Association of Sex with Risk of Kidney Graft Failure Differs by Age.

Prior studies of sex differences in kidney graft survival showed conflicting results. We hypothesized that the association between recipient sex and kidney graft failure risk differs by recipient age and donor sex. We evaluated 159,417 patients recorded in the Scientific Registry of Transplant Recipients database who received a first deceased-donor kidney transplant (1995-2013). We used time-varying Cox models to estimate the association between recipient sex and death-censored graft failure. Models, stratified on donor sex and adjusted for potential confounders, included a recipient sex by current age interaction term. Among recipients of male donors, females of all ages had significantly higher graft failure risks than males (adjusted hazard ratios 0-14 years: 1.51 [95% confidence intervals 1.19 to 1.90]; 15-24 years: 1.37 [1.18 to 1.59]; 25-44 years: 1.14 [1.03 to 1.26]; 45 years: 1.05 [1.01 to 1.09]). Among recipients of female-donor grafts, only female recipients aged 15-24 years had a significantly higher graft failure risk than their male counterparts had (1.28 [1.06 to 1.53]). Indeed, female recipients aged ≥45 years had a significantly lower graft failure risk than their male counterparts had (0.95 [0.91 to 0.99]). These observations might be explained by the combined influence of several factors, including recognition of sex-determined minor histocompatibility antigens, influence of sex hormones on immune activation, sex- and age-related differences in medication adherence, and sex-related differences in body size. Additional studies should determine whether sex- and age-specific immunosuppression strategies are warranted for kidney graft recipients.

Evidence from the Oxford Classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy.

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

Formulas for Calculated Osmolarity and Osmolal Gap: A Study of Diagnostic Accuracy.

BACKGROUND: The osmolal gap has been used for decades to screen for exposure to toxic alcohols. However, several issues may affect its reliability. We aimed to develop equations to calculate osmolarity with improved performance when used to screen for intoxication to toxic alcohols. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 7,525 patients undergoing simultaneous measurements of osmolality, sodium, potassium, urea, glucose, and ethanol or undergoing similar measurements performed within 30 minutes of a measurement of toxic alcohol levels at a single tertiary-care center from April 2001 to June 2016. Patients with detectable toxic alcohols were excluded. INDEX TEST: Equations to calculate osmolarity using multiple linear regression. OUTCOMES: The performance of new equations compared with published equations developed to calculate osmolarity, and to diagnose toxic alcohol intoxications more accurately. RESULTS: We obtained 7,525 measurements, including 100 with undetectable toxic alcohols. Among them, 3,875 had undetectable and 3,650 had detectable ethanol levels. In the entire cohort, the best equation to calculate osmolarity was 2.006×Na + 1.228×Urea + 1.387×Glucose + 1.207×Ethanol (values in mmol/L, R2=0.96). A simplified equation, 2.0×Na + 1.2×Urea + 1.4×Glucose + 1.2×Ethanol, had a similar R2 with 95% of osmolal gap values between -10.9 and 13.8. In patients with undetectable ethanol concentrations, the range of 95% of osmolal gap values was narrower than previous published formulas, and in patients with detectable ethanol concentrations, the range was narrower or similar. We performed a subanalysis of 138 cases for which both the toxic alcohol concentration could be measured and the osmolal gap could be calculated. Our simplified equation had superior diagnostic accuracy for toxic alcohol exposure. LIMITATIONS: Single center, no external validation, limited number of cases with detectable toxic alcohols. CONCLUSIONS: In a large cohort, coefficients from regression analyses estimating the contribution of glucose, urea, and ethanol were higher than 1.0. Our simplified formula to precisely calculate osmolarity yielded improved diagnostic accuracy for suspected toxic alcohol exposures than previously published formulas.

[Role of thrombospondin-1 in the development of kidney diseases]. / Rôle de la thrombospondine-1 dans le développement des maladies rénales.

Thrombospondin-1 (TSP-1) is a 450-kDa matricellar glycoprotein. By its various domains, it can interact with various partners and exhibit anti-angiogenic, pro-apoptotic and immunomodulatory activities. TSP-1 is also a major endogenous activator of the pro-fibrotic growth factor TGF-ß. In healthy adult renal parenchyma, TSP-1 expression is very scarce and limited to Bowman's capsule and interstitium. During nephropathies, many cell types can express or secrete TSP-1 (mesangial, endothelial, smooth muscle, tubular cells, podocytes and fibroblasts) depending on the nature of injury and the evolutive stage of the disease. Inhibition of the different domains of TSP-1 using specific antibodies or peptides, blockade of TSP-1 expression by antisense oligonucleotides and use of knock-out mice, allowed to identify the role of TSP-1 in various models of experimental nephropathy. All these studies demonstrated a deleterious effect of TSP-1 on renal repair by inducing TGF-ß and fibrosis, decreasing VEGF and capillary density, and enhancing inflammatory cells recruitment. Thus, TSP-1 represents a potential therapeutic target for the management of chronic kidney diseases.

