Impact of Acute Infection Requiring Hospitalization on Tacrolimus Blood Levels in Kidney Transplant Recipients.

BACKGROUND: Tacrolimus is metabolized by members of the cytochrome p450 3A subfamily, and its bioavailability depends also on P-glycoprotein. We have observed that some patients admitted for infection presented with increased tacrolimus trough levels (TLs). The aim of the study was to assess the impact of infection on tacrolimus TLs and to determine the factors involved in TL fluctuations. METHODS: This retrospective cohort study included patients transplanted with a kidney between 2009 and 2011 who were hospitalized for an acute infection. Tacrolimus TLs and dosages were recorded before hospitalization, at admission, and 1 month after discharge. Increased levels of tacolimus were defined as TL 25% higher on admission than those recorded at the last visit before hospitalization. RESULTS: Seventy-seven patients were hospitalized 138 times for infection. More than two thirds of first hospitalizations occurred during the first post-transplant year. Causes of hospitalization were urinary (33%), cytomegalovirus (27%), digestive (15%), and pulmonary (12%) infections. Thirty-five percent of kidney transplant recipients had increased tacrolimus TLs (27/77 patients) in 24% of the hospitalizations (34/138). In 34 hospitalizations occurring in 27 patients, TL at admission was ≥25% compared with the last visit before admission. Comparing these 34 hospitalizations with the other 104, no significant differences were noted, except for a greater fraction of digestive infections in the group with elevated tacrolimus TLs, independent of diarrhea occurrence. CONCLUSIONS: Up to 35% of kidney transplant recipients admitted for acute infection present with high tacrolimus TLs, requiring a dose reduction. How acute infection precisely affects metabolism and bioavailability of tacrolimus remains to be investigated.

Outcome of hepatitis B and C virus-associated hepatocellular carcinoma occurring after renal transplantation.

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case-control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6 ± 6.5 years (53.5 ± 5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7 ± 2.7 years. Six HCCs were related to HBV, six to HCV and two to co-infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha-fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2 years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.

Sclerostin Serum Levels and Vascular Calcification Progression in Prevalent Renal Transplant Recipients.

CONTEXT: Vascular calcification (VC) is prevalent and progressive in renal transplant recipients (RTRs). Recent cross-sectional data suggest that activated Wnt signaling contributes to VC. OBJECTIVE: The objective was to investigate whether circulating levels of the Wnt antagonist sclerostin associate with progression of VC. DESIGN: This was a post hoc analysis of the longitudinal observational Brussels Renal Transplant Cohort study. SETTING: The setting was a tertiary care academic hospital. PATIENTS: Coronary artery calcification and aorta calcification were measured by multislice spiral computerized tomography in 268 prevalent RTRs (age, 53 ± 13 y; 61% male) at baseline and remeasured in 189 patients after a median follow-up of 4.4 years. Baseline serum sclerostin levels were assessed on stored blood samples. Regression analysis was performed to identify determinants of baseline VC and progression. MAIN OUTCOME MEASURE: The main outcome measure was progression of VC. RESULTS: VC was present in up to 84% of participants at baseline. Almost half of the patients showed progression of VC, according to Hokanson criteria. The cross-sectional analysis at baseline demonstrated a direct association between sclerostin levels and VC score in univariate analysis, which became inverse after adjustment for age, gender and PTH level. Remarkably, a lower sclerostin level was identified as an independent determinant of a higher baseline aorta calcification score in the final regression model. Moreover, baseline sclerostin levels showed an inverse association with VC progression, at least after adjustment for traditional risk factors. CONCLUSIONS: Serum sclerostin levels inversely associated with VC burden and progression in prevalent RTRs after adjustment for traditional risk factors. Our data corroborate previous findings in nontransplanted chronic kidney disease patients and support the notion that sclerostin may be up-regulated in the vascular wall during the VC process as part of a local counterregulatory mechanism directed to suppress VC. Additional clinical and experimental data are required for confirmation.

