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.

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.

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)