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Pediatric Nephrology (Berlin, Germany) Feb 2020Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and... (Review)
Review
Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and growing neonates. The kidney, which represents the crucial ultimate line of defense against disturbances of acid-base balance, undergoes a complex maturation process during the transition from a fetal to an extra-uterine environment. This review article summarizes the physiology of acid-base regulation by the immature human kidney and discusses disorders of acid-base balance, such as metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. In conditions of metabolic acidosis, the serum anion gap and the urinary anion gap can be useful tools to define the nature of the acidosis. Metabolic acidosis can reflect a decrease in glomerular filtration rate, or be the consequence of selective disorders of proximal or distal tubular function. Most tubulopathies associated with metabolic acidosis observed in neonates are primary, hereditary, isolated tubulopathies. Proximal renal tubular acidosis is characterized by bicarbonate wasting, while the distal types of renal tubular acidosis are secondary to distal acidification defects. All tubulopathies are associated with hypokalemia, with the exception of type 4 hyperkalemic distal renal tubular acidosis. The transporter defects in the various acid-base tubulopathies are now well defined. Treatment of the acidosis varies according to the site and mechanism of the defect. Chronic renal tubular acidosis or alkalosis severely impair growth and calcium metabolism. Early rational therapeutic intervention can prevent some of the consequences of the disorders and improves the prognosis.
Topics: Acid-Base Imbalance; Female; Humans; Infant, Newborn; Kidney; Male
PubMed: 30456666
DOI: 10.1007/s00467-018-4142-9 -
Pediatric Nephrology (Berlin, Germany) Mar 2023The clinical manifestations of primary distal renal tubular acidosis usually begin in childhood, but the disease is caused by a genetic defect that persists throughout... (Review)
Review
The clinical manifestations of primary distal renal tubular acidosis usually begin in childhood, but the disease is caused by a genetic defect that persists throughout life. This review focuses on the complications of distal tubular acidosis that occur or remain long-term such as nephrocalcinosis and urolithiasis, growth impairment, bone mineralization, severe hypokalemia, kidney cysts, and progressive kidney failure, as well as other persistent manifestations that occur independent of acidosis but are associated with some inherited forms of the disease. The pathogenic factors responsible for kidney failure are discussed in particular because it is a complication to which different publications have recently drawn attention and which affects a high percentage of adults with primary distal renal tubular acidosis. The need to maintain optimal metabolic control of the disease and scheduled clinical follow-up throughout life and the importance of organizing protocols for the transition of patients to adult nephrology services are emphasized.
Topics: Adult; Humans; Acidosis, Renal Tubular; Hypokalemia; Acidosis; Nephrocalcinosis; Renal Insufficiency
PubMed: 35543873
DOI: 10.1007/s00467-022-05546-w -
Nephrology, Dialysis, Transplantation :... Aug 2015The [Formula: see text] exchanger pendrin (SLC26A4, PDS) is located on the apical membrane of B-intercalated cells in the kidney cortical collecting duct and the... (Review)
Review
The [Formula: see text] exchanger pendrin (SLC26A4, PDS) is located on the apical membrane of B-intercalated cells in the kidney cortical collecting duct and the connecting tubules and mediates the secretion of bicarbonate and the reabsorption of chloride. Given its dual function of bicarbonate secretion and chloride reabsorption in the distal tubules, it was thought that pendrin plays important roles in systemic acid-base balance and electrolyte and vascular volume homeostasis under basal conditions. Mice with the genetic deletion of pendrin or humans with inactivating mutations in PDS gene, however, do not display excessive salt and fluid wasting or altered blood pressure under baseline conditions. Very recent reports have unmasked the basis of incongruity between the mild phenotype in mutant mice and the role of pendrin as an important player in salt reabsorption in the distal tubule. These studies demonstrate that pendrin and the Na-Cl cotransporter (NCC; SLC12A3) cross compensate for the loss of each other, therefore masking the role that each transporter plays in salt reabsorption under baseline conditions. In addition, pendrin regulates calcium reabsorption in the distal tubules. Furthermore, combined deletion of pendrin and NCC not only causes severe volume depletion but also results in profound calcium wasting and luminal calcification in medullary collecting ducts. Based on studies in pathophysiological states and the examination of genetically engineered mouse models, the evolving picture points to important roles for pendrin (SLC26A4) in kidney physiology and in disease states. This review summarizes recent advances in the characterization of pendrin and the multiple roles it plays in the kidney, with emphasis on its essential roles in several diverse physiological processes, including chloride homeostasis, vascular volume and blood pressure regulation, calcium excretion and kidney stone formation.