[Focusing on peritoneal dialysis adequacy]. / Adéquation en dialyse péritonéale : mise au point.

The optimal method to assess the adequacy of peritoneal dialysis therapies is controversial. Today, the adequacy must not be considered as a number or a concept assessed only by two parameters (total KT/V urea and total solute clearance) but defined by many more items. In the absence of data, based on theoretical considerations, the reanalysis of the CANUSA study showed that renal kidney function, rather than peritoneal clearance, was associated with improved survival. Residual renal function is considered as a major predictor factor of cardiovascular mortality. Results of this reanalysis were supported by the adequacy data in ADEMEX, EAPOS and ANZDATA studies. Therefore, clinical assessment plays a major role in PD adequacy. The management of fluid balance, the regular monitoring of malnutrition, the control of mineral metabolism and particularly the glucose load, considered as the "corner-stone" of the system, are the main points to be considered in the adequacy of PD patients. The essential goal is to minimize glucose load by glucose-sparing strategies in order to reduce the neoangiogenesis of the peritoneal membrane.

Disseminated varicella zoster virus infection in adult renal transplant recipients: outcome and risk factors.

BACKGROUND: Disseminated varicella zoster virus (VZV) infection, whether due to primary infection or reactivation, may be life threatening in renal transplant recipients. The aims of this study were to assess the outcome of disseminated VZV infection in renal transplant recipients and to determine potential risk factors for mortality. METHODS: A search of the English literature from 1985 to 2011 using PUBMED was performed. Reports involving renal transplant recipients younger than 16 years of age were excluded. RESULTS: A total of 56 adult patients presenting with a disseminated cutaneous or visceral VZV infection was included. Seventy percent of cases occurred within 5 years after transplantation, and 89% within 10 years. Visceral complications including disseminated intravascular coagulation occurred in two thirds of patients. Mortality decreased significantly from 47% in the era before 1995 to 17% after 1995 (P = .04). Risk factors for mortality included visceral involvement, use of azathioprine as immunosuppressant, and longer time between transplantation and VZV infection. VZV seropositivity did not influence fatal outcome. CONCLUSION: Disseminated VZV infection can be life threatening in renal transplant recipients with a global mortality rate of 30%. This rate seems to have decreased since 1995. Seropositive VZV patients with disseminated infection are not protected from fatal outcome.

Ring-fused thiadiazines as core structures for the development of potent AMPA receptor potentiators.

Amongst ionotropic glutamatergic receptors, the AMPA receptor subtype has been recognized as a major contributor to the fast excitatory neurotransmission in the central nervous system and the expression and maintenance of longterm potentiation. This receptor subtype also represents an interesting target to develop innovative therapeutic drugs such as positive allosteric modulators (AMPA receptor potentiators) since the enhancement of AMPA signals is expected to be beneficial in the management of several neurological disorders such as depression, schizophrenia, Parkinson's disease and learning-memory deficits linked to Alzheimer's disease. This article is dedicated to the use of (hetero) aromatic ring-fused thiadiazines (i.e. benzo- pyrido- and thienothiadiazines) as core structures for the discovery of new positive allosteric modulators of AMPA receptors. Recent advances exploring other chemotypes in the field of AMPA potentiators is the object of a separate review of the present issue.

CRP measurement: does the assay matter in hemodialysis patients?

BACKGROUND: The serum level of C-reactive protein, an acute-phase marker of systemic inflammation, has been shown to predict cardiovascular events in the general population and cardiovascular and total mortality in hemodialysis patients. High-sensitivity CRP assays (hs-CRP) have been used in numerous studies. We hypothesized that the level of CRP as measured by the conventional assay (c-CRP) would predict mortality in hemodialysis patients with an accuracy similar to that of high-sensitivity assays. METHODS: In April 2001 CRP serum level was measured with both a conventional and a high-sensitivity assay in 102 prevalent hemodialysis patients. Mortality was prospectively monitored over 6 years. RESULTS: 49 patients (48%) died during follow-up. With both assays, almost 2/3 of patients had high CRP levels (> 1 mg/dl). Survival at 6 years was significantly lower in patients with high CRP levels, no matter which assay was used (31.5% for patients with high hs-CRP and 27.3% for patients with high c-CRP vs 48.4% for patients with low hs-CRP and 47.1% for patients with low c-CRP). Cardiovascular mortality was also higher in patients with high CRP levels, whatever the type of assay (conventional or high sensitivity) used. The correlation between the two tests was excellent. CONCLUSION: CRP level, measured by a conventional inexpensive assay, is predictive of mortality in hemodialysis patients.