Differential Pharmacokinetics of Liver Tropism for Iron Sucrose, Ferric Carboxymaltose, and Iron Isomaltoside: A Clue to Their Safety for Dialysis Patients.

Anemia is a major complication of end-stage kidney disease (ESKD). Erythropoiesis-stimulating agents and intravenous (IV) iron are the current backbone of anemia treatment in ESKD. Iron overload induced by IV iron is a potential clinical problem in dialysis patients. We compared the pharmacokinetics of liver accumulation of iron sucrose, currently used worldwide, with two third-generation IV irons (ferric carboxymaltose and iron isomaltoside). We hypothesized that better pharmacokinetics of newer irons could improve the safety of anemia management in ESKD. Liver iron concentration (LIC) was analyzed in 54 dialysis patients by magnetic resonance imaging under different modalities of iron therapy. LIC increased significantly in patients treated with 1.2 g or 2.4 g IV iron sucrose (p < 0.001, Wilcoxon test), whereas no significant increase was observed in patients treated with ferric carboxymaltose or iron isomaltoside (p > 0.05, Wilcoxon-test). Absolute differences in LIC reached 25 µmol/g in the 1.2 g iron sucrose group compared with only 5 µmol/g in the 1 g ferric carboxymaltose and 1 g iron isomaltoside groups (p < 0.0001, Kruskal−Wallis test). These results suggest the beneficial consequences of using ferric carboxymaltose or iron isomaltoside on liver structure in ESKD due to their pharmacokinetic ability to minimize iron overload.

Donor Age, Donor-Recipient Size Mismatch, and Kidney Graft Survival.

BACKGROUND AND OBJECTIVES: Small donor and/or kidney sizes relative to recipient size are associated with a higher risk of kidney allograft failure. Donor and recipient ages are associated with graft survival and may modulate the relationship between size mismatch and the latter. The aim of this study was to determine whether the association between donor-recipient size mismatch and graft survival differs by donor and recipient age. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENT: We performed a retrospective cohort study of first adult deceased donor kidney transplantations performed between 2000 and 2018 recorded in the Scientific Registry of Transplant Recipients. We used multivariable Cox proportional hazards models to assess the association between donor-recipient body surface area ratio and death-censored graft survival, defined as return to dialysis or retransplantation. We considered interactions between donor-recipient body surface area ratio and each of recipient and donor age. RESULTS: Among the 136,321 kidney transplant recipients included in this study, 23,614 (17%) experienced death-censored graft loss over a median follow-up of 4.3 years (interquartile range, 1.9-7.8 years). The three-way donor-recipient body surface area ratio by donor age by recipient age interaction was statistically significant (P=0.04). The magnitude of the association between severe size mismatch (donor-recipient body surface area ratio <0.80 versus ≥1.00) and death-censored graft survival was stronger with older donor age and recipient age. In all recipient age categories except the youngest (18-30 years), 5- and 10-year graft survival rates were similar or better with a size-mismatched donor aged <40 years than a nonsize-mismatched donor aged 40 years or older. CONCLUSIONS: The association of donor-recipient size mismatch on long-term graft survival is modulated by recipient and donor age. Size-mismatched kidneys yield excellent graft survival when the donor is young. Donor age was more strongly associated with graft survival than size mismatch.

Impact of updated recommendations on acetylsalicylic acid use for primary prevention of cardiovascular disease in Canada: a population-based survey.

