Common variants in mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

MAP/ERK kinase kinase 1 (MEKK1) mediates transcriptional repression by interacting with polycystic kidney disease-1 (PKD1) promoter-bound p53 tumor suppressor protein.

Mitogen-activated protein kinase (MAPK) cascades regulate a wide variety of cellular processes that ultimately depend on changes in gene expression. We have found a novel mechanism whereby one of the key MAP3 kinases, Mekk1, regulates transcriptional activity through an interaction with p53. The tumor suppressor protein p53 down-regulates a number of genes, including the gene most frequently mutated in autosomal dominant polycystic kidney disease (PKD1). We have discovered that Mekk1 translocates to the nucleus and acts as a co-repressor with p53 to down-regulate PKD1 transcriptional activity. This repression does not require Mekk1 kinase activity, excluding the need for an Mekk1 phosphorylation cascade. However, this PKD1 repression can also be induced by the stress-pathway stimuli, including TNFα, suggesting that Mekk1 activation induces both JNK-dependent and JNK-independent pathways that target the PKD1 gene. An Mekk1-p53 interaction at the PKD1 promoter suggests a new mechanism by which abnormally elevated stress-pathway stimuli might directly down-regulate the PKD1 gene, possibly causing haploinsufficiency and cyst formation.

Damage spreading transition in glasses: A probe for the ruggedness of the configurational landscape

We consider damage spreading transitions in the framework of mode-coupling theory. This theory describes relaxation processes in glasses in the mean-field approximation which are known to be characterized by the presence of an exponentially large number of metastable states. For systems evolving under identical but arbitrarily correlated noises, we demonstrate that there exists a critical temperature T0 which separates two different dynamical regimes depending on whether damage spreads or not in the asymptotic long-time limit. This transition exists for generic noise correlations such that the zero damage solution is stable at high temperatures, being minimal for maximal noise correlations. Although this dynamical transition depends on the type of noise correlations, we show that the asymptotic damage has the good properties of a dynamical order parameter, such as (i) independence of the initial damage; (ii) independence of the class of initial condition; and (iii) stability of the transition in the presence of asymmetric interactions which violate detailed balance. For maximally correlated noises we suggest that damage spreading occurs due to the presence of a divergent number of saddle points (as well as metastable states) in the thermodynamic limit consequence of the ruggedness of the free-energy landscape which characterizes the glassy state. These results are then compared to extensive numerical simulations of a mean-field glass model (the Bernasconi model) with Monte Carlo heat-bath dynamics. The freedom of choosing arbitrary noise correlations for Langevin dynamics makes damage spreading an interesting tool to probe the ruggedness of the configurational landscape.

Evidence for a sodium-induced activation of central neurogenic mechanisms in one-kidney, one-clip renal hypertensive rats

The mechanisms sustaining high blood pressure in conscious one-kidney, one-clip Goldblatt rats were evaluated with the use of SK&F 64139, a phenylethanolamine N-methyltransferase inhibitor capable of crossing the blood-brain barrier and of captopril, an angiotensin converting enzyme inhibitor. The rats were studied 3 weeks after left renal artery clipping and contralateral nephrectomy. During the developmental phase of hypertension, two groups of rats were maintained on a regular salt (RNa) intake, whereas two other groups were given a low salt (LNa) diet. On the day of the experiment, the base-line mean blood pressure measured in the LNa rats (177.4 +/- 5.2 mm Hg, mean +/- S.E., n = 15) was similar to that measured in the RNa rats (178.7 +/- 5.4 mm Hg, n = 16). SK&F 64139 (12.5 mg p.o.) induced a significantly more pronounced (P less than .001) blood pressure decrease in the RNa rats (-25.6 +/- 3.6 mm Hg, n = 8) than in the LNa rats (-4.3 +/- 3.3 mm Hg, n = 7) during a 90-min observation period. On the other hand, captopril (10 mg p.o.) normalized blood pressure in LNa rats (n = 8), but produced only a 13.4 mm Hg blood pressure drop in RNa rats (n = 8). RNa rats treated with SK&F 64139 were found to have decreased phenylethanolamine N-methyltransferase activity by an average 80% in selected brain stem nuclei when compared with nontreated rats. No significant difference in plasma catecholamine levels was found between the RNa and LNa rats. These results suggest that, in this experimental model of hypertension, the sodium ion might increase the model of hypertension, the sodium ion might increase the vasoconstrictor contribution of the sympathetic system via a centrally mediated neurogenic mechanism while at the same time it decreases the renin-dependency of the high blood pressure.

Effect of weather and climatological background on snow damage of forests in Southern Finland in November 1991

Summary

Association between mannose-binding lectin (MBL) deficiency and cytomegalovirus (CMV) infection after kidney transplantation