Lamivudine for nephrotic syndrome related to hepatitis B virus (HBV) infection.

A 57-year-old man presented with nephrotic syndrome associated with active HBV infection. Liver biopsy showed severe portal and moderate lobular inflammation, patchy necrosis, moderate fibrosis and several "ground glass" cells. Immunofluorescence microscopical view of the renal biopsy showed diffuse granular IgG deposits along the glomerular basement membrane, compatible with MN. As symptomatic therapy with ACE inhibitors did not improve the nephrotic syndrome, lamivudine 100 mg o.d. was initiated. HBV-DNA became undetectable after 10 weeks and seroconversion of HBeAg and HBsAg to anti-HBe and anti-HBs occurred after 2 additional months; proteinuria normalized subsequently. This observation documents for the first time in an adult the beneficial effect of lamivudine in glomerulonephritis related to HBV infection with HBV seroconversion and complete remission of the nephrotic syndrome.

Vaccinations for adult solid organ transplant recipient: current recommendations.

The need for immunization in solid organ transplant recipient can arise from three factors: immune deficit owing to underlying disease, rejection of the organ graft, and immunosuppressive therapy given after transplantation. As a general rule, primary immunizations should be given as early as possible before transplantation because the immune response to vaccines is decreased in patients with end-stage organ disease. There are three categories of vaccines: Live vaccines--oral polio, vaccinia, bacillus Calmette-Guerin, live oral typhoïd, and intranasal influenza vaccines--are contraindicated in solid organ transplant recipients. The use of varicella vaccine remains controversial. The use of rubella vaccine is recommended in young women of childbearing age. Of the killed vaccines or genetically engineered vaccines, the following are recommended: pneumococcal vaccine, influenza vaccine, hepatitis A vaccine, hepatitis B vaccine, diphtheria, and tetanus vaccine. Vaccination of household contacts and health care workers in transplant centers is recommended. However, live vaccine (with the exception of varicella vaccine) should be avoided in these contacts.

Bone disorders after organ transplantation.

Three main bone disorders may occur after organ transplantation: epiphyseal impactions, avascular bone necrosis, and osteoporosis. Their main clinical characteristics, causes, diagnostic approaches, and therapies are discussed in this review.

Pancreas transplantation for treatment of generalized allergy to human insulin in type 1 diabetes.

We report the case of a 29-year-old man with a 14-year history of type 1 diabetes, normal renal function, and mild diabetic retinopathy. The patient progressively developed a generalized allergic reaction to two insulin excipients--protamine and metacresol--with systemic manifestations of tremor, tachycardia, vertigo, shortness of breath, and short episodes of unconsciousness causing him to be out of work. In June 2003, he received a vascularized cadaveric pancreas transplant using induction with polyclonal antibodies along with tacrolimus and sirolimus but without steroids. A hyperglycemic episode following corticosteroid therapy for rejection treatment required reintroduction of insulin therapy with prompt reappearance of allergic manifestations. Now, the patient is euglycemic without insulin or allergic manifestations and a glycated hemoglobin of 6.4%.

Multiple bilateral fibroadenomas of the breasts requiring mastectomy in a renal transplant patient.

