Altered expression of renal acid-base transporters in rats with lithium-induced NDI

2003 ◽  
Vol 285 (6) ◽  
pp. F1244-F1257 ◽  
Author(s):  
Young-Hee Kim ◽  
Tae-Hwan Kwon ◽  
Birgitte M. Christensen ◽  
Jakob Nielsen ◽  
Susan M. Wall ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Lithium Treatment ◽  
Immunoblot Analysis ◽  
Acid Base ◽  
Urine Ph ◽  
Outer Medulla ◽  
Altered Expression ◽  
And Control

Prolonged lithium treatment of humans and rodents often results in hyperchloremic metabolic acidosis. This is thought to be caused by diminished net H+ secretion and/or excessive back-diffusion of acid equivalents. To explore whether lithium treatment is associated with changes in the expression of key renal acid-base transporters, semiquantitative immunoblotting and immunocytochemistry were performed using kidneys from lithium-treated ( n = 6) and control ( n = 6) rats. Rats treated with lithium for 28 days showed decreased urine pH, whereas no significant differences in blood pH and plasma [Formula: see text] levels were observed. Immunoblot analysis revealed that lithium treatment induced a significant increase in the expression of the H+-ATPase (B1-subunit) in cortex (190 ± 18%) and inner stripe of the outer medulla (190 ± 9%), and a dramatic increase in inner medulla (900 ± 104%) in parallel to an increase in the expression of type 1 anion exchanger (400 ± 40%). This was confirmed by immunocytochemistry and immunoelectron microscopy, which also revealed increased density of intercalated cells. Moreover, immunoblotting and immunocytochemistry revealed a significant increase in the expression of the type 1 electrogenic [Formula: see text] cotransporter (NBC) in cortex (200 ± 23%) and of the electroneutral NBCn1 in inner stripe of the outer medulla (250 ± 54%). In contrast, there were no changes in the expression of Na+/H+ exchanger-3 or of the [Formula: see text] exchanger pendrin. These results demonstrate that the expression of specific renal acid-base transporters is markedly altered in response to long-term lithium treatment. This is likely to represent direct or compensatory effects to increase the capacity for [Formula: see text] reabsorption, [Formula: see text] reabsorption, and proton secretion to prevent the development of systemic metabolic acidosis.

The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins

2009 ◽  
Vol 297 (2) ◽  
pp. F499-F509 ◽  
Author(s):  
Nilufar Mohebbi ◽  
Marija Mihailova ◽  
Carsten A. Wagner
Keyword(s):  
Metabolic Acidosis ◽  
Collecting Duct ◽  
Transport Proteins ◽  
Protein Abundance ◽  
Cortical Collecting Duct ◽  
Acid Base ◽  
Urine Ph ◽  
Altered Expression ◽  
Connecting Tubule ◽  
Baseline Conditions

Calcineurin inhibitors like FK506 (tacrolimus) are routinely used for immunosuppression following transplantation. Its use is limited by many side effects, including renal tubular acidosis (RTA), mainly of the distal type. In this study, rats were treated with FK506 and at baseline (after 9 days) systemic acid-base status was similar to that in control animals. However, FK506-treated rats given NH4Cl in the drinking water for 2 days developed a more severe metabolic acidosis than control animals. Urine pH was more alkaline, but net acid excretion was normal. After 7 days of acid load, all differences related to acid-base homeostasis were equalized in both groups. Protein abundance of type IIa Na-Pi cotransporter, type 3 Na+/H+ exchanger, and electrogenic Na+-bicarbonate cotransporter, and both a4 and B2 subunits of the vacuolar H+-ATPase were reduced under baseline conditions, while induction of metabolic acidosis enhanced protein abundance of these transporters in FK506-treated animals. In parallel, protein expression of AE1 was reduced at baseline and increased together with pendrin during NH4Cl loading in FK506 rats. Protein abundance of the Na+-bicarbonate cotransporter NBCn1 was reduced under baseline conditions but remained downregulated during metabolic acidosis. Morphological analysis revealed an increase in the relative number of non-type A intercalated cells in the connecting tubule and cortical collecting duct at the expense of principal cells. Additionally, subcellular distribution of the a4 subunit of the vacuolar H+-ATPase was affected by FK506 with less luminal localization in the connecting tubule and outer medullary collecting duct. These data suggest that FK506 impacts on several major acid-base transport proteins in the kidney, and its use is associated with transient metabolic acidosis and altered expression of key renal acid-base transport proteins.

