Inherited Tubulopathies: Fanconi, Bartter, Gitelman, Liddle & SAME

Fanconi syndrome: global proximal tubule failure

What leaks. The proximal convoluted tubule normally reclaims essentially all filtered glucose and amino acids, most phosphate and bicarbonate, and much of the filtered urate. In Fanconi syndrome these systems fail together, so the urine contains glucose despite a normal plasma glucose, a generalized aminoaciduria, phosphate, bicarbonate, urate, potassium and low-molecular-weight proteins.

Consequences. Phosphate wasting produces hypophosphatemic rickets in children and osteomalacia in adults. Bicarbonate wasting produces type 2 (proximal) renal tubular acidosis: the reabsorptive threshold for HCO₃⁻ is lowered, so a normal–anion-gap metabolic acidosis develops, yet once plasma bicarbonate falls below the new threshold the distal nephron can still acidify the urine below pH 5.5. Hypokalemia, polyuria with dehydration, and growth failure complete the picture.

Inherited causes. Nephropathic cystinosis (autosomal recessive CTNS mutations in the lysosomal cystine transporter cystinosin) is the leading inherited cause in children; cystine crystals deposit in the kidney and cornea, causing photophobia, and cysteamine depletes lysosomal cystine. Others include Wilson disease, tyrosinemia type 1, Lowe (oculocerebrorenal) syndrome, an X-linked OCRL disorder with congenital cataracts, hypotonia and intellectual disability, and Dent disease, an X-linked CLCN5 disorder with low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis.

Acquired causes. In adults, think of multiple myeloma (filtered light chains injure PCT cells), drugs (ifosfamide, tenofovir, and outdated tetracycline whose degradation products are toxic) and heavy metals such as lead.

Cystinosis is not cystinuria: cystinosis traps cystine inside lysosomes and causes Fanconi syndrome, whereas cystinuria is a defect of the PCT dibasic amino acid transporter (cystine, ornithine, lysine, arginine) that forms hexagonal cystine stones without Fanconi syndrome.

Bartter and Gitelman: salt-wasting diuretic mimics

Common ground. Both are autosomal recessive salt-wasting disorders with normal or low blood pressure. Lost NaCl reabsorption contracts volume and raises renin and aldosterone (with juxtaglomerular hyperplasia); more Na⁺ reaching the collecting duct under high aldosterone drives K⁺ and H⁺ secretion, producing hypokalemic metabolic alkalosis. Before making either diagnosis, exclude look-alikes: a low urine chloride points to surreptitious vomiting, and a urine diuretic screen exposes diuretic abuse.

Bartter syndrome. The thick ascending limb loses Na⁺-K⁺-2Cl⁻ reabsorption through defects in NKCC2, the apical K⁺ channel ROMK (which recycles K⁺ for NKCC2), the basolateral Cl⁻ channel ClC-Kb, or its subunit barttin (with sensorineural deafness). Because the lumen-positive voltage of the TAL drives paracellular Ca²⁺ reabsorption, calcium is wasted, causing hypercalciuria and nephrocalcinosis. Antenatal forms cause fetal polyuria, polyhydramnios and preterm birth. Renal prostaglandin E2 is high, so indomethacin is added to K⁺ supplements.

Gitelman syndrome. Loss of the thiazide-sensitive NaCl cotransporter (NCC, encoded by SLC12A3) in the DCT reproduces chronic thiazide use: hypokalemic alkalosis with prominent hypomagnesemia and hypocalciuria. It is milder and presents later, typically in adolescence or adulthood with fatigue, cramps, weakness or tetany, and is treated with K⁺ and Mg²⁺ replacement.

Low-renin hypertension: Liddle and apparent mineralocorticoid excess

Liddle syndrome. Autosomal dominant gain-of-function mutations in the β or γ subunit of ENaC delete the PY motif that binds Nedd4-2, the ubiquitin ligase that tags channels for removal from the apical membrane. Channels accumulate in principal cells and reabsorb Na⁺ without restraint, driving K⁺ and H⁺ secretion: early, often severe hypertension with hypokalemic alkalosis, while volume expansion suppresses renin and aldosterone. Because the lesion lies in the channel, downstream of the mineralocorticoid receptor (MR), spironolactone fails; amiloride or triamterene with salt restriction corrects it.

Apparent mineralocorticoid excess (AME, or SAME). The MR binds cortisol as avidly as aldosterone, and cortisol circulates at far higher levels. Principal cells protect the receptor with 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts cortisol to inactive cortisone. Autosomal recessive HSD11B2 mutations, or inhibition of the enzyme by glycyrrhetinic acid in real licorice, leave cortisol free to activate the MR, reproducing hyperaldosteronism with low renin and low aldosterone. MR antagonists (spironolactone, eplerenone) work, and licorice must be stopped. Extreme cortisol excess, as in ectopic ACTH syndrome, can saturate 11β-HSD2 and cause the same hypokalemic alkalosis.

Hyperkalemic tubulopathies: PHA1 and Gordon syndrome

Pseudohypoaldosteronism type 1 (PHA1). The tubule cannot respond to aldosterone. The autosomal recessive form, caused by loss-of-function mutations in ENaC subunits, is systemic and severe; the autosomal dominant form, caused by MR loss of function, is limited to the kidney and tends to improve with age. Infants present with salt wasting, dehydration, hypotension, hyperkalemia and metabolic acidosis despite very high renin and aldosterone, the functional opposite of Liddle syndrome. Treatment is generous sodium supplementation.

Gordon syndrome (PHA2, familial hyperkalemic hypertension). WNK kinases normally restrain NCC; mutations in WNK1, WNK4, KLHL3 or CUL3 release that brake. The DCT reabsorbs NaCl excessively, less Na⁺ reaches the collecting duct to drive K⁺ and H⁺ secretion, and ROMK activity is also reduced. The result is hypertension, hyperkalemia and hyperchloremic metabolic acidosis with low renin and a normal GFR, the mirror image of Gitelman syndrome. Low-dose thiazides correct all of it.

Congenital nephrogenic diabetes insipidus

Genetics. About 90% of congenital cases are X-linked, caused by loss-of-function mutations in AVPR2, the vasopressin V2 receptor of collecting-duct principal cells, so patients are boys with an affected maternal line. Most of the rest result from autosomal (usually recessive) mutations in AQP2, the water channel that ADH signaling inserts into the apical membrane.

Presentation. Affected infants have polyuria with very dilute urine, irritability, fever, failure to thrive and hypernatremic dehydration. ADH levels are high and desmopressin does not concentrate the urine, unlike central DI (including familial AVP-mutation DI), which responds to desmopressin.

Treatment. Free access to water and a low-salt, low-protein diet reduce the solute load and therefore the obligatory urine volume. A thiazide paradoxically reduces urine output: mild volume contraction increases proximal Na⁺ and water reabsorption, so less filtrate reaches the ADH-unresponsive collecting duct. NSAIDs such as indomethacin add to the effect by lowering renal prostaglandin E2.