Renal Tubular Disorders

Renal Tubular Disorders
Lisa M. Guay-Woodford

I

nherited renal tubular disorders involve a variety of defects in renal tubular transport processes and their regulation. These disorders generally are transmitted as single gene defects (Mendelian traits), and they provide a unique resource to dissect the complex molecular mechanisms involved in tubular solute transport. An integratedapproach using the tools of molecular genetics, molecular biology, and physiology has been applied in the 1990s to identify defects in transporters, channels, receptors, and enzymes involved in epithelial transport. These investigations have added substantial insight into the molecular mechanisms involved in renal solute transport and the molecular pathogenesis of inherited renal tubular disorders. Thischapter focuses on the inherited renal tubular disorders, highlights their molecular defects, and discusses models to explain their underlying pathogenesis.

CHAPTER

12

12.2

Tubulointerstitial Disease

Overview of Renal Tubular Disorders
OVERVIEW OF RENAL TUBULAR DISORDERS INHERITED AS MENDELIAN TRAITS
Inherited disorder
Renal glucosuria Glucose-galactose malabsorption syndromeAcidic aminoaciduria Cystinuria Lysinuric protein intolerance Hartnup disease Blue diaper syndrome Neutral aminoacidurias: Methioninuria Iminoglycinuria Glycinuria Hereditary hypophosphatemic rickets with hypercalciuria X-linked hypophosphatemic rickets Inherited Fanconi’s syndrome isolated disorder Inherited Fanconi’s syndrome associated with inborn errors of metabolism Carbonic anhydrase IIdeficiency Distal renal tubular acidosis Bartter-like syndromes: Antenatal Bartter variant Classic Bartter variant Gitelman’s syndrome Pseudohypoparathyroidism: Type Ia Type Ib Low-renin hypertension: Glucocorticoid-remedial aldosteronism Liddle’s syndrome Apparent mineralocorticoid excess Pseudohypoaldosteronism: Type 1 Type 2 (Gordon’s syndrome) Nephrogenic diabetes insipidus: X-linked AutosomalUrolithiases: Cystinuria Dent’s disease X-linked recessive nephrolithiasis X-linked recessive hypophosphatemic rickets Hereditary renal hypouricemia

Transmission mode
?AR, AD AR AR AR AR ? AR AR

Defective protein
Sodium-glucose transporter 2 Sodium-glucose transporter 1 Sodium-potassium–dependent glutamate transporter Apical cystine-dibasic amino acid transporter Basolateral dibasic amino acidtransporter ? Kidney-specific tryptophan transporter ?

FIGURE 12-1 Inherited renal tubular disorders generally are transmitted as autosomal dominant, autosomal recessive, X-linked dominant, or X-linked recessive traits. For many of these disorders, the identification of the disease-susceptibility gene and its associated defective protein product has begun to provide insight into the molecularpathogenesis of the disorder.

AR X-linked dominant AR and AD AR AR AR AD AR AR AR AD ? AD AD AR AR and AD AD X-linked recessive AR and AD AR X-linked X-linked X-linked AR

? Sodium-phosphate cotransporter Phosphate-regulating with endopeptidase features on the X chromosome ? – Carbonic anhydrase type II ? Basolateral anion exchanger (AE1) NKCC2, ROMK, ClC-K2 ClC-K2b NCCT Guaninenucleotide–binding protein

Chimeric gene (11 -hydroxylase and aldosterone synthase) and subunits of the sodium channel 11- -hydroxysteroid dehydrogenase and subunits of the sodium channel ? Arginine vasopressin 2 receptor Aquaporin 2 water channel Apical cystine–dibasic amino acid transporter Renal chloride channel (ClC-5) Renal chloride channel (ClC-5) Renal chloride channel (ClC-5) ? Urate transporterAD—autosomal dominant; AR—autosomal recessive; ClC-K2—renal chloride channel; NCCT—thiazide-sensitive cotransporter; NKCC2—bumetanide-sensitive cotransporter; ROMK—inwardly rectified.

Renal Tubular Disorders

12.3

Renal Glucosuria
400
Observed curve Threshold Tmax

200 Glucose reabsorption, mg/min 1.73m2

0 0 400
Normal Type B renal glucosuria

200

400

600

200
Type A...