Fibroadenomas of the breast have been reported in female renal graft recipients and associated with the use of cyclosporin A (CsA). We report the case of a young patient given CsA who developed multiple bilateral fibroadenomas of the breasts 3 years after renal transplantation, leading to bilateral mastectomy. We discuss the association of CsA with fibroadenomas, the mechanisms by which the drug can act and review the literature. Based on these observations, an early conversion from CsA to tacrolimus should be considered; further observations are needed to assess the reversibility of the breast(s) lesions after such immunosuppressive regimen switch.

FT-IR measurement of tagitinin C after solvent extraction from Tithonia diversifolia.

Tagitinin C, an antiplasmodial compound, identified as one major compound of the subtropical medicinal plant, Tithonia diversifolia, was determined by FT-IR spectroscopy method. The crude ether extracts from aerial parts of the plant were evaporated to dryness and re-dissolved in tetrachloroethylene (C(2)Cl(4)) before analysis. The magnitude of the absorbance of the very specific CO stretching vibration (nu(CO)) at 1664.8cm(-1) was exploited in order to quantify tagitinin C. The determination coefficient (r(2)) of the calibration scale was 0.9994, the detection limit was lower than 3mugml(-1) and the quantification limit was lower than 10mugml(-1). Recovery values from 100.5 to 101.7% were found for spiked concentration levels from 19.91 to 89.95mugml(-1). The main characteristics of the curves obtained from the calibration standards and from the standard addition technique were not statistically different (Student t-test) suggesting that matrix effects were negligible. The results obtained for the determination of tagitinin C in the crude ether extract from aerial parts of T. diversifolia by LC and FT-IR spectroscopic method agreed well: 0.76+/-0.02 and 0.773+/-0.009, of tagitinin C in dried plant respectively.

Evaluation of bone mineral density after renal transplantation under a tacrolimus-based immunosuppression: a pilot study.

BACKGROUND: Progressive bone loss consistently complicates renal transplantation (TP) in patients given an immunosuppression including prednisolone. The adjunction of cyclosporine in the immunosuppressive regimen does not reverse the negative impact of renal TP on the skeleton. The post-transplant effect of tacrolimus on bone mass is still unknown. METHODS: We evaluated the evolution of bone mineral density (BMD) and various biochemical markers over the first 12 months following renal TP in 23 patients given an immunosuppression combining tacrolimus and low-dose prednisolone. BMD of lumbar spine, total hip and hip subregions was measured by dual-energy X-ray absorptiometry within the first 15 days and 1 year after TP. RESULTS: At the time of TP, the average BMD was low in both the lumbar spine and the hip. After TP, a normalization of serum creatinine and a decrease in serum phosphate and iPTH levels occurs. Serum alkaline phosphatase level significantly rose transiently within the first 6 months and decreased thereafter. At 1 year post TP, BMD remained unchanged in the lumbar and in the trochanter subregions and rose in the other sites. BMD increased by at least 2% in 8, 13, 10 and 10 out of the 23 patients in the lumbar, neck, trochanter and total hip subregions, respectively. No correlation was found between evolution in BMD and age, sex, dialysis duration, level of hyperparathyroidism, prednisolone and tacrolimus cumulative intake and prescription of calcium, vitamin D or hormone replacement therapy. CONCLUSIONS: An immunosuppression combining tacrolimus and low-dose prednisolone might avoid the usual post-TP bone loss. Further randomized double-blind studies evaluating a larger cohort of patients should be undertaken to compare the effect of cyclosporine and tacrolimus on bone mass.

Post-renal transplant syndrome of transient lower limb joint pain: description under a tacrolimus-based immunosuppression.

The occurrence of a post-renal transplant syndrome of lower limbs joint pain has been reported extensively over the last decade. Clinical examination of the symptomatic joints is often unremarkable and magnetic resonance imaging reveals abnormalities of the bone marrow suggestive of edema and/or hemorrhage. The main striking features of this syndrome are the spontaneous resolution of the symptoms within a few weeks as well as of the marrow abnormalities. This syndrome has been attributed to cyclosporine, given in the immunosuppression regimen or to epiphyseal impactions. We here document the occurrence of this syndrome in 5 kidney graft recipients given a tacrolimus-based immunosuppression.