BACKGROUND: The debate over acetylsalicylic acid (ASA) therapy for primary prevention of cardiovascular disease (CVD) has recently resurfaced, but scarce data are available on prophylactic ASA use in Canada for this purpose. This study aimed to evaluate the prevalence and factors associated with ASA use, and the potential impact of implementing the most recent (2016) US Preventive Services Task Force recommendations for primary CVD prevention in a Canadian setting. METHODS: We performed a cross-sectional analysis using data from the CARTaGENE study, which included a representative sample (n = 20 004) of the 2018 general population of the province of Quebec. We assessed eligibility for ASA treatment using US Preventive Services Task Force criteria (age 50-69 yr, no past history of myocardial infarction or stroke, and 10-year risk of CVD of at least 10%). We extrapolated to the entire 2018 Quebec population the number of people who would need to start ASA treatment. RESULTS: A total of 6231 respondents in the CARTaGENE study (54.2% of those aged 50-69 yr with no prior history of CVD) were found to be potentially eligible for ASA use for primary CVD prevention. Of the 6231, 1379 (22.1%) were receiving prophylactic ASA treatment. Factors found to be related to ASA use included age, male sex, regular medical visits, lower education level, obesity, hypertension, diabetes and dyslipidemia. Income and smoking status were not found to be significantly associated with ASA use. Our results indicate that 885 261 people would potentially have started ASA treatment if the US Preventive Services Task Force recommendations had been implemented in Quebec in 2018. INTERPRETATION: Prevalent ASA use for primary CVD prevention was low. Implementation of the 2016 US Preventive Services Task Force recommendations would require initiating ASA treatment in a substantial proportion of people, with undetermined potential benefits.

Histological Scores Validate the Accuracy of Hepatic Iron Load Measured by Signal Intensity Ratio and R2* Relaxometry MRI in Dialysis Patients.

Almost all haemodialysis patients are treated with parenteral iron to compensate for blood loss and to allow the full therapeutic effect of erythropoiesis-stimulating agents. Iron overload is an increasingly recognised clinical situation diagnosed by quantitative magnetic resonance imaging (MRI). MRI methods have not been fully validated in dialysis patients. We compared Deugnier's and Turlin's histological scoring of iron overload and Scheuer's classification (with Perls' stain) with three quantitative MRI methods for measuring liver iron concentration (LIC)-signal intensity ratio (SIR), R2* relaxometry, and R2* multi-peak spectral modelling (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL-IQ®)) relaxometry-in 16 haemodialysis patients in whom a liver biopsy was formally indicated for medical follow-up. LIC MRI with these three different methods was highly correlated with Deugnier's and Turlin's histological scoring (SIR: r = 0.8329, p = 0.0002; R2* relaxometry: r = -0.9099, p < 0.0001; R2* relaxometry (IDEAL-IQ®): r = -0.872, p = 0.0018). Scheuer's classification was also significantly correlated with these three MRI techniques. The positive likelihood ratio for the diagnosis of abnormal LIC by Deugnier's histological scoring was > 62 for the three MRI methods. This study supports the accuracy of quantitative MRI methods for the non-invasive diagnosis and follow-up of iron overload in haemodialysis patients.

Liver Iron Load Influences Hepatic Fat Fraction in End-Stage Renal Disease Patients on Dialysis: A Proof of Concept Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases including steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and end-stage liver failure. Hepatic iron accumulation has been linked to hepatic fibrosis severity in NASH and NAFLD. Iron overload induced by parenteral (IV) iron therapy is a potential clinical problem in dialysis patients. We analyzed the hypothetical triggering and aggravating role of iron on NAFLD in patients on dialysis. METHODS: Liver iron concentration (LIC) and hepatic proton density fat fraction (PDFF) were analyzed prospectively in 68 dialysis patients by magnetic resonance imaging (MRI). Follow up of LIC and PDFF was performed in 17 dialysis patients during iron therapy. FINDINGS: PDFF differed significantly among dialysis patients classified according to LIC: patients with moderate or severe iron overload had increased fat fraction (PDFF: 7.9% (0.5-14.8%)) when compared to those with normal LIC (PDFF: 5% (0.27-11%)) or mild iron overload (PDFF: 5% (0.30-11.6%); P = 0.0049). PDFF correlated with LIC, and ferritin and body mass index. In seven patients monitored during IV iron therapy, LIC and PDFF increased concomitantly (PDFF: initial 2.5%, final 8%, P = 0.0156; LIC: initial 20 µmol/g, final 160 µmol/g: P = 0.0156), whereas in ten patients with iron overload, PDFF decreased after IV iron withdrawal or major dose reduction (initial: 8%, final: 4%; P = 0.0098) in parallel with LIC (initial: 195 µmol/g, final: 45 µmol/g; P = 0.002). INTERPRETATION: Liver iron load influences hepatic fat fraction in dialysis patients. Iron overload induced by iron therapy may aggravate or trigger NAFLD in dialysis patients. TRIAL REGISTRATION NUMBER (ISRCTN): 80100088.

