Renal and major clinical outcomes and their determinants after nephrectomy in patients with pre-existing chronic kidney disease: A retrospective cohort study.

The consequences of partial nephrectomy (PN) compared to radical nephrectomy (RN) are less documented in patients with pre-existing chronic kidney disease (CKD) or with solitary kidney (SK). We assessed renal outcomes, and their determinants, after PN or RN in a retrospective cohort of patients with moderate-to-severe CKD (RN-CKD and PN-CKD) or SK (PN-SK). All surgical procedures conducted between 2013 and 2018 in our institution in patients with pre-operative estimated glomerular filtration rate (eGFR)<60 mL/min/1.73m2 or with SK were included. The primary outcome was a composite criterion including CKD progression or major adverse cardio-vascular events (MACE) or death, assessed one year after surgery. Predictors of the primary outcome were determined using multivariate analyses. A total of 173 procedures were included (67 RN, and 106 PN including 27 SK patients). Patients undergoing RN were older, with larger tumors. Preoperative eGFR was not significantly different between the groups. One year after surgery, PN-CKD was associated with lower rate of the primary outcome compared to RN-CKD (43% vs 71% p = 0.007). In multivariate analysis, independent risk factors for the primary outcome were postoperative AKI (stage 1 to stage 3 ranging from OR = 8.68, 95% CI 3.23-23.33, to OR = 28.87, 95% CI 4.77-167.61), larger tumor size (OR = 1.21 per cm, 95% CI 1.02-1.45), while preoperative eGFR, age, sex, diabetes mellitus, and hypertension were not. Postoperative AKI after PN or RN was the major independent determinant of worse outcomes (CKD progression, MACE, or death) one year after surgery.

Circulating Oxalate Levels in Short Bowel Syndrome as a Severity Marker of CKD.

Introduction: Patients with short bowel syndrome (SBS) may exhibit enteric hyperoxaluria (EH), and the prevalence of oxalate nephropathy in SBS is likely underestimated. Plasma oxalate (POx) is a surrogate of systemic oxalate deposition and, consequently, may increase the risk of developing chronic kidney disease (CKD). The main objective of this study was to explore the distribution of POx levels in patients with SBS. Methods: Patients followed for SBS were recruited prospectively in the OXAGO study (NCT04119765) to assess POx during their annual renal follow-up including iohexol clearance. The inclusion criteria were age ≥18 years, and SBS type 2 and type 3 for more than 6 months. Results: A total of 47 patients were included but only 45 patients has a measured POx (55% males, 80% SBS type 2, 66% parenteral nutrition, 61% kidney stone history). POx levels were 6.8 ± 4.4 µmol/l, 29% of patients had POx ≥5 µmol/l. In the whole cohort, mean urinary oxalate (UOx) was 648±415 and 54% were >500 µmol/24h. In the group of patients with high POx levels (HPO), 24-hour urine oxalate was significantly higher than in the group with normal POx levels (NPO) (919 ± 566 vs. 526 ± 257 µmol/l; P = 0.003). Glomerular filtration rate (GFR) was 66 ± 22 ml/min per 1.73 m2, and 91% had CKD. GFR was significantly lower in the HPO than in the NPO group (49 ± 23 vs. 73 ± 18 ml/min per 1.73 m2; P = 0.0005. Conclusion: Patients with SBS can display increased POx levels even with GFR >30 ml/min per 1.73 m2. POx may be an interesting biomarker to assess the severity of EH.

Pruritus in Hemodialysis Patients: Longitudinal Associations With Clinical and Patient-Reported Outcomes.

