Potassium-related inherited tubulopathies (original) (raw)
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Inherited Tubulopathies of the Kidney
Clinical Journal of the American Society of Nephrology, 2020
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.
Renal Potassium Handling and Associated Inherited Tubulopathies Leading to Hypokalemia
Basic Nephrology and Acute Kidney Injury, 2012
Basic Nephrology and Acute Kidney Injury 90 patients with chronic kidney disease. Generalized defects in proximal tubule handling of solutes result in Fanconi syndrome syndrome. Specific proximal tubular handling defects leading to hypokalemia include proximal renal tubular acidosis, and have been recently reviewed elsewhere (Fry &Karet, 2007). 2.2 Potassium movement in the thin loop of Henle Potassium may be secreted in the thin descending loops of Henle that penetrate the inner medulla, whilst the thin ascending loop is permeable to sodium and potassium and allows some uptake. The thin ascending limbs of the loops of Henle (among other nephron segments) express the CLC-KA chloride channel, with its subunit Barttin. Polymorphisms in CLCNKA have recently been associated with a hyperreninemic hyperaldosteronism, implicating a key role for this channel in regulating renal salt handling and determining a set point for renin and angiotensin levels (Cappola, et al., 2011). 2.3 Potassium movement in thick ascending loop of Henle In this part of nephron, ~25% of filtered sodium is reabsorbed together with ~15% of the filtered potassium. Transcellular sodium and potassium transport is achieved by the Na + K + 2Cl-cotransporter (NKCC2) in the apical membrane, driven by the basolateral Na + K + ATPase pump. Alternative names for NKCC2 include the bumetanide sensitive cotransporter, (BSC). NKCC2 is exclusively expressed in kidney tissue and is encoded by SLC12A1 gene (Simon, et al., 1996a). The NKCC2 transporter may also transport ammonium ions, which compete with potassium ions. Potassium entering the cell via NKCC2 is recycled back into tubule lumen via the apical membrane channel, ROMK1 (Simon, et al., 1996b), generating a lumen positive potential driving paracellular resorption of calcium and magnesium. Tight junction proteins, such as paracellin 1, mediate this divalent cation transport. ROMK1, also known as a KCNJ, is an ATPase sensitive potassium channel. Functional coupling of ROMK1 with NKCC2 is essential for NaCl reabsorption. Chloride exits the basolateral membrane of the TAL via the CLC chloride channel, CLC-KB, which is co-expressed with the subunit Barttin. 2.4 The distal convoluted tubule The distal convoluted tubule is responsible for ~8% of filtered sodium reabsorption. This is achieved via an apical Na + Clcotransporter (NCCT, alias the thiazide sensitive sodium chloride transporter). This transporter is regulated by a group of serine-threonine protein kinases, incluidng WNK4. In healthy individuals, WNK4 inhibits NCCT function by reducing its expression on the membrane. Recent data has suggested that potassium channels control DCT function. An apically expressed potassium channel Kv1.1 is postulated to stabilise the luminal membrane potential in this nephron segment (Glaudemans, et al., 2009). and facilitates effective magnesium transport via the apical TRPM6 magnesium channel. At the basolateral membrane of the DCT a potassium channel Kir4.1 is thought to allow potassium recycling, allowing maintenance of the basolateral Na + K + ATPase activity, the driving force for NaCl reabsorption via NCCT in this nephron segment (Bockenhauer, et al., 2009, Scholl, et al., 2009).
The Pharmacological Characteristics of Molecular-Based Inherited Salt-Losing Tubulopathies
The Journal of Clinical Endocrinology & Metabolism, 2010
Our understanding of inherited salt-losing tubulopathies has improved with recent advances in molecular genetics. However, the terminology of Bartter syndrome and Gitelman syndrome does not always accurately reflect their pathophysiological basis or clinical presentation, and some patients are difficult to diagnose from their clinical presentations. Objective: In the present study, we conducted molecular analysis and diuretic tests for patients with inherited salt-losing tubulopathies to clarify the pharmacological characteristics of these disorders. Patients: We detected mutations and subsequently conducted diuretic tests using furosemide and thiazide for 16 patients with salt-losing tubulopathies (two with SLC12A1; two with KCNJ1; nine with CLCNKB; and three with SLC12A3). Results: Patients with SLC12A1 mutations showed no response to furosemide, whereas those with SLC12A3 mutations showed no response to thiazide. However, patients with CLCNKB mutations showed no response to thiazide and a normal response to furosemide, and those with KCNJ1 mutations showed a good response to both diuretics. This study revealed the following characteristics of these disorders: 1) subjects with CLCNKB mutations showed one or more biochemical features of Gitelman syndrome (including hypomagnesemia, hypocalciuria, and fractional chloride excretion insensitivity to thiazide administration); and 2) subjects with KCNJ1 mutations appeared to show normal fractional chloride excretion sensitivity to furosemide and thiazide administration. Conclusions: These results indicate that these disorders are difficult to distinguish in some patients, even when using diuretic challenge. This clinical report provides important findings that can improve our understanding of inherited salt-losing tubulopathies and renal tubular physiology.
