Cost effectiveness of a new combined immunosuppressive and antiviral regimen on the one-year follow-up of kidney transplant patients.

Background: Medical prescription after organ transplant must prevent both rejection and infectious complications. We assessed the 1-year effectiveness and cost of introducing a new combined regimen in kidney transplantation. Methods: Patients transplanted from January 2000 to March 2003 (Period 1) were compared to patients transplanted from April 2003 to July 2005 (Period 2). In period 1, patients were treated with Basiliximab, Cyclosporin, steroids and Mycophenolate (MMF) or Azathioprine. Prophylaxis with Valacyclovir was prescribed only in CMV D+/R- patients. In period 2, immunosuppressive drugs were Basiliximab, Tacrolimus, steroids and MMF. A 3-month universal CMV prophylaxis with Valganciclovir was used. Medical charts of outpatient visits allowed identifying drug, laboratory and radiological tests use, and hospital information system causes of hospitalisation and length of stay (LOS) over the first year after transplant. Patients with incomplete costs data were excluded. Results: 53 patients were analysed in period 1, and 60 in period 2. CMV serostatus patterns were not significantly different between the 2 periods. Over 12 months, acute rejection decreased from 22 patients (42%) in period 1 to 4 patients (7%) in period 2 (p<0.001), and CMV infection from 25 patients (47%) to 9 patients (15%, p<0.001). Average total rehospitalisation LOS decreased from 28±19 to 20±11 days (p<0.007). Average outpatient visits decreased from 49±10 to 39±8 (p<0.001). Average immunosuppression and CMV prophylaxis costs increased from US$ 18,362±6,546 to 24,637±5,457 (p<0.001), while average graft rejection costs decreased form US$ 4,135±9,164 to 585±2,850 (p=0.005), and average CMV treatment costs from US$ 2,043±5,545 to 91±293 (p=0.008). Average outpatient visits costs decreased from US$ 7,619±1,549 to 6,074±1,043 (p<0.001), and other hospital costs from US$ 3,801±6,519 to 1,196±3,146 (p=0.007). Altogether, average 1-year treatment costs decreased from US$ 35,961±14,916 to 32,584±6,211 (p=0.115). Cost-effectiveness ratios to avoid graft rejection and CMV infection decreased from US$ 61,482±9,292 to 34,911± 1,639 (p=0.006) and US$ 68,070±11,122 to 39,899±2,650 (p=0.015), respectively. Conclusion: The new combined regimen administered in period 2 was significantly more effective. Its additional cost was more than offset by savings linked with complications avoidance.

Renal sodium handling in acute and chronic salt loading/depletion protocols: the confounding influence of acute water loading.

OBJECTIVES: Renal tubular sodium handling was measured in healthy subjects submitted to acute and chronic salt-repletion/salt-depletion protocols. The goal was to compare the changes in proximal and distal sodium handling induced by the two procedures using the lithium clearance technique. METHODS: In nine subjects, acute salt loading was obtained with a 2 h infusion of isotonic saline, and salt depletion was induced with a low-salt diet and furosemide. In the chronic protocol, 15 subjects randomly received a low-, a regular- and a high-sodium diet for 1 week. In both protocols, renal and systemic haemodynamics and urinary electrolyte excretion were measured after an acute water load. In the chronic study, sodium handling was also determined, based on 12 h day- and night-time urine collections. RESULTS: The acute and chronic protocols induced comparable changes in sodium excretion, renal haemodynamics and hormonal responses. Yet, the relative contribution of the proximal and distal nephrons to sodium excretion in response to salt loading and depletion differed in the two protocols. Acutely, subjects appeared to regulate sodium balance mainly by the distal nephron, with little contribution of the proximal tubule. In contrast, in the chronic protocol, changes in sodium reabsorption could be measured both in the proximal and distal nephrons. Acute water loading was an important confounding factor which increased sodium excretion by reducing proximal sodium reabsorption. This interference of water was particularly marked in salt-depleted subjects. CONCLUSION: Acute and chronic salt loading/salt depletion protocols investigate different renal mechanisms of control of sodium balance. The endogenous lithium clearance technique is a reliable method to assess proximal sodium reabsorption in humans. However, to investigate sodium handling in diseases such as hypertension, lithium should be measured preferably on 24 h or overnight urine collections to avoid the confounding influence of water.

