Tommaso Maria Manzia

The Tor Vergata weaning off immunosuppression protocol in stable HCV liver transplant patients: The updated follow up at 78 months

BACKGROUND We report the update of the Tor Vergata immunosuppression (IS) weaning protocol in stable hepatitis C virus (HCV) liver transplant (LT) recipients. METHODS The weaning off IS was attempted in 34 patients who had received a LT 63.5+/-20.1 month earlier, for HCV-related end stage liver disease. Patients were observed over a period of 6.5 years. During this time, yearly protocol liver biopsies were performed. Primary endpoints were determined as the feasibility of weaning off IS and its impact on the long term disease progression. Secondary endpoints were defined as the impact on patient morbidity and quality of life. RESULTS Of the 8 originally tolerant patients, 7 remain alive and in good condition, while 1 died of severe HCV recurrence 10 years post-LT and 6 years after complete removal of IS. Four out of 26 intolerant individuals died of HCV recurrence (2x), lung carcinoma (1x) and acute myocardial infarction (1x), after a mean follow up period from LT of 115 (range 100-124). The 10-year survival from LT was comparable (89% vs. 87.5%). Liver graft pathology showed no significant differences between the two groups in terms of staging, fibrosis progression rate, and grading. Quantitative HCV RNA assay showed a significant non-logarithmic difference between the two groups (p = 0.03). The two groups were comparable in terms of liver function tests and lipid profile, whereas they differed with regards to glycaemia. While all tolerant individuals were euglicemic, 11 intolerant individuals developed new onset diabetes that required specific treatment (p = 0.03). Finally, significantly more intolerant patients are suffering from either cardiovascular (14/22 vs. 0/7, p = 0.01) or infectious diseases (13/22 vs. 0/7, p = 0.01). CONCLUSIONS After a 6.5-year follow up, the complete withdrawal of IS in HCV LT recipient remains safe and beneficial to patients, because it reduces the IS-related morbidity and increases the quality of life. The impact on HCV disease recurrence is less marked than after 3.5 years.

Saline contrast echocardiography in patients with hepatopulmonary syndrome awaiting liver transplantation.

BACKGROUND Patients with hepatopulmonary syndrome (HPS) with end-stage liver disease (ESLD) have higher cardiorespiratory mortality than those without. The aims of this study were to determine whether echocardiography could distinguish patients with ESLD with and without HPS and whether the diagnosis of HPS by contrast echocardiography (CE) was altered by the performance of the test in a supine or standing position. METHODS Subjects were recruited prospectively from patients with end-stage liver disease undergoing assessment for liver transplantation. Hepatopulmonary syndrome was diagnosed on the basis of arterial blood gas analysis, lung function testing and agitated saline contrast echocardiography in the absence of primary cardiac or pulmonary disease. Bubble contrast injections were performed supine or standing in a randomised order and read by a blinded observer. RESULTS CE showed late right-to-left shunting in 13 of 50 consecutive patients with cirrhosis (26%). Eight patients (16%) had definite diagnoses of HPS. CE in the standing position consistently increased both the number and the size of shunts compared with supine injection. CE detected intrapulmonary shunting before a change in arterial blood gases. Standard echocardiographic parameters did not distinguish between those with and without HPS. CONCLUSION This study suggests that screening for HPS in patients with advanced cirrhosis should be done using CE with patients in the upright position.

Combination of biological and morphological parameters for the selection of patients with hepatocellular carcinoma waiting for liver transplantation

Lai Q, Avolio AW, Manzia TM, Sorge R, Agnes S, Tisone G, Berloco PB, Rossi M. Combination of biological and morphological parameters for the selection of patients with hepatocellular carcinoma waiting for liver transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01572.x. 
© 2011 John Wiley & Sons A/S.