Haemofiltration in the Management of Severe Paediatric Burns – Experience in a UK Burns Centre and Systematic Review

2021 ◽  
Author(s):  
Michael Rice ◽  
Ibrahim Ibrahim ◽  
Mohamed Ismail Aly
Keyword(s):  
Systematic Review ◽  
Metabolic Acidosis ◽  
Acute Injury ◽  
Secondary Complications ◽  
Paediatric Burns ◽  
Life Threatening ◽  
Age Range ◽  
And Control ◽  
Renal Support

Abstract Paediatric burns are life-threatening injuries due to the acute injury and secondary complications. In acute phase burns, hypovolaemia and vasoconstriction cause renal impairment. Sepsis and multi-organ failure compound the problem resulting in morbidity and mortality. This paper outlines 5 years’ experience using haemofiltration in major paediatric burns, and a review of the current literature.Retrospective patient data collection was undertaken identifying relevant paediatric burns undergoing Continuous Veno-Venous Haemofiltration. Data were analysed to identify demographics, indication, duration of therapy, and outcomes. A systematic review was also performed using PRISMA principles. PubMed, Science Direct and OVID databases were explored and relevant papers were included.From January 2015-December 2019, haemofiltration was utilised in 5 cases. Age range 3-15 years (mean: 12), 4 males / 1 female, mean weight 56kg (12-125kg). TBSA 21-61% (mean: 37.6%), mechanism of injury was scald-60%, flame-40%. Overall survival was 100%. 3 patients were filtered for a brief period during the first 24 hours to correct metabolic acidosis and control temperature. 2 patients required prolonged therapy. All patients recovered without further long term renal support. A total of 3814 papers were identified for systematic review. 3 were considered relevant for inclusion.This paper reflects the benefits of haemofiltration in the management of severe paediatric burns. Renal replacement therapy is useful in managing metabolic acidosis, temperature control and renal failure. The current literature supports judicious use on a patient-by-patient basis. Given the lack of evidence in the literature, further studies are required to establish guidelines for the use of haemofiltration in paediatric burns.

Altered expression of selected genes in kidney of rats with lithium-induced NDI

2005 ◽  
Vol 288 (6) ◽  
pp. F1276-F1289 ◽  
Author(s):  
Aleksandra Rojek ◽  
Jakob Nielsen ◽  
Heddwen L. Brooks ◽  
Hong Gong ◽  
Young-Hee Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Cellular Proliferation ◽  
Collecting Duct ◽  
Lithium Treatment ◽  
Altered Expression ◽  
Ezrin Expression ◽  
Microarray Screening ◽  
And Control ◽  
Thin Limb

Lithium treatment is associated with development of nephrogenic diabetes insipidus, caused in part by downregulation of collecting duct aquaporin-2 (AQP2) and AQP3 expression. In the present study, we carried out cDNA microarray screening of gene expression in the inner medulla (IM) of lithium-treated and control rats, and selected genes were then investigated at the protein level by immunoblotting and/or immunohistochemistry. The following genes exhibited significantly altered transcription and mRNA expression levels, and these were compatible with the changes in protein expression. 11β-Hydroxysteroid dehydrogenase type 2 protein expression in the IM was markedly increased (198 ± 25% of controls, n = 6), and immunocytochemistry demonstrated an increased labeling of IM collecting duct (IMCD) principal cells. This indicated altered renal mineralocorticoid/glucocorticoid responses in lithium-treated rats. The inhibitor of cyclin-dependent kinases p27 (KIP) protein expression was significantly decreased or undetectable in the IMCD cells, pointing to increased cellular proliferation and remodeling. Heat shock protein 27 protein expression was decreased in the IM (64 ± 6% of controls, n = 6), likely to be associated with the decreased medullary osmolality in lithium-treated rats. Consistent with this, lens aldose reductase protein expression was markedly decreased in the IM (16 ± 2% of controls, n = 6), and immunocytochemistry revealed decreased expression in the thin limb cells in the middle and terminal parts of the IM. Ezrin protein expression was upregulated in the IM (158 ± 16% of controls, n = 6), where it was predominantly expressed in the apical and cytoplasmic domain of the IMCD cells. Increased ezrin expression indicated remodeling of the actin cytoskeleton and/or altered regulation of IMCD transporters. In conclusion, the present study demonstrates changes in gene expression not only in the collecting duct but also in the thin limb of the loop of Henle in the IM, and several of these genes are linked to altered sodium and water reabsorption, cell cycling, and changes in interstitial osmolality.