Renal and neurohormonal responses to increasing levels of lower body negative pressure in men.

BACKGROUND: The stimulation of efferent renal sympathetic nerve activity induces sequential changes in renin secretion, sodium excretion, and renal hemodynamics that are proportional to the magnitude of the stimulation of sympathetic nerves. This study in men investigated the sequence of the changes in proximal and distal renal sodium handling, renal and systemic hemodynamics, as well as the hormonal profile occurring during a sustained activation of the sympathetic nervous system induced by various levels of lower body negative pressure (LBNP). METHODS: Ten healthy subjects were submitted to three levels of LBNP ranging between 0 and -22.5 mm Hg for one hour according to a triple crossover design, with a minimum of five days between each level of LBNP. Systemic and renal hemodynamics, renal water and sodium handling (using the endogenous lithium clearance technique), and the neurohormonal profile were measured before, during, and after LBNP. RESULTS: LBNP (0 to -22.5 mm Hg) induced an important hormonal response characterized by a significant stimulation of the sympathetic nervous system and gradual activations of the vasopressin and the renin-angiotensin systems. LBNP also gradually reduced water excretion and increased urinary osmolality. A significant decrease in sodium excretion was apparent only at -22.5 mm Hg. It was independent of any change in the glomerular filtration rate and was mediated essentially by an increased sodium reabsorption in the proximal tubule (a significant decrease in lithium clearance, P < 0.05). No significant change in renal hemodynamics was found at the tested levels of LBNP. As observed experimentally, there appeared to be a clear sequence of responses to LBNP, the neurohormonal response occurring before the changes in water and sodium excretion, these latter preceding any change in renal hemodynamics. CONCLUSIONS: These data show that the renal sodium retention developing during LBNP, and thus sympathetic nervous stimulation, is due mainly to an increase in sodium reabsorption by the proximal segments of the nephron. Our results in humans also confirm that, depending on its magnitude, LBNP leads to a step-by-step activation of neurohormonal, renal tubular, and renal hemodynamic responses.

Quality of life transformations before and after kidney transplantation: A prospective qualitative study.

The aim of this IRB-approved study was to analyze prospectively quality of life (QOL) and psychological changes in 30 ESRD patients before and after kidney transplantation (KT). Semi-structured interviews were conducted after inclusion on the waiting list (A). Follow-up interviews were performed 6 months later with patients still awaiting KT (B6, n= 15), and with transplant recipients 6, 12 and 24 months after KT (C6, n=15; C12, n=15; C24, n=14). Qualitative thematic analysis was performed. A: All patients reported loss of freedom, 87% tried to maintain normality; 57% modified medical directives. All mentioned emotional fragility, negative thoughts (43%), and suicidal thoughts (20%) related to loss of QOL from dialysis (D), and professional tension (26%). B6: 40% reported no change compared to baseline, while 60% mentioned increase of illness intrusiveness, 46% D side effects, 40% communication problems, and 33% concerns about the waiting list handling. Fear of emotional breakdown (40%), couple problems (47%), and worsened professional difficulties (20%) were reported. C6: All patients reported recovery of QOL and concerns about acute rejection. 73% were anxious about laboratory results. 93% felt dependent on immunosuppressants (IS), 47% reported difficulties coping with their regimen, and 47% were concerned about side effects; 67% had resumed work, but medical constraints led 40% to professional stigmatization. C12: All enjoyed good QOL. Adherence to IS was mandatory (100%). All were aware of the limited long-term graft survival and 47% anxious about a possible return to D. 60% underlined positive life value; 47% resumed a full time job; 40% were on social security. C24: Good QOL was underlined (86%). Patients stated they would prefer re-TX to resuming D (71%). Post-TX health problems were mentioned (64%); increase of creatinine levels induced fear (36%). 79% complained about side effects. 64% reported changes in life values. This study reveals positive QOL and psychological transformations after KT, which are associated with positive changes related to graft survival and freedom from D. Psychological follow-up should be offered to patients who face relapsing ESRD or post-TX co-morbidities.

IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction.