Estimating the Change in Renal Function During the First Year of Therapy in ANCA-Associated Vasculitis.

INTRODUCTION: Studies in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) consistently show that the months following diagnosis have the greatest impact on the long-term renal function. Yet, it remains uncertain how much early gain should be expected with treatment. We sought to determine the factors associated with the change in glomerular filtration rate (GFR) throughout the first year. METHODS: We retrospectively reviewed patients from 3 university hospitals who received treatments. We assessed the proportions of glomeruli with crescents, with global sclerosis, the AAV glomerulonephritis classification, the severity of chronic vascular and tubulo-interstitial disease, and the presence of acute tubular injury (ATI). We used repeated-measures analyses of variance (ANOVAs) to determine factors associated with the change in GFR throughout the first year. RESULTS: There were 162 individuals with AAV identified, 96 with a valid renal biopsy and 82 with at least 12 months of follow-up. The initial GFR of 30 ± 25 ml/min per 1.73 m2 rose by 15 ± 20 during the first year. The severity of pathology findings, myeloperoxidase positivity, and those with kidney- and lung-limited disease presented with a lower GFR. Younger patients with a lower initial GFR and the presence of ATI correlated with a greater increase in GFR by 12 months. A higher proportion of crescents did not predict the change in GFR, contrary to global glomerulosclerosis, where each 10% increase added a loss of 2.7 ± 1.3 ml/min per 1.73 m2 per year (P = 0.03). These factors remained independent of each other. CONCLUSION: Multiple factors influence renal recovery during the first year of therapy. Estimating the change in GFR early on will help identify and reassess outliers.

Uric acid association with pulsatile and steady components of central and peripheral blood pressures.

OBJECTIVE: Whether the cardiovascular risk attributed to elevated uric acid levels may be explained by changes in central and peripheral pulsatile and/or steady blood pressure (BP) components remains controversial. METHODS: In a cross-sectional analysis of normotensive and untreated hypertensive participants of the CARTaGENE populational cohort, we examined the relationship between uric acid, and both pulsatile and steady components of peripheral and central BP, using sex-stratified linear regressions. RESULTS: Of the 20 004 participants, 10 161 individuals without antihypertensive or uric acid-lowering drugs had valid pulse wave analysis and serum uric acid levels. In multivariate analysis, pulsatile components of BP were not associated with uric acid levels, whereas steady components [mean BP (MBP), peripheral and central DBP] were all associated with higher levels of uric acid levels in women and men (all P < 0.001). Furthermore, there was a gradual increase of central SBP (cSBP), DBP and MBP from the lowest to the highest quintiles of uric acid levels but not for MBP-adjusted cSBP. Peripheral and cSBP, which are aggregate measures of pulsatile and steady BP, were also associated with uric acid levels in women (ß = 0.063 and 0.072, respectively, both P < 0.001) and men (ß = 0.043 and 0.051, both P ≤ 0.003). After further adjustments for MBP to account for the concomitant increase in steady component of BP, SBPs were no longer associated with uric acid levels. CONCLUSION: Serum uric acid levels appear to be associated with both central and peripheral steady but not pulsatile BP, regardless of sex.

The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients.

Background: The aim of this study was to assess the impact of follow-up in renal protection clinics on the prescription of and adherence to cardioprotective drugs in patients with chronic kidney disease (CKD). Methods: We studied stage 4 and 5 CKD patients who initiated follow-up in three renal protection clinics. The prescription pattern of antihypertensive agents (AHA) and lipid-lowering agents (LLAs) was measured as the percentage of patients who are prescribed the agents of interest at a given time. Adherence to drug therapy was defined as the percentage of days, during a pre-defined observation period, in which patients have an on-hand supply of their prescribed medications. Results: A total of 259 CKD patients were enrolled and followed for up to 1 year after referral to renal protection clinics. There was a significant increase in the prescription of angiotensin-converting enzyme inhibitors (34-39%), angiotensin II receptor blockers (11-14%), beta-blockers (40-51%), calcium channel blockers (62-74%), diuretics (66-78%) and LLAs (39-47%) during follow-up in the renal protection clinic compared with baseline (P-values <0.01 for all comparisons). The proportions of patients with good (≥ 80%) and poor (< 80%) adherence to AHA (P = 0.41) and LLAs (P = 0.11) were similar in the year preceding and the year following the first visit to the renal protection clinics. Conclusion: Our results suggest that referral and follow-up in a renal protection clinic may increase the prescription of cardioprotective agents in CKD patients, but does not appear to improve adherence to these medications.