Successful pregnancy in a living-related kidney transplant recipient who received sirolimus throughout the whole gestation.

tuoso AI, Alcazar R, et al. Higher graft salvage rate in renal allograft rupture associated with acute tubular necrosis. Transplant Proc 2004; 36: 3016. 11. Busi N, Capocasale E, Mazzoni MP, et al. Spontaneous renal allograft rupture without acute rejection. Acta Biomed 2004; 75: 131. 12. He B, Rao MM, Han X, et al. Surgical repair of spontaneous renal allograft rupture: A new procedure. ANZ J Surg 2003; 73: 381. 13. Guleria S, Khazanchi RK, Dinda AK, et al. Spontaneous renal allograft rupture: Is graft nephrectomy an option? Transplant Proc 2003; 35: 339. 14. Ramos M, Martins L, Dias L, et al. Renal allograft rupture: A clinicopathologic review. Transplant Proc 2000; 32: 2597. 15. Richardson AJ, Higgins RM, Jaskowski AJ, et al. Spontaneous rupture of renal allografts: The importance of renal vein thrombosis in the cyclosporin era. Br J Surg 1990; 77: 558. 16. Azar GJ, Zarifian AA, Frentz GD, et al. Renal allograft rupture: A clinical review. Clin Transplant 1996; 10(6 pt 2): 635. 17. Nghiem DD, Corry RJ. Long-term result of conservative surgical management of the ruptured renal transplant. Am Surg 1983; 49: 392. 18. Chopin DK, Abbou CC, Lottmann HB, et al. Conservative treatment of renal allograft rupture with polyglactin 910 mesh and gelatin resorcin formaldehyde glue. J Urol 1989; 142(2 pt 1): 363.

Prospect for kidney bioengineering: shortcomings of the status quo

Introduction: Dialysis and renal transplantation are the only two therapeutic options offered to patients affected by end-stage kidney disease; however, neither treatment can be considered definitive. In fact, dialysis is able to replace only the filtration function of the kidney without substituting its endocrine and metabolic roles, and dramatically impacts on patient’s quality of life. On the other hand, kidney transplantation is severely limited by the shortage of transplantable organs, the need for immunosuppressive therapies and a narrow half-life. Regenerative medicine approaches are promising tools aiming to improve this condition. Areas covered: Cell therapies, bioartificial kidney, organ bioengineering, 3D printer and kidney-on-chip represent the most appealing areas of research for the treatment of end-stage kidney failure. The scope of this review is to summarize the state of the art, limits and directions of each branch. Expert opinion: In the future, these emerging technologies could provide definitive, curative and theoretically infinite options for the treatment of end-stage kidney disease. Progress in stem cells-based therapies, decellularization techniques and the more recent scientific know-how for the use of the 3D printer and kidney-on-chip could lead to a perfect cellular-based therapy, the futuristic creation of a bioengineered kidney in the lab or to a valid bioartificial alternative.

Long-term, maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (LT) is universal. We designed a retrospective case–control study to evaluate the effect of mycophenolate mofetil (MMF) monotherapy in patients with recurrent hepatitis C. Fifteen patients with histologically proven hepatitis C recurrence after LT were switched from calcineurin inhibitors (CNIs) to MMF monotherapy because of impairment of kidney function and/or metabolic side effects, and treated for 48 months (MMF group). Fifteen well‐matched LT recipients who continued to receive CNIs therapy over the same period served as control group. Demographics, clinical data, time after LT, and baseline liver biopsies were similar in the two groups. There was no worsening of hepatic fibrosis during the study in the MMF group [2.6 ± 1.5 (baseline) Ishak Units vs. 2.7 ± 1.8 (after 48 months of MMF treatment), P = 0.6]. In contrast, a significant increase in the fibrosis score [2 ± 1.1 (baseline) vs. 3.2 ± 1.7 (after 48 months of CNI treatment), P = 0.0002] was observed in the control group. The yearly fibrosis progression rate was of 0.05 ± 0.44 in the MMF group and 0.33 ± 0.24 in the CNI group (P = 0.04). MMF monotherapy is associated with a favourable effect on hepatic fibrosis progression in HCV liver transplant recipients.

The Tor Vergata weaning of immunosuppression protocols in stable hepatitis C virus liver transplant patients: the 10-year follow-up.

