Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis.

Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.

Is shrunken pore syndrome also a reality in children?

BACKGROUND: Shrunken pore syndrome (SPS) is defined as cystatin C-based-eGFR (eGFRcys)/creatinine-based-eGFR (eGFRcreat) <0.6 or 0.7 and is associated with an increased cardiovascular risk. SPS has been described in children, but no link to increased morbi-mortality was demonstrated. OBJECTIVES: Study the prevalence of SPS in a pediatric population using several glomerular filtration rate (GFR) estimating formulas and measured GFR and evaluate the potential link with cardiovascular risk. METHODS: In 307 renal risk pediatric patients, we studied prevalence of SPS either with CKiDU25creat and cyst or with FAScreat and cyst and EKFCcreat. The characteristics of patients with SPS (defined with Full-age spectrum equation (FAS) and/or European Kidney Function Consortium equation (EKFC)) were compared. RESULTS AND CONCLUSION: The prevalence of SPS varies widely depending on the threshold and the formulas used. Higher C-reactive protein (CRP) and phosphate levels and smaller size are observed in children with SPS defined with FAS and/or EKFC and might be associated with long-term increased cardiovascular risk. Further studies in wider general pediatric populations are warranted.

Redefining the concept of residual renal function with kidney sodium MRI: a pilot study.

RATIONALE & OBJECTIVE: The concept of residual kidney function (RKF) is exclusively based upon urine volume and small solute clearance, making RKF challenging to assess in clinical practice. The aim of this study was to test the technical feasibility of obtaining useable 23Na-MRI kidney images in hemodialysis (HD) participants. STUDY DESIGN: We conducted an exploratory prospective study to quantify the cortico-medullary sodium gradient in healthy and HD participants. Participants fasted for eight hours prior to their study visit. Urine samples were collected to measure urinary osmolarity, before MRI. Proton and sodium pictures were merged; ROIs were delineated for the medulla and cortex when feasible. In cases where cortex could not be identified, we considered the cortico to medulla gradient (CMG) to be no longer present, resulting in a medulla-to-cortex ratio of 1. SETTING & PARTICIPANTS: 17 healthy volunteers and 21 HD participants. FINDINGS: Median (IQR) fasting medulla to cortex ratio was significantly higher 1.56 [1.5-1.61] in healthy volunteers compared to HD patients 1.22 [1.13-1.3], p < 0.0001. Medulla to cortex ratio and median urinary osmolarity were correlated (r = 0.87, p < 0.0001) in the whole population. We found a significant association between HD vintage and medulla to cortex ratio whereas we did not find any association with urine volume. Sodium signal intensity distribution within healthy kidney describes two different peaks- relating to well defined cortex and medulla; whereas HD participants displays only a single peak indicative of the markedly lower sodium concentration. LIMITATIONS: This study is only an exploratory study with a modest number of patients. CONCLUSIONS: the application of kidney sodium MRI to the study of RKF in patients receiving maintenance HD is practical and provides a previously unavailable ability to interrogate the function of remnant tubular function.

Creatinine-based formulas are not ideal to estimate glomerular filtration rate in selected pediatric patients: data from a tertiary pediatric nephrology center.