RATIONALE & OBJECTIVE: Cross-sectional studies have reported an association of chronic kidney disease-associated pruritus (CKD-aP) with adverse clinical events and patient-reported outcomes (PROs). We studied the longitudinal associations between changes in CKD-aP and clinical outcomes among patients receiving maintenance hemodialysis. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,976 hemodialysis recipients across 21 countries in phases 4-6 (2009-2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS) who had 2 CKD-aP assessments approximately 12 months apart. EXPOSURES: Exposure status was based on the assessment of pruritis initially and again approximately 1 year later. Four groups were identified, including those with moderate or more severe pruritis only at the initial assessment (resolved), only at the second assessment (incident), at neither assessment (absent), or at both assessments (persistent). OUTCOMES: Laboratory values and PROs ascertained at the initial assessment of pruritis and 1 year later. ANALYTICAL APPROACH: Linear mixed model to investigate changes in laboratory values and PROs over the 1-year study period across the 4 exposure groups. RESULTS: 51% of patients had moderate to severe CKD-aP symptoms at either assessment (22% at both). The prevalences of depression, restless sleep, and feeling drained increased over the study period (+13%,+10%, and+14%, respectively) among patients with incident pruritus and decreased (-5%, -8%, and -12%, respectively) among patients with resolved pruritus. Minimal changes in PROs over time were observed for the absent and persistent groups. Changes over time in laboratory values (phosphorus, Kt/V) were not detected for either of these groups. Compared with patients with absent CKD-aP, the adjusted HRs for patients with persistent CKD-aP were 1.29 (95% CI, 1.09-1.53) for all-cause mortality, 1.17 (1.07-1.28) for all-cause hospitalization, and 1.48 (1.26-1.74) for cardiovascular events. LIMITATIONS: No interim evaluation of CKD-aP symptoms between the 2 assessments; potential selection bias from patients who died or were otherwise lost to follow-up before the second assessment. CONCLUSIONS: CKD-aP symptoms are chronic, and these findings highlight the potential value of repeated assessment of this symptom using standardized approaches. Future research should systematically investigate potential causes of CKD-aP and options for its effective treatment. PLAIN-LANGUAGE SUMMARY: Previous research has studied itching and its consequences in hemodialysis recipients only at a single time point. We surveyed 7,976 patients receiving maintenance hemodialysis to assess itching over a period of 1 year. We found that, among those experiencing itching at the initial assessment, more than half had persistent symptoms 1 year later. Those in whom itching developed during follow-up were more likely to experience depression, poor sleep, long recovery times after dialysis, and feeling faint or drained. These patients also rated their quality of life as poorer than those who did not experience itching. These findings emphasize the potential value of clinical detection of itching and the pursuit of effective treatments for patients receiving dialysis experiencing these symptoms.

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.

Oxalate: from physiology to pathology / Oxalate : de la physiologie à la pathologie

Hyperoxaluria is defined by an increase of urinary oxalate, leading to kidney stones, nephrocalcinosis and/or chronic kidney disease. There are different diseases related to hyperoxaluria: (1) kidney stones, 50% of them being explained by intermittent hyperoxaluria, secondary to dietary mistakes such as low hydration, excess of oxalate consumption and/or low calcium consumption; (2) primary hyperoxaluria, a genetic orphan disease inducing a massive production of oxalate by the liver, leading to increased plasma oxalate increase and saturation, and further systemic oxalosis with oxalate deposition, nephrocalcinosis and ultimately kidney failure, the management of this disease being currently dramatically modified by the onset of new therapeutic tools such as RNA interference; and (3) enteric hyperoxaluria, resulting from increased intestinal oxalate absorption because of intestinal malabsorption (short bowel syndrome, bariatric surgery, exocrine pancreatic insufficiency, etc.). Diagnosis and therapeutic management of these diseases require a full understanding of oxalate physiology that we detail in this review.

L'hyperoxalurie, définie par une élévation de l'oxalate urinaire, favorise la survenue d'une maladie lithiasique, d'une néphrocalcinose et/ou d'une insuffisance rénale chronique. L'hyperoxalurie peut témoigner de différentes maladies : (1) l'hyperoxalurie diététique, responsable de 50 % de la maladie lithiasique par le biais d'erreurs alimentaires (hydratation insuffisante, consommation excessive d'oxalate et/ou consommation insuffisante de calcium) ; (2) les hyperoxaluries primaires, maladies génétiques orphelines responsables d'une production massive d'oxalate aboutissant à des dépôts tissulaires précoces (dès l'enfance) et sévères (à l'origine d'une insuffisance rénale terminale puis d'une thésaurismose avec atteinte multiviscérale) et dont le pronostic est aujourd'hui transformé par les nouvelles thérapies (ARN interférents) ; (3) l'hyperoxalurie entérique, résultant d'une augmentation de l'absorption digestive de l'oxalate dans une situation de malabsorption (syndrome du grêle court, chirurgie bariatrique, insuffisance pancréatique exocrine, etc.). La physiologie de l'oxalate, détaillée dans cet article, permet d'appréhender la prise en charge diagnostique et thérapeutique de ces maladies.

