Renal tubular deficiency

LRP2/ megalin Loss-of-function (familial, autosomal recessive) Donnai-Barrow syndrome (brain malformation, renal tubular deficiency, diaphragmatic hernia)... 

It is only when the renal tubular function becomes disturbed that hyperamino aciduria appears, in comparison to normal subjects, under the influence of protein overloading in the diet (S34). Dubois et al. attribute also to the same renal tubular deficiency the temporary rise in amino aciduria observed in the first days of high-protein dietary treatment of kwashiorkor cases (D25, D26), a situation which has also been seen by others (C9, M4). It has been attributed both to hepatic and renal deficiencies (C3). 

Carbonic anhydrase (CA) exists in three known soluble forms in humans. All three isozymes (CA I, CA II, and CA III) are monomeric, zinc metalloenzymes with a molecular weight of approximately 29,000. The enzymes catalyze the reaction for the reversible hydration of C02. The CA I deficiency is known to cause renal tubular acidosis and nerve deafness. Deficiency of CA II produces osteopetrosis, renal tubular acidosis, and cerebral calcification. More than 40 CA II-defi-cient patients with a wide variety of ethnic origins have been reported. Both syndromes are autosomal recessive disorders. Enzymatic confirmation can be made by quantitating the CA I and CA II levels in red blood cells. Normally, CA I and CAII each contribute about 50% of the total activity, and the CAI activity is completely abolished by the addition of sodium iodide in the assay system (S22). The cDNA and genomic DNA for human CA I and II have been isolated and sequenced (B34, M33, V9). Structural gene mutations, such as missense mutation, nonsense... 

Sly WS, Hewett-Emmett D, Whyte MP, Yu YS, Tashian RE (1983) Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci USA 80 2752-2756... 

Lai, L. W, Chan, D. M, Erickson, R. P, Hsu, S. J. and Lien, Y. H. (1998). Correction of renal tubular acidosis in carbonic anhydrase Il-deficient mice with gene therapy. J. Clin. Invest. 101, 1320-1325. 

Schaefer L, Malchow M, Schaefer RM et al. (1996) Effects of parathyroid hormone on renal tubular proteinases. Miner Electrolyte Metabol 22 182-186 Shimizu T, Hata S, Kuroda T et al. (1999) Different roles of two types of endothelin receptors in partial ablation-induced chronic renal failure in rats. Eur J Pharmacol 381 39-49 Stockelman MG, Lorenz JN, Smith FN et al. (1998) Chronic renal failure in a mouse model of human adenine phos-phoribosyltransferase deficiency. Am J Physiol 275 Renal Physiol 44 F154-F163... 

A classic example of essential metal deficiency resulting from nonessential metal exposure is Itai itai disease. Cadmium pollution in the Jinzu River basin in Japan resulted in severe nephrotoxicity in approximately 184 people. Renal tubule damage caused excessive loss of electrolytes and small proteins from the urine. In severe cases, urinary Ca loss was so severe that bone Ca was mobilized, resulting in osteomalacia. Renal tubular defects persisted for life and induced hypophosphatemia, hyperuricemia, and hyperchloremia, which are characteristic biochemical features of Itai-itai disease (see Section 21.6.1). 

Q13 Magnesium is a major intracellular cation which acts as a co-factor in many intracellular enzyme reactions. Plasma concentration is normally 2 mg dl-1. This ion is abundant in the diet, and hypomagnesaemia is relatively uncommon, unless there is malabsorption or excessive loss via the kidney. However, when present, hypomagnesaemia can lead to hypoparathyroidism. Adjustment to the levels of magnesium can shift the function of the parathyroid glands back to normal. Chronic alcoholism, malnutrition, malabsorption, renal tubular dysfunction and excessive use of diuretics, such as loop and thiazide diuretics, may lead to hypomagnesaemia. Symptoms of magnesium deficiency include depression, confusion, muscle weakness and sometimes convulsions. 

Hjq)onatremia is rare, and persistent hyponatremia very rare in patients taking cisplatin (162). In a detailed description of the biochemical abnormalities that can result from renal tubular dysfunction after cisplatin therapy, it was noted that hypocalciuria is more common than hypomagnesemia, and that there tends to be a state of reduced serum bicarbonate. The most severe renal tubular damage caused by cisplatin is characterized by hypocalciuria, total body magnesium deficiency, and hypokalemic metabolic alkalosis (163). 

Concurrent acidosis in patients with trimethoprim-induced hyperkalemia is uncommon, which could be explained if the action of trimethoprim, like that of amiloride, is hmited to the cortical collecting tubule but does not affect the medullary collecting tubule, which has a large capacity to secrete hydrogen ions and may therefore prevent the development of acidosis. Predisposing factors for the rare adverse effect of renal tubular acidosis in this case may have been aldosterone deficiency or resistance, medullary dysfunction of sickle cell anemia, and renal insufficiency. All these factors could contribute to impaired renal handling of secretion of hydrogen ions (72). 

Firstly, Cd causes renal damage with effects principally on renal tubular cells, i.e. the site of la,25-dihy-droxyvifamin D synfhesis resulfing in an infrinsic vitamin D deficiency. This will impair the gastrointestinal absorption of calcium, reduce the calcium incorporation in bone and ultimately result in the development of osteomalacia. It is well known that la,25-dihydroxyvi-tamin D is the biologically active metabolite of vitamin D. As there is a sequential relationship between the synthesis of la,25-dihydroxyvitamin D in the kidney and cyclic-adenosine monophosphate, adenylcyclase, parathyroid hormone, a direct interference of Cd with any of these steps cannot be excluded. 