BACKGROUND: Evaluating glomerular filtration rate (GFR) remains challenging in pediatrics; new formulas were developed to increase performance of GFR estimation (eGFR). We aimed to evaluate the recently published formulas as applied to another pediatric population. METHODS: A retrospective study was conducted in a cohort of 307 patients with a "kidney risk" (mean age 12.1 ± 4.5 years, sex ratio 1/1) assessed in a tertiary pediatric nephrology center and a mean measured GFR (mGFR) using plasma iohexol clearance of 85.5 ± 25.3 mL/min/1.73 m2; creatinine levels were measured by IDMS-standardized enzymatic method and cystatin C by immunonephelometry. The following eGFRs were calculated: Schwartz2009, Schwartz-Lyon, CKiDU25creat, and EKFC for eGFR using creatinine (eGFR-creat), CKiDU25cys and FAScys for eGFR using cystatin (eGFR-cys) as well as combined SchwartzCreat-Cys, average (CKiDU25creat-CKiDU25cys), and average (EKFC-FAScys) for eGFR using both biomarkers. The performance of the different formulas was evaluated compared to mGFR by absolute bias measurement and accuracy (p10%, p30%). Results are expressed as mean ± SD. RESULTS: Creatinine-based formulas and especially the new CKiDU25 and EKFC overestimate GFR, even in children with normal kidney function. However, the bias is constant with these two formulas whatever the age group or gender, contrary to the previously published formulas. In contrast, cystatin C-based equations and combined formulas showed good performance in all age groups and all medical conditions with an acceptable bias and p30%. CONCLUSIONS: In our pediatric population, the performance of all creatinine-based formulas is inadequate with significant GFR overestimation, mainly in subjects with mGFR > 75 mL/min/1.73 m2. Conversely, cystatin C-based or combined formulas have acceptable performance in patients followed in a tertiary pediatric nephrology unit.

Extending the cystatin C based EKFC-equation to children - validation results from Europe.

BACKGROUND: A new cystatin C based European Kidney Function Consortium (EKFCCysC) equation was recently developed for adults, using the same mathematical form as the previously published full age spectrum creatinine based EKFC-equation (EKFCCrea). In the present study the cystatin C based EKFC-equation is extended to children, by defining the appropriate cystatin C rescaling factor QCysC. METHODS: Rescaling factor QCysC for cystatin C was defined as: a) 0.83 mg/L, exactly as it was defined for young adults in the adult equation, and b) a more complex QCysC-age relationship based on 4th degree cystatin C-age polynomials after evaluation of data from Uppsala, Stockholm and Canada and aggregated data from Germany. The EKFCCysC equation was then validated in an independent dataset in European children (n = 2,293) with measured GFR, creatinine, cystatin C, age, height and sex available. RESULTS: The EKFCCysC with the simple QCysC-value of 0.83 had a bias of -7.6 [95%CI -8.4;-6.5] mL/min/1.73 m2 and a P30-value of 85.8% [95%CI 84.4;87.3] equal to the EKFCCysC with the more complex 4th degree QCysC-value. The arithmetic mean of the EKFCCrea and EKFCCysC with the simple QCysC of 0.83 had a bias of -4.0 [95%CI -4.5;-3.1] mL/min/1.73 m2 and P30 of 90.4% [95%CI 89.2;91.6] similar to using the more complex 4th degree QCysC-polynomial. CONCLUSION: Using exactly the same QCysC of 0.83 mg/L, the adult EKFCCysC can easily be extended to children, with some bias but acceptable P30-values. The arithmetic mean of EKFCCrea and EKFCCysC results in bias closer to zero and P30 slightly over 90%.

Effects of pediatric chronic kidney disease and its etiology on tissue sodium concentration: a pilot study.

BACKGROUND: Sodium-23 magnetic resonance imaging (23Na MRI) allows non-invasive assessment of tissue sodium concentration ([Na+]). Age and chronic kidney disease (CKD) are associated with increased tissue [Na+] in adults, but limited information is available pertaining to children and adolescents. We hypothesized that pediatric CKD is associated with altered tissue [Na+] compared to healthy controls. METHODS: This was a case-control exploratory study on healthy children and adults and pediatric CKD patients. Study participants underwent an investigational visit, blood/urine biochemistry, and leg 23Na MRI for tissue [Na+] quantification (whole leg, skin, soleus muscle). CKD was stratified by etiology and patients' tissue [Na+] was compared against healthy controls by computing individual Z-scores. An absolute Z-score > 1.96 was deemed to deviate significantly from the mean of healthy controls. Pearson correlation was used to compute the associations between tissue [Na+] and kidney function. RESULTS: A total of 36 pediatric participants (17 healthy, 19 CKD) and 19 healthy adults completed the study. Healthy adults had significantly higher tissue [Na+] compared with pediatric groups; conversely, no significant differences were found between healthy children/adolescents and CKD patients. Four patients with glomerular disease and one kidney transplant recipient due to atypical hemolytic-uremic syndrome had elevated whole-leg [Na+] Z-scores. Reduced whole-leg [Na+] Z-scores were found in two patients with tubular disorders (Fanconi syndrome, proximal-distal renal tubular acidosis). All tissue [Na+] measures were significantly associated with proteinuria and hypoalbuminemia. CONCLUSIONS: Depending on etiology, pediatric CKD was associated with either increased (glomerular disease) or reduced (tubular disorders) tissue [Na+] compared with healthy controls. A higher resolution version of the Graphical abstract is available as Supplementary information.