scholarly journals ASIDOSIS TUBULAR RENAL DISTAL

2020 ◽  
Vol 5 (1) ◽  
pp. 265
Author(s):  
Ayu Pathya ◽  
Harnavi Harun
Keyword(s):  
Metabolic Acidosis ◽  
Renal Tubular Acidosis ◽  
Bone Growth ◽  
Hydrogen Ion ◽  
Genetic Mutations ◽  
Growth Disorders ◽  
Urine Ph ◽  
Renal Tubular ◽  
Hands And Feet

<p><em>Asidosis tubular renal (ATR) merupakan tubulopati ginjal yang jarang terjadi, dimana terdapat ketidakmampuan ginjal untuk menjaga perbedaan pH normal antara darah dan lumen tubulus ginjal. Pada kondisi ini terjadi gangguan pengasaman urin disebabkan gangguan reabsorbsi bikarbonat, gangguan ekskresi ion hidrogen, atau keduanya sehingga mengakibatkan asidosis metabolik. ATR ditandai dengan adanya asidosis metabolik dengan senjang anion plasma yang normal, hiperkloremik dan laju filtrasi glomerulus normal. ATR terbagi menjadi 3 tipe utama, yaitu ATR tipe 1 (ATR distal), tipe-2 (ATR proksimal), dan tipe 4 (ATR hiperkalemia). ATR distal merupakan ATR yang disebabkan oleh defek pada tubulus distal ginjal, dimana defek ini menyebabkan gangguan pada sekresi ion hidrogen. Beberapa penelitian menunjukkan bahwa ATR tipe 1 dikaitkan dengan mutasi genetik. Mutasi genetik herediter dapat autosomal dominan atau autosomal resesif. Gambaran klinis dapat mencakup kelainan pertumbuhan tulang, kelemahan atau kelumpuhan otot, deposit kalsium di ginjal, anoreksia, muntah, konstipasi, diare, dehidrasi, dan poliuria. Telah dilaporkan kasus pasien wanita usia 19 tahun dengan keluhan utama kelemahan di kedua tangan dan kaki. Dari penelusuran klinis dan laboratorium  didapatkan hipokalemia dan berdasarkan pendekatan hipokalemia dengan HCO3- rendah dan pH urine &gt;5,5, diagnosis pada pasien ini ditegakkan sebagai asidosis tubulus renal distal (ATRd).</em></p><p><strong><em>Kata kunci:</em></strong><em> </em><em>ATR, ATRd,  asidosis metabolik, hiperkloremik, hipokalemia </em><em></em></p><p><strong><em>Abstract</em></strong></p><p><em>Renal tubular acidosis (RTA) is a condition caused by the inability of the kidneys to maintain normal pH differences between the blood and tubules lumen of the kidney. Renal tubular acidosis is a rare kidney tubulopathy. In this condition, urine acidification is caused by bicarbonate reabsorption, disruption of hydrogen ion excretion, or both, resulting in metabolic acidosis. RTA is characterized by metabolic acidosis with normal plasma anion, hyperchloremic gaps and normal glomerular filtration rates. RTA is divided into 3 main types, namely type 1 RTA (distal RTA), type-2 (proximal RTA), and type 4 (hyperkalemia RTA). Distal RTA caused by defects in the distal tubules of the kidney, where these defects cause interference with the hydrogen ion secretion. Several studies have shown that type 1 RTA is associated with genetic mutations. Hereditary genetic mutations can be autosomal dominant or autosomal recessive. Clinical features can include bone growth disorders, muscle weakness or paralysis, calcium deposits in the kidneys, anorexia, vomiting, constipation, diarrhea, dehydration, and polyuria. There has been a reported case of a 19-year-old female patient with a chief complaint weakness in both hands and feet. From clinical and laboratory investigations, it was found that hypopotassium and based on the hypokalemia approach with low HCO3- and urine pH &gt;5,5, the diagnosis in this patient was established as a distal renal tubular acidosis (RTAd)</em> <strong><em> </em></strong></p><p><strong><em>Keywords: </em></strong><em>RTA, RTAd ,metabolic acidosis, hypopotassium, hiperchloremic</em></p><p><em> </em></p>

Altered expression of renal AQPs and Na+transporters in rats with Lithium-induced NDI

