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Kidney360 Oct 2021
Topics: Acidosis, Renal Tubular; Humans; Hypokalemia; Lupus Nephritis
PubMed: 35372981
DOI: 10.34067/KID.0005302021 -
Nephron 2023Serum creatinine and albuminuria are primary markers of glomerular function and injury, respectively. Tubular secretion, acid-base homeostasis, protein reabsorption,... (Review)
Review
BACKGROUND
Serum creatinine and albuminuria are primary markers of glomerular function and injury, respectively. Tubular secretion, acid-base homeostasis, protein reabsorption, among other tubular functions, are largely ignored. This mini-review aimed to discuss how two tubular functions, secretion, and acid-base homeostasis are associated with major adverse kidney events (MAKEs).
SUMMARY
Proximal tubular secretion is an essential function that allows the elimination of endogenous substances and drugs. Recently discovered endogenous markers in urine and plasma allow a noninvasive way of assessing tubular secretion markers. Several studies have found an association between these markers and a higher risk of chronic kidney disease (CKD) progression and mortality. In a study we recently performed among patients with CKD and at risk of cardiovascular events, lower tubular secretion was associated with an increased risk of acute kidney injury and metabolic acidosis, independent of baseline eGFR and albuminuria. The kidney tubules also play a crucial role in acid-base homeostasis. Although the standard clinical assessment of acidosis consists of measuring serum bicarbonate, urinary ammonium excretion decreases before over metabolic acidosis. Urinary ammonium excretion is associated with CKD progression, a higher risk of kidney failure, and an increased mortality risk, independent of baseline eGFR and albuminuria.
KEY MESSAGES
Novel biomarkers of kidney tubular health consistently associate with MAKEs, above and beyond baseline eGFR, albuminuria, and other CKD risk factors. Tubular markers may provide new opportunities to improve kidney prognosis, drug dosing, and monitoring for adverse events.
Topics: Humans; Albuminuria; Kidney Tubules; Renal Insufficiency, Chronic; Biomarkers; Acidosis; Ammonium Compounds; Glomerular Filtration Rate
PubMed: 37524063
DOI: 10.1159/000531946 -
Journal of Hospital Medicine Jun 2018
Topics: Acidosis, Renal Tubular; Adult; Female; Humans; Muscle Weakness
PubMed: 29261817
DOI: 10.12788/jhm.2893 -
Pediatric Nephrology (Berlin, Germany) Dec 2015In the absence of a gastrointestinal origin, a maintained hyperchloremic metabolic acidosis must raise the diagnostic suspicion of renal tubular acidosis (RTA). Unlike... (Review)
Review
In the absence of a gastrointestinal origin, a maintained hyperchloremic metabolic acidosis must raise the diagnostic suspicion of renal tubular acidosis (RTA). Unlike adults, in whom RTA is usually secondary to acquired causes, children most often have primary forms of RTA resulting from an inherited genetic defect in the tubular proteins involved in the renal regulation of acid-base homeostasis. According to their pathophysiological basis, four types of RTA are distinguished. Distal type 1 RTA, proximal type 2 RTA, mixed-type 3 RTA, and type 4 RTA can be differentiated based on the family history, the presenting manifestations, the biochemical profile, and the radiological findings. Functional tests to explore the proximal wasting of bicarbonate and the urinary acidification capacity are also useful diagnostic tools. Although currently the molecular basis of the disease can frequently be discovered by gene analysis, patients with RTA must undergo a detailed clinical study and laboratory work-up in order to understand the pathophysiology of the disease and to warrant a correct and accurate diagnosis.
Topics: Acidosis, Renal Tubular; Child; Child, Preschool; Humans; Kidney
PubMed: 25823989
DOI: 10.1007/s00467-015-3083-9 -
Cureus Nov 2018Topiramate (TMP) is a broad-spectrum anticonvulsant drug used to treat a wide variety of seizure disorders, for migraine prophylaxis, and for many other indications. An... (Review)
Review
Topiramate (TMP) is a broad-spectrum anticonvulsant drug used to treat a wide variety of seizure disorders, for migraine prophylaxis, and for many other indications. An important side effect of TMP is metabolic acidosis, which is mediated by renal tubular defects. TMP inhibits carbonic anhydrase, an enzyme that is necessary for acid handling in the proximal renal tubule. Patients can present with asymptomatic serum electrolyte derangements, acute change in mental status, hyperventilation, cardiac arrhythmias, or other sequelae of metabolic acidosis and associated respiratory compensation. If taken chronically, TMP can cause renal stone formation, bone mineralization defects, and several other effects secondary to changes in serum and urine pH and electrolytes. There is no well-studied way to prevent metabolic acidosis in patients taking TMP, but physicians should be vigilant when prescribing this drug to patients with the history of renal diseases and other comorbidities, and aware of this potential etiology of metabolic acidosis. We present a literature review of the underlying mechanisms involved in the development of renal tubular acidosis secondary to TMP and its clinical consequences.