Impact of race-independent equations on estimating glomerular filtration rate for the assessment of kidney dysfunction in liver disease.

BACKGROUND: Altered hemodynamics in liver disease often results in overestimation of glomerular filtration rate (GFR) by creatinine-based GFR estimating (eGFR) equations. Recently, we have validated a novel eGFR equation based on serum myo-inositol, valine, and creatinine quantified by nuclear magnetic resonance spectroscopy in combination with cystatin C, age and sex (GFRNMR). We hypothesized that GFRNMR could improve chronic kidney disease (CKD) classification in the setting of liver disease. RESULTS: We conducted a retrospective multicenter study in 205 patients with chronic liver disease (CLD), comparing the performance of GFRNMR to that of validated CKD-EPI eGFR equations, including eGFRcr (based on creatinine) and eGFRcr-cys (based on both creatinine and cystatin C), using measured GFR as reference standard. GFRNMR outperformed all other equations with a low overall median bias (-1 vs. -6 to 4 ml/min/1.73 m2 for the other equations; p < 0.05) and the lowest difference in bias between reduced and preserved liver function (-3 vs. -16 to -8 ml/min/1.73 m2 for other equations). Concordant classification by CKD stage was highest for GFRNMR (59% vs. 48% to 53%) and less biased in estimating CKD severity compared to the other equations. GFRNMR P30 accuracy (83%) was higher than that of eGFRcr (75%; p = 0.019) and comparable to that of eGFRcr-cys (86%; p = 0.578). CONCLUSIONS: Addition of myo-inositol and valine to creatinine and cystatin C in GFRNMR further improved GFR estimation in CLD patients and accurately stratified liver disease patients into CKD stages.

Challenges and Opportunities in Titrating Disease-Modifying Therapies in Heart Failure with Reduced Ejection Fraction and Chronic Kidney Disease.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is highly prevalent in patients with heart failure and reduced ejection fraction (HFrEF), representing a major factor of adverse outcomes. In clinical practice, it is one of the main reasons for not initiating, not titrating, and even withdrawing efficient heart failure drug therapies in patients. RECENT FINDINGS: Despite limited data, studies show that HFrEF therapies maintain their benefits on cardiovascular outcomes in patients with CKD. Most HF drugs cause acute renal haemodynamic changes, but with stabilisation or even improvement after the acute phase, thus with no long-term worsening of the renal function. In this expert opinion-based paper, we challenge the pathophysiology misunderstandings that impede HF disease-modifying therapy implementation in this setting and propose a strategy for HF drug titration in patients with moderate, severe, and end-stage chronic kidney disease.

Heat Shock Protein 70 Is Involved in the Efficiency of Preconditioning with Cyclosporine A in Renal Ischemia Reperfusion Injury by Modulating Mitochondrial Functions.