Sulforaphane exhibits potent renoprotective effects in preclinical models of kidney diseases: A systematic review and meta-analysis.

AIMS: Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, has received extensive attention as a natural activator of the Nrf2/Keap1 cytoprotective pathway. In this review, a meta-analysis and systematic review of the renoprotective effects of SFN were performed in various preclinical models of kidney diseases. MAIN METHODS: The primary outcome was the impact of SFN on renal function biomarkers (uremia, creatininemia, proteinuria or creatinine clearance) and secondary outcomes were kidney lesion histological indices/kidney injury molecular biomarkers. The effects of SFN were evaluated according to the standardized mean differences (SMDs). A random-effects model was applied to estimate the overall summary effect. KEY FINDINGS: Twenty-five articles (out of 209 studies) were selected from the literature. SFN administration significantly increased creatinine clearance (SMD +1.88 95 % CI: [1.09; 2.68], P < 0.0001, I2 = 0 %) and decreased the plasma creatinine (SMD -1.24, [-1.59; -0.88], P < 0.0001, I2 = 36.0 %) and urea (SMD -3.22 [-4.42, -2.01], P < 0.0001, I2 = 72.4 %) levels. SFN administration (median dose: 2.5 mg/kg, median duration: 3 weeks) significantly decreased urinary protein excretion (SMD -2.20 [-2.68; -1.73], P < 0.0001, I2 = 34.1 %). It further improved two kidney lesion histological indices namely kidney fibrosis (SMD -3.08 [-4.53; -1.63], P < 0.0001, I2 = 73.7 %) and glomerulosclerosis (SMD -2.24 [-2.96; -1.53], P < 0.0001, I2 = 9.7 %) and decreased kidney injury molecular biomarkers (SMD -1.51 [-2.00; -1.02], P < 0.0001, I2 = 0 %). SIGNIFICANCE: These findings provide new insights concerning preclinical strategies for treating kidney disease or kidney failure with SFN supplements and should stimulate interest in clinical evaluations of SFN in patients with kidney disease.

Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

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.

Cyclic thrombocytopenia related to erythropoietin-dependent anti-platelet anti-GPIV/IIIb antibody in hemodialysis.

We describe herein the case of a 65-year-old patient on chronic hemodialysis with a medical history of idiopathic thrombocytopenia who experienced numerous episodes of severe thrombocytopenia with no specific diagnosis. Further analysis of the evolution of the platelet count showed that cyclic thrombocytopenia occurred after each injection of recombinant erythropoietin (rHu-EPO). Exploration of the involved mechanisms revealed the presence of a rHu-EPO-dependent anti-GPIV/IIIb antibody associated with a significant increase in GPIV/IIIb expression on her platelets after the addition of rHu-EPO. EPO was discontinued and the patient was treated with roxadustat with favorable results on her hemoglobin and platelet counts.

Assessing Global Kidney Nutrition Care.

BACKGROUND AND OBJECTIVES: Nutrition intervention is an essential component of kidney disease management. This study aimed to understand current global availability and capacity of kidney nutrition care services, interdisciplinary communication, and availability of oral nutrition supplements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The International Society of Renal Nutrition and Metabolism (ISRNM), working in partnership with the International Society of Nephrology (ISN) Global Kidney Health Atlas Committee, developed this Global Kidney Nutrition Care Atlas. An electronic survey was administered among key kidney care stakeholders through 182 ISN-affiliated countries between July and September 2018. RESULTS: Overall, 160 of 182 countries (88%) responded, of which 155 countries (97%) answered the survey items related to kidney nutrition care. Only 48% of the 155 countries have dietitians/renal dietitians to provide this specialized service. Dietary counseling, provided by a person trained in nutrition, was generally not available in 65% of low-/lower middle-income countries and "never" available in 23% of low-income countries. Forty-one percent of the countries did not provide formal assessment of nutrition status for kidney nutrition care. The availability of oral nutrition supplements varied globally and, mostly, were not freely available in low-/lower middle-income countries for both inpatient and outpatient settings. Dietitians and nephrologists only communicated "sometimes" on kidney nutrition care in ≥60% of countries globally. CONCLUSIONS: This survey reveals significant gaps in global kidney nutrition care service capacity, availability, cost coverage, and deficiencies in interdisciplinary communication on kidney nutrition care delivery, especially in lower-income countries.

