Advances in chronic kidney disease最新文献

Evaluation of acid-base status depends on accurate measurement of acid-base variables and their appropriate assessment. Currently, 3 approaches are utilized for assessing acid-base variables. The physiological or traditional approach, pioneered by Henderson and Van Slyke in the early 1900s, considers acids as H⁺ donors and bases as H⁺ acceptors. The acid-base status is conceived as resulting from the interaction of net H⁺ balance with body buffers and relies on the H₂CO₃/HCO₃⁻ buffer pair for its assessment. A second approach, developed by Astrup and Siggaard-Andersen in the late 1950s, is known as the base excess approach. Base excess was introduced as a measure of the metabolic component replacing plasma [HCO₃⁻]. In the late 1970s, Stewart proposed a third approach that bears his name and is also referred to as the physicochemical approach. It postulates that the [H⁺] of body fluids reflects changes in the dissociation of water induced by the interplay of 3 independent variables—strong ion difference, total concentration of weak acids, and PCO₂. Here we focus on the physiological approach and Stewart's approach examining their conceptual framework, practical application, as well as attributes and drawbacks. We conclude with our view about the optimal approach to assessing acid-base status.

The various mechanisms responsible for the development of metabolic acidosis are briefly reviewed, and the metabolic acidoses are categorized both by mechanism and by the presence or absence of an increased anion gap. When a diagnosis of metabolic acidosis is established, it becomes imperative to identify the primary causative etiology as quickly as possible. This is often readily apparent from the history and physical exam (ie, diabetic ketoacidosis when the glucose is very high in a patient with diabetes mellitus; lactic acidosis in a patient with sepsis and hypotension, etc.). However, when the etiology is not obvious, it is very helpful to determine if the metabolic acidosis is of the hyperchloremic or high-anion-gap type (or a combination of both). Once this categorization has been established, a stepwise consideration of each of the potential causative etiologies will usually direct the clinician to order the appropriate diagnostic studies.

Acid accumulation sufficient to reduce plasma bicarbonate concentration, thereby recognized as chronic metabolic acidosis, harms bones and muscles and appears to enhance progression of CKD. Evolving evidence supports that progressive acid accumulation that is not enough to cause chronic metabolic acidosis nevertheless has deleterious effects. Measurable acid retention without reduced plasma bicarbonate concentration, called eubicarbonatemic acidosis, also appears to cause kidney injury and exacerbate CKD progression. Furthermore, chronic engagement of mechanisms to mitigate the ongoing acid challenge of net acid-producing diets of developed societies also appears to be deleterious, including for kidney health. This review challenges clinicians to consider the growing evidence for a spectrum of acid-accumulation disorders that include lesser degrees of acid accumulation than metabolic acidosis yet are harmful. Further research will develop clinically useful tools to identify individuals suffering from these earlier stages of acid stress and determine if the straightforward and comparatively inexpensive intervention of dietary acid reduction relieves or eliminates the harm they appear to cause.

Human kidneys are well adapted to excrete the daily acid load from diet and metabolism in order to maintain homeostasis. In approximately 30% of patients with more advanced stages of CKD, these homeostatic processes are no longer adequate, resulting in metabolic acidosis. Potential deleterious effects of chronic metabolic acidosis in CKD, including muscle wasting, bone demineralization, hyperkalemia, and more rapid progression of CKD, have been well cataloged. Based primarily upon concerns related to nutrition and bone disease, early Kidney Disease Outcomes Quality Initiative guidelines recommended treating metabolic acidosis with alkali therapy targeting a serum bicarbonate ≥22 mEq/L. More recent guidelines have suggested similar targets based upon potential slowing of CKD progression. However, appropriately powered, long-term, randomized controlled trials to study efficacy and safety of alkali therapy for these outcomes are largely lacking. As a result, practice among physicians varies, underscoring the complexity of treatment of chronic metabolic acidosis in real-world CKD practice. Novel treatment approaches and rigorous phase 3 trials may resolve some of this controversy in the coming years. Metabolic acidosis is an important complication of CKD, and where it “falls” in the priority schema of CKD care will depend upon the generation of strong clinical evidence.