Cyclosporine A (CsA) preconditioning is known to target mitochondrial permeability transition pore and protect renal function after ischemia reperfusion (IR). The upregulation of heat-shock protein 70 (Hsp70) expression after CsA injection is thought to be associated with renal protection. The aim of this study was to test the effect of Hsp70 expression on kidney and mitochondria functions after IR. Mice underwent a right unilateral nephrectomy and 30 min of left renal artery clamping, performed after CsA injection and/or administration of the Hsp70 inhibitor. Histological score, plasma creatinine, mitochondrial calcium retention capacity, and oxidative phosphorylation were assessed after 24 h of reperfusion. In parallel, we used a model of hypoxia reoxygenation on HK2 cells to modulate Hsp70 expression using an SiRNA or a plasmid. We assessed cell death after 18 h of hypoxia and 4 h of reoxygenation. CsA significantly improved renal function, histological score, and mitochondrial functions compared to the ischemic group but the inhibition of Hsp70 repealed the protection afforded by CsA injection. In vitro, Hsp70 inhibition by SiRNA increased cell death. Conversely, Hsp70 overexpression protected cells from the hypoxic condition, as well as the CsA injection. We did not find a synergic association between Hsp70 expression and CsA use. We demonstrated Hsp70 could modulate mitochondrial functions to protect kidneys from IR. This pathway may be targeted by drugs to provide new therapeutics to improve renal function after IR.

Functional Sodium MRI Helps to Measure Corticomedullary Sodium Content in Normal and Diseased Human Kidneys.

Background To the knowledge of the authors, urinary osmolarity is the only tool currently available to assess kidney corticomedullary gradient (CMG). Comparisons between CMG and urinary osmolarity and the use of modalities such as sodium MRI to evaluate renal disease in humans are lacking. Purpose To investigate the ability of sodium MRI to measure CMG dynamics compared with urinary osmolarity after water load in healthy volunteers and CMG in participants with kidney disease. Materials and Methods A prospective study was conducted from July 2020 to January 2021 in fasting healthy volunteers undergoing water load and participants with chronic kidney disease (CKD) from cardiorenal syndrome included in a clinical trial. In both groups, CMG was estimated by measuring the medulla-to-cortex signal ratio from sodium MRI at 3.0 T. A custom-built two-loop (diameter, 18 cm) butterfly radiofrequency surface coil, tuned for sodium frequency (33.786 MHz), was used to acquire renal sodium images. Two independent observers measured all sodium MRI cortical and medullary values for each region of interest to compute the intraclass correlation coefficient. Pearson correlation was performed between urinary osmolarity and CMG. Results Five participants with CKD (mean age, 77 years ± 12 [standard deviation]; all men) and 10 healthy volunteers (mean age, 42 years ± 15; six men, four women) were evaluated. A reduction was observed between baseline and peak urinary dilution time for both mean medulla-to-cortex ratios (1.55 ± 0.11 to 1.31 ± 0.09, respectively; P < .001) and mean urinary osmolarity (756 mOsm/L ± 157 to 73 mOsm/L ± 14, respectively; P < .001) in healthy volunteers. Medulla-to-cortex and corresponding urinary osmolarity were correlated in both groups (r2 = 0.22; P < .001). Kidney sodium tissue content was successfully acquired in all five participants with CKD. The intraclass correlation coefficient measurement was 0.99 (P < .001). Conclusion Functional sodium MRI accurately depicted corticomedullary gradient (CMG) dynamic changes in healthy volunteers and demonstrated feasibility of CMG measurement in participants with reduced kidney function. Clinical trial registration no. NCT04170855. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Laustsen and Bøgh in this issue.

Tubular phosphate handling: references from child to adulthood in the era of standardized serum creatinine.

