Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions.

A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

Outcome of hepaticojejunostomy for biliary tract obstruction following liver transplantation.

BACKGROUND: Strictures and concrements are the most common biliary complications following liver transplantation. Endoscopic treatment might not lead to a definitive cure in all patients, especially in strictures involving the biliary bifurcation. The aim of this study was to determine the efficacy and the long-term outcome of hepaticojejunostomy (HJS) for post-transplant biliary tract obstruction. MATERIAL AND METHODS: Thirty-seven patients were retrospectively studied for resolving of cholestasis and the incidence of recurring biliary obstruction. RESULTS: Surgery was performed because of anastomotic strictures in 11, ischemic strictures at the donor common bile duct in seven, strictures involving the bile duct bifurcation in 10, hepatolithiasis without strictures in one and biliary cast formation diagnosed by endoscopic retrograde cholangiography or T-tube cholangiography in eight patients. Cholestasis instantly improved in 82% of the patients. After a long-term follow-up of median 33 months (range 3-149), 28 of the patients (76%) required no further intervention for recurring biliary obstruction following HJS. Anastomotic strictures were observed in six (16%), recurring biliary concrements in two patients (5%). CONCLUSION: HJS did prevent recurrent biliary obstruction in the majority of the patients. We therefore recommend early HJS for complicated post-transplant biliary tract obstruction not treatable by a limited number of endoscopic interventions.

Efficacy of interferon in immunocompromised HCV patients after liver transplantation or with HIV co-infection.

BACKGROUND: Interferon (IFN)-based antiviral therapy is increasingly used in immunocompromised patients with chronic hepatitis C after orthotopic liver transplantation (OLT) and HIV-HCV co-infection. Differences in early viral kinetics have not been compared in these patients. MATERIALS AND METHODS: We retrospectively analysed 76 patients (31 OLT, 20 HIV-HCV and 25 HCV control patients) undergoing IFN sensitivity testing before starting antiviral therapy with pegylated IFN-alpha 2a (180 microg week(-1)) plus ribavirin (0.8-1.2 g day(-1)) for 48 weeks. We compared baseline parameters, response to IFN and treatment outcome between the groups and assessed the influence of specific calcineurin inhibitors in OLT patients and immune status in HIV-HCV patients on treatment response. RESULTS: Viral loads pretherapy were higher in OLT compared to nontransplanted HCV controls (P = 0.003). The same trend was present in HIV-HCV (P = 0.09). The log-drop after test dose was less in OLT compared to HCV (P = 0.02), while no significant difference was found between HIV-HCV and HCV. In HIV-HCV patients viral load log-drop correlated significantly with CD4(+) cell counts (P = 0.001). No difference in viral load pretherapy, log-drop and treatment outcome was noted between different calcineurin inhibitors in OLT patients. Sustained virological response rates were 28% in OLT, 50% in HIV-HCV and 56% in HCV patients. CONCLUSIONS: Immunosuppression results in high HCV viral loads. Initial efficacy of IFN is significantly impaired in OLT patients, but not in HIV-HCV with largely preserved CD4(+) cell counts. Sustained virological response rates of 28% in OLT patients are suboptimal, but encouraging results are shown for HIV-HCV patients with relatively high CD4(+) cell counts.

Retrieval-oriented design of clinical research forms.

Computerized clinical forms are subject to a wide variety of different requirements. They have to allow detailed documentation and must be user-friendly. State-of-the-art applications for design permit clinicians themselves to create their own forms as needed, with the various variables presented in different ways depending on their intended use. Often, however, only aspects of clinical documentation are considered, with no thought being given to subsequent data retrieval. This article presents guidelines for the retrieval-oriented design of clinical forms. It discusses where anticipatory measures for structuring forms are easier to accomplish than complex data linkage at the time of retrieval and analysis.

Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients.