Eating a net acid-producing diet can produce an “acid stress” of severity proportional to the diet net acid load, as indexed by the steady-state renal net acid excretion rate. Depending on how much acid or base is ingested or produced from endogenous metabolic processes and how well our homeostatic mechanisms can buffer or eliminate the additional acids or bases, we can alter our systemic acid-base balance. With increasing age, the kidney's ability to excrete daily net acid loads declines (a condition similar to that of mild CKD), invoking increased utilization of potential base stores (eg, bone, skeletal muscle) on a daily basis to mitigate the acid accumulation, thereby contributing to development of osteoporosis, loss of muscle mass, and age-related renal insufficiency. Patients suffering from more advanced CKD often present with more severe acid stress or metabolic acidosis, as the kidney can no longer excrete the entire acid load. Alkaline diets based on fruits and vegetables may have a positive effect on long-term preservation of renal function while maintaining nutritional status. This chapter discusses the biochemistry of dietary precursors that affect acid or base production.

Acid can have ill effect on bone health in the absence of frank clinical acidosis but affecting the bone mioneral matrix and bone cells via complex pathways botyh ascute;y and chronically. While the reaction of bone to an acid load is conserved in evolution and is adaptive, the capacity can be overwhelmed resulting in dire consequences. The preclinical an clincl evidence of the acdi effect on bone is very convincing and the clinical evidence in both association and interventiopn studies are also quite credible, The adverse effects of acid on bone is underappreoicated, under-investigated, and the potential benefits of alkali therapy is not generrally known.

Metabolic acidosis affects about 15% of patients with chronic kidney disease. As kidney function declines, the kidneys progressively fail to eliminate acid, primarily reflected by a decrease in ammonium and titratable acid excretion. Several studies have shown that the net acid load remains unchanged in patients with reduced kidney function; the ensuing acid accumulation can precede overt metabolic acidosis, and thus, indicators of urinary acid or potential base excretion, such as ammonium and citrate, may serve as early signals of impending metabolic acidosis. Acid retention, with or without overt metabolic acidosis, initiates compensatory responses that can promote tubulointerstitial fibrosis via intrarenal complement activation and upregulation of endothelin-1, angiotensin II, and aldosterone pathways. The net effect is a cycle between acid accumulation and kidney injury. Results from small- to medium-sized interventional trials suggest that interrupting this cycle through base administration can prevent further kidney injury. While these findings inform current clinical practice guidelines, large-scale clinical trials are still necessary to prove that base therapy can limit chronic kidney disease progression or associated adverse events.

Chronic kidney disease (CKD) is a major global epidemic associated with increased morbidity and mortality. Despite the effectiveness of kidney protection strategies of hypertension, diabetes, and lipid control and use of newer hypoglycemic agents and anti-angiotensin II drugs, the nephropathy in CKD continues unabated toward irreversible kidney failure. Thus, interventions targeting modifiable risk factors in CKD such as metabolic acidosis (MA) are needed. Acid reduction with sodium-based alkali has been shown to be an effective kidney-protection strategy for patients with CKD and reduced glomerular filtration rate (GFR). Small-scale studies reveal diets emphasizing ingestion of plant-sourced over animal-sourced protein reduce dietary acid, improve MA, and slow further nephropathy progression in patients with CKD and reduced GFR. Additionally, veverimer, an investigational, nonabsorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as a novel treatment for MA. As further studies define how to best use these interventions for kidney protection, clinicians must become aware of their potential utility in the management of patients with CKD. The aim of the present review is to explore the various intervention strategies that increase or normalize serum [HCO₃^-] in patients with CKD-associated MA or low normal serum [HCO₃^-] that may further slow progression of CKD.

Metabolic acidosis is common in people with chronic kidney disease and can contribute to functional decline, morbidity, and mortality. One avenue through which metabolic acidosis can result in these adverse clinical outcomes is by negatively impacting skeletal muscle; this can occur through several pathways. First, metabolic acidosis promotes protein degradation and impairs protein synthesis, which lead to muscle breakdown. Second, metabolic acidosis hinders mitochondrial function, which decreases oxidative phosphorylation and reduces energy production. Third, metabolic acidosis directly limits muscle contraction. The purpose of this review is to examine the specific mechanisms of each pathway through which metabolic acidosis affects muscle, the impact of metabolic acidosis on physical function, and the effect of treating metabolic acidosis on functional outcomes.