by the underlying severity of cardiac disease (i.e., New York Heart Association class III–IV, decreasing blood pressure, presence of atrial fibrillation and severe mitral regurgitation), whereas increasing age showed no sign of predicting all‐cause or cardiovascular mortality (both p ≥ 0.4). In HT recipients, age did not retain significance at multivariate analysis as an independent predictor (p ≥ 0.14 for both all‐cause and cardiovascular death), whereas ischemic etiology of pre‐existing CHF did (p ≤ 0.02). Conclusions: Age did not appear to be a primary determinant of all‐cause or cardiovascular mortality among potential HT candidates or eventual recipients (ischemic etiology of CHF turned out to be the major determinant of post‐transplant outcome). These results support the concept that HT may be considered a treatment option in patients with more advanced age strata, particularly when affected by non‐ischemic cardiomyopathy.     

Serum cholestasis markers as predictors of early outcome after liver transplantation

BACKGROUND: Early cholestasis is not uncommon after liver transplantation and usually signifies graft dysfunction. The aim of this study was to determine if serum synthetic and cholestatic parameters measured at various time points after transplantation can predict early patient outcome, and graft function. METHODS: The charts of 92 patients who underwent 95 liver transplantations at Rabin Medical Center between 1991 and 2000 were reviewed. Findings on liver function tests and levels of serum bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGT) on days 2, 10, 30, and 90 after transplantation were measured in order to predict early (6 months) patient outcome (mortality and sepsis) and initial poor functioning graft. Pearson correlation, chi(2) test, and Student's t-test were performed for univariate analysis, and logistic regression for multivariate analysis. RESULTS: Univariate analysis. Serum bilirubin >/=10 mg/dL and international normalized ratio (INR) >1.6 on days 10, 30, and 90, and high serum ALP and low albumin levels on days 30 and 90 were risk factors for 6-month mortality; serum bilirubin >/=10 mg/dL on days 10, 30, and 90, high serum ALP, high GGT, and low serum albumin, on days 30 and 90, and INR >/=1.6 on day 10 were risk factors for sepsis; high serum alanine aminotransferase, INR >1.6, and bilirubin >/=10 mg/dL on days 2 and 10 were risk factors for poor graft function. The 6-month mortality rate was significantly higher in patients with serum bilirubin >/=10 mg/dL on day 10 than in patients with values of <10 mg/dL (29.4% vs. 4.0%, p = 0.004). Patients who had sepsis had high mean serum ALP levels on day 30 than patients who did not (364.5 +/- 229.9 U/L vs. 70.8 +/- 125.6 U/L, p = 0.005). Multivariate analysis. Significant predictors of 6-month mortality were serum bilirubin >/=10 mg/dL [odds ratio (OR) 9.05, 95% confidence intervals (CI) 1.6-49.6] and INR >1.6 (OR 9.11, CI 1.5-54.8) on day 10; significant predictors were high serum ALP level on day 30 (OR 1.005, 1.001-1.01) and high GGT level on day 90 (OR 1.005, CI 1.001-1.01). None of the variables were able to predict initial poor graft functioning. CONCLUSIONS: Several serum cholestasis markers may serve as predictors of early outcome of liver transplantation. The strongest correlation was found between serum bilirubin >/=10 mg/dL on day 10 and early death, sepsis, and poor graft function. Early intervention in patients found to be at high risk may ameliorate the high morbidity and mortality associated with early cholestasis.     

Mesenchymal stem cell transplantation attenuates cardiac fibrosis associated with isoproterenol‐induced global heart failure

We aimed to examine the ability of transplanted mesenchymal stem cells (MSCs) to attenuate cardiac fibrosis caused by global heart failure, and investigate the mechanisms that are possibly mediating this effect. Global heart failure was induced in Wistar rats by isoproterenol injection. Four weeks later, MSCs were transplanted by intramyocardial injection, while control groups were treated by injection of cell culture medium alone. Four weeks after transplantation, heart function was assessed, and histologic and molecular analyses conducted. Compared with the medium‐treated group, MSC transplantation significantly decreased the expression of collagens I and III, and matrix metalloproteinase 2 and 9, but heart function was improved in MSC‐treated animals. In addition, expression of antifibrotic factor, hepatocyte growth factor (HGF), was detected in cultured MSCs, suggesting a possible mechanism underlying antifibrotic effects. Importantly, HGF expression levels were higher in MSC‐treated hearts, compared with medium‐treated hearts. Therefore, we could conclude that MSC transplantation can attenuate myocardial fibrosis in a rat model of global heart failure, and this may be at least partially mediated by paracrine signaling from MSCs via antifibrotic factors such as HGF.     

Simultaneous heart and kidney transplantation in patients with end-stage heart and renal failure.

Combined simultaneous organ transplantation has become more common as selection criteria for transplantation have broadened. Broadening selection criteria is secondary to improved immunosuppression and surgical techniques. The kidney is the most common extrathoracic organ to be simultaneously transplanted with the heart. A series of 13 patients suffering from both end-stage heart and renal failure underwent 14 simultaneous heart and kidney transplantations at Temple University Hospital between 1990 and 1999. This is the largest series reported from a single center. Three patients died during the initial hospitalization for an in-hospital mortality of 21%. Of 10 patients who left the hospital, 1-year survival was 100% and 2-year survival 75%. One patient required retransplant for rejection within the first year. Overall mortality at 1 and 2 years was 25 and 41%, respectively. Four out of nine (44%) patients greater than 5 years post-transplant were alive. Of the 10 patients who left the hospital, 66% were alive at 5 years. One patient succumbed to primary nonfunction of the cardiac allograft, while the four other deaths were secondary to bacterial or fungal sepsis. The patient's racial backgrounds were equally divided between African-American and white. These results are similar to those reported in a United Network of Organ Sharing Database (UNOS) registry analysis of 84 simultaneous heart and kidney transplants that found 1- and 2-year survival to be 76 and 67%, respectively. Simultaneous heart and kidney transplantation continues to be a viable option for patients suffering from failure of these two organ systems, although the results do not match those of heart transplant alone.