We report herein the 10‐year outcome of the Tor Vergata weaning off immunosuppression protocol in hepatitis C virus (HCV) liver transplant patients. Thirty‐four patients who had received a liver graft for HCV‐related cirrhosis were enrolled in a prospective study in which they were progressively weaned off immunosuppression. The primary endpoints were feasibility and safety of the weaning; the second aim was to assess fibrosis progression. At the 10‐year follow‐up, of the eight original tolerant patients, six remained IS‐free. Of the 26 individuals who could not be weaned, 22 were alive. When the baseline biopsies were compared with the 10‐year biopsies, the tolerant group showed no differences in staging, whereas the nontolerant group showed a significant increase in staging. The fibrosis progression rates calculated for the tolerant and the nontolerant groups were −0.06 ± 0.12 and 0.1 ± 0.2, respectively (P = 0.04). Furthermore, with the last taken biopsies, nine nontolerant patients were showing frank cirrhosis versus no cirrhosis among the tolerant patients. After a 10‐year follow‐up of a Tor Vergata weaning protocol, 6/34 patients completed follow‐up without reinstitution of immunosuppression and this appeared beneficial regarding a reduction in fibrosis progression.

Impact of mTOR-I on fertility and pregnancy: state of the art and review of the literature

Successful transplantation should lead to improvements in sexual function and sex hormone disturbances in both men and women, but immunosuppressive drugs may interfere with hormone metabolism. In this regard, several studies have showed a potential negative effect of mTOR inhibitors (mTORi) on male gonadal function, while their role in the female patients is not well documented in the literature. Successful pregnancy is possible after solid organ transplantation. The fetal effects of mTORi are still poorly defined but they seem not to represent an absolute contraindication for pregnancy. The aim of our study would be to review the impact of mTORi on fertility and pregnancy in order to have a clearer picture about their possible use after organ transplantation.

Role of alpha-fetoprotein in selection of patients with hepatocellular carcinoma waiting for liver transplantation: must we reconsider it?

Background Milan criteria (MC) represent the most commonly adopted criteria for the selection of patients with hepatocellular carcinoma (HCC) waiting for liver transplantation (LT). However, MC are exclusively based on morphological aspects. The aim of the present study was to evaluate pre-LT–detectable biological parameters, to compare them with morphological ones in terms of tumor recurrence prediction and patient survival. Methods A cohort of 153 consecutive adult patients who underwent LT for HCC on cirrhosis from January 1999 to March 2009 was retrospectively analyzed. Results HCC recurrence was observed in 12 patients (7.8%). At multivariate logistic regression analysis, serum alpha-fetoprotein (AFP) was the unique independent negative risk factor for the development of HCC recurrence (odds ratio 2.0, p=0.03). Adopting a cutoff value of 210 ng/mL, patients who presented serum AFP ≥210 ng/mL showed a 5-year survival rate of 23.3% versus 76.2% observed in patients with pre-LT serum AFP <210 ng/mL (log-rank test: <0.0001). Conclusions In our experience, AFP was the strongest predictor of HCC recurrence, stronger than tumor morphology. AFP could ameliorate the selection of LT candidates. Further studies to evaluate the combination of morphological and biological criteria are needed.

Liver Transplantation in Primary Hepatic Carcinoid Tumor: Case Report and Literature Review

Ninety percent of all carcinoid tumors develop in the gastrointestinal tract. Although the liver is a usual site for metastases, primary hepatic carcinoid tumors (PHCTs) are extremely rare. The diagnosis is based on histopathologic characteristics and on exclusion of a nonhepatic primary tumor. While liver transplantation (OLT) is a well-established surgical treatment in selected cases of unresectable metastatic carcinoid tumor, its use in PHCT has not been widely described. We report the case of a 50-year-old woman with unresectable PHCT treated with OLT. After 64 months, disease recurred in the liver and mesentery. Laparotomy with multiple radiofrequency ablations of liver lesions and resection of peritoneal deposits was performed; however, in the postoperative period, a fatal myocardial infarct occurred. Our case is the fourth one reported in literature. It confirms long-term survival after OLT in patients with unresectable PHTCs.