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV), with potential development of cirrhosis and hepatocellular carcinoma. Despite the availability of new antiviral agents, treatment remains suboptimal. Genome-wide association studies (GWAS) identified rs12979860, a polymorphism nearby IL28B, as an important predictor of HCV clearance. We report the identification of a novel TT/-G polymorphism in the CpG region upstream of IL28B, which is a better predictor of HCV clearance than rs12979860. By using peripheral blood mononuclear cells (PBMCs) from individuals carrying different allelic combinations of the TT/-G and rs12979860 polymorphisms, we show that induction of IL28B and IFN-γ-inducible protein 10 (IP-10) mRNA relies on TT/-G, but not rs12979860, making TT/-G the only functional variant identified so far. This novel step in understanding the genetic regulation of IL28B may have important implications for clinical practice, as the use of TT/G genotyping instead of rs12979860 would improve patient management.

Frequency and impact of autosomal dominant polycystic kidney disease in the Seychelles (Indian Ocean).

BACKGROUND: As little such data is available in African populations, we investigated the prevalence of ADPKD and the impact of the disease in the Seychelles islands, where approximately 65% of the population is of African descent and 30% of Caucasian or mixed descent. METHODS: Prevalent cases were identified over a 3-year period by requesting all the doctors in the country (most of them are employed within a national health system) to refer all presumed or confirmed cases and by systematically examining the family members of all confirmed cases. The diagnosis was based on standard criteria including ultrasonographic findings and family history. RESULTS: Forty-two cases were identified in this population of 74,331 inhabitants, a total prevalence (per 100,000 total population) of 57 (95% CI, 41-76). All but one of the cases were of Caucasian descent so that the prevalence rates of the disease in the populations of Black and Caucasian descents were respectively 2 (0-11) and 184 (132-249). The prevalence rates of the gene(s) carriers were estimated to be 75 (45-117) in the total population respectively 6 (0-33) and 236 (140-372) in the Black and Caucasian populations. Haplotype analysis in 58 cases from three families showed a common DNA fragment in all affected individuals. Cases had significantly higher blood pressure compared to the general population and 21% had serum creatinine higher than 120 mumol/l. Among the established pedigrees, mean age of death between 1960 and 1995 (haemodialysis was introduced in 1992) was younger in subjects with than those without ADPKD (50.5 vs 67.7 years; P < 0.001). CONCLUSIONS: In the Seychelles, ADPKD clusters in the Caucasian population (possibly a founder effect), is rare in individuals of black descent, and is associated with substantial clinical and survival impact.

Bicarbonate de sodium pour ralentir la progression de la maladie rénale chronique [Sodium bicarbonate to slow the progression of chronic kidney disease].

Metabolic acidosis is a prevalent complication in moderate and late stages of chronic kidney disease (CKD). It is established that the correction of metabolic acidosis may improve metabolic bone disorders and protein degradation in the skeletal muscle, two characteristic complications of patients with advanced CKD. In the last 18 months, three randomized controlled trials have drawn the attention on a novel indication to correct metabolic acidosis in these patients, i.e., halting CKD progression. These data show that sodium bicarbonate, a cheap and easily manageable treatment, may delay the progression of CKD and the need of a renal replacement therapy such as dialysis or kidney transplantation.

CO-EXPRESSION OF GCDH AND OAT1 IN NEURONS AND PROXIMAL TUBULE CELLS

Tissue-specific expression studies of Glutaryl-CoA dehydrogenase (Gcdh) in adult rats revealed expression in the whole rat brain, almost exclusively in neurons, and surprisingly high expression in the juxtamedullar cortex of the kidney. The organic anion transporter 1 (OAT1) mediates basolateral uptake of glutarate derivatives from proximal tubule cells and contributes to their renal clearance. In brain, OAT1 is expressed at the choroid plexus, in neurons of cortex and hippocampus. We hypothesized that Gcdh and Oat1 are co-expressed in the same cells in kidney and brain and analyzed their mRNA expression by in situ hybridization on cryosections of adult rat brain, kidney and liver. In brain, Gcdh and Oat1 were found co-expressed in most neurons. Only the Purkinje neurons of the cerebellum were found to be Oat1 negative. In the kidney Gcdh and Oat1 are widely co-expressed with a specific high expression in proximal tubule cells. In conclusion there seems to be a functional coupling of Gcdh and Oat1 on a renal and neuronal level. Further studies are ongoing to confirm these findings in human tissues.

Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.

PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

The E3-Ubiquitin Ligase TRIM50 Interacts with HDAC6 and p62, and Promotes the Sequestration and Clearance of Ubiquitinated Proteins into the Aggresome.

