Association of pretransplant renal replacement therapy duration with outcome in kidney transplant recipients: a prevalent cohort study in Slovenia

The effect of renal replacement therapy (RRT) duration on kidney transplant outcome is controversial. The aim of this study was to analyze the association between pretransplant RRT duration versus patient and graft survival. The study cohort included 445 recipients of a deceased-donor kidney transplant between January 2000 and December 2009. Pretransplant RRT duration as a continuous variable and divided into time categories was the risk factor of interest. Patient and death-censored graft survival were the outcomes. Survival since the onset of RRT was calculated to avoid lead-time bias. Median pretransplant RRT duration was 4.7 years. The duration of RRT was longer in 33 patients who died (median 6.8 vs. 4.6 years; P = 0.022) and 56 patients who lost their graft (5.7 vs. 4.6 years; P = 0.035). Pretransplant RRT duration, as a continuous variable, was associated with a non-significant increase in the risk of recipient death (hazard ratio [HR] 1.01 per year of RRT; P = 0.09) and death-censored graft loss (HR 1.02; P = 0.12). When RRT was studied as a categorical variable, the mortality risk reached statistical significance when the patient had been on RRT for more than 4.7 years (HR 2.12; P = 0.042). Pretransplant RRT duration was not associated with an increased risk for recipient death if patient survival was calculated since the onset of RRT (HR 0.98 per year; P = 0.21). This study suggests that a longer RRT duration negatively impacts on post-transplant patient and graft survival; however, when pretransplant patient survival is accounted for, RRT duration has no significant effect on patient outcome.     

Dialysis patients after kidney graft failure: Slovenian experience

Increased mortality has been reported in patients starting dialysis after kidney graft failure. In this study we analyzed this subgroup of dialysis patients based on the data from the Slovenian Renal Replacement Therapy Registry. Patients starting dialysis after graft failure in the period between 2004 and 2008 were identified from the registry. Demographic, clinical and treatment data, as well as survival were compared to incident dialysis patients, who were on the waiting list or preparing for enrollment. There were 49 patients starting dialysis after 7.9 ± 6.4 years spent with a functioning graft and a total of 13.7 ± 7.4 years on renal replacement therapy. Their mean age was 48.3 ± 11.0 years (vs. 48.2 ± 13.9 years in incident patients, P = 0.96), 53% were male, and all were on hemodialysis. By the end of 2008, 8 (16%) patients had been re-transplanted (after a median of 27.5 months) and 11 (23%) had died (after a median of 1.4 months of dialysis). The cause of death was infection in five patients, a cardiovascular event in three, malignancy in two, and a cerebrovascular event in one patient. Deceased patients were significantly older, but similar to survivors in other parameters. Unadjusted one- and three-year survival rates after graft failure were both 77%, which was significantly worse than in incident patients (P < 0.001). To conclude, patients after graft failure have increased mortality in the first year after starting dialysis, but patients surviving the first year have good survival thereafter. Studies focusing on the early period after graft failure are necessary to improve outcomes.     

Survey of Renal Transplantation in Slovenia

This brief survey presents data on renal transplantation in Slovenia, a country with a population of 2 million, which has one renal transplant center. The establishment of an appropriate national transplantation organization resulted in an increase in transplantations and the acceptance of Slovenia into Eurotransplant (ET) at the beginning of 2000. Current immunosuppression is composed of cyclosporine microemulsion (Neoral), mycophenolate mofetil, methylprednisolone, and anti‐interleukin‐2 receptor monoclonal antibodies. By the end of 2008, 766 renal transplantations had been performed, and from 1970 to 2007, 125 patients had been transplanted from living related donors. From 1986 to 1999, 239 patients received renal grafts from deceased donors. From 2000 to 2008, 402 patients were transplanted from deceased donors. In 2004, 55 renal transplantations were done. Two hundred and twenty‐eight (56.7%) renal grafts were shipped from other ET countries. The HLA‐antigen mismatch of 2.7 ± 1.1 was not significantly different to that before 2000. From 2000 to 2008, the one‐ and five‐year patient survival rates were 98.2% and 95.2%, respectively. The concomitant graft survival rates were 94.4% and 90.9%, respectively. In the ET era, the number of deceased donor renal transplants per year was 2.6 times higher than in the 14 years before. In 2004 we reached the average number of deceased donor renal transplants per million population of ET. Short‐ and medium‐term results of the last nine‐year period have been very good and entirely comparable to those in large reports.     

Third intracellular loop of glucagon like-peptide-1 receptor is coupled with endogenous mono-ADP-ribosyltransferase - novel type of receptor regulation?

