Paeds · nephrology-urology-fluids-and-electrolytes
Inherited tubulopathies
Also known as Inherited tubulopathies · Bartter syndrome · Gitelman syndrome · Fanconi syndrome · Liddle syndrome · Salt-losing tubulopathy · Congenital chloride-losing diarrhoea mimic · Pseudoaldosteronism
Fellowship guide to the four archetypal inherited tubulopathies of childhood: Bartter syndrome (thick ascending limb, hypercalciuria, antenatal polyhydramnios), Gitelman syndrome (distal convoluted tubule, hypomagnesaemia and hypocalciuria), Fanconi syndrome (generalised proximal tubular failure with glycosuria, phosphaturia and proximal RTA), and Liddle syndrome (collecting duct ENaC gain-of-function with hypertension and suppressed renin and aldosterone). The blood pressure and the renin/aldosterone axis separate Liddle from the salt-losing trio, and the urine calcium and serum magnesium separate Bartter from Gitelman.
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- A hypokalaemic metabolic alkalosis with HYPERTENSION is Liddle syndrome until proven otherwise, not Bartter or Gitelman, which run a normal or low blood pressure, because the blood pressure is the single most reliable discriminator and getting it wrong leads to aldosterone antagonists that fail in Liddle
- Antenatal Bartter syndrome presents with polyhydramnios, prematurity, severe salt wasting and nephrocalcinosis in a neonate and needs aggressive salt and water replacement with a prostaglandin synthesis inhibitor such as indometacin, because untreated neonatal salt wasting is rapidly fatal
- Gitelman syndrome can cause prolonged QT and ventricular arrhythmia from hypokalaemia and hypomagnesaemia, and symptomatic tetany or seizures from severe hypomagnesaemia, so a patient with palpitations or tetany needs urgent electrolyte correction, not reassurance
- Cystinosis is the commonest inherited cause of Fanconi syndrome in children and progresses to end-stage kidney disease without cysteamine, so every infant with failure to thrive, polyuria and a Fanconi urine needs a leukocyte cystine and a slit-lamp examination for corneal crystals
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- Bartter and Gitelman as hypokalaemic metabolic alkalosis with high renin and aldosterone and a normal or low blood pressure
- Liddle syndrome as hypokalaemic alkalosis with HYPERTENSION and suppressed renin and aldosterone
- Fanconi syndrome as generalised proximal tubular dysfunction with glycosuria, phosphaturia and proximal RTA
- Gene-to-segment mapping: Bartter at the thick ascending limb, Gitelman at the distal convoluted tubule, Fanconi at the proximal tubule, Liddle at the collecting duct
- The urine calcium and serum magnesium separating Bartter (hypercalciuria, normal magnesium) from Gitelman (hypocalciuria, hypomagnesaemia)
- Cystinosis as the commonest inherited cause of Fanconi syndrome in children and the role of cysteamine
- Diagnostic approach to a child with hypokalaemic metabolic alkalosis using blood pressure, renin, aldosterone, urine calcium and magnesium
- Liddle versus primary hyperaldosteronism versus Bartter and Gitelman at the bedside
- Management principles: magnesium and potassium-sparing diuretics in Gitelman, indometacin in antenatal Bartter, amiloride in Liddle
- Short case: an adolescent with cramps, tetany and a low serum magnesium
- Long case: a neonate with polyhydramnios and salt-wasting alkalosis
- Communication station explaining lifelong magnesium therapy and the inheritance of Gitelman syndrome
- Nephrology: inherited tubulopathies including Bartter, Gitelman, Fanconi and Liddle syndromes
- Investigation of hypokalaemic metabolic alkalosis in children
- Cystinosis and inherited Fanconi syndrome
- Segmental nephron physiology: NKCC2 in the thick ascending limb, NCC in the distal convoluted tubule, ENaC in the collecting duct
- Genetics of Bartter (SLC12A1, KCNJ1, CLCNKB, BSND, CASR), Gitelman (SLC12A3) and Liddle (SCNN1B, SCNN1G)
- Pharmacology of amiloride, eplerenone, indometacin and oral magnesium salts
- Clinical assessment of a child with salt wasting, failure to thrive and alkalosis
- Communication: explaining the diagnosis, treatment and inheritance of an inherited tubulopathy to a family
- Bartter, Gitelman, Fanconi and Liddle syndromes: genes, presentation and management
- Blood pressure and renin/aldosterone as discriminators between Liddle and the salt-losing tubulopathies
- Cystinosis as the commonest inherited cause of Fanconi syndrome
- Patient Care: management of hypokalaemic metabolic alkalosis and salt wasting in children
- Medical Knowledge: segmental nephron transport and its inherited defects
- Systems-Based Practice: lifelong therapy, adherence and transition in chronic tubulopathies
- Nephrology: inherited tubulopathies in children
- The renin-aldosterone-blood pressure algorithm for hypokalaemic alkalosis