In this study we report that, in response to proteasome inhibition, the E3-Ubiquitin ligase TRIM50 localizes to and promotes the recruitment and aggregation of polyubiquitinated proteins to the aggresome. Using Hdac6-deficient mouse embryo fibroblasts (MEF) we show that this localization is mediated by the histone deacetylase 6, HDAC6. Whereas Trim50-deficient MEFs allow pinpointing that the TRIM50 ubiquitin-ligase regulates the clearance of polyubiquitinated proteins localized to the aggresome. Finally we demonstrate that TRIM50 colocalizes, interacts with and increases the level of p62, a multifunctional adaptor protein implicated in various cellular processes including the autophagy clearance of polyubiquitinated protein aggregates. We speculate that when the proteasome activity is impaired, TRIM50 fails to drive its substrates to the proteasome-mediated degradation, and promotes their storage in the aggresome for successive clearance.

Population pharmacokinetics of ganciclovir in solid-organ transplant recipients receiving oral valganciclovir.

Valganciclovir (VGC) is an oral prodrug of ganciclovir (GCV) recently introduced for prophylaxis and treatment of cytomegalovirus infection. Optimal concentration exposure for effective and safe VGC therapy would require either reproducible VGC absorption and GCV disposition or dosage adjustment based on therapeutic drug monitoring (TDM). We examined GCV population pharmacokinetics in solid organ transplant recipients receiving oral VGC, including the influence of clinical factors, the magnitude of variability, and its impact on efficacy and tolerability. Nonlinear mixed effect model (NONMEM) analysis was performed on plasma samples from 65 transplant recipients under VGC prophylaxis or treatment. A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by the glomerular filtration rate (GFR), patient gender, and graft type (clearance/GFR = 1.7 in kidney, 0.9 in heart, and 1.2 in lung and liver recipients) with interpatient and interoccasion variabilities of 26 and 12%, respectively. Body weight and sex influenced central volume of distribution (V(1) = 0.34 liter/kg in males and 0.27 liter/kg in females [20% interpatient variability]). No significant drug interaction was detected. The good prophylactic efficacy and tolerability of VGC precluded the demonstration of any relationship with GCV concentrations. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of the GCV profile after treatment with oral VGC, routine TDM does not appear to be clinically indicated in solid-organ transplant recipients. However, GCV plasma measurement may still be helpful in specific clinical situations.

Psychological transformations in kidney transplantation: A prospective qualitative study

The aim of this IRB-approved study was to prospectively analyze psychological transformations in ESRD patients before and after transplantation (KT). Semi-structured interviews were conducted in 30 patients (mean age = 53±10) after their inclusion on the waiting-list (Gr. A). Follow-up interviews were performed 6 months later in 15 patients still awaiting KT (Gr. B6), and in 15 patients 6 months (Gr. C6) and 12 months (Gr. C12) after KT. Qualitative analysis was performed. Gr: A:All patients underlined loss of freedom, 87% devoted much energy to maintain normality, 57% modified medical directives. All reported emotional fragility related to dialysis and loss of quality of life (QOL), negative (43%) or suicidal thoughts (20%). Professional stigma was underlined (26%). Gr: B6:40% reported no change, 60% mentioned increase of illness intrusiveness, 46% dialysis side-effects, 40% communication problems, 33% tension with medical staff and waiting list handling. Fear of emotional breakdown (40%), couple problems (47%) and worsened professional difficulties (20%) were reported. Gr: C6:All patients mentioned improved QOL and freedom recovery (87%). All expressed concerns about possible acute rejection, 73% were anxious about laboratory results, 93% experienced dependence to immunosuppressants, 47% reported difficulties in handling medication, 21% feared to forget them, 47% were concerned about side-effects, 67% had resumed work but medical constraints led to professional tension (40%). Gr: C12:All mentioned recovered QOL. Medical controls were accepted as a routine (87%) and adherence to medication was mandatory (100%). All mentioned the limited long-term graft survival and 47% were anxious about possible return to dialysis, especially younger patients (27%). Positive identity and existential changes were reported (60%). This prospective qualitative study identifies psychological modifications in the course of KT. It provides a basis to adequately address concerns, but it shows also that KT is clearly associated with positive psychological transformations.