Topics: Acid-Base Equilibrium; Animals; Anion Transport Proteins; Humans; Kidney Diseases; Membrane Transport Proteins; Mice; Solute Carrier Family 12, Member 3; Sulfate Transporters; Water-Electrolyte Balance
PubMed: 25281699
DOI: 10.1093/ndt/gfu307 -
Advances in Chronic Kidney Disease Sep 2017Subjects with CKD and reduced glomerular filtration rate are at risk for chronic metabolic acidosis, and CKD is its most common cause. Untreated metabolic acidosis, even... (Review)
Review
Subjects with CKD and reduced glomerular filtration rate are at risk for chronic metabolic acidosis, and CKD is its most common cause. Untreated metabolic acidosis, even in its mildest forms, is associated with increased mortality and morbidity and should therefore be treated. If reduced glomerular filtration rate or the tubule abnormality causing chronic metabolic acidosis cannot be corrected, it is typically treated with dietary acid (H) reduction using Na-based alkali, usually NaHCO. Dietary H reduction can also be accomplished with the addition of base-producing foods such as fruits and vegetables and limiting intake of H-producing foods like animal-sourced protein. The optimal dose of Na-based alkali that prevents the untoward effects of metabolic acidosis while minimizing adverse effects and the appropriate combination of this traditional therapy with dietary strategies remain to be determined by ongoing studies. Recent emerging evidence supports a phenomenon of H retention, which precedes the development of metabolic acidosis by plasma acid-base parameters, but further studies will be needed to determine how best to identify patients with this phenomenon and whether they too should be treated with dietary H reduction.
Topics: Acid-Base Equilibrium; Acidosis; Acidosis, Renal Tubular; Animals; Bicarbonates; Diet; Dietary Proteins; Fruit; Glomerular Filtration Rate; Humans; Renal Insufficiency, Chronic; Sodium Bicarbonate; Vegetables
PubMed: 29031356
DOI: 10.1053/j.ackd.2017.06.006 -
Frontiers in Physiology 2022In 2009, two groups independently linked human mutations in the inwardly rectifying K channel Kir4.1 (gene name ) to a syndrome affecting the central nervous system... (Review)
Review
In 2009, two groups independently linked human mutations in the inwardly rectifying K channel Kir4.1 (gene name ) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na, K, and Mg with urine, activation of the renin-angiotensin-aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.
PubMed: 35370765
DOI: 10.3389/fphys.2022.852674 -
Current Opinion in Nephrology and... Sep 2016The purpose of this review is to provide a succinct description of the recent findings that advance our understanding of the fundamental renal process of ammonia... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide a succinct description of the recent findings that advance our understanding of the fundamental renal process of ammonia metabolism and transport in conditions relevant to the clinician.
RECENT FINDINGS
Recent studies advance our understanding of renal ammonia metabolism. Mechanisms through which chronic kidney disease and altered dietary protein intake alter ammonia excretion have been identified. Lithium, although it can acutely cause distal renal tubular acidosis, was shown with long-term use to increase urinary ammonia excretion, and this appeared to be mediated, at least in part, by increased Rhcg expression. Gene deletion studies showed that the ammonia recycling enzyme, glutamine synthetase, has a critical role in normal-stimulated and acidosis-stimulated ammonia metabolism and that the proximal tubule basolateral bicarbonate transporter, NBCe1, is necessary for normal ammonia metabolism. Finally, our understanding of the molecular ammonia species, NH3 versus NH4, transported by Rh glycoproteins continues to be advanced.
SUMMARY
Fundamental studies have been recently published that advance our understanding of the regulation of ammonia metabolism in clinically important circumstances, and our understanding of the mechanisms and regulation of proximal tubule ammonia generation, and the mechanisms through which Rh glycoproteins contribute to ammonia secretion.
