Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis.

How phosphate levels are detected in mammals is unknown. The bone-derived hormone fibroblast growth factor 23 (FGF23) lowers blood phosphate levels by reducing kidney phosphate reabsorption and 1,25(OH)2D production, but phosphate does not directly stimulate bone FGF23 expression. Using PET scanning and LC-MS, we found that phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production. Further, we found that G-3-P dehydrogenase 1 (Gpd1), a cytosolic enzyme that synthesizes G-3-P and oxidizes NADH to NAD+, is required for phosphate-stimulated G-3-P and FGF23 production and prevention of hyperphosphatemia. In proximal tubule cells, we found that phosphate availability is substrate-limiting for glycolysis and G-3-P production and that increased glycolysis and Gpd1 activity are coupled through cytosolic NAD+ recycling. Finally, we show that the type II sodium-dependent phosphate cotransporter Npt2a, which is primarily expressed in the proximal tubule, conferred kidney specificity to phosphate-stimulated G-3-P production. Importantly, exogenous G-3-P stimulated FGF23 production when Npt2a or Gpd1 were absent, confirming that it was the key circulating factor downstream of glycolytic phosphate sensing in the kidney. Together, these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis.

Chelation Therapy in Patients With Cardiovascular Disease: A Systematic Review.

Background EDTA is an intravenous chelating agent with high affinity to divalent cations (lead, cadmium, and calcium) that may be beneficial in the treatment of cardiovascular disease (CVD). Although a large randomized clinical trial showed benefit, smaller studies were inconsistent. We conducted a systematic review of published studies to examine the effect of repeated EDTA on clinical outcomes in adults with CVD. Methods and Results We searched 3 databases (MEDLINE, Embase, and Cochrane) from database inception to October 2021 to identify all studies involving EDTA treatment in patients with CVD. Predetermined outcomes included mortality, disease severity, plasma biomarkers of disease chronicity, and quality of life. Twenty-four studies (4 randomized clinical trials, 15 prospective before/after studies, and 5 retrospective case series) assessed the use of repeated EDTA chelation treatment in patients with preexistent CVD. Of these, 17 studies (1 randomized clinical trial) found improvement in their respective outcomes following EDTA treatment. The largest improvements were observed in studies with high prevalence of participants with diabetes and/or severe occlusive arterial disease. A meta-analysis conducted with 4 studies reporting ankle-brachial index indicated an improvement of 0.08 (95% CI, 0.06-0.09) from baseline. Conclusions Overall, 17 studies suggested improved outcomes, 5 reported no statistically significant effect of treatment, and 2 reported no qualitative benefit. Repeated EDTA for CVD treatment may provide more benefit to patients with diabetes and severe peripheral arterial disease. Differences across infusion regimens, including dosage, solution components, and number of infusions, limit comparisons across studies. Additional research is necessary to confirm these findings and to evaluate the potential mediating role of metals. Registration URL: https://www.crd.york.ac.uk/; Unique identifier: CRD42020166505.

Hallazgos ultraestructurales renales de pacientes con nefritis intersticial crónica de las comunidades agrícolas en El Salvador / Renal ultrastructural findings of patients with chronic interstitial nephritis from farming communities in El Salvador

Introducción: Desde hace 20 años se presenta en Centroamérica una enfermedad renal crónica que fundamentalmente afecta a hombres agricultores y no asociada a las causas tradicionales. Se caracteriza por presentar una nefritis intersticial crónica, en tanto las características ultraestructurales no se conocen con exactitud. En su origen se invoca el uso de agroquímicos y otros agentes nefrotóxicos, la deshidratación crónica, el consumo de medicamentos, entre otros factores. Objetivo: Describir las características ultraestructurales de la nefritis intersticial crónica en comunidades agrícolas. Método: Se realizó un estudio descriptivo de corte transversal. Se estudiaron muestras de biopsias renales de ocho pacientes con diagnóstico de nefritis intersticial crónica de las comunidades agrícolas. Resultados: De los ocho pacientes estudiados, dos (25 por ciento) trabajaban en labores agrícolas y cinco eran del sexo femenino (62,5 por ciento). Dos de los pacientes (25 por ciento) presentaban una enfermedad renal crónica estadio 2, y seis (75 por ciento) estadio 3. En cinco pacientes se hallaron fagolisosomas con presencia de componente lipídico entremezclado con material electrodenso en células del túbulo distal. En igual cantidad de pacientes se observaron cuerpos mieloides con zonas laminadas y núcleo central en células de túbulo proximal y de los vasos sanguíneos. Conclusiones: En pacientes de comunidades agrícolas que padecen nefritis intersticial crónica se evidencian fagolisosomas y estructuras mieloides en túbulos y vasos renales, cuyo contenido y origen se desconocen(AU)

