Hereditary Renal Tubular Disorders

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Summary

The multiple and complex functions of the renal tubule in regulating water, electrolyte, and mineral homeostasis make it prone to numerous genetic abnormalities resulting in malfunction. The phenotypic expression depends on the mode of interference with the normal physiology of the segment affected, and whether the abnormality is caused by loss of function or, less commonly, gain of function. In this review we address the current knowledge about the association between the genetics and clinical manifestations and treatment of representative disorders affecting the length of the nephron.

Section snippets

Dent Disease

Dent disease is an X-linked recessive disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, and/or nephrolithiasis, and slowly progressive renal failure.1 Other features may include phosphaturia, aminoaciduria, glycosuria, kaliuresis, impaired urinary acidification, and rickets. As a result, the disease may be considered a form of renal Fanconi syndrome. Since the recognition of the underlying genetic defect, 3 previously described disorders,

Bartter Syndrome

Bartter syndrome is a group of heterogeneous, mostly autosomal-recessive disorders with a clinical picture characterized by renal salt wasting, hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism with normal blood pressure, and hyperplasia of the juxtaglomerular apparatus. Since the first description of this syndrome by Bartter et al20 in 1962, several variants of this syndrome have been reported; all nonetheless affecting the salt reabsorption mechanisms in the TALH. Two

Gitelman Syndrome

Gitelman syndrome, initially described in 1966, is an autosomal-recessive disorder characterized by hypokalemic metabolic alkalosis, associated with hypocalciuria and hypermagnesuria.39 Patients with Gitelman syndrome typically are diagnosed in late childhood or adulthood with problems such as weakness, tetany, or seizures. Several investigators consider it a milder variant of Bartter syndrome, whereas others consider it a separate entity because of the characteristic hypocalciuria and

Terminology and Classification of Salt-Losing Tubulopathies

The 6 subtypes of Bartter syndrome were named based on the chronologic order of their discovery, and, as mentioned previously, Gitelman syndrome is considered another variant of Bartter syndrome by many researchers. The newer terminology described later, suggested recently by Seyberth,45 is based on the underlying pathophysiological mechanisms and provides an understanding of the clinical presentation and rationale of treatment.

In all salt-losing tubulopathies associated with secondary

Liddle Syndrome

Liddle syndrome was first described in 1963 as a familial disorder (autosomal dominant) characterized by severe hypertension, hypokalemia, and metabolic alkalosis that mimicked hyperaldosteronism. However, affected patients had exceptionally low aldosterone and renin levels and failed to respond to the aldosterone antagonist spironolactone but responded to triamterene.46

Apparent Mineralocorticoid Excess

The syndrome of apparent mineralocorticoid excess was first reported in 1977 and is characterized by severe hypertension, hypokalemia, metabolic alkalosis, suppressed renin, and low serum aldosterone levels.56 The fact that these patients respond to spironolactone suggested that the disease is mediated through the mineralocorticoid receptor.

Pseudohypoaldosteronism Type I

Type I pseudohypoaldosteronism is caused by loss-of-function mutations of either the MCR or ENaC, resulting in aldosterone unresponsiveness58 (Fig. 4). This condition typically manifests during infancy with failure to thrive, vomiting, and dehydration. Serum chemistries reveal hyperkalemia, metabolic acidosis, and markedly increased renin and aldosterone levels.59 Mutations of the MCR gene NR3C2 (chromosome location 4q31.1) are inherited in an autosomal-dominant fashion and the clinical picture

Pseudohypoaldosteronism Type II (PHAII; Gordon Syndrome)

Gordon syndrome is an autosomal-dominant disorder characterized by hypertension, hyperkalemia, and hyperchloremic metabolic acidosis; however, hypertension may not manifest until later in life.63, 64, 65 Because these patients readily respond to thiazide diuretics, it once was believed that this condition resulted from gain-of-function mutations of the Na+Cl− cotransporter NCCT in the DCT. However, recent genetic studies have identified the essential role of a novel family of serine-threonine

Nephrogenic Diabetes Insipidus

Hereditary forms of nephrogenic diabetes insipidus (NDI) resulting from renal insensitivity to the antidiuretic effect of arginine vasopressin (AVP) are relatively uncommon but provide exciting insight into underlying physiologic processes, especially in view of the discovery of the molecular identity of the first water channel by Agre et al71 in 1991. The latter has led to a veritable flood of research in this area, and to potentially novel strategies for therapeutic interventions.

Nephrogenic Syndrome of Inappropriate Antidiuresis

Feldman et al84 reported 2 infants with hyponatremia whose clinical and laboratory evaluations were consistent with syndrome of inappropriate antidiuretic hormone except that they had undetectable serum AVP levels. Investigations revealed that these patients had gain-of-function mutations of the V2R. Interestingly, mutations of the same amino acid (arginine) at position 137 caused 2 different genetic diseases: while R137H caused NDI, R137L and R137C caused the nephrogenic syndrome of

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