2000 ◽  
Vol 279 (3) ◽  
pp. F552-F564 ◽  
Author(s):  
Tae-Hwan Kwon ◽  
Ulla H. Laursen ◽  
David Marples ◽  
Arvid B. Maunsbach ◽  
Mark A. Knepper ◽  
...  
Keyword(s):  
Nephrogenic Diabetes Insipidus ◽  
Loop Of Henle ◽  
Low Doses ◽  
Altered Expression ◽  
Aquaporin 1 ◽  
High Doses ◽  
Type 3 ◽  
And Control

Lithium (Li) treatment is often associated with nephrogenic diabetes insipidus (NDI). The changes in whole kidney expression of aquaporin-1 (AQP1), -2, and -3 as well as Na-K-ATPase, type 3 Na/H exchanger (NHE3), type 2 Na-Pi cotransporter (NaPi-2), type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), and thiazide-sensitive Na-Cl cotransporter (TSC) were examined in rats treated with Li orally for 4 wk: protocol 1, high doses of Li (high Na+ intake), and protocol 2, low doses of Li (identical food and normal Na+ intake in Li-treated and control rats). Both protocols resulted in severe polyuria. Semiquantitative immunoblotting revealed that whole kidney abundance of AQP2 was dramatically reduced to 6% ( protocol 1) and 27% ( protocol 2) of control levels. In contrast, the abundance of AQP1 was not decreased. Immunoelectron microscopy confirmed the dramatic downregulation of AQP2 and AQP3, whereas AQP4 labeling was not reduced. Li-treated rats had a marked increase in urinary Na+ excretion in both protocols. However, the expression of several major Na+ transporters in the proximal tubule, loop of Henle, and distal convoluted tubule was unchanged in protocol 2, whereas in protocol 1significantly increased NHE3 and BSC-1 expression or reduced NaPi-2 expression was associated with chronic Li treatment. In conclusion, severe downregulation of AQP2 and AQP3 appears to be important for the development of Li-induced polyuria. In contrast, the increased or unchanged expression of NHE3, BSC-1, Na-K-ATPase, and TSC indicates that these Na+ transporters do not participate in the development of Li-induced polyuria.

scholarly journals pH-dependent regulation of the α-subunit of H+-K+-ATPase (HKα2)

2011 ◽  
Vol 301 (3) ◽  
pp. F536-F543 ◽  
Author(s):  
Juan Codina ◽  
Timothy S. Opyd ◽  
Zachary B. Powell ◽  
Cristina M. Furdui ◽  
Snezana Petrovic ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Immunoblot Analysis ◽  
Acid Base Balance ◽  
Acid Base ◽  
Membrane Expression ◽  
Α Subunit ◽  
Hek 293 ◽  
Genetic Ablation ◽  
Base Balance

The H+-K+-ATPase α-subunit (HKα2) participates importantly in systemic acid-base homeostasis and defends against metabolic acidosis. We have previously shown that HKα2 plasma membrane expression is regulated by PKA (Codina J, Liu J, Bleyer AJ, Penn RB, DuBose TD Jr. J Am Soc Nephrol 17: 1833–1840, 2006) and in a separate study demonstrated that genetic ablation of the proton-sensing Gs-coupled receptor GPR4 results in spontaneous metabolic acidosis (Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, Petrovic S. J Am Soc Nephrol 21: 1745–1755, 2010). In the present study, we investigated the ability of chronic acidosis and GPR4 to regulate HKα2 expression in HEK-293 cells. Chronic acidosis was modeled in vitro by using multiple methods: reducing media pH by adjusting bicarbonate concentration, adding HCl, or by increasing the ambient concentration of CO2. PKA activity and HKα2 protein were monitored by immunoblot analysis, and HKα2 mRNA, by real-time PCR. Chronic acidosis did not alter the expression of HKα2 mRNA; however, PKA activity and HKα2 protein abundance increased when media pH decreased from 7.4 to 6.8. Furthermore, this increase was independent of the method used to create chronic acidosis. Heterologous expression of GPR4 was sufficient to increase both basal and acid-stimulated PKA activity and similarly increase basal and acid-stimulated HKα2 expression. Collectively, these results suggest that chronic acidosis and GPR4 increase HKα2 protein by increasing PKA activity without altering HKα2 mRNA abundance, implicating a regulatory role of pH-activated GPR4 in homeostatic regulation of HKα2 and acid-base balance.