Topics: Ammonia; Animals; Biological Transport; Dietary Proteins; Glutamate-Ammonia Ligase; Glycoproteins; Humans; Kidney; Kidney Tubules, Proximal; Lithium; Renal Insufficiency, Chronic; Sodium-Bicarbonate Symporters
PubMed: 27367914
DOI: 10.1097/MNH.0000000000000255 -
Clinical Rheumatology Feb 2023To investigate the clinical features and factors associated with primary Sjögren's syndrome (pSS)-associated renal tubular acidosis (RTA).
OBJECTIVES
To investigate the clinical features and factors associated with primary Sjögren's syndrome (pSS)-associated renal tubular acidosis (RTA).
METHOD
This case-control study was based on a multicenter pSS registry established by the Chinese Rheumatism Data Center. Patients with pSS, including those with RTA and those without renal involvement, between May 2016 and March 2020 were included in the analysis. Demographic, clinical, and laboratory data were also collected. Univariate and multivariate logistic regression analyses were used to identify factors that were associated with pSS-RTA.
RESULTS
This study included 257 pSS patients with RTA and 4222 patients without renal involvement. Significantly younger age at disease onset (40.1 ± 14.1 vs. 46.2 ± 13.1 years, P < 0.001), longer diagnosis interval (15.0 interquartile range [IQR] [1.0, 48.0] vs. 6.0 IQR [0, 34.0] months, P < 0.001), higher EULAR Sjögren's syndrome disease activity index (9 IQR [5, 15] vs. 3 IQR [0, 8], P < 0.001), and a higher prevalence of decreased estimated glomerular filtration rate (25.0% vs. 6.6%, P < 0.001) were observed in pSS patients with RTA than in those without renal involvement. Factors that were independently associated with pSS-RTA included age at disease onset ≤ 35 years (odds ratio [OR] 3.00, 95% confidence interval [CI] 2.27-3.97), thyroid disorders (OR 1.49, 95% CI 1.04-2.14), subjective dry mouth (OR 3.29, 95% CI 1.71-6.35), arthritis (OR 1.57, 95% CI 1.10-2.25), anti-SSB antibody positivity (OR 1.80, 95% CI 1.33-2.45), anemia (OR 1.67, 95% CI 1.26-2.21), elevated alkaline phosphatase level (OR 2.14, 95% CI 1.26-3.65), decreased albumin level (OR 1.61, 95% CI 1.00-2.60), and elevated erythrocyte sedimentation rate (OR 1.78, 95% CI 1.16-2.73).
CONCLUSIONS
Delayed diagnosis and decreased kidney function are common in pSS patients with RTA. pSS should be considered in patients with RTA, and early recognition and treatment may be useful in slowing the deterioration of renal function in patients with pSS-RTA. Key Points • pSS patients with RTA have earlier disease onset and higher disease activity than pSS patients without RTA, but the diagnosis was frequently delayed. • Decreased kidney function are common in pSS patients with RTA. • Sjögren's syndrome should be considered in young female patients with unexplained RTA, whereas RTA should be screened in pSS patients with early disease onset and elevated ALP level.
Topics: Adult; Female; Humans; Acidosis, Renal Tubular; Arthritis; Case-Control Studies; Sjogren's Syndrome; Xerostomia; Middle Aged
PubMed: 36383239
DOI: 10.1007/s10067-022-06426-2 -
Advances in Chronic Kidney Disease Jul 2018
Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Ammonium Compounds; Bicarbonates; Humans; Osmolar Concentration; Renal Insufficiency, Chronic
PubMed: 30139456
DOI: 10.1053/j.ackd.2018.03.003 -
Clinical Journal of the American... Apr 2021The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no... (Review)
Review
The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we focus on genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of genetically defined patients have shaped our understanding of kidney physiology.
Topics: Humans; Kidney; Kidney Diseases; Kidney Tubules
PubMed: 32238367
DOI: 10.2215/CJN.14481119 -
Nephrology, Dialysis, Transplantation :... Jun 2019Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome.
BACKGROUND
Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome.
METHODS
We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form.
RESULTS
Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate.
CONCLUSION
Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.
Topics: Acidosis, Renal Tubular; Adolescent; Adult; Aged; Bicarbonates; Calcium; Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; Deafness; Female; Genetic Association Studies; Glomerular Filtration Rate; Hearing Loss, Sensorineural; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mutation; Nephrocalcinosis; Rare Diseases; Vacuolar Proton-Translocating ATPases; Young Adult
PubMed: 30773598
DOI: 10.1093/ndt/gfy409