Laboratory findings in rickets and osteomalacia include an increased serum ALP, with other alterations in bone and mineral metabolism dependent on the cause and severity of the disorder. ALP is usually increased because of the increased osteoblastic activity associated with producing unmineralized osteoid. Calcium may be low-normal or low in vitamin D deficiency depending on the severity of the disease. Phosphate may be normal or low, but falls with the development of secondary hyperparathyroidism. The serum calcium and PTH concentrations are usually normal in renal tubular defects of phosphate transport. Vitamin D nutrition may be assessed by the determination of serum 25(OH)D. Renal phosphate defects can be best assessed by determination of the renal phosphate threshold. 

Other unusual conditions that suggest aldosterone excess or deficiency but are not connected to the renin-angiotensin-aldosterone system include Liddle s syndrome (pseudo hyper aldosteronism),which resembles primary aldosteronism clinically, but aldosterone production is low and hypertension is absent and Barttefs syndrome,which involves a prostaglandin-mediated renal potassium wasting and renal chloride handling defect, in which both aldosterone concentrations and renin activities are elevated. In renal tubular acidosis and pseudohypoaldosteronism, the clinical picture of hypoaldosteronism is seen concurrent with greater-than-normal concentrations of aldosterone. 

CPT-I deficiency (liver and muscle types) 255120 600528 601987 Carnitine palmitoyl transferase I <1 100,000 Liver disease, hypotonia, renal tubular acidosis AFLP... 

Wilson s disease or ceruloplasmin deficiency (autosomal recessive) Excess secretion of glycine, serine, and cystine Lenticular degeneration, positive copper balance, low serum ceruloplasmin levels, and defects in renal tubular reabsorption Mental retardation, ataxia, extrapyramidal symptoms, and cirrhosis Chromatography low blood and high urine copper levels low serum cemlc Iasmin (B8. H18. H19, PU. S9, W16)... 

Tyrosinosis is presumably due to fumarylacetoacetate hydrolase deficiency and has a high prevalence in the French-Canadian population of Quebec. It is associated with abnormal liver function, renal tubular dysfunction, anemia, and vitamin D-resistant rickets. Transient tyrosinemia of the newborn, particularly in premature infants, is the most common form of tyrosinemia in infancy. 

Other chronic disorders cause osteomalacia. " " Phosphate depletion from low dietary intake, phosphate-binding antacids, and oncogenic osteomalacia (potentially phosphaturic effect) can cause osteomalacia. Hypophosphatasia is an inborn error of metabolism in which deficient activity of alkaline phosphatase causes impaired mineralization of bone matrix. Acidosis from renal dysfunction, distal renal tubular acidosis, hypergammaglobulinemic states (e.g., multiple myeloma), and drugs (e.g., chemotherapy) compromises bone mineralization. Renal tubular disorders secondary to Fanconi s syndrome, hereditary diseases (e.g., Wilson s disease, a defect in copper metabolism), acquired disease (e.g., myeloma), and toxins (e.g., lead) cause osteomalacia to varying degrees. Chronic wastage of phosphorus and/or calcium limits mineralization, which may be further compromised by acidosis and secondary hyperparathyroidism. 

The combination of hypophosphatemia, vitamin D resistance, osteomalacia, and rickets is seen in a number of syndromes (W24). These include (a) familial hypophosphatemic vitamin D-resistant rickets, a sex-linked, dominant disorder (P3), (b) familial vitamin D dependency, an autosomal recessive disorder due to la-hydroxylase deficiency (F19), and (c) nonfamilial hypophosphatemic osteomalacia (D9), considered by some workers (P3) to be a separate disease entity because of its late onset, its severity, and its lack of response to therapy. In addition, there are many inherited and acquired disorders which are associated with impairment of renal tubular reabsorption of phosphate, and these may be accompanied by hypophosphatemia, rickets, and relative vitamin D resistance. Serum alkaline phosphatase values in these disorders correlate poorly with the severity of the disease (A14) and with the response to therapy (E4, MclO, P7, S50). 

Saturation and Intradermal Tests. Ascorbic acid saturation tests, based on observations that subjects with low tissue reserves excreted less of a test dose of vitamin C in the urine than subjects with adequate stores, did not distinguish between varying degrees of deficiency at the lower levels of nutrition. Relatively high plasma levels must be attained before the effect of the renal tubular reabsorption is surpassed and significant excretion occurs (see Section 5). 

Galactosaemia This delect is present in approximately 1 100 000 babies in the UK. A deficiency of galactose 1-phosphate uridyl transferase means that the baby cannot utilize the galactose component of the lactose which is present in milk. Such infants may present with failure to thrive, vomiting and diarrhoea and if untreated may die in the neonatal period or go on to develop liver disease, mental retardation, cataracts and renal tubular damage... 

Adrenal insufficiency, mineralocorticoid deficiency, osmotic diuresis, renal tubular acidosis With normal ECF volume (euvolemia) ... 

Bergman, A.J., Donckerwolcke, R.A., Duran, M., Smeitink, J.A., Mousson, B., Vianey-Saban, C. Poll-The, B.T. (1994). Pediatr Res 36 582-588. Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase 1 deficiency. 

The sensitivity of the premature infant is probably associated with its low vitamin E status. It has been shown that in vitamin E-deficient rats, hemolysis and hemoglobinuria can be produced by intramuscular injection of several vitamin K substitutes (Allison et al., 1956 Marusich et al., 1956), but not by vitamin Ki, and that a-tocopherol will prevent hemolysis and hemoglobinuria even when given 4 hours prior to the injection (Marusich et al., 1956). These vitamin K substitutes do not produce hemolysis of erythrocytes in vitro. Allison et al. (1956) suggested that the hemoglobinuria might be secondary to renal tubular damage induced by vitamin E deficiency, but it now appears more Ukely that alterations in the erythrocyte fatty acids are responsible. 

---