BACKGROUND: Hyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T has been shown to result in increased total homocysteine concentrations on the basis of low folate levels caused by a decreased enzyme activity. The effect of this polymorphism on total homocysteine and folate plasma levels in renal transplant patients is unknown. METHODS: We screened 636 kidney graft recipients for the presence of the MTHFR C677T gene polymorphism. The major determinants of total homocysteine and folate plasma concentrations of 63 patients, who were identified to be homozygous for this gene polymorphism compared with heterozygotes (N = 63), and patients with wild-type alleles (N = 63), who were matched for sex, age, glomerular filtration rate (GFR), and body mass index, were identified by analysis of covariance. The variables included sex, age, GFR, body mass index, time since transplantation, folate and vitamin B12 levels, the use of azathioprine, and the MTHFR genotype. To investigate the impact of the kidney donor MTHFR genotype on total homocysteine and folate plasma concentrations, a similar model was applied in 111 kidney graft recipients with stable graft function, in whom the kidney donor C677T MTHFR gene polymorphism was determined. RESULTS: The allele frequency of the C677T polymorphism in the MTHFR gene was 0.313 in the whole study population [wild-type (CC), 301; heterozygous (CT), 272; and homozygous mutant (TT), 63 patients, respectively] and showed no difference in the patient subgroups with various renal diseases. The MTHFR C677T gene polymorphism significantly influenced total homocysteine and folate plasma concentrations in renal transplant recipients (P = 0.0009 and P = 0.0002, respectively). Furthermore, a significant influence of the GFR (P = 0.0001), folate levels (P = 0.0001), age (P = 0.0001), body mass index (P = 0.0001), gender (P = 0.0005), and vitamin B12 levels (P = 0.004) on total homocysteine concentrations was observed. The donor MTHFR gene polymorphism had no influence on total homocysteine and folate levels. Geometric mean total homocysteine levels in patients homozygous for the mutant MTHFR allele were 18.6 micromol/liter compared with 14.6 micromol/liter and 14.9 micromol/liter in patients heterozygous for the MTHFR gene polymorphism and those with wild-type alleles (P < 0.05 for TT vs. CT and CC). Geometric mean folate levels were lower in CT and TT patients (11.2 and 10.2 nmol/liter) compared with CC patients (13.6 nmol/liter, P < 0.05 vs. CT and TT). CONCLUSIONS: This study demonstrates that homozygosity for the C677T polymorphism in the MTHFR gene significantly increases total homocysteine concentrations and lowers folate levels in kidney graft recipients, even in patients with excellent renal function (GFR more than median). These findings have important implications for risk evaluation and vitamin intervention therapy in these patients who carry an increased risk for the development of cardiovascular disease.

Lytic effector cell activity and major depressive disorder in patients with breast cancer: a prospective study.

The study examined lymphokine-activated killer cell (LAK) and natural killer (NK) cell activity in breast cancer patients prior to surgery as compared to effector cell lysis in patients with non-malignant breast tumors, further in connection with lifetime diagnosis of major depression, severity of current depression, anxiety and coping styles. Follow up studies covered a period of 6 and 12 months. Prior to surgery, life time diagnosis of major depressive disorder, trait anxiety and coping styles did not discriminate patients as far as effector cell lysis is concerned. LAK activity but not NK activity was reduced in patients with actual depressive symptoms (P < 0.01) and high state anxiety (P < 0.05). These findings support the hypothesis that LAK activity is a state marker of actually existing depression and anxiety prior to surgery. Affective rather than coping measures showed significant differences in LAK activity. For LAK activity, 1 year after surgery the only predicting factors were Tamoxifen therapy and chemotherapy.

Viral reactivation as a cause of unexplained fever in patients with progressive metastatic breast cancer.