Introduction: Chronic kidney disease mainly affecting male farmers and not associated to traditional causes has been present in Central America for twenty years. The condition is characterized by the presence of chronic interstitial nephritis, but its ultrastructural features are not fully known. Factors suggested as responsible for its occurrence include the use of agrochemicals and other nephrotoxic agents, chronic dehydration and medicine consumption. Objective: Describe the ultrastructural characteristics of chronic interstitial nephritis in farming communities. Method: A cross-sectional descriptive study was conducted of renal biopsy samples from eight patients diagnosed with chronic interstitial nephritis in farming communities. Results: Of the eight patients studied, two (25 percent) were farm workers and five (62.5percent) were female. Two of the patients (25 percent) had stage 2 and six (75 percent) stage 3 chronic kidney disease. In five patients evidence was found of phagolysosomes with lipid component mixed with electrodense material in distal tubule cells. An equal number of patients had myeloid bodies with laminated areas and central nucleus in proximal tubule and blood vessel cells. Conclusions: Evidence of phagolysosomes and myeloid structures of unknown content and origin was found in renal tubules and vessels of patients from farming communities diagnosed with chronic interstitial nephritis(AU)

Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.

BACKGROUND: Preclinical studies have identified both NAD+ and sirtuin augmentation as potential strategies for the prevention and treatment of AKI. Nicotinamide riboside (NR) is a NAD+ precursor vitamin and pterostilbene (PT) is potent sirtuin activator found in blueberries. Here, we tested the effect of combined NR and PT (NRPT) on whole blood NAD+ levels and safety parameters in patients with AKI. METHODS: We conducted a randomized, double-blind, placebo-controlled study of escalating doses of NRPT in 24 hospitalized patients with AKI. The study was comprised of four Steps during which NRPT (5 subjects) or placebo (1 subject) was given twice a day for 2 days. NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD+ levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. RESULTS: AKI resulted in a 50% reduction in whole blood NAD+ levels at 48 h compared to 0 h in patients receiving placebo (p = 0.05). There was a trend for increase in NAD+ levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD+ response to treatment. Considering all Steps together, NRPT treatment increased NAD+ levels by 37% at 48 h compared to 0 h (p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. CONCLUSION: NRPT increases whole blood NAD+ levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. TRIAL REGISTRATION: NCT03176628 , date of registration June 5th, 2017.

Chronic interstitial nephritis of nontraditional causes in Salvadoran agricultural communities.

In El Salvador, a form of chronic kidney disease (CKD) of nontraditional causes (CKDnt) affecting farmers is being reported. Its behavior has been epidemic and is responsible for tens of thousands of deaths. This article summarizes the results obtained from a series of studies conducted to identify the epidemiology and clinical behavior of this disease, proposing a case definition and an etiopathogenic hypothesis. Methods included a survey of CKD in agricultural communities studying 2,388 people ≥ 18 years and 1,755 < 18, a descriptive clinical study followed by histopathological assessment conducted in 46 possible cases of CKDnt ≥ 18 years, and a national survey to study the prevalence of CKD and associated risk factors in 4,817 participants ≥ 20 years followed by a nested case-control study. In the agricultural communities, the prevalence of CKD in adults was 18% (men: 23.9%, women: 13.9%), 26.8% in agricultural workers (non-agricultural 13.8%), CKDnt accounted for 51.9% of cases. CKD in the population < 18 years was 3.9% (mean estimated glomerular filtration rate > 160 mL/1.73m2). The national CKD prevalence was 12.6% (urban: 11.3%; rural: 14.4%; males: 17.8%, females 8.5%), and CKDnt was only 3.8%; with associations between CKD and exposure to agrochemicals. The clinical study revealed the presence of markers of kidney damage (A3 albuminuria: 80.4%; ß2-microglobulin: 78.2%), urine electrolyte anomalies (100% hypermagnesuria, 45.7% hypernatriuria, 43.5% osmotic polyuria), abnormal osteotendinous reflexes (45.7%), sensorineural hearing loss (56.5%), and damage of the tibial arteries by Doppler imaging (66.7%). Biopsies revealed a chronic tubulointerstitial nephropathy. The etiopathogenesis of CKDnt is possibly multifactorial, including environmental contamination by agrochemicals, heat stress, and dehydration.