PubMed: 30755834
DOI: 10.7759/cureus.3635 -
Pediatric Nephrology (Berlin, Germany) Jan 2016Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia,... (Review)
Review
Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria. Bone-produced fibroblast growth factor 23 (FGF23) bound to Klotho in tubule cells and intracellular phosphate concentrations are regulators of 1-α-hydroxylase activity and cause proximal tubule phosphaturia. Aminoaciduria occurs when amino acid transporter synthesis is deficient, and 1,25(OH)2D along with retinoic acid up-regulate transporter synthesis by a vitamin D response element in the promoter region of the transporter gene. This review discusses evidence gained from studies in animals or cell lines, as well as from human disorders, that provide insight into vitamin D-proximal tubule interactions.
Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Fibroblast Growth Factor-23; Genetic Predisposition to Disease; Humans; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Prognosis; Receptors, Calcitriol; Receptors, Cell Surface; Renal Aminoacidurias; Risk Factors; Signal Transduction; Vitamin D; Vitamin D Deficiency; Vitamin D3 24-Hydroxylase
PubMed: 25618772
DOI: 10.1007/s00467-015-3050-5 -
Nefrologia 2021Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level.... (Review)
Review
Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium. To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3 groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described. The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA.
Topics: Acidosis, Renal Tubular; Ammonium Compounds; Bicarbonates; Citrates; Forkhead Transcription Factors; Humans; Vacuolar Proton-Translocating ATPases
PubMed: 36165107
DOI: 10.1016/j.nefroe.2021.09.004 -
Clinical and Experimental Nephrology Aug 2015Renal tubular acidosis (RTA) is essentially characterized by normal anion gap and hyperchloremic metabolic acidosis. It is important to understand that despite knowing... (Review)
Review
Renal tubular acidosis (RTA) is essentially characterized by normal anion gap and hyperchloremic metabolic acidosis. It is important to understand that despite knowing the disease for 60-70 years, complexities in the laboratory tests and their interpretation still make clinicians cautious to diagnose and label types of tubular disorder. Hence, we are writing this mini-review to emphasize on the step wise approach to RTA with some understanding on its basic etiopathogenesis. This will definitely help to have an accurate interpretation of urine and blood reports in correlation with the clinical condition. RTA can be a primary or secondary defect and results either due to abnormality in bicarbonate ion absorption or hydrogen ion secretion. Primary defects are common in children due to gene mutation or idiopathic nature while secondary forms are more common in adults. We are focusing and explaining here in this review all the clinical and laboratory parameters which are essential for making the diagnosis of RTA and excluding the extrarenal causes of hyperchloremic, normal anion gap metabolic acidosis.
Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Humans; Kidney Tubules
PubMed: 25951806
DOI: 10.1007/s10157-015-1119-x -
Advances in Chronic Kidney Disease Jul 2018Proximal renal tubular acidosis (pRTA) is an inherited or acquired clinical syndrome in which there is a decreased bicarbonate reclamation in the proximal tubule... (Review)
Review
Proximal renal tubular acidosis (pRTA) is an inherited or acquired clinical syndrome in which there is a decreased bicarbonate reclamation in the proximal tubule resulting in normal anion gap hyperchloremic metabolic acidosis. In children, pRTA may be isolated but is often associated with a general proximal tubular dysfunction known as Fanconi syndrome which frequently heralds an underlying systemic disorder from which it arises. When accompanied by Fanconi syndrome, pRTA is characterized by additional renal wasting of phosphate, glucose, uric acid, and amino acids. The most common cause of inherited Fanconi syndrome in the pediatric age group is cystinosis, a disease with therapeutic implications. In this article, we summarize the clinical presentation and differential diagnosis of pRTA and Fanconi syndrome and provide a practical approach to their evaluation in children.
Topics: Acidosis, Renal Tubular; Child; Cystinosis; Dent Disease; Fanconi Syndrome; Humans; Kidney Tubules, Proximal; Oculocerebrorenal Syndrome
PubMed: 30139461
DOI: 10.1053/j.ackd.2018.05.006 -
Journal of the American Society of... May 2018Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the...
Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.
Topics: Acidosis; Aldosterone; Amiloride; Ammonia; Animals; Cation Transport Proteins; Diuretics; Glutaminase; Hydrochlorothiazide; Hydrogen-Ion Concentration; Hyperkalemia; Kidney Tubules, Distal; Kidney Tubules, Proximal; Membrane Glycoproteins; Mice; Mice, Knockout; Protein Serine-Threonine Kinases; Proton-Translocating ATPases; Urinalysis
PubMed: 29483157
DOI: 10.1681/ASN.2017111163