ABSTRACT
Kidney stone disease is a common condition with an increasing prevalence. Diet is an important, modifiable risk factor of an individual's risk of developing kidney stone disease, particularly for those without genetic causes of kidney stone disease. Prospective and epidemiological evidence suggest that adequate fluid intake, limited sodium ingestion, and sufficient calcium and potassium intake can decrease the risk of developing kidney stones. Metabolic risk factors for KSD found on 24-hour urine studies can be used to tailor dietary modifications recommended to reduce subsequent risk of kidney stone formation.
Subject(s)
Calcium , Kidney Calculi , Humans , Prospective Studies , Kidney Calculi/etiology , Kidney Calculi/prevention & control , Kidney Calculi/epidemiology , Diet , Risk FactorsSubject(s)
Hemodialysis, Home , Kidney Failure, Chronic , Female , Humans , Kidney Failure, Chronic/therapy , Male , Renal DialysisABSTRACT
BACKGROUND: Acute kidney injury (AKI) has been reported as a complication of COVID-19. However, the epidemiology, management, and associated outcomes have varied greatly between studies. The pathophysiology remains unclear. Summary: The etiology of AKI in the setting of COVID-19 appears multifactorial. Systemic effects of sepsis, inflammation, and vascular injury likely play some role. Furthermore, SARS-CoV-2 binds to the angiotensin-converting enzyme 2 receptor, highly expressed in the kidney, providing a route for direct infection. Older age, baseline comorbidities, and respiratory failure are strong risk factors for the development of AKI. Regardless of etiology, AKI carries a significantly increased risk for in-hospital mortality, especially in those with critical illness. Currently, management of AKI in patients with COVID-19 remains supportive. Key Messages: AKI is common in patients with COVID-19. Future studies are needed to examine the response to anti-viral treatment as well as long-term renal outcomes in patients with AKI.
Subject(s)
Acute Kidney Injury , Betacoronavirus , Coronavirus Infections , Critical Illness , Kidney , Pandemics , Patient Care Management/methods , Pneumonia, Viral , Acute Kidney Injury/etiology , Acute Kidney Injury/mortality , Acute Kidney Injury/therapy , Acute Kidney Injury/virology , Angiotensin-Converting Enzyme 2 , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Coronavirus Infections/virology , Critical Illness/mortality , Critical Illness/therapy , Hospital Mortality , Humans , Kidney/metabolism , Kidney/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , Prognosis , Risk Assessment , Risk Factors , SARS-CoV-2 , Virus InternalizationABSTRACT
Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is striking that proliferator gamma coactivator 1-alpha (PGC1α), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here we report that PGC1α's induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1α knockout tubular cells were sensitized to the genotoxic stressor cisplatin whereas transgenic cells were protected. The biosensor mtKeima unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1α not only counteracted this effect but also raised basal mitophagy, as did the downstream mediator nicotinamide adenine dinucleotide (NAD+). PGC1α did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1α in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1α's exquisite reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a novel target for renal tubular stress resistance.
Subject(s)
Acute Kidney Injury/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cisplatin/toxicity , Kidney Tubules/metabolism , Lysosomes/metabolism , Mitochondria/metabolism , Organelle Biogenesis , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Acute Kidney Injury/chemically induced , Acute Kidney Injury/metabolism , Animals , Autophagy/drug effects , Autophagy/genetics , CRISPR-Cas Systems , Gene Transfer Techniques , Kidney Tubules/cytology , Mice , Mice, Knockout , Mice, Transgenic , Mitophagy/genetics , NAD/metabolism , Oxidative Stress/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Sequence Analysis, RNAABSTRACT
Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+ fell, quinolinate rose, and QPRT declined. QPRT+/- mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD+ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD+ biosynthesis may be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial.
Subject(s)
Acute Kidney Injury/metabolism , Biosynthetic Pathways , NAD/biosynthesis , Acute Kidney Injury/drug therapy , Acute Kidney Injury/urine , Aged , Animals , Cardiac Surgical Procedures , Humans , Ischemia/urine , Mice , Middle Aged , Niacinamide/administration & dosage , Niacinamide/therapeutic use , Pentosyltransferases/metabolism , Pilot Projects , Quinolinic Acid/metabolism , Quinolinic Acid/urine , Treatment Outcome , Tryptophan/urineABSTRACT
Acute kidney injury (AKI) arising from diverse etiologies is characterized by mitochondrial dysfunction. The peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC1α), a master regulator of mitochondrial biogenesis, has been shown to be protective in AKI. Interestingly, reduction of PGC1α has also been implicated in the development of diabetic kidney disease and renal fibrosis. The beneficial renal effects of PGC1α make it a prime target for therapeutics aimed at ameliorating AKI, forms of chronic kidney disease (CKD), and their intersection. This review summarizes the current literature on the relationship between renal health and PGC1α and proposes areas of future interest.