Synthesizing Markers of Kidney Injury in Acute Decompensated Heart Failure: Should We Even Keep Looking?

PURPOSE OF REVIEW: This review discusses evidence that has accumulated over the years on the diagnostic and prognostic utility of biomarkers of kidney injury in the setting of acute decompensated heart failure. RECENT FINDINGS: Despite numerous studies evaluating several different biomarkers both in the serum and urine, the current body of evidence does not support routine use of any of these biomarkers for the purposes of diagnosis of acute kidney injury or for prognosis after hospitalization for acute decompensated heart failure. All studies are observational in nature and, as such, are likely limited by numerous confounders, the most important of which is modification of decongestive therapy in response to worsening renal function. More recent evidence suggests that worsening renal function or kidney injury does not always portend poor outcomes after hospitalization for heart failure. There is currently no conclusive evidence to recommend the routine use of biomarkers of kidney injury in acute decompensated heart failure.

Evaluation of model performance to predict survival after transjugular intrahepatic portosystemic shunt placement.

BACKGROUND/AIMS: The MELD score was developed to predict survival after transjugular intrahepatic portosystemic shunt (TIPS) placement. Given changes in practice patterns and development of new prognostic tools in cirrhosis, we aimed to evaluate common models to predict mortality after TIPS placement. METHODS: Analysis of consecutive patients who underwent TIPS placement for ascites or bleeding. Performance to predict 90-day mortality was assessed by C statistic for six models (MELD, MELD-Na, CLIF-C ACLF, Child-Pugh, Platelet-Albumin-Bilirubin, and Emory score). Added predictive value to MELD score was assessed for univariate predictors of 90-day mortality. Stratified analysis by TIPS indication, emergent placement status, and TIPS stent type was performed. RESULTS: 413 patients were analyzed (248 with variceal bleeding, 165 with refractory ascites). 90-day mortality was 27% (113/413). Mean MELD score was 15 ± 7.9. MELD score best predicted mortality for all patients (c = 0.779), for variceal bleeding (c = 0.844), and for emergent TIPS (c = 0.817). CLIF-C ACLF score best predicted mortality for refractory ascites (c = 0.707). Addition of sodium to the MELD score did not improve predictive value across multiple strata. Addition of hemoglobin improved MELD score's predictive value in variceal bleeding. Addition of age improved MELD score's predictive value in refractory ascites. CONCLUSIONS: MELD score best predicted 90-day mortality. Addition of sodium to the MELD score did not improve its performance, though mortality prediction was improved using Age-MELD for ascites and Hemoglobin-MELD for bleeding. An individualized risk stratification approach may be best when considering candidates for TIPS placement.

Serum Angiopoietin-2 Predicts Mortality and Kidney Outcomes in Decompensated Cirrhosis.

Acute kidney injury in decompensated cirrhosis has limited therapeutic options, and novel mechanistic targets are urgently needed. Angiopoietin-2 is a context-specific antagonist of Tie2, a receptor that signals vascular quiescence. Considering the prominence of vascular destabilization in decompensated cirrhosis, we evaluated Angiopoietin-2 to predict clinical outcomes. Serum Angiopoietin-2 was measured serially in a prospective cohort of hospitalized patients with decompensated cirrhosis and acute kidney injury. Clinical characteristics and outcomes were examined over a 90-day period and analyzed according to Angiopoietin-2 levels. Primary outcome was 90-day mortality. Our study included 191 inpatients (median Angiopoietin-2 level 18.2 [interquartile range 11.8, 26.5] ng/mL). Median Model for End-Stage Liver Disease (MELD) score was 23 [17, 30] and 90-day mortality was 41%. Increased Angiopoietin-2 levels were associated with increased mortality (died 21.9 [13.9, 30.3] ng/mL vs. alive 15.2 [9.8, 23.0] ng/mL; P < 0.001), higher Acute Kidney Injury Network stage (stage I 13.4 [9.8, 20.1] ng/mL vs. stage II 20.0 [14.1, 26.2] ng/mL vs. stage III 21.9 [13.0, 29.5] ng/mL; P = 0.002), and need for renal replacement therapy (16.5 [11.3, 23.6] ng/mL vs. 25.1 [13.3, 30.3] ng/mL; P = 0.005). The association between Angiopoietin-2 and mortality was significant in unadjusted and adjusted Cox regression models (P ≤ 0.001 for all models), and improved discrimination for mortality when added to MELD score (integrated discrimination increment 0.067; P = 0.001). Conclusion: Angiopoietin-2 was associated with mortality and other clinically relevant outcomes in a cohort of patients with decompensated cirrhosis with acute kidney injury. Further experimental study of Angiopoietin/Tie2 signaling is warranted to explore its potential mechanistic and therapeutic role in this population.

