Uric acid, generated from the metabolism of purines, has proven and emerging roles in human disease. Serum uric acid is determined by production and the net balance of reabsorption or secretion by ...the kidney and intestine. A detailed understanding of epithelial absorption and secretion of uric acid has recently emerged, aided in particular by the results of genome-wide association studies of hyperuricemia. Novel genetic and regulatory networks with effects on uric acid homeostasis have also emerged. These developments promise to lead to a new understanding of the various diseases associated with hyperuricemia and to novel, targeted therapies for hyperuricemia.
Thick ascending limb of the loop of Henle Mount, David B
Clinical journal of the American Society of Nephrology,
2014-Nov-07, Letnik:
9, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The thick ascending limb occupies a central anatomic and functional position in human renal physiology, with critical roles in the defense of the extracellular fluid volume, the urinary concentrating ...mechanism, calcium and magnesium homeostasis, bicarbonate and ammonium homeostasis, and urinary protein composition. The last decade has witnessed tremendous progress in the understanding of the molecular physiology and pathophysiology of this nephron segment. These advances are the subject of this review, with emphasis on particularly recent developments.
Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A ...scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study.
Abstract Background Hyponatremia is the most common electrolyte abnormality in hospitalized individuals. Methods To investigate the association between serum sodium concentration and mortality, we ...conducted a prospective cohort study of 98,411 adults hospitalized between 2000 and 2003 at 2 teaching hospitals in Boston, Massachusetts. The main outcome measures were in-hospital, 1-year, and 5-year mortality. Multivariable logistic regression and Cox proportional hazards models were used to compare outcomes in patients with varying degrees of hyponatremia against those with normal serum sodium concentration. Results Hyponatremia (serum sodium concentration <135 mEq/L) was observed in 14.5% of patients on initial measurement. Compared with patients with normonatremia (135-144 mEq/L), those with hyponatremia were older (67.0 vs 63.1 years, P <.001) and had more comorbid conditions (mean Deyo-Charlson Index 1.9 vs 1.4, P <.001). In multivariable-adjusted models, patients with hyponatremia had an increased risk of death in hospital (odds ratio 1.47, 95% confidence interval CI, 1.33-1.62), at 1 year (hazard ratio 1.38, 95% CI, 1.32-1.46), and at 5 years (hazard ratio 1.25, 95% CI, 1.21-1.30). The increased risk of death was evident even in those with mild hyponatremia (130-134 mEq/L; odds ratio 1.37, 95% CI, 1.23-1.52). The relationship between hyponatremia and mortality was pronounced in patients admitted with cardiovascular disease, metastatic cancer, and those admitted for procedures related to the musculoskeletal system. Resolution of hyponatremia during hospitalization attenuated the increased mortality risk conferred by hyponatremia. Conclusion Hyponatremia, even when mild, is associated with increased mortality.
Objective
Hyperuricemia is closely associated with insulin resistance syndrome (and its many cardiometabolic sequelae); however, whether they are causally related has long been debated. We undertook ...this study to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout, by using bidirectional Mendelian randomization (MR) analyses.
Methods
We used genome‐wide association data (n = 288,649 for serum urate SU concentration; n = 763,813 for gout risk; n = 153,525 for fasting insulin) to select genetic instruments for 2‐sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual‐level, electronic medical record–linked data from the UK Biobank (n = 360,453 persons of European ancestry) to replicate our analyses via single‐sample MR analysis.
Results
Genetically determined SU levels, whether inferred from a polygenic score or strong individual loci, were not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU levels (0.37 mg/dl per log‐unit increase in fasting insulin 95% confidence interval (95% CI) 0.15, 0.58; P = 0.001). This persisted in outlier‐corrected (β = 0.56 mg/dl 95% CI 0.45, 0.67) and multivariable MR analyses adjusted for BMI (β = 0.69 mg/dl 95% CI 0.53, 0.85) (P < 0.001 for both). Polygenic scores for fasting insulin were also positively associated with SU level among individuals in the UK Biobank (P < 0.001). Findings for gout risk were bidirectionally consistent with those for SU level.
Conclusion
These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia but not the other way around. Reducing insulin resistance could lower the SU level and gout risk, whereas lowering the SU level (e.g., allopurinol treatment) is unlikely to mitigate insulin resistance and its cardiometabolic sequelae.
Diagnosis and treatment of hypernatremia Muhsin, Saif A., MBChB; Mount, David B., MD
Best Practice & Research Clinical Endocrinology & Metabolism,
03/2016, Letnik:
30, Številka:
2
Journal Article
Recenzirano
Hypernatremia is defined as a serum sodium level above 145 mmol/L. It is a frequently encountered electrolyte disturbance in the hospital setting, with an unappreciated high mortality. Understanding ...hypernatremia requires a comprehension of body fluid compartments, as well as concepts of the preservation of normal body water balance. The human body maintains a normal osmolality between 280 and 295 mOsm/kg via Arginine Vasopressin (AVP), thirst, and the renal response to AVP; dysfunction of all three of these factors can cause hypernatremia. We review new developments in the pathophysiology of hypernatremia, in addition to the differential diagnosis and management of this important electrolyte disorder.
Gout is a painful inflammatory arthritis associated with hyperuricemia, with a prevalence of almost 10 million in the USA. Reduced renal excretion of urate is the underlying hyperuricemic mechanism ...in the vast majority of gout patients; most of the genes that affect serum urate level (SUA) encode urate transporters or associated regulatory proteins. Acquired influences can also modulate SUA and renal urate excretion, sometimes precipitating acute gout. Coincidentally, the prevalence of renal comorbidities in gout - hypertension, chronic kidney disease (CKD), and nephrolithiasis - is very high.
Recent advances in genetics and molecular physiology have greatly enhanced the understanding of renal reabsorption and secretion of filtered urate. Moreover, baseline SUA appears to be set by the net balance of absorption and secretion across epithelial cells in the kidney and intestine. There have also been substantial advances in the management of gout in patients with CKD.
The stage is set for an increasingly molecular understanding of baseline and regulated urate transport by the kidney and intestine. The increasing prevalence of gout with CKD will be balanced by an expanding spectrum of therapeutic options for this important disease.
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