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...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 [HCO] in patients with CKD-associated MA or low normal serum [HCO] that may further slow progression of CKD.
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 ac...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.
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 outc...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.
Moe OW, Maalouf NM, Sakhaee K
… +1 more, Lederer E
Adv Chronic Kidney Dis
· 2022 Jul · PMID 36175076
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Full text
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 a...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.
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 ingest...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 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 tha...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.
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. Wh...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.
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 traditi...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 HCO/HCO 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 [HCO]. 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 PCO. 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.
Normallly the kidneys handle the daily acid load arising from net endogenous acid production from the metabolism of ingested animal protein (acid) and vegetables (base). With chronic kidney disease, reduced acid excretio...Normallly the kidneys handle the daily acid load arising from net endogenous acid production from the metabolism of ingested animal protein (acid) and vegetables (base). With chronic kidney disease, reduced acid excretion by the kidneys is primarily due to reduced ammonium excretion such that when acid excertion falls below acid porduction, acid accumulation occurs. With even mild reductions in glomerular filtration rate (60 to 90 ml/min), net acid excretion may fall below net acid production resulting in acid retention which may be initially sequestered in interstitial compartments in the kidneys, bones, and muscles resulting in no fall in measured systemic bicarbonate levels (eubicarbonatemic metabolic acidosis). With greater reductions in kidney function, the greater quantities of acid retained spillover systemically resulting in low pH (overt metabolic acidosis). The evaluation of acid-base balance in patients with CKD is complicated by the heterogeneity of clinical acid-base disorders and by the eubicarbonatemic nature of the early phase of acid retention. If supported by more extensive studies, blood gas analyses to confirm the acid-base disorder and newer ways for assessing the presence of acidosis such as urinary citrate measurements may become routine tools to evaluate and treat acid-base disorders in individuals with CKD.
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...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.
Health care transition (HCT) from pediatric to adult-focused services is a longitudinal process driven by the collaboration and interactions of adolescent/young adult patients, their families, providers, health care agen...Health care transition (HCT) from pediatric to adult-focused services is a longitudinal process driven by the collaboration and interactions of adolescent/young adult patients, their families, providers, health care agencies, and environment. Health care providers in both pediatric and adult-focused settings must collaborate, as patients' health self-management skills are acquired in the mid-20s, after they have transferred to adult-focused care. Our manuscript discusses the individual and family support systems as they relate to adolescents and young adults with chronic or end-stage kidney disease. In the individual domain, we discuss demographic/socioeconomic characteristics, disease complexity/course, cognitive capabilities, and self-management/self-advocacy. In the family domain, we discuss family composition/culture factors, family function, parenting style, and family unit factors. We provide a section dedicated to patients with cognitive and developmental disability. Furthermore, we discuss barriers for HCT preparation and offer solutions as well as activities for HCT preparation.
Common causes of pediatric ESRD are distinct from those seen in the adult population. In the pediatric population, the most common are congenital anomalies of the kidney and urinary tract (CAKUT), affecting approximately...Common causes of pediatric ESRD are distinct from those seen in the adult population. In the pediatric population, the most common are congenital anomalies of the kidney and urinary tract (CAKUT), affecting approximately 30% of children with CKD. These structural anomalies often require coordinated care with the pediatric urology team to address voiding issues, bladder involvement, and the potential need for surgical intervention. For pediatric nephrologists and urologists, common CAKUT that are encountered include antenatal hydronephrosis, obstructive uropathies (eg, posterior urethral valves), and vesicoureteral reflux. As more pediatric patients with CAKUT, CKD, and ESRD transition to adult care, it is important for receiving adult nephrologists to understand the clinical presentation, natural history, and prognosis for these diagnoses. This review outlines the diagnosis and potential interventions for these conditions, including strategies to address bladder dysfunction that is often seen in children with CAKUT. A discussion of these management decisions (including surgical intervention) for CAKUT, which are quite common to pediatric nephrology and urology practices, may provide unique learning opportunities for adult nephrologists who lack familiarity with these pediatric conditions.
Recent advances in the management of kidney tubular diseases have resulted in a significant cohort of adolescents and young adults transitioning from pediatric- to adult-focused care. Most of the patients under adult-foc...Recent advances in the management of kidney tubular diseases have resulted in a significant cohort of adolescents and young adults transitioning from pediatric- to adult-focused care. Most of the patients under adult-focused care have glomerular diseases, whereas rarer tubular diseases form a considerable proportion of pediatric patients. The purpose of this review is to highlight the clinical signs and symptoms of tubular disorders, as well as their diagnostic workup, including laboratory findings and imaging, during young adulthood. We will then discuss more common disorders such as cystinosis, cystinuria, distal kidney tubular acidosis, congenital nephrogenic diabetes insipidus, Dent disease, rickets, hypercalciuria, and syndromes such as Bartter, Fanconi, Gitelman, Liddle, and Lowe. This review is a practical guide on the diagnostic and therapeutic approach of tubular conditions affecting young adults who are transitioning to adult-focused care.
The pediatric patient with end-stage kidney disease who transitions to the adult dialysis unit or nephrology center requires a unique nutritional focus. Clinicians in the adult center may be faced with complex issues tha...The pediatric patient with end-stage kidney disease who transitions to the adult dialysis unit or nephrology center requires a unique nutritional focus. Clinicians in the adult center may be faced with complex issues that have often been part of the patient's journey since early childhood. The causes of kidney disease in children are often quite different than those which affect the adult population and may require different nutritional priorities. Abnormal growth including severe short stature, underweight, overweight or obesity, and poor musculature may affect the long-term health and psychosocial well-being of these patients. Nutritional assessment of these patients should include a focus on past growth and anthropometric data, dietary information, including appetite, quality of diet, and assessment of biochemical data through a pediatric lens. This review discusses the unique factors that must be considered when transitioning pediatric patients and notes major recommendations from a compilation of pediatric guideline statements.