Reconsidering adsorption in hemodialysis: is it just an epiphenomenon? A narrative review.

Since the first attempt at extracorporeal renal replacement therapy, renal replacement therapy has been constantly improved. In the field of hemodialysis, substantial efforts have been made to improve toxin removal and biocompatibility. The advent of hemodiafiltration (HDF) and, more recently, of mid cut-off membranes have contributed to management of patients with end-stage renal disease (ESRD). Although several uremic toxins have been discovered, we know little about the clinical impact of their clearance in hemodialysis patients. In addition, a great deal of progress has been made in the areas of filtration and diffusion, but the adsorptive properties of hemodialysis membranes remain under-studied. The mechanism of action of adsorption is based on the attraction between the polymer of the dialysis membrane and the solutes, through hydrophobic interactions, ionic or electrostatic forces, hydrogen bonds or van der Waals forces. Adsorption on the dialysis membrane depends on the membrane surface, pore size, structure and electric load. Its involvement in toxin removal and biocompatibility is significant, and is not just an epiphenomenon. Diffusive and convective properties cannot be improved indefinitely and high permeability membranes, despite their high performance in the clearance of many toxins, have several limitations for long-term use in hemodialysis. This review will discuss why adsorption should be reconsidered and better characterized to improve efficiency and adequacy of dialysis.

The protein-bound uremic toxin p-cresyl-sulfate promotes intracellular ROS production and lipid peroxidation in 3T3-L1 adipose cells.

Patients with chronic kidney disease (CKD) often exhibit increased level of oxidative stress that contribute to the deterioration of renal function and uremic complications. White adipose tissue (WAT) has been recognized as a major site of production of radical oxygen species (ROS) in the context of metabolic diseases. This study was designed to decipher whether the protein bound uremic toxin p-cresyl-sulfate (p-CS) could contribute to ROS production in WAT and promote oxidative stress. Mouse 3T3-L1 adipocytes were incubated for 2 h in culture medium containing 212 µM p-CS, a concentration chosen to mimic levels encountered in end stage renal disease patients or KCl as a control and intracellular ROS production was measured using the fluorescent probe 5-6-carboxy-2',7'-dichlorodihydrofluorescein diacetate. Oxidative insult was estimated by the measurement of malondialdehyde (MDA) content and glutathione content. The effects of probenecid (1 mM) a potent inhibitor of organic anion transporter, apocynin (1 mM) an inhibitor of NADPH oxidase or common antioxidants such as α-tocopherol (2.5 µM), ascorbate (200 µM), and N-acetylcysteine (500 µM) were further evaluated. p-CS triggered a striking increase in ROS production (+228%, p < 0.01), in MDA content (+214%, p < 0.005) and a decrease in glutathione (-47%, P < 0.01). Pre-treatment of cells with probenecid, apocynin or antioxidants prevented the p-CS induced ROS production and oxidative insults. These results suggest that in uremic state, the intracellular accumulation of p-CS in adipose cells could contribute, through an activation of NADPH oxidase, to the redox imbalance often reported in CKD patients.