BACKGROUND: The assessment of phosphate homeostasis in clinical practice relies not only on circulating phosphate levels but also on phosphate tubular reabsorption, ideally assessed using the tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR). TmP/GFR reference values were established before the onset of isotope-dilution mass spectrometry-standardized (IDMS) creatinine assays and thus need to be updated. Our objective is to provide reference values for TmP/GFR from childhood to adulthood, using the gold-standard of GFR assessment and IDMS-standardized creatinine values. METHODS: We retrospectively analysed all the inulin and iohexol clearances [measured glomerular filtration rate (mGFR)] performed in children and in adults screened for a living-donation in our unit since the beginning of IDMS-creatinine assays. TmP/GFR was calculated on a fasting sample, using the conventional formula without correction for tubular reabsorption of phosphate (TRP) in subjects below 19 years of age. RESULTS: A total of 2051 subjects (1711 children, 340 adults), aged from 1.9 to 73.4 years with normal GFR, normal phosphate and normal calcium levels, were included for TmP/GFR analysis. As expected, there was a progressive decrease along puberty in both genders of plasma phosphate and TmP/GFR, the decrease occurring earlier in girls. After the age of 19 years, there was a stabilization of plasma phosphate and TmP/GFR levels until the age of 55 years, phosphate levels and TmP/GFR being slightly lower in men than in women. CONCLUSION: We present the largest cohort describing TmP/GFR reference values in the era of IDMS-standardized creatinine assays. We believe that these data will help physicians to better diagnose and manage patients with abnormal phosphate metabolism in daily clinical routine.

Pregnancy in cystinosis patients with chronic kidney disease: A European case series.

Cystinosis is a rare autosomal recessive disease leading to end-stage renal disease within the second or third decade of life. Since the era of specific treatment with cysteamine, prognosis has substantially improved and pregnancy becomes an increasing concern. Pregnancy data in patients with cystinosis were collected through an anonymized survey. We collected data for 19 pregnancies in 12 women. Seventeen patients were transplanted, 1 was on hemodialysis and 1 had chronic kidney disease (CKD) stage 4. These 19 pregnancies resulted in 13 live births (68.4%): 3 spontaneous early miscarriages, 1 ectopic pregnancy, 1 early pre-eclampsia (at 21 weeks), and 1 preterm birth with neonatal death at 24 weeks were reported. After exclusion of early miscarriage or termination, pregnancy success rate was 86.7%. In successful pregnancies, median gestational age at delivery was 34 weeks (24-37). Preeclampsia occurred in seven pregnancies (7/15, 46.7%). A cesarean section was performed in all pregnancies. Median baby weight at delivery was 2175 g (620-3374 g). After pregnancy, one patient reached end-stage renal disease, but she already had advanced CKD before pregnancy (creatinine 239 µmol/L, eGFR 23 ml/min/1.73 m2 ). In three other patients, there was a decrease of eGFR of 8, 20, and 53 ml/min/1.73 m2 , respectively. The majority of pregnancies were successful, but severe antenatal and post-natal complications may occur, in particular preeclampsia that was noticed in nearly half of patients and fetal loss in one-third of them. These results may help pre-pregnancy counseling and pregnancy management.

Intracellular Phosphate and ATP Depletion Measured by Magnetic Resonance Spectroscopy in Patients Receiving Maintenance Hemodialysis.

BACKGROUND: The precise origin of phosphate that is removed during hemodialysis remains unclear; only a minority comes from the extracellular space. One possibility is that the remaining phosphate originates from the intracellular compartment, but there have been no available data from direct assessment of intracellular phosphate in patients undergoing hemodialysis. METHODS: We used phosphorus magnetic resonance spectroscopy to quantify intracellular inorganic phosphate (Pi), phosphocreatine (PCr), and ßATP. In our pilot, single-center, prospective study, 11 patients with ESKD underwent phosphorus (31P) magnetic resonance spectroscopy examination during a 4-hour hemodialysis treatment. Spectra were acquired every 152 seconds during the hemodialysis session. The primary outcome was a change in the PCr-Pi ratio during the session. RESULTS: During the first hour of hemodialysis, mean phosphatemia decreased significantly (-41%; P<0.001); thereafter, it decreased more slowly until the end of the session. We found a significant increase in the PCr-Pi ratio (+23%; P=0.001) during dialysis, indicating a reduction in intracellular Pi concentration. The PCr-ßATP ratio increased significantly (+31%; P=0.001) over a similar time period, indicating a reduction in ßATP. The change of the PCr-ßATP ratio was significantly correlated to the change of depurated Pi. CONCLUSIONS: Phosphorus magnetic resonance spectroscopy examination of patients with ESKD during hemodialysis treatment confirmed that depurated Pi originates from the intracellular compartment. This finding raises the possibility that excessive dialytic depuration of phosphate might adversely affect the intracellular availability of high-energy phosphates and ultimately, cellular metabolism. Further studies are needed to investigate the relationship between objective and subjective effects of hemodialysis and decreases of intracellular Pi and ßATP content. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Intracellular Phosphate Concentration Evolution During Hemodialysis by MR Spectroscopy (CIPHEMO), NCT03119818.