Chronic kidney disease is common and causes significant morbidity including shortened lifespans and decrease in quality of life for patients. The major cause of mortality in chronic kidney disease is cardiovascular disea...Chronic kidney disease is common and causes significant morbidity including shortened lifespans and decrease in quality of life for patients. The major cause of mortality in chronic kidney disease is cardiovascular disease. Cardiovascular disease within the chronic kidney disease population is closely tied with disordered calcium and phosphorus metabolism and driven in part by renal bone disease. The complex nature of renal, bone, and cardiovascular diseases was renamed as mineral and bone disorder of chronic kidney disease to encompass how bone disease drives vascular calcification and contributes to the development of long-term cardiovascular disease, and recent data suggest that managing bone disease well can augment and improve cardiovascular disease status. Pediatric nephrologists have additional obstacles in optimal mineral and bone disorder of chronic kidney disease management such as linear growth and skeletal maturation. In this article, we will discuss cardiovascular and bone diseases in chronic kidney disease and end-stage kidney disease patients with a focus on pediatric issues and concerns.
Hypertension (HTN) is an important cause of morbidity and mortality in children as well as adults. HTN and related adverse cardiovascular health develop and progress on a continuum across an individual's life course. Ped...Hypertension (HTN) is an important cause of morbidity and mortality in children as well as adults. HTN and related adverse cardiovascular health develop and progress on a continuum across an individual's life course. Pediatric HTN, or even isolated elevated blood pressure as a child, increases the risk of sustained HTN and cardiovascular disease in later adulthood. Transitioning the care of adolescents and young adults who have HTN is an important but unmet health care need that could potentially have a dramatic effect on mitigating the risk of cardiovascular disease in adulthood. However, very little has been published about the transition process in this population, and considerable gaps in the field remain. We discuss the epidemiology, etiology, and management approach in youth with HTN and how they differ from adults. We contextualize HTN and cardiovascular health on a continuum across the life course. We discuss key considerations for the transition process for adolescents and young adults with HTN including the major barriers that exist. Finally, we review key immediate health care needs that are particularly important around the time of the transfer of care.
Adolescent obesity and CKD are both significant public health issues independently. When seen as comorbid conditions, they can cause deleterious health outcomes that put them on the fast track to necessitate dialysis or...Adolescent obesity and CKD are both significant public health issues independently. When seen as comorbid conditions, they can cause deleterious health outcomes that put them on the fast track to necessitate dialysis or transplantation. This paper analyzes the effects of various biomarkers and comorbidities seen in the intersection of obesity and CKD in the adolescent population. We illustrate the estimated prevalence of these biomarkers and comorbidities through a review of the literature, available treatment, and obesity-related glomerulopathies. We found significant prevalence of the biomarkers, microalbuminuria (9.42% ± 9.31% and interquartile range [IQR] of 9.5%), hypertension (23.60% ± 22.5% and IQR of 9.5%), low high-density lipoprotein (14.34% ± 5.46% and IQR of 5%), hyperfiltration (3.12% ± 5.16% and IQR of 4%), and lower estimated glomerular filtration rate 4.59 ± 2.75 and IQR of 3%. Identification of prevalent biomarkers and their manifestations can serve to inform clinicians what to look for in daily setting and help elucidate the magnitude of this growing issue. Additionally, pertinent treatment options from pharmacotherapy to bariatric surgery are outlined to provide care providers with the full spectrum of treatment options for obesity in adolescent populations.
Gaining insight into the complex cycle of renal programming and its early-life clinical associations is essential to understand the origins of kidney disease. Prematurity and intrauterine growth restriction are associate...Gaining insight into the complex cycle of renal programming and its early-life clinical associations is essential to understand the origins of kidney disease. Prematurity and intrauterine growth restriction are associated with low nephron endowment. This increases the risk of developing hypertension and chronic kidney disease later in life. There is appreciable evidence to support mechanistic links between low nephron endowment secondary to intrauterine events and kidney size, kidney function, and blood pressure in postnatal life. A clear understanding of the cycle of developmental programming and consequences of fetal insults on the kidney is critical. In addition, the impact of events in the early postnatal period (accelerated postnatal growth, development of obesity, exposure to nephrotoxins) on the cardiovascular system and blood pressure of individuals born prematurely or with low birth weight is discussed. In summary, this review draws attention to the concepts of renal programming and nephron endowment and underscores the associations between intrauterine growth restriction, prematurity, and its clinical consequences in adult life.
Atypical hemolytic uremic syndrome and C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis are ultra-rare chronic, complement-mediated diseases with childhood manifestation in a majority of cases. T...Atypical hemolytic uremic syndrome and C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis are ultra-rare chronic, complement-mediated diseases with childhood manifestation in a majority of cases. Transition of clinical care of patients from pediatric to adult nephrologists-typically with controlled disease in native or transplant kidneys in case of atypical hemolytic uremic syndrome and often with chronic progressive disease despite treatment efforts in case of C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis-identifies a challenging juncture in the journey of these patients. Raising awareness for the vulnerability of this patient cohort; providing education on disease pathophysiology and management including the use of new, high-precision complement antagonists; and establishing an ongoing dialog of patients, families, and all members of the health care team involved on either side of the age divide will be inevitable to ensure optimal patient outcomes and a safe transition of these patients to adulthood.