Inherited Tubular Transport Abnormalities

Proximal Tubule Abnormalities

Hypophosphatemic rickets (Vitamin D resistant rickets)

Clinical Features: Presents within 1-2 years of birth with bowing of lower extremities, dental abnormalities, and growth failure

Biochemical features: ß serum phosphorus, Ý urine phosphate, normal serum calcium and PTH, and inappropriately normal to low 1,25 OH (active) Vitamin D levels.

Similar biochemical abnormality: oncogenic hypophosphatemic osteomalacia: acquired disorder in adults associated with certain tumors; disease resolves after removal of the tumor.

Hypophosphatemic rickets recurs after kidney transplantation – therefore, not just kidney involved.

Mutated gene: PHEX = phosphate-regulating gene with homologies to endopetidases on the X chromosome.

Expressed in bone; found to be mutated in kindred.

Mode of Inheritance: X-linked inheritance.

Current theory: "unmodified phosphatonin" in the blood Þ ß vitamin D uptake, Ý degradation of active vitamin D. Bone modified "phosphatonin" usually Þ Ý vitamin D uptake and ß degradation of active vitamin D; however, mutated PHEX does not modify the "phosphatonin" correctly and get Ý unmodified "phosphatonin".

Loop of Henle and Distal Nephron Abnormalities

Bartter/Gittelman Syndromes

Clinical features: vary, depending on form. Infantile patients. tend to have episodes of dehydration and failure to thrive.

Biochemical features: hypokalemic, hypochloremic metabolic alkalosis. Ý renin and Ý aldosterone.

Bartter’s patients: labs look similar to taking loop diuretics; blocks Na⁺, K⁺, 2 Cl^- pump; including hypercalciuria.
Gittelman’s patients: looks like on thiazide diuretics, blocks Na⁺-Cl^- cotransporter; hypocalcuria and hypomagnesemia.

3 types: Neonatal, Classic, Gittelman – can have history of intimate muscle weakness, chronic dermatitis

	Neonatal Bartter's Syndromes ( types I and II)	"Classic" Bartter's Syndrome (type III)	Gittelman's Syndrome
Transporter defect (Mutated Gene)	Loop of Henle: NKCC2 (type I) ROMK (type II)	CIC-Kb	Distal Convolute Tubule: NCCT
Age of presentation	Antenatal/Neonate	Infancy/Childhood	Childhood/Adulthood
Recurrent dehydration	Very common	Common	Unusual
Recurrent tetany	Rare	Rare	Often present
Serum magnesium	Normal	Normal	Low
Urine calcium	Very High	Normal-High	Low

NKCC2 = sodium-potassium-2 chloride cotransporter; ROMK = inwardly rectifying potassium channel; CIC-Kb = renal chloride channel; NCCT = sodium-chloride cotransporter.

Note: Calcium reabsorption decreases with inhibition of NKCC2 channel because there will be less K recycling and a lessening of the lumen-positive electrical gradient which drives the passive reabsorption of calcium in this segment.

Familial Hypocalciuric Hypercalcemia (FHH)

Clinical Features: often asymptomatic in heterzygotes. Severe cases seen in homozygotes for the mutation (consanguineous kindred) Þ hyperparathyroidism Þ Ý Ý serum Ca⁺⁺ levels and bony abnormalities.

Biochemical features: mildly elevated serum Ca⁺⁺, ß urine calcium, normal or Ý PTH. Poor response to parathyroidectomy.

Mode of inheritance: Autosomal dominant. (AD)

Mutated gene: Extracellular calcium receptor (Ca-R)

Expressed in the PTH gland and kidney (loop of henle)

In parathyroid gland – mediates extracellular calcium induced suppression of PTH.

Kidney – inhibits ROMK. Loss of function mutation: ß ROMK inhibition Þ Ý Na, Ý Ca absorption Þ Ý serum calcium, ß urine calcium.

Note: if Ca-R undergoes a gain-of-function (activating) mutation: Ý ROMK inhibitionÞ ß Na⁺,ß Ca⁺⁺absorptionÞ hypocalcemia, hypercalciuria

Collecting Tubule Abnormalities

Liddle syndrome

Clinical features: hypertension.

Biochemical abnormalities: hypokalemia, metabolic alkalosis, ß renin, ß aldosterone.

Mode of inheritance: AD with highly variable penetrance

Mutated Gene: Epithelial Sodium Channel (ENaC) – composed of alpha, beta, gamma; sensitive to amiloride; gain of function mutations in beta and gamma and produce constitutive activation of the channel and inappropriate sodium retention (Figure 3).

Nephrogenic Diabetes Insipidus

Clinical features: massive polyuria, polydipisia, recurrent dehydration (volume depletion) especially in infants, recurrent episodes of hypernatremia (can lead to neurologic symptoms), and growth failure.

Biochemical features: Low urine specific gravity and osmolality, inability to concentrate urine even in the face of volume depletion. No response to exogenous vasopressin. Ý ADH.

Mutated gene: Loss of function mutation in genes encoding aquaporin 2 (AQP2) or the vasopressin (ADH) V₂ receptor. (Figure 3)

Mode of Inheritance: X-linked recessive inheritance is the most common form; AD and AR have been described