Mild Therapeutic Hypothermia Protects from Acute and Chronic Renal Ischemia-Reperfusion Injury in Mice by Mitigated Mitochondrial Dysfunction and Modulation of Local and Systemic Inflammation.

Renal ischemia-reperfusion (IR) injury can lead to acute kidney injury, increasing the risk of developing chronic kidney disease. We hypothesized that mild therapeutic hypothermia (mTH), 34 °C, applied during ischemia could protect the function and structure of kidneys against IR injuries in mice. In vivo bilateral renal IR led to an increase in plasma urea and acute tubular necrosis at 24 h prevented by mTH. One month after unilateral IR, kidney atrophy and fibrosis were reduced by mTH. Evaluation of mitochondrial function showed that mTH protected against IR-mediated mitochondrial dysfunction at 24 h, by preserving CRC and OX-PHOS. mTH completely abrogated the IR increase of plasmatic IL-6 and IL-10 at 24 h. Acute tissue inflammation was decreased by mTH (IL-6 and IL1-ß) in as little as 2 h. Concomitantly, mTH increased TNF-α expression at 24 h. One month after IR, mTH increased TNF-α mRNA expression, and it decreased TGF-ß mRNA expression. We showed that mTH alleviates renal dysfunction and damage through a preservation of mitochondrial function and a modulated systemic and local inflammatory response at the acute phase (2-24 h). The protective effect of mTH is maintained in the long term (1 month), as it diminished renal atrophy and fibrosis, and mitigated chronic renal inflammation.

Cystinuria: clinical practice recommendation.

Cystinuria (OMIM 220100) is an autosomal recessive hereditary disorder in which high urinary cystine excretion leads to the formation of cystine stones because of the low solubility of cystine at normal urinary pH. We developed clinical practice recommendation for diagnosis, surgical and medical treatment, and follow-up of patients with cystinuria. Elaboration of these clinical practice recommendations spanned from June 2018 to December 2019 with a consensus conference in January 2019. Selected topic areas were chosen by the co-chairs of the conference. Working groups focusing on specific topics were formed. Group members performed systematic literature review using MEDLINE, drafted the statements, and discussed them. They included geneticists, medical biochemists, pediatric and adult nephrologists, pediatric and adult urologists experts in cystinuria, and the Metabolic Nephropathy Joint Working Group of the European Reference Network for Rare Kidney Diseases (ERKNet) and eUROGEN members. Overall 20 statements were produced to provide guidance on diagnosis, genetic analysis, imaging techniques, surgical treatment (indication and modalities), conservative treatment (hydration, dietetic, alkalinization, and cystine-binding drugs), follow-up, self-monitoring, complications (renal failure and hypertension), and impact on quality of life. Because of the rarity of the disease and the poor level of evidence in the literature, these statements could not be graded. This clinical practice recommendation provides guidance on all aspects of the management of both adults and children with cystinuria, including diagnosis, surgery, and medical treatment.

Comparison of iohexol plasma clearance formulas vs. inulin urinary clearance for measuring glomerular filtration rate.