Sickle Cell Nephropathy in the Pediatric Population.

BACKGROUND: Compared to the past, patients with sickle cell disease (SCD) currently live longer due to improvements in diagnosis and comprehensive care. Due to these advances, long-term chronic complications pose a greater challenge in the management of patients with SCD. In particular, sickle cell nephropathy (SCN) is associated with significant morbidity and mortality across all age groups. Furthermore, SCN is an understudied condition with relatively few symptoms and therefore requires close surveillance. In this review, we sought to explore the epidemiology, natural history, and treatment options for SCN with an emphasis on the pediatric population. SUMMARY: SCN invariably begins in childhood with evidence of structural changes detected as early as infancy. These indolent changes can progress undetected to advanced chronic kidney disease by late adolescence or early adulthood. The risk factors for progression are not well defined, but significant albuminuria (which is also the most common presentation in childhood) is a key factor in progression. One of the main challenges in understanding SCN in children is the poor correlation between estimated and measured glomerular filtration rates. Another challenge is the lack of large-scale longitudinal studies that track the clinical outcomes of pediatric patients over time. Several studies aim to identify early biomarkers of SCN in children, as albuminuria presents only following significant chronic damage. The utility of angiotensin converting enzyme inhibitors and hydroxyurea in treating albuminuria is addressed here as well as novel treatments that may be of benefit.

Protein Carbamylation in Chronic Kidney Disease and Dialysis.

Protein carbamylation is a nonenzymatic posttranslational protein modification that can be driven, in part, by exposure to urea's dissociation product, cyanate. In humans, when kidney function is impaired and urea accumulates, systemic protein carbamylation levels increase. Additional mediators of protein carbamylation have been identified including inflammation, diet, smoking, circulating free amino acid levels, and environmental exposures. Carbamylation reactions on proteins are capable of irreversibly changing protein charge, structure, and function, resulting in pathologic molecular and cellular responses. Carbamylation has been mechanistically linked to the biochemical pathways implicated in atherosclerosis, dysfunctional erythropoiesis, kidney fibrosis, autoimmunity, and other pathological domains highly relevant to patients with chronic kidney disease. In this review, we describe the biochemical impact of carbamylation on human proteins, the mechanistic role carbamylation can have on clinical outcomes in kidney disease, the clinical association studies of carbamylation in chronic kidney disease, including patients on dialysis, and the promise of therapies aimed at reducing carbamylation burden in this vulnerable patient population.

Toward a Comprehensive Hypothesis of Chronic Interstitial Nephritis in Agricultural Communities.

Over the past 20 years, there has been an increase in chronic interstitial nephritis in agricultural communities (CINAC) not associated with traditional risk factors. This disease has become an important public health problem and is observed in several countries in Central America and Asia. CINAC predominantly affects young male farmers between the third and fifth decades of life with women, children, and adolescents less often affected. Clinically, CINAC behaves like a chronic tubulointerstitial nephropathy but with systemic manifestations not attributable to kidney disease. Kidney biopsy reveals chronic tubulointerstitial nephritis with variable glomerulosclerosis and mild chronic vascular damage, with the severity depending on sex, occupation, and CKD stage. The presence of toxicological, occupational, and environmental risk factors within these communities suggests a multifactorial etiology for CINAC. This may include exposure to agrochemicals, a contaminated environment, repeated episodes of dehydration with heat stress, and an underlying genetic predisposition. An understanding of these interacting factors using a multidisciplinary approach with international cooperation and the formulation of a comprehensive hypothesis are essential for the development of public health programs to prevent this devastating epidemic.

Epidemiological characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities of El Salvador.