Self-reported Pruritus and Clinical, Dialysis-Related, and Patient-Reported Outcomes in Hemodialysis Patients.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD)-associated pruritus, generalized itching related to CKD, affects many aspects of hemodialysis patients' lives. However, information regarding the relationship between pruritus and several key outcomes in hemodialysis patients remains limited. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 23,264 hemodialysis patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018). EXPOSURE: Pruritus severity, based on self-reported degree to which patients were bothered by itchy skin (5-category ordinal scale from "not at all" to "extremely"). OUTCOMES: Clinical, dialysis-related, and patient-reported outcomes. ANALYTICAL APPROACH: Cox regression for time-to-event outcomes and modified Poisson regression for binary outcomes, adjusted for potential confounders. RESULTS: The proportion of patients at least moderately bothered by pruritus was 37%, and 7% were extremely bothered. Compared with the reference group ("not at all"), the adjusted mortality HR for patients extremely bothered by pruritus was 1.24 (95% CI, 1.08-1.41). Rates of cardiovascular and infection-related deaths and hospitalizations were also higher for patients extremely versus not at all bothered by pruritus (HR range, 1.17-1.44). Patients extremely bothered by pruritus were also more likely to withdraw from dialysis and miss hemodialysis sessions and were less likely to be employed. Strong monotonic associations were observed between pruritus severity and longer recovery time from a hemodialysis session, lower physical and mental quality of life, increased depressive symptoms, and poorer sleep quality. LIMITATIONS: Residual confounding, recall bias, nonresponse bias. CONCLUSIONS: Our findings demonstrate how diverse and far-reaching poor outcomes are for patients who experience CKD-associated pruritus, specifically those with more severe pruritus. There is need for change in practice patterns internationally to effectively identify and treat patients with pruritus to reduce symptom burden and improve quality of life and possibly even survival.

Citric Acid-Containing Dialysate and Survival Rate in the Dialysis Outcomes and Practice Patterns Study.

Background: Metabolic acidosis is a common threat for patients on hemodialysis, managed by alkaline dialysate. The main base is bicarbonate, to which small amounts of acetic, citric, or hydrochloric acid are added. The first two are metabolized to bicarbonate, mostly by the liver. Citric acid-containing dialysate might improve dialysis efficiency, anticoagulation, calcification propensity score, and intradialytic hemodynamic stability. However, a recent report from the French dialysis registry suggested this dialysate increases mortality risk. This prompted us to assess whether citric acid-containing bicarbonate-based dialysate was associated with mortality in the international Dialysis Outcomes and Practice Patterns Study (DOPPS). Methods: Detailed patient-based information on dialysate composition was collected in DOPPS phases 5 and 6 (2012-2017). Cox regression was used to model the association between baseline bicarbonate dialysate containing citric acid versus not containing citric acid and mortality among DOPPS countries and phases where citric acid-containing dialysate was used. Results: Citric acid-containing dialysate was most commonly used in Japan, Italy, and Belgium (25%, 25%, 21% and of patients who were DOPPS phase 6, respectively) and used in <10% of patients in other countries. Among 11,306 patients in DOPPS country and phases with at least 15 patients using citric acid-containing dialysate, patient demographics, comorbidities, and laboratories were similar among patients using (14%) versus not using (86%) citric acid-containing dialysate. After accounting for case mix, we did not observe a directional association between citric acid-containing dialysate use (any versus none) and mortality (HR, 1.14; 95% CI, 0.97 to 1.34), nor did we find evidence of a dose-dependent relationship when parameterizing the citric acid concentration in the dialysate as 1, 2, and 3+ mEq/L. Conclusions: The use of citric acid-containing dialysate was not associated with greater risk of all-cause mortality in patients on hemodialysis participating in DOPPS. Clinical indications for the use of citric acid-containing dialysate deserve further investigation.

The International Society of Renal Nutrition and Metabolism Commentary on the National Kidney Foundation and Academy of Nutrition and Dietetics KDOQI Clinical Practice Guideline for Nutrition in Chronic Kidney Disease.

