Tubular reabsorption deficiency

Dent s classification is the basis of most classifications of abnormal types of amino aciduria. He divides the pathological conditions into three categories (D9) (A) Overflow amino aciduriain which the blood level of the amino acid concerned is definitely raised above normal [example Section 4.2.1.L (a)] (B) Renal amino aciduria, in which case the blood level is either normal or below normal, and yet the urinary excretion is above normal [tubular reabsorption deficiency example Section 4.2.I.I. (e)] (C) No threshold amino aciduria, in which Dent attributes the condition to an extrarenal disturbance of the metabolism of an amino acid with a high blood clearance, and in which, on account of this latter circumstance, the corresponding blood level may stay normal or is hardly increased. 

Most doctors use the plasma concentrations of creatinine, urea and electrolytes to determine renal function. These measures are adequate to determine whether a patient is suffering from kidney disease. Protein and amino acid catabolism results in the production of ammonia, which in turn is converted via the urea cycle into urea, which is then excreted via the kidneys. Creatinine is a breakdown product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass). Creatinine is mainly filtered by the kidney, though a small amount is actively secreted. There is little to no tubular reabsorption of creatinine. If the filtering of the kidney is deficient, blood levels rise. 

Renal Disease. The potential causes of conditioned deficiency of zinc in patients with renal disease include proteinuria and failure of tubular reabsorption. In the former instance, the loss of zinc—protein complexes across the glomerulus is the mechanism. In the latter an impairment in the metabolic machinery of tubular reabsorption attributable to a genetic abnormality or to toxic substances would result in zinc loss. While low plasma zinc concentrations have been described in patients with massive proteinuria, no reports of low plasma levels of zinc in patients with tubular reabsorption defects have appeared in literature (9). 

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)... 

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). 

Conservation of amino acids filtered at the glomerulus is made possible by the existence of four main transport systems for specific amino acids that facilitate active reabsorption of these amino acids from the proximal tubule. A lack or deficiency of the transport system responsible for the absorption of valine, alanine, cystine, and tryptophan, and of the transport system for arginine, lysine, cystine, and ornithine, leads to excretion of these specific amino acids in urine, which is characterized as renal aminoaciduria to distinguish it from overflow aminoaciduria. In the latter situation, the production of amino acids far exceeds the proximal tubular reabsorption capacity, thus leading to overflow of amino acids into urine. This can occur due to defective metabolism of amino acids, as is the case when phenylalanine cannot be metabolized due to the deficiency of the enzyme phenylalanine hydroxylase, or to the inability to deaminate amino acids in liver disease. 

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). 

B. Effects and Clinical Uses ADH and desmopressin reduce urine volume and increase its concentration. ADH and desmopressin are useful in pituitary diabetes insipidus. They are of no value in the nephrogenic form of the disease, but salt restriction, thiazides, and loop diuretics may be used. These therapies reduce blood volume, a very strong stimulus to proximal tubular reabsorption. The proximal tubule thus substitutes— in part— for the deficient concentrating function of the collecting tubule. 

We are facing the same diflSculty here as in so many of the other experiments with vitamin D, namely that when vitamin D is given to a vitamin D-deficient subject three variables are brought simultaneously into play. Although proof is lacking, the sequence of events in Ca and P metabolism following vitamin D administration (clearly demonstrated in Table II) are such that (Wolf and Ball s experiments taken into consideration) the tubular reabsorption effect may be secondary to the primary increase in circulating calcium. 

If vitamin D has no effect on calcium absorption, it does affect calcium mobilization and thereby restores plasma concentrations of calcium. This finding explains why vitamin D deficiency was associated with hypocalcemia. The effect on the bone seems to require a synergetic action of vitamin D and parathormone. The 1,25-hydroxylated derivative seems to be the major active compound causing calcium release from the bone. The 25-hydroxyl derivative has, however, been shown to be active as well. Finally, vitamin D increases renal proximal tubular reabsorption of phosphate in normal and vitamin D deficient animals. Consequently phosphate excretion is decreased. Inasmuch as this effect occurs in parathyroidectomized animals, the effect of vitamin D or its metabolites must be direct. Again, the active metabolites are the 25 and 1,25-hydroxy derivatives. A calcium binding protein has been isolated from the kidney cortex, but its role in renal reabsorption is not known. 

Animal studies and studies using brush border membrane vesicles from human kidney cortex indicate that biotin is reclaimed from the glomerular filtrate against a concentration gradient by a saturable, Na -depen-dent, structurally specific system, but biocytin does not inhibit tubular reabsorption of biotin. Subsequent egress of biotin from the tubular cells occurs via a basolateral membrane transport system that is not dependent on Na. Studies of patients with biotinidase deficiency surest that there may be a role for biotinidase in the renal handling of biotin. 

Vitamin D deficiency in young children causes rickets. As a child becomes vitamin D deficient, this results in a decrease in the efficiency of intestinal calcium absorption. There is a decline in blood-ionized calcium, which causes the parathyroid glands to produce and secrete more parathyroid hormone (PTH). PTH tries to conserve calcium by enhancing tubular reabsorption of calcium in the kidney. However, in the face of developing hypocalcemia, which could disturb neuromuscular function and a wide variety of metabolic and cellular processes, the body calls upon l,25(OH)2D and PTH to mobilize stem cells to become functional osteoclasts, which, in turn, mobilize calcium from the skeleton. In addition, PTH causes a loss of phosphorus into the urine causing hypophosphatemia. Thus, in early vitamin D deficiency the serum calcium is normal it is the low serum phosphorus that causes the extracellular CaXP04 to be too low for normal mineralization of... 

Specific defects in particular functions of the nephrons can also be identified and evaluated. For example, assessment of the maximum concentrating capacity of the kidneys gives an estimate of antidiuretic hormone (ADH)-controUed reabsorption of solute-free water in the distal portion of the tubule. Pinpoint defects, caused by genetically determined deficiencies of specific tubular transport systems or ion channels and giving rise to characteristic biochemical disorders, are considered in Chapter 45. 

Glucocorticoids also exert effects on fluid and electrolyte balance, largely due to permissive effects on tubular function and actions that maintain glomerular filtration rate. In part, the inability of patients with glucocorticoid deficiency to excrete free water results from the increased secretion of vasopressin, which stimulates water reabsorption in the kidney. 

A polypeptide hormdne secreted by the posterior pituitary gland. It is involved in fluid homeostasis, exerting its action in the distal renal tubular cells where it increases passive water reabsorption along the osmotic gradient produced by the countercurrent mechanism. This results in a concentrated urine being produced. Deficient production of the hormone, or failure of the renal tubules to respond to it, results in diabetes insipidus. Alternatively inappropriate ADH secretion can occur in conditions such as infections or as a result of ectopic ADH secretion by a tumour. This results in water retention which reveals itself as hyponatraemia. ADH can be measured by radioimmunoassay. 

---