A child who loses salt cannot hold their blood pressure, their potassium or their growth together for long, and the inherited tubulopathies are the prototypic salt-losing and potassium-shifting disorders of childhood. Each maps onto one segment of the nephron, and each segment has a characteristic transporter whose inherited failure produces a predictable biochemistry. Bartter is the thick ascending limb defect, the loop-diuretic equivalent, with hypercalciuria and nephrocalcinosis. Gitelman is the distal convoluted tubule defect, the thiazide equivalent, with hypocalciuria and hypomagnesaemia. Liddle is the collecting duct epithelial sodium channel gone into overdrive, and it is the one that raises the blood pressure. Fanconi is different in kind, a wholesale failure of the proximal tubule that loses glucose, phosphate, amino acids and bicarbonate and causes a metabolic acidosis rather than an alkalosis. [5] [6]
The bedside power of the topic comes from two branching questions. First, is the blood pressure high or normal and low, because a hypokalaemic alkalosis with hypertension points straight to Liddle while the same biochemistry with a normal or low blood pressure points to Bartter or Gitelman. Second, where do the renin and aldosterone sit, because Liddle suppresses both, primary hyperaldosteronism raises the aldosterone but not the renin, and Bartter and Gitelman raise both. Nail this two-step branch and you have answered the spine of every tubulopathy viva before you reach the genes. [7] [10]
Overview & Definition
An inherited tubulopathy is a monogenic disorder in which a single transporter or channel along the nephron fails, producing a predictable pattern of electrolyte and fluid loss. The defining biochemistry is determined by which segment broke. The salt-losing syndromes, Bartter and Gitelman, and the sodium-retaining syndrome, Liddle, all produce a hypokalaemic metabolic alkalosis. Fanconi syndrome stands apart, because a generalised proximal tubular failure wastes bicarbonate and produces a normal anion gap metabolic acidosis with glycosuria, phosphaturia and aminoaciduria. [5] [6]
The four syndromes are best held against the segment of nephron each one breaks. Bartter syndrome is the inherited failure of salt reabsorption in the thick ascending limb of the loop of Henle, and it mimics a loop diuretic given for life. Gitelman syndrome is the failure of the thiazide-sensitive sodium chloride cotransporter in the distal convoluted tubule, and it mimics a thiazide diuretic. Liddle syndrome is a gain-of-function of the epithelial sodium channel in the collecting duct, so the kidney retains sodium and loses potassium without any aldosterone driving it. Fanconi syndrome is a diffuse failure of proximal tubular reabsorption, so everything the proximal tubule normally reclaims, glucose, phosphate, amino acids and bicarbonate, is spilled into the urine. [3] [4]
What unifies the topic clinically is that all four present in childhood with electrolyte disturbance and growth failure, and that each has a treatment aimed at the segment that broke. The magnesium and potassium-sparing diuretic strategy suits Gitelman, the prostaglandin synthesis inhibitor strategy suits antenatal Bartter, the amiloride strategy suits Liddle, and the bicarbonate, phosphate and cause-specific strategy suits Fanconi. The examiner rewards the candidate who can move fluently from the bedside biochemistry to the segment, the gene and the treatment, and that fluency is what this page builds. [1] [2]
References12ShowHide
- [1]Konrad M, et al Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders. Kidney Int, 2021.PMID 33509356
- [2]Blanchard A, et al Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 2017.PMID 28003083
- [3]Fulchiero R, et al Bartter Syndrome and Gitelman Syndrome. Pediatr Clin North Am, 2019.PMID 30454738
- [4]Foreman JW Fanconi Syndrome. Pediatr Clin North Am, 2019.PMID 30454741
- [5]Kleta R, et al Salt-Losing Tubulopathies in Children: What's New, What's Controversial? J Am Soc Nephrol, 2018.PMID 29237739
- [6]Iancu D, et al Inherited Renal Tubulopathies-Challenges and Controversies. Genes (Basel), 2020.PMID 32150856
- [7]Kermond R, et al A clinical approach to tubulopathies in children and young adults. Pediatr Nephrol, 2023.PMID 35585366
- [8]Do C, et al Metabolic Alkalosis Pathogenesis, Diagnosis, and Treatment: Core Curriculum 2022. Am J Kidney Dis, 2022.PMID 35525634
- [9]Tetti M, et al Liddle Syndrome: Review of the Literature and Description of a New Case. Int J Mol Sci, 2018.PMID 29534496
- [10]Athimulam S, et al Low-Renin Hypertension. Endocrinol Metab Clin North Am, 2019.PMID 31655771
- [11]Albuquerque ALB, et al Inherited Fanconi syndrome. World J Pediatr, 2023.PMID 36729281
- [12]Elmonem MA, et al Cystinosis: a review. Orphanet J Rare Dis, 2016.PMID 27102039