The Academy of Nutrition and Dietetics and the National Kidney Foundation collaborated to provide an update to the Clinical Practice Guidelines (CPG) for nutrition in chronic kidney disease (CKD). These guidelines provide a valuable update to many aspects of the nutrition care process. They include changes in the recommendations for nutrition screening and assessment, macronutrients, and targets for electrolytes and minerals. The International Society of Renal Nutrition and Metabolism assembled a special review panel of experts and evaluated these recommendations prior to public review. As one of the highlights of the CPG, the recommended dietary protein intake range for patients with diabetic kidney disease is 0.6-0.8 g/kg/day, whereas for CKD patients without diabetes it is 0.55-0.6 g/kg/day. The International Society of Renal Nutrition and Metabolism endorses the CPG with the suggestion that clinicians may consider a more streamlined target of 0.6-0.8 g/kg/day, regardless of CKD etiology, while striving to achieve intakes closer to 0.6 g/kg/day. For implementation of these guidelines, it will be important that all stakeholders work to detect kidney disease early to ensure effective primary and secondary prevention. Once identified, patients should be referred to registered dietitians or the region-specific equivalent, for individualized medical nutrition therapy to slow the progression of CKD. As we turn our attention to the new CPG, we as the renal nutrition community should come together to strengthen the evidence base by standardizing outcomes, increasing collaboration, and funding well-designed observational studies and randomized controlled trials with nutritional and dietary interventions in patients with CKD.

Measurement of glomerular filtration rate in lung transplant recipients highlights a dramatic loss of renal function after transplantation.

BACKGROUND: Chronic kidney disease (CKD) after lung transplantation (LT) is underestimated. The aim of the present study was to measure the loss of glomerular filtration rate (GFR) 1 year after LT and to identify the risk factors for developing Stage ≥3 CKD. METHODS: LT patients in the University Hospital of Lyon had a pre- and post-transplantation measurement of their GFR (mGFR), and GFR was also estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: During the study period, 111 patients were lung transplant candidates, of which 91 had a pre-transplantation mGFR, and 29 had a mGFR at 1 year after LT. Six patients underwent maintenance haemodialysis after transplantation. Mean mGFR was 106 mL/min/1.73 m2 before LT and 58 mL/min/1.73 m2 1 year after LT (P < 0.05) with a mean loss of 48 mL/min/1.73 m2 per patient. The risk of developing Stage ≥3 CKD after LT was higher in patients with lower pre-LT mGFR (odds ratio for each 1 mL/min/1.73 m2 increase: 0.94, 95% confidence interval 0.88-0.99). Receiver operator characteristics curves for the sensitivity and specificity of eGFR and mGFR for the prediction of CKD Stage ≥3 after LT found that pre-LT mGFR of 101 mL/min/1.73 m2 and pre-LT eGFR of 124 mL/min/1.73 m2 were the optimal thresholds for predicting Stage ≥3 CKD after LT. CONCLUSION: The present study underlines the value of mGFR in the pre-LT stage and found major renal function loss after LT, and consequently two-thirds of patients have Stage ≥3 CKD at 1 year. All patients with a pre-LT mGFR <90 mL/min/1.73 m2 warrant particular attention.

Two Toxic Lipid Aldehydes, 4-hydroxy-2-hexenal (4-HHE) and 4-hydroxy-2-nonenal (4-HNE), Accumulate in Patients with Chronic Kidney Disease.

Lipid aldehydes originating from the peroxidation of n-3 and n-6 polyunsaturated fatty acids are increased in hemodialysis (HD) patients, a process already known to promote oxidative stress. However, data are lacking for patients with chronic kidney disease (CKD) before the initiation of HD. We prospectively evaluated the changes of plasma concentrations of two major lipid aldehydes, 4-HHE and 4-HNE, according to the decrease of glomerular filtration rate (GFR) in 40 CKD and 13 non-CKD participants. GFR was measured by inulin or iohexol clearance. Thus, 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) were quantitated in plasma by gas chromatography coupled with mass spectrometry and their covalent adducts on proteins were quantified by immunoblotting. On the one hand, 4-HHE plasma concentration increased from CKD stage I-II to CKD stage IV-V compared to non-CKD patients (4.5-fold higher in CKD IV-V, p < 0.005). On the other hand, 4-HNE concentration only increased in CKD stage IV-V patients (6.2-fold, p < 0.005). The amount of covalent adducts of 4-HHE on plasma protein was 9.5-fold higher in CKD patients than in controls (p < 0.005), while no difference was observed for 4-HNE protein adducts. Plasma concentrations of 4-HNE and 4-HHE are increased in CKD IV-V patients before the initiation of hemodialysis.

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.

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate.

Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.