Renal disease reabsorption mechanisms

Thiazide diuretics such as chlorothiazide act on the distal tubule, a portion of the tubule that is permeable to sodium. The mechanism of action of these diuretics involves inhibition of NaCl reabsorption by blocking the Na+, CL symporter in the luminal membrane. The thiazide diuretics are only moderately effective due to the location of their site of action. Approximately 90% of the filtered Na+ ions have already been reabsorbed when the filtrate reaches the distal tubule. These drugs may be used for treatment of edema associated with heart, liver, and renal disease. Thiazide diuretics are also widely used for the treatment of hypertension. 

Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan and other large neutral amino acids. The result is that the intestinal absorption of free tryptophan is impaired, although dipeptide absorption is normal. There is a considerable urinary loss of tryptophan (and other amino acids) as a result of the failure of the normal reabsorption mechanism in the renal tubules - renal aminoaciduria. In addition to neurological signs that can be attributed to a deficit of tryptophan for the synthesis of serotonin in the central nervous system, the patients show clinical signs of pellagra, which respond to the administration of niacin. 

Similarly, in the case of renal disease, Giacomini and others have clearly demonstrated the stereoselectivity of renal drug excretory processes (14,27). Again with decreased renal function, including glomerular filtration, proximal reabsorption, and secretion, no information is available to determine whether the stereoselective processes decline in parallel with nonstereoselective mechanisms, such that after the administration of a racemic drug, the isomeric ratio in plasma remains the same. 

The renal clearance of the drug is proportional to endogenous creatinine clearance, irrespective of the mechanisms (i.e., filtration, reabsorption, or secretion), and the creatinine clearance is used as an indicator of the severity of the disease. Furthermore, it is possible to predict the half-life of a drug in a patient with renal disease based on the creatinine clearance and on a knowledge of the pharmacokinetics of the drug in normal subjects, as illustrated with cefazolin in Fig. 3. 

Demers, et al [137] described the observation of pretibial edema and sodium retention in lithium treated patients, in the absence of clear evidence of renal, hepatic or cardiac disease. The mechanism for such fluid retention remains unclear, but two plausible mechanisms have been suggested an excessive sodium intake, perhaps related to the manic phase and a lithium-induced reduction in maximum sodium excretory capacity which tends to be negligible when sodium intake is normal. Such patients manifested varying degrees of edema, combined with significantly increased urinary sodium > 200 mEqs/ day. Furthermore, due to increased urinary excretion of lithium, actual serum lithium levels may fall below therapeutic ranges, thereby leading to precipitation of manic crises. As volume expands, there is decreased reabsorption of sodium in the proximal tubules similarly, since hthium is reabsorbed via the same channels and transporters as sodium, lithium reabsorption also decreases [11]. 

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). 

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. 

Probenecid is a uricosuric agent that blocks the tubular reabsorption of uric acid, increasing its excretion. Because of its mechanism of action, probenecid is contraindicated in patients with a history of uric acid stones or nephropathy. Probenecid loses its effectiveness as renal function declines and should be avoided when the creatinine clearance is 50 mL/minute or less. Its uricosuric effect is counteracted by low aspirin doses, which many patients receive for prophylaxis of coronary heart disease. 

This mixed disorder often occurs in patients with chronic obstructive pulmonary disease and chronic respiratory acidosis who are treated with salt restriction, dinretics, and possibly glncocorticoids. When diuretics are initiated, the plasma bicarbonate may increase because of increased renal bicarbonate generation and reabsorption, providing mechanisms for both generating and maintaining metabolic alkalosis. The elevated pH diminishes respiratory drive and may therefore worsen the respiratory acidosis. 

A number of processes occur in the kidney which affect the rate of drug excretion. The most important processes are glomerular filtration, tubular secretion and tubular reabsorption. These processes are compared in Table 1.3. Drug excretion mechanisms are vulnerable to renal insults such as toxins, other drugs, or disease states. Because drugs, metabolites and toxins are concentrated in the kidney, the organ is frequently the site of chemical-induced toxicity. Undesirable symptoms in a patient with renal failure may be due to drug accumulation rather than the disease process itself. 

The amount of salt excreted by the kidney is dependent on the amount ingested in the absence of significant sweating. When the diet is very low in salt, almost no sodium or chloride is excreted, owing to the efficient regulatory mechanism controlling reabsorption by the renal tubules. This activity is controlled in part by adrenal cortical hormones. In adrenal insufficiency, large amounts of salt are lost in the urine many of the features of Addison s disease are attributable to salt depletion. In hyperfunction of the adrenal cortex, salt is retained and there is an associated retention of water. 

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