scholarly journals Effects of dietary electrolyte balance and calcium supply on mineral and acid−base status of piglets fed a diversified diet

2020 ◽  
Vol 9 ◽  
Author(s):  
M. Bournazel ◽  
M. J. Duclos ◽  
F. Lecompte ◽  
D. Guillou ◽  
C. Peyronnet ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Mineral Metabolism ◽  
Venous Blood ◽  
Electrolyte Balance ◽  
Low Grade ◽  
Acid Base Balance ◽  
Acid Base ◽  
Urine Ph ◽  
Skeletal Health ◽  
Acid Base Status

Abstract Dietary electrolyte balance (dEB) is known to affect acid−base status and mineral metabolism, but is rarely considered in diet formulation for pigs. Yet, the use of a wide variety of local feedstuffs in Europe contributes to lowering the dEB and increasing the fibre content. Hence, mineral requirements may be modified and skeletal health affected. Therefore, the effects of a lower dEB and a higher dietary Ca level on acid−base balance and mineral status were assessed in young pigs fed a diversified diet. A total of twenty-four weaned pigs were fed a control moderate-dEB diet (C) or a diversified moderate-dEB (D), low-dEB (D-A) or low-dEB supplemented with Ca (D-CA) diet. Growth performance, venous blood gas and chemistry, urine pH, mineral balance and femur characteristics were determined. With an equivalent dEB compared with the C diet, the D diet caused an acidification of the urine and increased the excretion of P as a result of a higher dietary content of S. Low-grade metabolic acidosis occurred in piglets fed the D-A diet with changes at systemic and urine levels. A higher excretion of ammonia and P in urine was observed and some bone characteristics tended to be negatively affected. Ca supplementation partially counteracted the effects of low-grade acidosis. Urine excretion of P and ammonia was alleviated and bone characteristics improved. In conclusion, a higher Ca supply must be considered in more diversified diets to counteract the risk of evolving towards low-grade metabolic acidosis which can negatively affect bone.

scholarly journals Role of the Rhesus glycoprotein, Rh B glycoprotein, in renal ammonia excretion

2010 ◽  
Vol 299 (5) ◽  
pp. F1065-F1077 ◽  
Author(s):  
Jesse M. Bishop ◽  
Jill W. Verlander ◽  
Hyun-Wook Lee ◽  
Raoul D. Nelson ◽  
Arthur J. Weiner ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Glutamine Synthetase ◽  
Collecting Duct ◽  
Ammonia Excretion ◽  
Acid Excretion ◽  
Urine Ph ◽  
Outer Medulla ◽  
Intercalated Cell ◽  
Titratable Acid ◽  
Acid Loading

Rh B glycoprotein (Rhbg) is a member of the Rh glycoprotein family of ammonia transporters. In the current study, we examine Rhbg's role in basal and acidosis-stimulated acid-base homeostasis. Metabolic acidosis induced by HCl administration increased Rhbg expression in both the cortex and outer medulla. To test the functional significance of increased Rhbg expression, we used a Cre-loxP approach to generate mice with intercalated cell-specific Rhbg knockout (IC-Rhbg-KO). On normal diet, intercalated cell-specific Rhbg deletion did not alter urine ammonia excretion, pH, or titratable acid excretion significantly, but it did decrease glutamine synthetase expression in the outer medulla significantly. After metabolic acidosis was induced, urinary ammonia excretion was significantly less in IC-Rhbg-KO than in control (C) mice on days 2–4 of acid loading, but not on day 5. Urine pH and titratable acid excretion and dietary acid intake did not differ significantly between acid-loaded IC-Rhcg-KO and C mice. In IC-Rhbg-KO mice, acid loading increased connecting segment (CNT) cell and outer medullary collecting duct principal cell Rhbg expression. In both C and IC-Rhbg-KO mice, acid loading decreased glutamine synthetase in both the cortex and outer medulla; the decrease on day 3 was similar in IC-Rhbg-KO and C mice, but on day 5 it was significantly greater in IC-Rhbg-KO than in C mice. We conclude 1) intercalated cell Rhbg contributes to acidosis-stimulated renal ammonia excretion, 2) Rhbg in CNT and principal cells may contribute to renal ammonia excretion, and 3) decreased glutamine synthetase expression may enable normal rates of ammonia excretion under both basal conditions and on day 5 of acid loading in IC-Rhbg-KO mice.