Our previous studies revealed the main role of the third intracellular loop (IC(3)) of glucagon-like peptide-1 receptor (GLP-1 receptor), in G-protein activation, where the presence or absence of agonist and the receptor phosphorylation seemed to be the only regulatory mechanisms. In order to further study the signaling mechanisms of GLP-1 receptor, we investigated the effect of the third intracellular loop-derived peptide on endogenous mono-ADP-ribosyltransferase mediated mono-ADP-ribosylation of G-proteins β subunit in CHO cells. Results showed an inhibitory effect of IC(3) peptide on mono-ADP-ribosylation of β subunit, obviously via the mechanism of competitive inhibition. Excluding the activity of this inhibitory mechanism via pertussis toxin-sensitive G proteins, the direct functional coupling of IC(3) of GLP-1 receptor and endogenous mono-ADP-ribosyltransferase was confirmed. We suggest that this arginine specific enzymatic posttranslational modification of third intracellular loop of GLP-1 receptor might represent a possible novel mechanism of receptor activity regulation and the pharmacological potential in treatment of diabetes mellitus type 2.     

The expression and role of insulin-like growth factor II in malignant hemangiopericytomas

Hemangiopericytoma is a rare soft tissue tumor originating from contractile pericapillary pericytes. To address the issue of molecular genetic events that participate in genesis and progression of hemangiopericytoma we analyzed insulin-like growth factor (IGF) II and IGF I receptor in 29 tumors collected from a human tumor bank network. Seven of these tumors were associated with severe hypoglycemia; six were retroperitoneal and one was located in the leg. Of 22 tumors tested 12 (54.5%) exhibited IGF II mRNA, while almost 90% (17 of 19) of hemangiopericytomas exhibited IGF I receptor mRNA. Sera from some patients whose tumors expressed IGF II mRNA contained elevated levels of IGF II. Removal of the tumor eliminated most of the IGF II immunoreactivity from the sera. The potential role of IGF II as a growth-promoting factor was examined on three malignant primary hemangiopericytoma cell cultures. Extracellular addition of IGF II significantly enhanced cell proliferation in a dose-dependent manner. Antisense oligodeoxynucleotides that specifically inhibit IGF II mRNA, at a concentration of 40 or 80 micrograms/ml, inhibited the growth of hemangiopericytoma cells significantly, by 40%. Simultaneous administration of antisense deoxyoligonucleotides to both IGF II and IGF I receptor inhibited tumor cell proliferation by even 80%. Our data suggest that tumor cells produce IGF II, and that this in turn stimulates their proliferation by autocrine mechanisms.     

Asymmetric Lévy flight in financial ratios

Because financial crises are characterized by dangerous rare events that occur more frequently than those predicted by models with finite variances, we investigate the underlying stochastic process generating these events. In the 1960s Mandelbrot [Mandelbrot B (1963) J Bus 36:394-419] and Fama [Fama EF (1965) J Bus 38:34-105] proposed a symmetric Lévy probability distribution function (PDF) to describe the stochastic properties of commodity changes and price changes. We find that an asymmetric Lévy PDF, L, characterized by infinite variance, models several multiple credit ratios used in financial accounting to quantify a firm's financial health, such as the Altman [Altman EI (1968) J Financ 23:589-609] Z score and the Zmijewski [Zmijewski ME (1984) J Accounting Res 22:59-82] score, and models changes of individual financial ratios, ΔX(i). We thus find that Lévy PDFs describe both the static and dynamics of credit ratings. We find that for the majority of ratios, ΔX(i) scales with the Lévy parameter α ≈ 1, even though only a few of the individual ratios are characterized by a PDF with power-law tails X(i)(-1-α) with infinite variance. We also find that α exhibits a striking stability over time. A key element in estimating credit losses is the distribution of credit rating changes, the functional form of which is unknown for alphabetical ratings. For continuous credit ratings, the Altman Z score, we find that P(ΔZ) follows a Lévy PDF with power-law exponent α ≈ 1, consistent with changes of individual financial ratios. Estimating the conditional P(ΔZ|Z) versus Z, we demonstrate how this continuous credit rating approach and its dynamics can be used to evaluate credit risk.     

Multifragment fracture of the patellar apex: basket plate osteosynthesis compared with partial patellectomy

Introduction The purpose of the present study was to evaluate and compare the long-term results of operative treatment of a multifragment fracture of the inferior patellar pole by basket plate osteosynthesis and partial patellectomy. Materials and methods We retrospectively studied two groups of patients who had operative treatment of a multifragment fracture of the inferior patellar pole between 1988 and 2004. Seventy-one patients who had osteosynthesis by basket plate (Group 1) and 49 patients who had partial patellectomy (Group 2) were followed for an average of 5.3 years. The final evaluation was based on the modified Cincinnati Knee rating system test. Results The results were excellent or good in 90.1% patients of Group 1, and 73.5% patients of Group 2. Significant differences between the groups were noted with regard to knee pain, swallowing, level activity, compression pain, range of motion, muscular atrophy, muscular strength, and final patellofemoral score which confirms statistical analysis. Conclusion The stability of the osteosynthesis by basket plate allows osseous consolidation of the fracture and permits immediate mobilization and early weight bearing. Osteosynthesis by basket plate can provide better clinical results.     