Patients suffering from metastatic breast cancer and recurrent fever were investigated for viral reactivation or new viral infection as a possible cause of these febrile episodes. Three groups of patients were included in the study: (a) patients under adjuvant chemotherapy with cyclophosphamide, methotrexate and fluoruracil, (b) patients with stable metastatic disease treated with cyclophosphamide, fluoruracil and Adriamycin or mitoxantrone and (c) patients with progressive metastatic disease who also received the latter treatment. During the time of observation, patients under adjuvant chemotherapy did not present with fever or asymptomatic viral reactivation or bacterial infections at all. Out of 7 patients with stable disease, 2 had bacterial infections that coincided with the leukocyte nadir, and 1 presented with asymptomatic reactivation of cytomegalovirus. In contrast, fever in 9 of 11 patients with progressive disease was associated with a reactivation of herpes simplex virus (HSV) and in 3 of them with a consecutive reactivation of varicella zoster virus (VZV). The increase in complement-fixing anti-HSV or anti-VZV antibodies occurred in close association with a rise of the respective preexisting antibodies of the IgG class. In addition, HSV-infected cells were recovered from the urine of 7 patients with progressive disease further corroborating the serological data. Incidentally, natural killer cell activity, which has been postulated to be connected with the defense against viral infections, was found to be significantly lower in the group of patients with progressive disease, as compared to the group of patients under adjuvant chemotherapy (P less than 0.05) or to the group of patients with stable disease (P less than 0.05). We conclude that unexplained fever in patients with progressive metastatic breast cancer may result from viral reactivation.

Diagnostic value of mucin-like carcinoma-associated antigen (MCA) in breast cancer.

The diagnostic value of mucin-like carcinoma-associated antigen (MCA) was compared to that of carcinoembryonic antigen (CEA) and/or CA 15.3 in patients with breast cancer. A total of 368 patients with breast cancer were studied, of whom 253 were free of metastases, whereas 94 had either skeletal or visceral metastases or diffuse metastatic disease. The diagnostic sensitivity of MCA proved to be comparable to that of CA 15.3 and superior to that of CEA in patients with metastatic breast cancer. In contrast, the specificity of MCA was superior to that of CA 15.3. Finally, the diagnostic sensitivity of each of the tested tumour markers, i.e. MCA, CEA and CA 15.3, could be improved by their combined use. We conclude that MCA, either alone or in combination with CA 15.3 and CEA, can improve the monitoring of disease progression in patients with metastatic breast cancer.

Renin-angiotensin-aldosterone system and vasopressin in cyclosporine-treated renal allograft recipients.

Eleven patients, who had undergone renal transplantation and who had hypertension, aged 19-56 years, were treated with cyclosporine and prednisolone. We measured plasma renin activity, aldosterone and vasopressin (RIAs) at the first, second and third week and again 9 to 12 months after transplantation. Plasma renin activity was in the low-normal range throughout (0.31 +/- 0.05, 0.30 +/- 0.03, 0.32 +/- 0.05 ng/ml/h on short- vs. 0.32 +/- 0.04 ng/ml/h on long-term), aldosterone showed a tendency to decrease (114 +/- 27, 72 +/- 18, 71 +/- 11 pg/ml on short- vs. 54 +/- 23 pg/ml on long-term), whereas vasopressin remained moderately increased during the observation period (10.5 +/- 0.8, 10.4 +/- 1.6, 8.9 +/- 0.6 pg/ml on short- vs. 9.6 +/- 1.0 pg/ml on long-term). We then investigated the reactivity of the renin-system in 5 of the patients by stimulating renin release by captopril. Increases in plasma renin activity were only moderate (0.35 +/- 0.03 vs. 0.66 +/- 0.21 ng/ml/h) and blood pressure dropped only slightly (148 +/- 2.0/98 +/- 1.2 vs. 141 +/- 4.6/95 +/- 4.2 mmHg). Levels of plasma aldosterone were significantly suppressed from a low baseline (46.4 +/- 13.5 vs. 25.3 +/- 6.1 pg/ml, p less than 0.05). The increase in vasopressin was unaffected by captopril (9.6 +/- 1.0 vs. 8.8 +/- 0.4 pg/ml). Our results suggest that in renal transplantation patients with good graft function, the activity of the renin system is unaffected by cyclosporine treatment on short- and on long-term. Vasopressin stimulation does not seem to depend on the renin system and might play a role as a vasoconstrictor in the face of a denervated kidney.