scholarly journals Renal ammonia excretion in response to hypokalemia: effect of collecting duct-specific Rh C glycoprotein deletion

2013 ◽  
Vol 304 (4) ◽  
pp. F410-F421 ◽  
Author(s):  
Hyun-Wook Lee ◽  
Jill W. Verlander ◽  
Jesse M. Bishop ◽  
Mary E. Handlogten ◽  
Ki-Hwan Han ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Metabolic Alkalosis ◽  
Collecting Duct ◽  
Ammonia Excretion ◽  
Immunogold Electron Microscopy ◽  
Acid Base ◽  
Outer Medulla ◽  
Rhesus Factor ◽  
Base Disorder ◽  
Urine Alkalinization

The Rhesus factor protein, Rh C glycoprotein (Rhcg), is an ammonia transporter whose expression in the collecting duct is necessary for normal ammonia excretion both in basal conditions and in response to metabolic acidosis. Hypokalemia is a common clinical condition associated with increased renal ammonia excretion. In contrast to basal conditions and metabolic acidosis, increased ammonia excretion during hypokalemia can lead to an acid-base disorder, metabolic alkalosis, rather than maintenance of acid-base homeostasis. The purpose of the current studies was to determine Rhcg's role in hypokalemia-stimulated renal ammonia excretion through the use of mice with collecting duct-specific Rhcg deletion (CD-Rhcg-KO). In mice with intact Rhcg expression, a K+-free diet increased urinary ammonia excretion and urine alkalinization and concurrently increased Rhcg expression in the collecting duct in the outer medulla. Immunohistochemistry and immunogold electron microscopy showed hypokalemia increased both apical and basolateral Rhcg expression. In CD-Rhcg-KO, a K+-free diet increased urinary ammonia excretion and caused urine alkalinization, and the magnitude of these changes did not differ from mice with intact Rhcg expression. In mice on a K+-free diet, CD-Rhcg-KO increased phosphate-dependent glutaminase (PDG) expression in the outer medulla. We conclude that hypokalemia increases collecting duct Rhcg expression, that this likely contributes to the hypokalemia-stimulated increase in urinary ammonia excretion, and that adaptive increases in PDG expression can compensate for the absence of collecting duct Rhcg.

Inherited Proximal and Distal Renal Tubular Acidosis

2017 ◽  
Author(s):  
Patricia Valles ◽  
Jesus Moran-Farias ◽  
Daniel Batlle
Keyword(s):  
Metabolic Acidosis ◽  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Anion Gap ◽  
Intercalated Cells ◽  
Acid Excretion ◽  
Acid Base ◽  
Urine Ph ◽  
Renal Tubular ◽  
Net Acid Excretion

Acid-base homeostasis by the kidney is maintained through proximal tubular reclamation of filtered bicarbonate and the excretion of the daily acid load by collecting duct type A intercalated cells. The impairment of either process results in renal tubular acidosis (RTA), a group of disorders characterized by a reduced net acid excretion and a persistent hyperchloremic, non–anion gap metabolic acidosis. The primary or hereditary forms of proximal (pRTA) and distal renal tubular acidosis (dRTA) have received increased attention because of advances in the understanding of the molecular mechanism, whereby mutations in the main proteins involved in acid-base transport result in either reduced bicarbonate reabsorption or reduced H+ secretion and impaired acid excretion. dRTA is characterized by reduced net acid excretion and an inability to lower urine pH despite severe acidemia (but minimal HCO3– wastage). pRTA (type 2), by contrast, is characterized by marked HCO3– wastage but preserved ability to lower urine pH when plasma HCO3– (and therefore filtered HCO3–) is below a certain threshold. In children with dRTA, growth retardation caused by chronic metabolic acidosis is the key manifestation but is fully reversible with appropriate alkali therapy if initiated early in life. A striking manifestation of many patients with dRTA is the development of severe hypokalemia that may cause muscle paralysis. In this review, we discuss these types of hereditary RTA and the mechanisms involved in the genesis of these inherited tubular disorders. This review contains 5 figures, 1 table, and 103 references. Key words: Proximal renal tubular acidosis (pRTA), Distal renal tubular acidosis (dRTA), Hyperchloremic, non–anion gap metabolic acidosis, Hypokalemia, Fractional HCO3– excretion, Urinary gap, Fanconi Syndrome.ATP6V1B1 and ATP6V0A4 gene mutations . Intercalated cells ,

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