|Year : 1997 | Volume
| Issue : 3 | Page : 247-259
|Hereditary and Acquired Renal Tubular Disorders: The Saudi Experience
Sami A Sanjad
Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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|How to cite this article:|
Sanjad SA. Hereditary and Acquired Renal Tubular Disorders: The Saudi Experience. Saudi J Kidney Dis Transpl 1997;8:247-59
|How to cite this URL:|
Sanjad SA. Hereditary and Acquired Renal Tubular Disorders: The Saudi Experience. Saudi J Kidney Dis Transpl [serial online] 1997 [cited 2020 Nov 26];8:247-59. Available from: https://www.sjkdt.org/text.asp?1997/8/3/247/39351
| Introduction|| |
The renal tubular disorders present as specific transport defects involving one or multiple solutes, with little or no evidence of glomerular impairment. If unrecognized, however, some of these tubulopathies are associated with progressive interstitial nephropathy, glomerular involvement and renal failure. Hence the importance, of early diagnosis and treatment in an effort to prevent these complications.
Because the majority of renal tubular disorders are hereditary in nature and transmitted by autosomal recessive genes, their frequency is expectedly high in populations where mutant genes exist and consanguineous marriages prevail such as in Saudi Arabia.
A detailed account of the different reabsorptive and secretory processes occuring along the renal tubules is beyond the scope of this discussion, but a brief description will contribute to a better understanding of the different pathophysiological states associated with renal tubular disorders.
| Proximal Tubular Function|| |
Tubular reabsorption of the glomerular filtrate and its accompanying solutes constitutes one of the most important functions of the kidney. Because of the large number of invaginations, or microvilli, along its luminal membrane, the proximal tubular cell is particularly fit for that purpose. The microvilli have a brush border containing specific carrier proteins that translocate solutes across the cell. Many of these have been determined by DNA sequencing and seem to exhibit a high degree of homology, but in many instances the molecular mechanism for a carrier protein to transport a specific substance has not been determined  .
Both active and passive transport mechanisms are operative in solute reabsorption. The energy for active transport is provided by a Na-K-ATPase pump located in the basolateral cell membrane [Figure - 1].
Sodium is co-transported across the luminal membrane with several other solutes. These include D-glucose, D-galactose, L-amino acids, phosphate, lactate, sulfate, urate and other organic metabolites. Sodium is also exchanged for hydrogen ion secreted from the cell to the tubular fluid. This phase of sodium reabsorption is responsible for 2/3 of the bicarbonate reabsorbed. The proximal tubular cell is also equipped with an electrogenie HATPase pump located in the apical cell membrane, which contributes about 1/3 of the proton secretion and bicarbonate reabsorption  . Normally, 85% of the filtered bicarbonate is reabsorbed in the proximal tubules by these mechanisms.
| Distal Tubular Function|| |
The distal tubular cells are involved in further reabsorption of sodium and chloride, absorption and secretion of potassium, hydrogen secretion into the lumen (urine acidification), and concentration of the urine. In the thick ascending limb of the loop of Henle, sodium is co-transported by an electroneutral process with K and 2C1. Loop diuretics such as furosemide and bumetanide are known inhibitors of this Na-K-2C1 cotransport. Bartter's syndrome is caused by mutations in this Na-K-2C1 co-transporter gene NKCC2  . This is very much in keeping with the biochemical similarities seen between patients receiving loop diuretics and patients with Bartter's syndrome.
In the distal convoluted tubule (DCT), sodium and chloride are reabsorbed by a co-transport mechanism. The Na-Cl cotransport in this part of the tubule is inhibited by the thiazide group of diuretics. Gitelman's variant of Bartter's syndrome is caused by mutations in this thiazide sensitive Na-Cl co-transporter  . Further down in the cortical collecting duct (CCD) sodium transport takes place across channels in the apical membrane by simple diffusion. These sodium channels are inhibited by the diuretics amiloride and triamterene. Mutations in the sodium epithelial channel beta and gamma sub-units cause Liddle's disease, an autosomal form of salt-sensitive hypertension associated with hypokalemic alkalosis  .
About 2/3 of the filtered potassium is reabsorbed in the proximal convoluted tubule regardless of the final urinary excretion. Another 25% of the filtered potassium is reabsorbed along with sodium and chloride in the thick ascending limb of Henle (Na-K-2C1 co-transporter).
Hydrogen Secretion: Urine Acidification [Figure - 2]
Hydrogen secretion takes place in the CCD and MCD by the electrogenic H-ATPase and H-K-ATPase pumps, which can establish much steeper hydrogen ion gradients than the Na-H antiporter mechanism that prevails in the proximal tubule. Thus, a 1000 fold gradient (3pH units) may be attained between plasma and urine at maximum urine acidity with a pH of 4.4.
The distal tubules and collecting ducts are also the site of urinary concentration. Vasopressin (ADH) increases water permeability in the CCD and MCD and results in the formation of a concentrated urine. This occurs through passive reabsorption of water by means of an elaborate countercurrent mechanism generated by the hairpin configuration of the limbs of Henle.
| Renal Tubular Diseases|| |
Diseases affecting the renal tubules occur due to structural or functional abnormalities in the different segments of the nephron. Many tubulopathies involve both proximal and distal tubular functions, but conceptually it helps to differentiate proximal from distal disorders. The diseases discussed below reflect our experience with various tubulopathies studied at King Faisal Specialist Hospital and Research Center over a 9year period ending December 1996.
| The Proximal Tubular Disorders|| |
Disorders of proximal tubular function may be hereditary or acquired in nature.The hereditary proximal tubular defects are due to (a) absent or defective Na-solute co-transport system in the proximal tubular cells, such as seen in cystinuria, vitamin D resistant rickets and proximal renal tubular acidosis, (b) altered gene affecting more than one transport system e.g., idiopathic Fanconi syndrome, (c) mutant genes resulting in endogenous tubulotoxic substances accumulated from extrarenal metabolic pathways e.g., cystinosis, galactosemia, tyrosinemia, hereditary fructose intolerance and Wilson's disease.
Acquired defects of proximal tubular function are usually drug induced or related to intrinsic renal diseases.
| Fanconi Syndrome|| |
The Fanconi syndrome represents a heterogeneous group of disorders with abnormalities in the transport of multiple solutes by the proximal tubular cells. Solutes normally reabsorbed by the proximal tubules are lost in the urine in variable proportions. These include glucose, amino acids, phosphate, bicarbonate, uric acid and Iowmole-cular-weight proteins and cations.
The pathogenesis of the Fanconi syndrome is incompletely understood and probably varies with the underlying etiology. A dysfunction of the basolateral membrane Na-K-ATPase pump, brought about by an endogenous or exogenous toxin, would result in impaired energy production for solute reabsorption by the proximal tubule. This has been observed in several clinical 'and experimental disorders associated with the Fanconi syndrome  .
The clinical manifestations of the Fanconi syndrome and the onset of symptoms are variable but most patients with the inherited disorder present in the first year of life with failure to thrive, frequently with anorexia and vomiting. Polyuria and polydypsia with bouts of fever and dehydration may also be present. Rickets is invariably seen at some stage of the disease and may be the presenting manifestation in some children.
The diagnosis of the Fanconi syndrome is easily made when the above findings are seen in association with normoglycemic glucosuria and mild proteinuria on urinalysis. Proteinuria is primarily tubular in origin and is characteized by low-molecular weight proteins, usually less than 30,000 daltons. Serum analysis reveals hyperchloremic acidosis, normal urea and creatinine levels, hypopho-sphatemia, hypokalemia, hypouricemia and hyponatremia.
[Table - 1]
| Hereditary Causes of the Fanconi Syndrome|| |
Cystinosis is cited in the western literature as the most common cause of the Fanconi syndrome with an incidence of 1:200,000 live births. It is not to be confused with cystinuria which (a) does not cause the Fanconi syndrome (b) is predominantly associated with increased urinary excretion of cystine, ornithine, lysine and arginine and (c) is frequently associated with cystine urolithiasis.
Cystinosis is an autosomal recessive storage disease characterised by lysosomal accumulation of cystine in several organs including the kidney, liver, gut, spleen, bone marrow, lymphatic system, leukocytes, cornea, thyroid and other organs. The biochemical defect is unknown but a defective transport of cystine across the lysosomal membrane is the most likely cause.
The clinical and laboratory manifestations of infantile or nephropathic cystinosis are those of the Fanconi syndrome described above and become apparent in early infancy. Glomerular filtration rate is normal in the early phases of the disease but progressive deterioration is the rule. By the end of the first decade most children will develop end-stage renal disease necessitating dialysis and renal transplantation  .
The extrarenal manifestations of cystinosis are due to the accumulation of cystine crystals in different organs. Thus, corneal deposition is responsible for photophobia, excessive tearing and blepharospasm. Hypo thyroidism, with high TSH levels, is frequent is older children but clinical hypo thy roidism is uncommon. Muscular weakness and hypotonia secondary to hypokalemia and carnitine deficiency are also observed. The central nervous system, initially thought to be spared in cystinosis, is now a well known site of involvement in older patients.
Cystinosis may be diagnosed by slit lamp examination of the cornea where cystine crystals are deposited. Bone marrow, liver or kidney biopsy may also reveal cystine crystals. Definitive diagnosis is made by demonstrating increased cystine content in leukocytes or rectal mucosa from affected individuals. The leukocyte cystine content is 5 to 15 nanomols of 1/2 cystine/mg protein in the infantile form and less than 0.2 in normals. Prenatal diagnosis is now possible by measuring amniotic fluid or cultured fibroblasts for cystine content. Molecular genetic studies have recently shown linkage of the cystmosis gene to markers on the short arm of chromosome 17 (D17S1584)  .
Glycogen Storage Disease (GSD)
Hepatorenal glycogenosis with Fanconi syndrome was first described in 1949 by Fanconi and Bickel. Patients present in early infancy with failure to thrive, hypotonia, hepatomegaly and rickets. Hyperchloremic acidosis with bicarbonate wasting is usually severe. The kidneys are usually enlarged and loaded with glycogen. Many patients develop hypoglycemia with prolonged fasting and show impaired galactose utilisation  . The most striking abnormality is the massive glucosuria which may exceed 100gin/m2/day in some patients.
GSD appears to be relatively common in Saudi Arabia. It was diagnosed in almost one half of the cases of Fanconi syndrome (15 of 35) referred to our center over an 8-year period. In our experience many, if not most, of these patients have a deficient or absent activity of the enzyme phosphorylase-b kinase (as in type IX GSD) involving liver and kidney. This has been documented in liver and kidney homogenates from several patients with GSD and Fanconi syndrome  [Table - 3]. Most of the patients come from the southwestern part of the Kingdom and are members of the same tribe, implicating a founder's effect.
Tyrosinemia Type I
Also known as hepatorenal tyrosinemia, this autosomal recessive disorder is characterised clinically by early onset of nodular hepatic cirrhosis, failure to thrive and Fanconi syndrome. Rickets may be severe and crippling in untreated patients. Abdominal ultrasonography reveals hepatosplenomegaly and enlarged kidneys which, combined with the biochemical findings of the Fanconi syndrome, should arouse suspicion of tyrosinemia. A presumptive diagnosis of tyrosinemia is made if the urinary excretion of succinyl acetone (SA) and delta aminolevulenic acid (DALA) are elevated. The metabolic defect is related to deficiency of the enzyme fumaryl aceto acetate hydrolase (FAH) which leads to accumulation of toxic precursors including SA and DALA. The FAH gene has been cloned recently and mapped to chromosome 15 (15q23-q25) and several missense mutations have been described  .
Galactosemia results from many inherited enzyme deficiencies, but only Gal-l-PO4 uridyl transferase deficiency causes the Fanconi syndrome. The diagnosis should be suspected in any infant with a history of failure to thrive, jaundice, hepatomegaly with or without cataracts and non-glucose reducing substance in the urine. Definitive diagnosis is made by determining red blood cell Gal-1PCM uridyl transferase activity. The molecular diagnosis of galactosemia has been identified recently by mutations in the GALT gene located on chromosome 9pl3  .
Hereditary Fructose Intolerance
Hereditary fructose intolerance is an autosomal recessive disorder caused by deficiency of fructose-1-phosphate (F1-PO4) aldolase B activity in the liver, renal cortex and small intestine. Several mutations in the human aldolase B gene have been identified, the most common being the A149P mutation in exon 5 located on chromosome 9q21.3-q 22.2  . The clinical manifestations develop following fructose ingestion and are acute in nature and consist of nausea, vomiting and diarrhea. Liver failure may develop within days. The mutant gene seems to be relatively common in northern Europe but appears to be rare in the Middle Eastern countries. I am not aware of any documented cases from Saudi Arabia.
Lowe's syndrome is an X-linked recessive disease characterized by congenital cataracts, glaucoma, developmental and growth retardation, hypotonia and the Fanconi syndrome. The gene locus (OCRL) has been mapped recently to X 25-26 by linkage analysis  .
Other Hereditary Causes of the Fanconi Syndrome
The Fanconi syndrome has been described in association with several rare inborn errors of metabolism including Wilson's disease, mitochondrial myopathies, met achromatic leukodystrophy, pyruvate carboxylase deficiency (Leigh's syndrome) and pyroglutamic academia. [Table - 4] outlines some of the inherited disorders of proximal tubular function with and without the Fanconi syndrome, It includes some of the salient clinical findings, enzymatic defects inheritance patterns and known genetic mutations.
Acquired Disorders Causing the Fanconi Syndrome
These are usually due to heavy metal exposure (lead, mercury, platinum), drugs (ifosfamide, outdated tetracyclines, aminoglycosides, toluene inhalation) and abnormalities in protein metabolism as in amyloidosis, Sjogren's syndrome and nephrotic syndrome.
Of the drugs causally related to the Fanconi syndrome, ifosfamide is probably the most predictable since tubular dysfunction occurs in a relatively high percentage of treated patients. The tubular toxicity is thought to be due to chloracetaldehyde, one of the metabolites of ifosfamide  .
Symptomatic Treatment of the Fanconi Syndrome
Large doses of bicarbonate or citrate are needed to replace the ongoing losses through the urine, with some patients requiring 10-20 mEq/kg/day in four or more divided doses. Potassium supplements are frequently needed. Calcium and magnesium salts are used in patients with hypocalcemia and renal magnesium wasting. Prostaglandin synthetase inhibitors such as indomethacin (1-3 mg/kg/ day) may be used to reduce the urinary sodium, potassium and water losses. Vitamin D therapy in the form of calcitriol or one-alpha hydroxy D3 is required to correct rickets. Doses vary from 0.25 to 3.0 meg/ day. Phosphate supplements are used in high and frequent doses, depending on the severity of the phosphaturia. Most patients require 1 to 2 gins/day in four divided doses.
| Specific Therapy of the Fanconi Syndrome|| |
The aminothiols cysteamine and phosphocysteamine, have shown promising results in depleting cystine from lysosomes. This is accomplished by an intralysosomal reaction between cystine and cysteamine to form a cystine - cysteamine disulfide which exits the cell via a lysine carrier system. Treatment is started as soon as the diagnosis of cystinosis is confirmed. The starting dose is 10 mg/Kg/ day in four divided doses. This is progressively raised to 60 mg/Xg/day and titrated against leukocyte cystine content. Cysteamine treatment has been associated with improvement in the Fanconi syndrome and possible delay in the onset of renal failure  . When renal failure develops, dialysis and transplantation offer the only hope for prolonged survival. The Fanconi syndrome does not recur following transplantation but interstitial and mesangial accumulation of cystine has been reported.
Until recently the only effective therapy for tyrosinemia type I was liver transplantation, preferably prior to the development of severe liver failure and hepatocellular carcinoma, a known complication of nodular cirrhosis. An experimental drug, currently undergoing clinical trials appears to offer promising results for patients with Tyrosinemia I. The drug, 2-nitro-trifluoromethylbenzoyl-l,3-cyclohexanedione (NTBC), inhibits 4~OHphenylpyruvate dioxygenase, the second enzyme in the degradation pathway of tyrosine which is two steps proximal to the enzyme defect in tyrosinemia. Preliminary studies with NTBC therapy show an impressive reduction in the plasma level and the urinary excretion of SA and DALA and alpha fetoprotein levels with a marked reduction in hepatosplenomegaly. Tubular dysfunction also improves significantly with NTBC treatment  . We have treated five patients with NTBC and have been very impressed with the results so far.
| Proximal Renal Tubular Acidosis (Type II RTA)|| |
The basic defect in proximal RTA is impaired renal bicarbonate reabsorption by the proximal tubules. This could be brought on by a defective sodium-hydrogen antiporter or abnormalities in H-ATPase [Figure - 1]. Deficiency in carbonic anhydrase II or IV or a defective Na-HC03 co-transporter could also lead to incomplete bicarbonate reabsorption. The urine pH will be alkaline and remain so until plasma bicarbonate falls below the renal threshold, after which it becomes free of bicarbonate and properly acidified by the intact distal secretion of hydrogen ion.
The clinical features of isolated proximal RTA are those of failure to thrive and vomiting, usually detected in early infancy, but the disease may not be diagnosed until early childhood. Most reported cases have been sporadic but familial incidence with autosomal pattern of inheritance has been described.
A unique autosomal recessive syndrome of proximal RTA associated with osteopetrosis, cerebral calcification and carbonic anhydrase II deficiency has been reported in several families from the Arab world. It is characterized clinically by failure to thrive, recurrent fractures, mental retardation in the majority of patients and cranial nerve abnormalities. Over 2/3 of the cases have been from Middle Eastern and North African countries where genetic heterogeneity is suggested by a more severe, and at times lethal, variant of the disease. In addition to the proximal RTA, a distal acidification defect has been detected in many patients. The gene locus has been mapped recently to chromosome 8q22  . Several mutations have been identified, but the most common is the Arabic one which is a splice junction mutation in intron 2. At least 20 patients with this syndrome are currently followed by the Genetics and Renal Service in our center.
The diagnosis of proximal RTA should be considered in any infant, particularly male, with failure to thrive and unexplained hyperchloremic acidosis. A urinary pH below 5.5 is a strong evidence against distal RTA. The urine pH in proximal RTA is variable and depends on the plasma bicarbonate concentration. The diagnosis is confirmed by demonstrating a fractional excretion of bicarbonate (FEhcos) in excess of 15%.
Treatment consists of large and frequent doses of sodium bicarbonate or citrate (5-20 mEq/kg/day); potassium supplements may be necessary in some patients. When large doses of alkali are needed, a thiazide diuretic may be used to reduce ECV expansion and enhance bicarbonate reabsorption by the proximal tubules.
| Hypophosphatemic Vitamin D Resistant Rickets (HVDRR)|| |
This disease represents the most common form of rachitic bone disease in industrialized countries where nutritional rickets is no longer a problem. HVDRR is transmitted as an X-linked dominant trait. Thus, affected males (hemizygotes) will always manifest the disease whereas females (heterozygotes) have a milder form of hypophopshatemia with bowing of the legs. In addition to this classic mode of inheritance, autosomal dominant, recessive and even sporadic cases also occur. The mutant gene of X-linked HVDDR has been mapped recently to the short arm of the X chromosome (Xp 22). The gene (hyp) is located in the 350-650Kb region between DXS1365 and DXS1683. One third ofcases occur sporadically and may represent new mutations  .
Clinically, children with HVDRR present at the onset of walking or later when weight-bearing will lead to the classical bone deformities and growth failure. Biochemically, there is hypophosphatemia, normal serum calcium, elevated alkaline phosphatase and normal or slightly elevated PTH levels. In the urine, there is high phosphate excretion exceeding 20 mg/kg/day. Tubular reabsorption of phosphate (TRP) which normally ranges between 0.80 and 0.90 is frequently below 0.50 (0.40 -0.70) in patients with HYDRR.
Treatment consists of phosphate and vitamin D analogs. Oral phosphate supplement 1-2 grams per day, in four divided doses and calcitriol, 0.25-1.0 meg/day are usually sufficient but some patients require higher doses. Lower limb deformities correct better if treatment is started before the age of six years.
| Distal Tubular Disorders|| |
The distal tubulopathies may be classified under three main categories a) impaired urinary acidification and hydrogen ion secretion as seen with various types of RTA, b) impaired urinary concentration (nephregenic diabetes insipidus), and c) disorders of cation absorption or secretion.
| Distal Renal Tubular Acidosis|| |
Distal Renal Tubular Acidosis (dRTA) is one of the most common tubulopathies encountered in clinical practice. Both hereditary and acquired forms are recognized. The hereditary types of dRTA usually occur as an isolated defect in urinary acidification. Both recessive and dominant patterns of inheritance have been observed but the majority appear to be autosomal recessive. A detailed account of the pathophysiology of dRTA is beyond the scope of this text but in recent years the cellular and molecular aspects of renal acidification have been refined significantly to allow a precise classification of dRTA  .
a. Abnormalities in H-ATPase or H-KATPase pumps in alpha-intercalated cells could lead to defective protonsecretion (secretory defect). These abnormalities are thought to be responsible for classic dRTA and rate dependent RTA (with transplant rejection and various interstitial nephropathies).
b. Abnormal permeability of the luminal membrane of the alpha-intercalated cells and principal cells allowing back diffusion of protons from lumen to cell commonly seen with arnphotericin B therapy.
c. Voltage dependent defects associated with hyperkalemia and seen in with severe ECF volume contraction, urinary obstruction, sickle cell disease, lupus nephritis, and with several drug amiloride, triamterene, lithium and trimethoprim.
d. Combined voltage and secretory defects. This probably explains the distal RTA with reduced nephron mass, aldosterone deficiency or resistance (type IV RTA).
The clinical manifestations of primary dRTA are similar to those of proximal RTA, namely, growth failure, vomiting and recurrent bouts of dehydration. Hypokalemia occurs in about 30% of patients. Muscle weakness, sometimes progressing to skeletal or respiratory muscle paralysis may occur if hypokalemia is severe. Potassium depletion will also cause impaired urinary concentration resulting in polyuria and polydypsia with a tendency to ECV contraction and secondary hyperaldosteronism which will further aggravate renal potassium wasting.
Nephrocalcinosis and nephrolithiasis are commonly seen in older, untreated patients with dRTA. Both are secondary to hypercalciuria and hypocitraturia due to the chronic metabolic acidosis and its effect on bone calcium as a source of buffer. The negative calcium balance raises parathyroid hormone levels (secondary hyper parathyroidism) and contributes to rickets and osteomalacia.
Of the secondary causes of dRTA, those associated with underlying renal diseases are relatively common in our experience. Obstructive uropathies due to congenital malformations of the urinary tract, tubulointerstitial nephropathies and post renal transplantation, together with amphotericin B nephropathy account for the majority of children with acquired dRTA.
In addition, some interstitial nephropathies and several drugs may be causally related to type IV RTA associated with hyporeninemic hypoaldosteronism. Diabetic nephropathy, non-steroidal anti-inflammatory drugs, cyclosporine, trimethoprim and ACE inhibitors belong to this category.
The treatment of dRTA consists of adequate alkali replacement to normalize plasma bicarbonate. Infants with the classical variety require 2-3 mEq/kg/daily in 3 divided doses. This corresponds to the endogenous acid production. Those with renal bicarbonate wasting may require higher doses of alkali (3-14 mEq/kg/day) in four or more divided doses depending on the extent of their urinary losses. For patients with moderate or severe hypokalemic RTA, potassium citrate alone or in combination with sodium citrate (Polycitra), is the treatment of choice.
In patients with hyperkalemic RTA, treatment is tailored to the underlying disease process. In voltage dependent hyperkalemic RTA, a high sodium and low potassium intake with or without a thiazide or loop diuretic will lower serum potassium and raise bicarbonate to normal levels, but alkali therapy may be required in some patients.
| Nephrogenic Diabetes Insipidus (NDI)|| |
Nephrogenic diabetes insipidus is a polyuric syndrome characterised by normal antidiure-tic hormone secretion (ADH) and varying degrees of resistance to its waterretaining action in the collecting ducts. Hereditary NDI is usually transmitted by an X-linked dominant pattern with complete expression in males and variable penetrance in females. In the majority of cases of hereditary NDI the mutation occurs in the V2R gene (Xq28)  . In a few families with an autosomal mode of inheritance the mutant gene is the AQP2 gene located on chromosome 12  . Both variants are ADH resistant but in patients with AQP2 gene mutations, urinary cyclic AMP increases with ADH stimulation. Clinically, hereditary NDI in males is characterized by polyuria in early infancy. If this goes unnoticed and water intake is not kept up, the patient may present with non-specific symptoms such as vomiting, fever, dehydration and hypernatremia. If these bouts of hypernatremic dehydration go on unrecognised, mental retardation is a common complication. Females with hereditary NDI have milder symptoms and usually go undetected until later in childhood. We currently follow seven males with NDI from three families. Two have reached adulthood and have mild renal impairment due to obstructive uropathy.
Acquired NDI is seen frequently in our practice and is related to disorders interfering with ADH action on the collecting ducts (hypokalemia, hypercalcemia, lithium) or disorders affecting medullary solute concentration as seen in obstructive uropathies and chronic tubulointerstitial nephropathies. The degree of polyuria in these acquired forms of NDI is seldom of the magnitude seen with the hereditary form.
Treatment of NDI consists of adequate free water replacement to correct hypernatremic dehydration. Long-term management consists of dietary therapy with a reduced renal solute load (low Na, low protein diet) and free access to water. Thiazide diuretics in combination with a low Na diet may reduce urine volume by 50%. Prostaglandin synthetase inhibitors will help further reduce the urinary volume. The long-term prognosis for hereditary NDI is reasonably good if bouts of hypernatremic dehydration are prevented in infancy. In the acquired forms of NDI prognosis will vary with the underlying condition.
| Disorders of Cation Absorption or Secretion|| |
In children, Bartter's syndrome is characterized by failure to thrive, hypokalemic alkalosis, polyuria and secondary hyperaldosteronism with high plasma renin levels. Blood pressure is normal to low and there is a blunted response to angiotensin II infusion-Vasodilator prostaglandins are elevated. Hy-perplasia of the juxtaglomerular apparatus and the medullary interstitial cells underlies the hyper-reninemia and hyperprostaglandism.
In the absence of diuretic intake the diagnosis of Bartter's syndrome should be suspected in a child with hypokalemic alkalosis, normal blood pressure and high urinary chloride.
We have diagnosed Bartter's syndrome in 14 children presenting with the above clinical and biochemical pictures. All, but two, underwent free water clearance studies with hypotonic saline diuresis, which confirmed the diagnosis of low distal tubular chloride reabsorption (mean of 43% vs normal of 87%). Hypercalciuria was found in 73% and nephrocalcinosis in 45% of the patients.
Treatment of these patients with various combinations of ACE and PG inhibitors, together with spironolactone and potassium supplements resulted in significant improvement in their clinical and biochemical profiles. Recent genetic studies in Bartter's syndrome have revealed linkage to a cluster of loci at chromosome 15ql5-q21. Several mutations have been identified in NKCC2 co-transporter encoding the furosemide sensitive Na-K-2C1 cotransporter of the thick ascending limb of Henle's loop  . In addition, genetic heterogeneity was identified very recently by mutations in the K + channel ROMK, one of the regulators of this co-transporter  . Gitelman's variant of Bartter's syndrome, seen in older children and adults, presents with a less severe from of hypokalemic alkalosis. Growth is usually normal. Distinguishing laboratory findings from Bartter's syndrome include hypomagnesemia and hypocalciuria. Mutations in NCCT encoding the thiazide sensitive Na-Cl cotransporter in the distal convoluted tubule have been identified at chromosome 16ql3-q21  .
Liddle's syndrome is an autosomal dominant form of salt sensitive hypertension, associated with hypokalemia, alkalosis, low plasma renin and low aldosterone levels. The genetic abnormality has been characterized recently by detecting mutations in the beta and gamma subunits of the amiloride-sensitive Na epithelial channel in the cortical collecting duct  . The mutant genes are located in chromosome 16pl3-pl2.
We have studied seven patients with presumed Liddle's syndrome, who fulfilled all the above clinical characteristics, but DNA studies did not reveal the mutations described above. They were subsequently found to have the syndrome of apparent mineralocorticoid excess (AME) which is phenotypically identical to Liddle's.
| Hypomagnesemia of Renal Tubular Origin|| |
Hypomagnesemia is commonly seen in patients with renal magnesium wasting. Most often this is due to drugs, including diuretics (thiazides, furosemide), cisplatin, aminoglycosides, cyclosporin A and amphotericin B. Renal tubular magnesium wasting is also a feature of Gitelraan's variant of Bartter's syndrome (see above).
A rare syndrome of renal tubular magnesium wasting with RTA and nephrocalcinosis has been described in both children and adults. The syndrome is known as familial hypomagnesemia hypercalciura (FHH). Clinically, patients may be asymptomatic or present with tetany, polyuria and progressive renal insufficiency. Myopia and nystagmus have been observed in many patients but this has not been our experience in several affected children with this syndrome. We currently follow several families afflicted with this syndrome. The majority of patients come from the Jizan area, again implicating a founder's effect.
The pathophysiology of FHH remains elusive. Since 60-70% of the filtered magnesium load is reabsorbed in the thick ascending limb of Henle, it is quite possible that a defective transport in this segment of the nephron could affect both magnesium and calcium reabsorption.
Biochemically, FHH is characterised by moderate to severe hypomagnesmia, hypercalciuria, distal RTA (sometimes incomplete) and mild hyperuricemia. Fractional excretion of magnesium is increased but potassium clearance is usually normal or only slightly Increased. Parathyroid hormone levels are modestly elevated, most likely secondary to hypercalciuria. The disease tends to progress to chronic renal failure and end stage renal disease develops in most patients by the third decade of life. The progression to chronic renal failure seems to correlate with the severity of nephrocalcinosis  . Treatment of FHH has not been successful in preventing deterioration of renal function. Thiazides are recommended to reduce the hypercalciuria. Magnesium supplements seldom correct the hypomagnesemia. Amiloride or triamterene may have a more selective effect in enhancing distal tubular reabsorption of magnesium. In patients undergoing renal transplantation, serum magnesium and urinary calcium have remained normal indicating an intrinsic defect in magnesium transport limited to the kidney.
| Summary|| |
I have presented an overview of some of the hereditary and acquired renal tubular disorders observed at King Faisal Specialist Hospital and Research Center over a 9-year period ending in 1996. Whenever possible I have included up-to-date information on the molecular genetics and biochemical abnormalities underlying the hereditary disorders [Table - 4].
Glycogen Storage Disease, followed by cystinosis and tyrosinemia were the most common etiologies for the proximal tubulopathies associated with the Fanconi syndrome. Among the distal tubulopathies, Bartter's syndrome, renal tubular acidosis and familial hypomagnesemia hypercalciuria, were the most commonly observed.
The acquired tubulopathies were primarily associated with an underlying tubulointerstitial and obstructive nephropathy. The most common drug induced tubulopathies were those caused by amphotericin B, ifosphamide, cisplatinum and aminoglycosides.
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Sami A Sanjad
Consultant Nephrologist, King Faisal Specialist Hospital and Research Center, P O Box 3354, Riyadh 11211
[Figure - 1], [Figure - 2]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]
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