MBLdeficiency is thought to be a risk factor for the development of viral infection, such as genital herpes and HSV-2 meningitis. However, there is limited data on the possible interaction between MBL and CMV, especially after organ transplantation. Between 2003 and 2005, we measured MBL levels in 16 kidney transplant recipients with high-risk CMV serostatus (donor positive/recipient negative, D+/R−). All patients receivedCMV prophylaxis of valganciclovir 450 mg/day for 3 months after transplantation. After stopping valganciclovir, CMV-DNA was measured in whole blood by real time PCR every 2 weeks for 3 months. CMV infections were diagnosed according to the recommendations of the AST. MBL levels were measured in stored pre-transplantation sera by an investigator blinded to the CMV complications. MBL levels below 500 ng/ml were considered as being functionally deficient. After a follow-up of at least 10 months, seven patients out of 16 developed CMV disease (three CMV syndrome, and four probable invasive disease, i.e. two colitis and two hepatitis), four patients developed asymptomatic CMV infection, and five patients never developed any sign of CMV replication. Peak CMV-DNA was higher in patients with CMV disease than in those with asymptomatic infection (4.64 versus 2.72 mean log copy CMV-DNA/106 leukocytes, p < 0.05). Overall, 9/16 patients (56%) had MBL deficiency: 5/7 (71%) of patients with CMV disease, 4/4 (100%) of patients with asymptomatic CMVinfection, and 0/5 (0%) of patients withoutCMVinfection (p < 0.005, between CMV infection/disease versus no infection or control blood donors). There were no significant differences in age, gender or immunosuppressive regimens between the groups. MBL deficiency may be a significant risk factor for the development of post-prophylaxisCMVinfection in D+/R−kidney recipients, suggesting a new role of innate immunity in the control of CMV infection after organ transplantation.

Economics of dialysis dependence following renal replacement therapy for critically ill acute kidney injury patients.

BACKGROUND: The obective of this study was to perform a cost-effectiveness analysis comparing intermittent with continuous renal replacement therapy (IRRT versus CRRT) as initial therapy for acute kidney injury (AKI) in the intensive care unit (ICU). METHODS: Assuming some patients would potentially be eligible for either modality, we modeled life year gained, the quality-adjusted life years (QALYs) and healthcare costs for a cohort of 1000 IRRT patients and a cohort of 1000 CRRT patients. We used a 1-year, 5-year and a lifetime horizon. A Markov model with two health states for AKI survivors was designed: dialysis dependence and dialysis independence. We applied Weibull regression from published estimates to fit survival curves for CRRT and IRRT patients and to fit the proportion of dialysis dependence among CRRT and IRRT survivors. We then applied a risk ratio reported in a large retrospective cohort study to the fitted CRRT estimates in order to determine the proportion of dialysis dependence for IRRT survivors. We conducted sensitivity analyses based on a range of differences for daily implementation cost between CRRT and IRRT (base case: CRRT day $632 more expensive than IRRT day; range from $200 to $1000) and a range of risk ratios for dialysis dependence for CRRT as compared with IRRT (from 0.65 to 0.95; base case: 0.80). RESULTS: Continuous renal replacement therapy was associated with a marginally greater gain in QALY as compared with IRRT (1.093 versus 1.078). Despite higher upfront costs for CRRT in the ICU ($4046 for CRRT versus $1423 for IRRT in average), the 5-year total cost including the cost of dialysis dependence was lower for CRRT ($37 780 for CRRT versus $39 448 for IRRT on average). The base case incremental cost-effectiveness analysis showed that CRRT dominated IRRT. This dominance was confirmed by extensive sensitivity analysis. CONCLUSIONS: Initial CRRT is cost-effective compared with initial IRRT by reducing the rate of long-term dialysis dependence among critically ill AKI survivors.

Natural killer cell genes and functions after kidney transplantation

Natural Killer (NK) cells are of special interest in solid organ transplantation (SOT) because classical immunosuppressive drugs could enhance NK cells activity.We studied NK cells after kidney transplantation in three different situations. First, we analysed the peripheral repertoire reconstitution and function of NK cells after a polyclonal rabbit anti-thymocytes globulin (rATG) induction therapy, in 20 patients transplanted with living donor and with a low immunological risk. Second, we analysed the influence of KIR genes on the risk of CMV primo-infection or reactivation in 224 transplanted patients during the first year. Finally, we studied the risk of rejection and graft function during the first 5 years according to the KIR genes. Our study demonstrates that after an intial drop, NK cell reconstitution is fast with a ratio of CD56+/CD3− cells versus CD3+ cells that remains identical. The fraction of NK cells expressing the inhibitory receptor NKG2A significantly increases and the activating receptor NKG2D decreases after transplantation to retrieve the pretransplantation value after one year. The secretion of INF-f × and the cytotoxicity is maintained over time after transplantation. Then, we demonstrated that the presence of 2 KIR missing ligands and a large number of activating KIR gene protected against CMV primo-infection or reactivation during the first year post transplantation. Finally, the KIR genes and their HLA ligands do not influence the long term graft function after univariate and multivariate analysis. Our data suggest that despite the modification of the receptor repertoire, NK cell activity is preserved. NK cells are an important player of the immune response in the first year after transplantation mainly thanks to their anti-infectious activity.

Immunosuppression in hepatitis C virus-infected patients after kidney transplantation.

Hepatitis C virus (HCV) infection is an important health problem in kidney transplant recipients with a significantly higher prevalence than in the general population. Kidney transplantation remains the treatment of choice for most HCV-infected patients with end-stage kidney disease, in spite of lower patient and graft survival as compared to HCV-negative patients. Immunosuppression likely has significant consequences on HCV replication and/or disease after transplantation. However, determining the best immunosuppressive strategies after kidney transplantation in the presence of HCV infection remains challenging. The use of induction therapy is not contraindicated, and a short-course induction may actually be beneficial in HCV-infected kidney transplant recipients. Corticosteroid withdrawal may be an acceptable option in HCV-infected patients with specific comorbidities such as diabetes mellitus or osteoporosis. The best calcineurin inhibitor to be used in HCV-infected patients remains to be determined, as there is a lack of large controlled trials addressing this particular issue. Overall, immunosuppressive regimens need to be individualized according to clinical parameters other than HCV, such as the patient's immunological risk and other comorbidities. In conclusion, there is a need for prospective controlled studies to define the optimal immunosuppressive regimen in HCV-infected kidney transplant recipients.