Diagnosis and clinical biochemistry of inherited tubulopathies
Epithelial ion channels and transporter proteins have physiologically important roles throughout the length of the nephron. Discovering the molecular identities of tubular epithelial cell proteins and their functional roles has increased understanding of both renal physiology and tubular diseases. Defects in tubular handling of solutes may present with nephrocalcinosis or nephrolithiasis, rickets, acid±base, electrolyte or blood pressure disturbances. Biochemical analysis of both serum and urine, together with clinical history and examination, remain fundamental for their diagnosis, whilst understanding of underlying molecular mechanisms allows appropriate management.
The molecular basis of renal tubular transport disorders
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2000
Sodium and water homeostasis are key to the survival of organisms. Reabsorption of sodium and water occurs throughout the tubule structure of the nephron, the basic functional unit of the kidney, by various transport mechanisms. Altered transport protein function can lead to renal tubular disorders resulting in metabolic alkalosis, hypokalemia, hypertension, and decreased capacity to concentrate urine, for instance. However, recent advances in molecular physiology, molecular genetics and expression cloning systems have aided in unraveling the molecular basis of some renal tubular disorders. This review will examine the molecular basis of Bartter's syndrome, Gitelman's syndrome, Liddle's syndrome, and autosomal nephrogenic diabetes insipidus. An understanding of the molecular basis of these disorders of the human kidney can give us a better understanding of basic renal function of lower mammals and other vertebrates.
Molecular Pathophysiology of Renal Tubular Acidosis
Current Genomics, 2009
Renal tubular acidosis (RTA) is characterized by metabolic acidosis due to renal impaired acid excretion. Hyperchloremic acidosis with normal anion gap and normal or minimally affected glomerular filtration rate defines this disorder. RTA can also present with hypokalemia, medullary nephrocalcinosis and nephrolitiasis, as well as growth retardation and rickets in children, or short stature and osteomalacia in adults. In the past decade, remarkable progress has been made in our understanding of the molecular pathogenesis of RTA and the fundamental molecular physiology of renal tubular transport processes. This review summarizes hereditary diseases caused by mutations in genes encoding transporter or channel proteins operating along the renal tubule. Review of the molecular basis of hereditary tubulopathies reveals various loss-of-function or gain-of-function mutations in genes encoding cotransporter, exchanger, or channel proteins, which are located in the luminal, basolateral, or endosomal membranes of the tubular cell or in paracellular tight junctions. These gene mutations result in a variety of functional defects in transporter/channel proteins, including decreased activity, impaired gating, defective trafficking, impaired endocytosis and degradation, or defective assembly of channel subunits. Further molecular studies of inherited tubular transport disorders may shed more light on the molecular pathophysiology of these diseases and may significantly improve our understanding of the mechanisms underlying renal salt homeostasis, urinary mineral excretion, and blood pressure regulation in health and disease. The identification of the molecular defects in inherited tubulopathies may provide a basis for future design of targeted therapeutic interventions and, possibly, strategies for gene therapy of these complex disorders.
American Journal of Kidney Diseases, 2011
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive renal tubular disorder that typically presents with disturbances in magnesium and calcium homeostasis, recurrent urinary tract infections, and polyuria and/or polydipsia. Patients with FHHNC have high risk of the development of chronic kidney disease and end-stage renal disease in early adolescence. Multiple distinct mutations in the CLDN16 gene, which encodes a tight junction protein, have been found responsible for this disorder. In addition, mutations in another member of the claudin family, CLDN19, were identified in a subset of patients with FHHNC with visual impairment. The claudins belong to the family of tight junction proteins that define the intercellular space between adjacent endo-and epithelial cells. Claudins are especially important for the regulation of paracellular ion permeability. We describe a Brazilian family with 2 affected siblings presenting with the typical FHHNC phenotype with ocular anomalies. The clinical diagnosis of FHHNC was confirmed using mutational analysis of the CLDN19 gene, which showed 2 compound heterozygous mutations. In the context of the case vignette, we summarize the clinical presentation, diagnostic criteria, and therapeutic options for patients with FHHNC. We also review recent advances in understanding the electrophysiologic function of claudin-16 and -19 in the thick ascending limb of the loop of Henle and implications for ion homeostasis in the human body. Am J Kidney Dis. 57(2):320-330.
Journal of the American Society of Nephrology, 2021
BackgroundThe transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.MethodsA candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.ResultsWe identified mutations in the KCNJ16 gene encoding KCNJ16, whic...
Journal of the American Society of Nephrology : JASN, 2017
Mice lacking distal tubular expression of , the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinar...