Renal tubular reabsorption defects

Glycinuria results from a defect in renal tubular reabsorption. The defect in primary hyperoxaluria is the failure to catabolize glyoxylate formed by deamination of glycine. Subsequent oxidation of glyoxylate to oxalate results in urohthiasis, nephrocalcinosis, and early mortality from renal failure or hypertension. 

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). 

Much that is known about renal reabsorption mechanisms has been learned from the study of various forms of aminoaciduria. Three types of aminoaciduria have been identified (1) overflow aminoaciduria occurs when the plasma level of one or more amino acids exceeds the renal threshold (tubular capacity for reabsorption) (2) renal aminoaciduria occurs when plasma levels are normal but the renal transport system has a congenital or acquired defect and (3) no-threshold aminoaciduria occurs when excessive amounts of an amino acid, arising from an inherited metabolic block, are present in urine, but plasma levels are essentially normal because ah the amino acid is excreted. The no-threshold aminoacidurias, such as homocystinuria, are not due to congenital or acquired kidney defects but solely to saturation of the normal renal tubular reabsorption mechanisms. 

Cystinuria is an autosomal recessive condition in which there is excessive urinary excretion of cystine because of a defect in proximal renal tubular reabsorption. In the most common form of the disease there is also excess excretion of the dibasic amino acids (lysine, ornithine, and arginine). These share the same renal tubular transporter although their presence in excess in urine appears benign. More rarely, isolated cystinuria is seen. The reader should note that cystinuria should not be confused with cystinosis, which is a condition associated with intracellular accumulation of cystine but not excess urinary excretion of cystine. 

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)... 

There have been reports in the literature of hypouricemia coincident with specific inborn metabolic errors, but many of these cases are attributable to defects in the kidney leading to failure of renal tubular reabsorption. It was mentioned above that the excretion of uric acid by the Dalmatian coach hound can be attributed to such a mechanism (Fll). Similarly, the hypouricemia found in the Fanconi syndrome (L4) and Wilson s disease (B12) can be attributed to kidney malfunction. These are not true examples of underproduction of oxypurines, including uric acid, since the daily output of uric acid is normal. The large number of healthy people who have extremely low serum urate values, however, may indicate that there are individuals who underproduce oxypurines but suffer no ill effects because of this. The one well-documented inborn error that results in underproduction of uric acid is xanthinuria. It has been reported in relatively few cases, probably because individuals with this metabolic abnormality who suffer no ill effects would not come to the attention of a physician. 

Cystinuria An Increased excretion of the amino acids cystine, lysine, arginine and ornithine leads to an increased incidence of renal calculi. A defective carrier protein causes impaired renal tubular reabsorption of these amino acids from the glomerular filtrate... 

Patients with a proximal renal tubular acidification defect had a basal urate excretion not different from controls or hyperuricosuric patients. Their response to pyrazinamide was, however, more pronounced than in controls and hyperuricosuric patients. The calculated tubular reabsorption of filtered urate was higher than in both controls and hyperuricosuric patients. It is suggested that this may contribute to the higher serum urate and the lower urate clearance in stone formers with a proximal renal acidification defect compared to patients with a normal acidification of the urine that we have reported on previously (4). 

A pyrazinamide suppression test (Table l) indicated defective renal tubular reabsorption of urate. The clearance of urate and the ratio of the urate clearance... 

The results obtained by studying the effect of probenecid on the clearance of urate were consistent with the pyrazinamide test, indicating defective renal tubular reabsorption of urate. Administration of probenecid, which normally increases the urate clearance by two to five- fold (7), affected the uric acid clearance in the patient only slightly, increasing it from 55.3 ml/minute to 74.8 ml/minute. The ratio of the urate clearance to the inulin clearance increased from 65% to 84%. 

On June 6, this patient developed severe loin pain after he participated in two 150-m sprints at a town athletics meeting. After 5 days, he was referred to the outpatient clinic of our department. His serum creatinine and uric acid levels and FEUA, were 2.9mg/dl, 2.1 mg/dl, and 49.7%, respectively. His creatine phosphokinase (CPK) level was normal. When his serum creatinine level decreased to 1.58 mg/dl, a contrast medium was administered. A delayed computed tomography (CT) scan after 24 and 48 h confirmed patchy wedge-shaped contrast enhancement (Fig. 58). Under a diagnosis of ALPE, his body water balance (hydration) was controlled. In this patient, recovery was achieved 4 weeks after onset, and his serum creatinine and uric acid levels were then 1.0 mg/dl and 0.6 mg/dl, respectively. Furthermore, load tests with a uric acid reabsorption inhibitor (benzbromarone) and a uric acid excretion inhibitor (pyrazinamide) suggested presecretory reabsorption defect-related renal hypouricemia. A kidney biopsy 16 days after onset confirmed the recovery from acute tubular necrosis. 

Renal magnesium wasting is the main mechanism responsible for the hypomagnesemia associated with cisplatin (172), and it can be associated with enhanced tubular reabsorption of calcium and consequent hypocalciuria (173). This dissociation in the renal handling of calcium and magnesium is similar to what is found in Bartter s syndrome. The site of the renal tubular defect in these conditions is not known, but there is evidence that active renal tubular transport systems are disrupted. 

Overproduction of uric acid can occur due to excessive de novo purine synthesis, excessive dietary purines, or the conversion of tissue nucleic acid to purine nucleotides. When these purines are metabolized, the by-products are converted to uric acid by the enzyme xanthine oxidase. Increased levels of uric acid result if the overproduction exceeds excretion. Underexcretion of uric acid can be due to defects in the renal tubular mechanisms that regulate uric acid levels in the body, causing decreased filtration, decreased secretion, or increased reabsorption. 

As intestinal absorption of calcium increases, urinary calcium excretion also increases. When the latter exceeds 300 mg/d, formation of calcium phosphate or calcium oxalate stones (urolithiasis) may occur. Hypercalciuria may result from decreased reabsorption of calcium due to a renal tubular defect or from increased intestinal absorption of calcium. Hypercalciuria may be due to an intrinsic defect in the intestinal mucosa or secondary to increased synthesis of 1,25-(OH)2D in the kidney. Disordered regulation of 1,25-(0H)2D synthesis is relatively common in idiopathic hypercalciuria. Treatment usually includes reduction in dietary calcium. Increased vitamin D intake, hyperparathyroidism, and other disorders can also cause hypercalciuria and urolithiasis. 

Urine concentrations of cAMP are normally KM) times higher than those in plasma or cytoplasm. Urinary cAMP is formed by action of PTH on the renal tubules. In hypocalcemia due to pseudohypoparathyroidism, reabsorption of Ca " " from the collecting ducts is impaired because the cells do not respond to PTH. Serum levels of PTH are high, but the urine contains very little cAMP. The defect may be in the receptors for PTH or distal to the receptor. PTH may also affect tubular reabsorption by cAMP-independent mechanisms. 

Besides hypoglycemia, D-fructose-induced renal acidification in the HFI defect involves a lowered hydrogen-ion secretory capacity of the proximal nephron, as evidenced by a 20 to 30% diminution in renal-tubular (T) reabsorption of bicarbonate (THCO3) and simultaneous occurrence, and persistence throughout D-fructose administration, of impaired tubular reabsorption of phosphate, cc-amino nitrogen, and uric acid. This abnormality of renal metabolism affects the renal cortex, which contains aldolase B, but does not affect the renal medulla. Thus, the abnormality may result from accumulation of D-fructose 1-phosphate in the renal cortex. The intimate, biochemical mechanism for renal, tubular acidosis is still unknown.164... 

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. 

In type II renal tubular acidosis there is a defect in the secretion of hydrogen ions by the proximal tubule. Because the proximal tubule is the major site of bicarbonate reabsorption (4000 mEq of bicarbonate per day as compared to 70 mEq in the distal tubule), the defect in secretion of hydrogen ions in this condition leads to the flooding of the distal tubule with bicarbonate. The capacity of hydrogen ions secreted by the distal tubule to buffer this massive efflux of bicarbonate is soon overwhelmed and, as a result, large quantities of bicarbonate are excreted in the urine. Much more bicarbonate needs to be administered in this condition to correct the acidosis than is necessary in type I renal tubular acidosis. In general, in renal tubular acidosis the impairment in hydrogen ion secretion leads to excretion of potassium ions in urine. 

Familial iminoglycinuria iminoglycinuria Renal tubular defect for reabsorption of glycine, proline, and hydroxyproline Rosenberg, L.E., Durant, J.L., and Elsas, L.J. II. Familial iminoglycinuria an inborn error of renal tubular transport. N. Engl. J. Med. 278, 1407-1413... 

Tubular acidosis is primary (an isolated inherited metabolic disorder) or secondary (a metabolic disorder associated with inherited or acquired lesions). It is characterized by the inability to maintain normal blood pH as a result of interference with bicarbonate reabsorption or a defect in renal hydrogen excretion. By definition, glomerular filtration is not altered in renal tubular acidosis. 

It is also believed that a fraction of HCO3 is reabsorbed independently of any form of excretion, whether it be carbonic anhydrase dependent or independent. Thus, proximal tubular acidosis could result from low carbonic anhydrase activity, ineffective diffusion of hydrogen ions, or a defect in the -independent reabsorption of bicarbonate. It is not known which distortion is responsible for proximal renal tubular acidosis. 

A group of patients forming calcium oxalate stones are hyperuri-cosuric and it is thought that their excessive urate excretion contributes to calcium-stones formationl. The pathomechanisms invoked are dietary purine excess and endogenous uric acid overproduction, being defective tubular reabsorption of urate "unattractive because uricemia was found to be normal in patients with recurrent calcium nephrolithiasis (RCN) and hyperuricosuria. Current studies were undertaken to define the incidence, role of diet, abnormalities of the renal handling of urate, and associated metabolic disturban-c"es in patients with RCN and hyperuricosuria. 

Add-base balance In some patients topiramate can cause metabolic acidosis, whose susceptibility factors, underlying mechanisms, and clinical effects have been reviewed [318 ]. Topiramate impairs both the normal reabsorption of filtered HCO by the proximal renal tubule and the excretion of by the distal renal tubule. This combination of defects is termed mixed renal tubular acidosis. The mechanism involves inhibition of carbonic anhydrase. This mechanism can make patients acutely ill, and chronically can lead to nephrolithiasis, osteoporosis, and in children growth retardation. The usefulness of monitoring HCO concentrations has not been proven and is not routine. Hence, there is no proven method for predicting or preventing the effect of topiramate on acid-base balance. However, patients with a history of renal calculi or known mixed renal tubular acidosis should not receive topiramate. 

These results suggest acute renal failure (ARF) due to tubular necrosis caused by phenol. Plasma sodium is low due mainly to impaired reabsorption in the nephron, although the slightly low albumin suggests haemodilution possibly as a result of excessive i.v. fluids. Potassium is raised due to poor exchange with sodium in the distal tubule and the acidosis (low pH and low bicarbonate concentration) arises from defective acidification of the glomerular filtrate acidosis is often associated with hyperkalaemia (raised plasma... 

While alcohol abuse may be associated with a variety of electrolyte and acid-base disorders, the role of the kidneys in this process has only recently been fully defined [164]. Renal functional abnormalities have now been related to chronic alcoholism in patients without liver disease and these defects have reverted to normal with abstinence from alcohol abuse. These abnor-mahties include decreases in the maximal reabsorptive abihty and threshold for glucose, a decrease in the threshold for phosphate excretion, and increases in the fractional excretion of P2-microglobulin, uric acid, calcium, magnesium, and amino acids. Defective tubular acidification and impaired renal concentrating ability... 

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