OBJECTIVES: The one-compartment iohexol plasma clearance has been proposed as a reliable alternative to renal inulin clearance. However, this method's performance depends on the formula used to calculate glomerular filtration rate (GFR). This study reports on performance comparisons between various mathematical formulas proposed for iohexol plasma clearance vs. inulin urinary clearance. METHODS: GFR was simultaneously determined by inulin and iohexol clearance in 144 participants (age: 10-84 years; glomerular filtration rate: 15-169 mL/min/1.73 m2). A retrospective cross-sectional study evaluated the performance of four formulas proposed to calculate plasma iohexol clearance (Brøchner-Mortensen, Fleming et al., Jødal-Brøchner-Mortensen, and Ng-Schwartz-Munoz). The performance of each formula was assessed using bias, precision (standard deviation of the bias), accuracy (percentage iohexol within 5, 10, and 15%), root mean square error, and concordance correlation coefficient vs. renal inulin clearance as reference. RESULTS: Regarding accuracy, there was no difference in root mean square error (RMSE), P5, P10, or P15 between the four formulas. The four concordance correlation coefficients (CCC) between the value from each formula and in-GFR were high and not significantly different. At in-GFR ≥90 mL/min/1.73 m2, Ng-Schwartz-Munoz formula performed slightly better than other formulas regarding median bias (-0.5; 95% CI [-3.0 to 2.0] and accuracy P15 (95.0; 95% CI [88.0-100.0]). CONCLUSIONS: The studied formulas were found equivalent in terms of precision and accuracy, but the Ng-Schwartz-Munoz formula improved the accuracy at higher levels of in-GFR.

Adherence to cysteamine in nephropathic cystinosis: A unique electronic monitoring experience for a better understanding. A prospective cohort study: CrYSTobs.

INTRODUCTION: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems. METHODS: Patients with confirmed NC, aged > 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up. RESULTS: Seventeen patients (10 girls, median age: 13.9 (5.4-33.0) years) were included. Median age at diagnosis was 17.0 (3.0-76.9) months and age at start of cysteamine was 21.0 (15.5-116.3) months. Median daily dose of cysteamine was 1.05 (0.55-1.63) g/m2/day. Over the year, the median percentage of days with a good adherence score was 80 (1-99)% decreasing to 68 (1-99)% in patients > 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1-23.9) versus 14.9 (9.2-20.5) hours for delayed release versus short acting cysteamine. CONCLUSION: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract.

CKD Increases Carbonylation of HDL and Is Associated with Impaired Antiaggregant Properties.

BACKGROUND: CKD is associated with increased oxidative stress that correlates with occurrence of cardiovascular events. Modifications induced by increased oxidative stress particularly affect circulating lipoproteins such as HDL that exhibit antiatheromatous and antithrombotic properties in vitro. METHODS: To explore the specific role of oxidative modifications of HDL in CKD and their effect on the platelet-targeting antiaggregant properties of HDL, we used a CKD (5/6 nephrectomy) rabbit model. For ex vivo assessment of the antiaggregant properties of HDL, we collected blood samples from 15 healthy volunteers, 25 patients on hemodialysis, and 20 on peritoneal dialysis. We analyzed malondialdehyde, 4-hydroxynonenal (HNE), and 4-hydroxy-2-hexenal protein adduct levels. Platelet aggregation and activation were assessed by aggregometry, thromboxane B2 assay, or FACS. We modified HDL from controls by incubating it overnight at 37°C with 100 µM of HNE. RESULTS: HDL from CKD rabbits and patients on hemodialysis had HNE adducts. The percentage of platelet aggregation or activation induced by collagen was significantly higher when platelets were incubated with HDL from CKD rabbit and hemodialysis groups than with HDL from the control group. In both rabbits and humans, platelet aggregation and activation were significantly higher in the presence of HNE-modified HDL than with HDL from their respective controls. Incubation of platelets with a blocking antibody directed against CD36 or with a pharmacologic inhibitor of SRC kinases restored the antiaggregative phenotype in the presence of HDL from CKD rabbits, patients on hemodialysis and peritoneal dialysis, and HNE-modified HDL. CONCLUSIONS: HDL from CKD rabbits and patients on hemodialysis exhibited an impaired ability to inhibit platelet aggregation, suggesting that altered HDL properties may contribute to the increased cardiovascular risk in this population.