Resting heart rate variability and heart rate recovery after submaximal exercise

Purpose

Aerobic training accelerates Heart Rate Recovery after exercise in healthy subjects and in patients with coronary disease. As shown by pharmacological autonomic blockade, HRR early after exercise is dependent primarily on parasympathetic reactivation. Thus, accelerated HRR early after exercise in endurance-trained athletes may be attributed to augmented parasympathetic reactivation. In the present study, we tested the hypothesis that the HRR early after submaximal exercise is related to the pre-exercise parasympathetic modulation.

Methods

Thirty endurance-trained athletes (20 males, 50 ± 7 years) and thirty control subjects (20 males, 52 ± 6 years) performed a submaximal exercise on a cyclo-ergometer. Pre-exercise resting short-term heart rate variability (HRV) parameters in time and frequency-domains were correlated with HRR during the first 30 s, 1 and 2 min after cessation of exercise.

Results

We found that HRR was statistically significantly faster in athletes than in controls at all examination time points (p < 0.05). HF, SDNN and RMSSD were statistically significantly higher in athletes than in controls (p < 0.05), but other resting HRV parameters were not statistically different between groups. After 30 s, 1 and 2 min of recovery, HRR correlation with total power, HF, HFnu and RMSSD was positive, while the correlation with LF/HF was negative for small and positive for larger values. The opposite was true for SDNN.

Conclusions

These findings support the hypothesis that HRR early after submaximal exercise is related to resting parasympathetic modulation in the middle-aged subjects. In addition, they suggested an optimal range of HRV for maximal HRR after exercise.     

Molecular characterization of specific H<Subscript>1</Subscript>-receptor agonists histaprodifen and its N<Superscript>α</Superscript>-substituted analogues on bovine aortic H<Subscript>1</Subscript>-receptors

We determined the molecular properties of the selective and potent H(1)-receptor agonist histaprodifen and its N(alpha) substituted analogues: methyl-, dimethyl-, and imidazolylethyl-histaprodifen (suprahistaprodifen). All derivatives show high affinity for (3)H-mepyramine labeled bovine aortic H(1)-receptor binding sites with the following order of potency: suprahistaprodifen > dimethylhistaprodifen > methylhistaprodifen > histaprodifen > histamine. Suprahistaprodifen and dimethylhistaprodifen were the most potent displacers of (3)H-mepyramine binding (K(i)=4.3 and 4.9 nM, respectively). Histaprodifen, methylhistaprodifen and suprahistaprodifen binding was differentially influenced by GTP, whereas dimethylhistaprodifen was not affected. All drugs, except dimethylhistaprodifen, were activators of G-proteins. Their order of potency was suprahistaprodifen > histamine > histaprodifen > methylhistaprodifen. Their effect on G-protein activation was abolished by the addition of the H(1)-receptor antagonist triprolidine (10 microM), which given alone did not activate G-proteins. Our data suggest that histaprodifens are potent but heterogeneous H(1)-receptor ligands with diverse effects on the molecular level in our model system. While the histaprodifen, methylhistaprodifen and suprahistaprodifen data are in agreement with their agonistic nature, as shown in the functional studies performed on different species (rat and guinea pig H(1)-receptor), dimethylhistaprodifen behaved as an antagonist in our study.     

Treatment of anemia with epoetin in kidney transplant recipients

The aim of this study was to analyze the prevalence and efficacy of renal anemia treated with epoetin in maintenance kidney transplant recipients in Slovenia. By the end of 2009, 107 out of 537 patients (19.9%) had been treated with epoetin. A cohort of 49 patients (45.8%) were analyzed in detail: 11 patients received epoetin alpha, 18 epoetin beta, 10 darbepoetin alpha, and 10 patients received methoxy polyethylene glycol-epoetin beta. The median epoetin dose was 0.36 μg/kg body weight per week. The median serum laboratory parameters were as follows: hemoglobin 120 g/L, hematocrit 0.36, ferritin 332 ng/mL, transferrin saturation 34%, serum creatinine 145 μmol/L, serum albumin 41 g/L, intact parathyroid hormone 79 ng/L, and C-reactive protein 3 mg/L. We concluded that the prevalence of renal anemia in kidney transplant recipients treated with epoetin was approximately 20%, and laboratory parameters suggested that the treatment of renal anemia in this study cohort was optimal.