INTRODUCTION: In El Salvador end-stage renal disease (ESRD) was the first cause of hospital mortality overall, the first cause of hospital deaths in men, and the fifth cause of hospital mortality in women in 2013. In agricultural communities, chronic kidney disease (CKD) occurs predominantly in male agricultural workers, but it also affects women to a lesser degree, even those who are not involved in agricultural work. Internationally, most epidemiological CKD studies emphasize men and no epidemiological studies focused exclusively on women. OBJECTIVE: To describe the epidemiological characteristics of CKD in females in agricultural communities of El Salvador. METHODS: A cross-sectional epidemiological study was carried out in 2009 - 2011 based on active screening for CKD and risk factors in women aged ≥ 18 years in 3 disadvantaged populations of El Salvador: Bajo Lempa (Usulután Department), Guayapa Abajo (Ahuachapán Department), and Las Brisas (San Miguel Department). Epidemiological and clinical data were gathered through personal history, as well as urinalysis for renal damage markers, determinations of serum creatinine and glucose, and estimation of glomerular filtration rates. CKD cases were confirmed at 3 months. RESULTS: Prevalence of CKD was 13.9% in 1,412 women from 1,306 families studied. Chronic kidney disease of nontraditional causes (CKDu), not attributed to diabetes mellitus, hypertension, or proteinuric primary glomerulopathy (proteinuria > 1 g/L) was 6.6%. Prevalence of chronic renal failure was 6.8%. Prevalence of renal damage markers was 9.8% (microalbuminuria (30 - 300 mg/L) 5.7%; macroalbuminuria (> 300 mg/L) 2%; and hematuria, 2.1%. Prevalence of chronic kidney disease risk factors was: diabetes mellitus, 9.3%; hypertension, 23%; family history of CKD, 16%; family history of diabetes mellitus (DM), 18.7%; family history of hypertension (HT), 31.9%; obesity, 21%; central obesity, 30.7%; NSAID use, 84.3%; agricultural occupation, 15.2%; and contact with agrochemicals, 33.1%. CONCLUSIONS: CKD in women of Salvadoran agricultural communities is associated with disadvantaged populations, traditional (DM, HT, obesity) and non-traditional causes (environmental and occupational exposure to toxic agents and inadequate working conditions). Our results reinforce the hypotheses emerging from other studies, suggesting a multifactorial etiopathology including environmental and occupational nephrotoxic exposure.

Clinical characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities in El Salvador.

INTRODUCTION: A chronic kidney disease of non-traditional causes (CKDu) has emerged in Central America and elsewhere, predominantly affecting male farmworkers. In El Salvador (2009), it was the second cause of death in men > 18 years old. Causality has not been determined. Most available research focused on men and there is scarce data on women. OBJECTIVES: Describe the clinical and histopathologic characteristics of CKDu in women of agricultural communities in El Salvador. METHODOLOGY: A descriptive study was carried out in 10 women with CKDu stages 2, 3a, and 3b. Researchers studied demographics, clinical examination; hematological and biochemical analyses, urine sediment, renal injury markers, and assessed renal, cardiac, and peripheral arteries, liver, pancreas, and lung anatomy and functions. Kidney biopsy was performed in all. Data was collected on the Lime Survey platform and exported to SPSS 19.0. RESULTS: Patient distribution by stages: 2 (70%), 3a (10%), 3b (20%). Occupation: agricultural 7; non-agricultural 3. RISK FACTORS: agrochemical exposure 100%; farmworkers 70%; incidental malaria 50%, NSAIDs use 40%; hypertension 40%. SYMPTOMS: nocturia 50%; dysuria 50%; arthralgia 70%; asthenia 50%; cramps 30%, profuse sweating 20%. Renal markers: albumin creatinine ratio (ACR) > 300 mg/g 90%; ß microglobulin and neutrophil gelatinase- associated lipocalin (NGAL) presence in 40%. Kidney function: hypermagnesuria 100%; hyperphosphaturia 50%, hypercalciuria 40%; hypernatriuria 30%; hyponatremia 60%, hypocalcemia 50%. Doppler: tibial artery damage 40%. Neurological: reflex abnormalities 30%; Babinski and myoclonus 20%. Neurosensorial hypoacusis 70%. Histopathology: damage restricted mostly to the tubulo-interstitium, urine was essentially bland. CONCLUSIONS: CKDu in women is a chronic tubulointerstitial nephropathy with varied extrarenal symptoms.