Kidney Uric acid reabsorption

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. 

In most patients with gout, the flow of plasma in the kidney, the glomerular filtration rate, and the renal clearance are normal, and no excess urates are found. Some investigators have claimed that gout is associated with abnormal tubular reabsorption of uric acid (93% in patients with gout versus 91% in normal individuals), leading to an absolute increase in total uric acid reabsorption and an accumulation of uric acid in the blood. 

In 1961 Gutman and Yu proposed a three component system for the regulation of the renal excretion of uric acid in man. The first component of this system is filtration of plasma urate at the glomerulus. While this process is certain to be operative in the human kidney, its quantitative role in the renal excretion of uric acid in man depends upon the extent of urate binding to plasma proteins in vivo. This is a subject that is being discussed in another section of this symposium and will not be considered further in this paper. The second and third component of this system relate to uric acid reabsorption and secretion by the human nephron. Ample data is available to document that both of these processes are operable in the human kidney (Gutman and Yu, 1957 Gutman, et al., 1959), but the relative contribution of each to the final excretion of uric acid has been difficult to determine with conventional clearance techniques. However, a potential solution to this problem of bidirectional uric acid transport appeared in 1967 when Steele and Rieselbach introduced the "pyrazinamide suppression test . 

Pharmacokinetics Allopurinol is approximately 90% absorbed from the Gl tract. Effective xanthine oxidase inhibition is maintained over 24 hours with single daily doses. Allopurinol is cleared essentially by glomerular filtration oxipurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid. 

It increases the excretion of uric acid (by inhibiting its reabsorption from kidney tubules) and hence causes reduced serum levels of uric acid. 

Since the kidneys are the main depot for cadmium, they are of greatest concern for cadmium toxicity. Cadmium interferes with the proximal tubule s reabsorption function. This leads to abnormal actions of uric acid, calcium, and phosphorus. Amino aciduria (amino acids in the urine) and glucosuria (glucose in the urine) result in later stages, proteinuria (protein in the urine) results. When this happens, it is assumed that there is a marked decrease in glomerular filtration. Long-term exposure to cadmium leads to anemia, which may result from cadmium interfering with iron absorption. 

The degradation of purines varies with the species. Actually uric acid is excreted as the principal end product of purine metabolism by very few mammals, of which man is unfortunately one. Most nonuricotelio animals possess the enzyme uricase, which converts uric acid to the much more soluble end product allantoin. Man and certain of the higher apes, as well as fowl and reptiles, do not possess this enzyme, so that they must excrete uric acid as the end product of purine metabolism. Despite the fact that it possesses uricase, as do other dogs, the Dalmatian coach hound is peculiar in that it excretes uric acid. This anomaly results from the absence of tubular reabsorption of uric acid in the kidney (Fll). 

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. 

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... 

Allopurinol Probenecid and sulfinpyrazone Inhibits xanthine oxidase and reduces purine metabolism into uric acid Reduce reabsorption of uric acid in the kidney... 

Probenecid (available on a named-patient basis only) and sulfinpyrazone lower the uric acid level in blood by increasing the amount of uric acid passed in the urine. They do this by competing for the transport mechanism responsible for mbular reabsorption of uric acid in the kidney. 

Another transporter expressed in proximal tubule epithelial cells is URATl. URATl is responsible for the reabsorption of urate in the kidney. Gout, an inflammatory disease, results from elevated body levels of uric acid. It is believed that an inherited deficiency in URATl expression is a causative factor in the disease. Treatment includes administration of uricosuric agents such a probenecid and sulfinpyrazone increase uric acid excretion through inhibition of URATl. 

Uricosuric agents increase the rate of excretion of uric acid. In humans, urate is filtered, secreted, and reabsorbed by the kidneys. Reabsorption predominates, and the amount excreted usually is 10% of that filtered. This process is mediated by a specific transporter, which can be inhibited see Chapter 2). 

EFFECTS ON URINARY EXCRETION Inhibitors of the Na -Cl symporter increase Na and CF excretion, but are only moderately efficacious (i.e., maximum excretion of filtered load of Na+ is only 5%) because -90% of the filtered Na load is reabsorbed before reaching the DCT. Some thiazide diuretics also are weak inhibitors of carbonic anhydrase, an effect that increases HCO and phosphate excretion and probably accounts for their weak proximal tubular effects. Inhibitors of the Na+-Cl symporter increase the excretion of and titratable acid by the same mechanisms discussed for loop diuretics. Acute administration of thiazides increases the excretion of uric acid, but uric acid excretion is reduced following chronic administration by the same mechanisms as for loop diuretics. Acute effects of inhibitors of the Na+-Cl symporter on Ca + excretion are variable when administered chronically, thiazide diuretics decrease Ca + excretion. The mechanism involves increased proximal reabsorption owing to volume depletion, as well as direct effects of thiazides to increase Ca + reabsorption in the DCT. Thiazide diuretics may cause a nfild mag-nesuria by a poorly understood mechanism. Since inhibitors of Na+-Q symport inhibit transport in the cortical diluting segment, thiazide diuretics attenuate the abdity of the kidney to excrete a... 

Effects Uricosuric drugs act primarily in the kidney and inhibit the secretion of a large number of other weak acids (eg, penicillin, methotrexate) in addition to inhibiting the reabsorption of uric acid. 

Not fully understood. Sulfinpyrazone competes successfully with salicylate for seeretion by the kidney tubules so that salicylate excretion is re-dueed, but the salieylate bloeks the inhibitory effect of sulfinpyrazone on the tubular reabsorption of urie aeid eausing the uric acid to accumulate within the body. ... 

This phenomenon is believed to be due to excretion by the kidneys of the uric acid passing in the plasma from extrahepatic tissues to the liver where uricase is located. Uric acid is completely filtered at the glomerulus and both actively reabsorbed and actively secreted in the proximal tubule (39, 40). In the dalmatian the reabsorptive process is deficient, and active secretion leads to the urinary excretion of uric acid. 

Blood uric acid is unbound to proteins, and its concentration in other body fluids is the same as in serum. Uric acid filters freely through the glomeruli but is quite efficiently reabsorbed (90%) through the tubules. Thus, kidney diseases responsible for interference with glomerular filtration are associated with increased blood levels of uric acid, whereas those diseases causing defective tubular reabsorption (Wilson s disease and Fanconi s disease) are sometimes responsible for low levels of uric acid in blood. It seems safe to assume, with Wyngaarden, that uric acid appears in the urine as a result of active tubular secretion. 

Serum uric acid concentration in man is the result of complex biosynthetic, catabolic, and excretory processes. Recent investigations of the urate transport system in the human kidney have provided evidence for a four-component model glomerular filtration, presecretory reabsorption, tubular secretion, and postsecretory reabsorption. ... 

Since there was no data available in 1967 which conflicted with these assumptions, the "pyrazinamide suppression test" appeared to be a useful clinical tool for quantitating uric acid secretion and reabsorption in man. However, recent studies of pyrazinamide and uric acid handling by the kidney provide data that have led us to question all three of the assumptions underlying the "pyrazinamide suppression test" (Holmes, Wyngaarden, and Kelley, 1972). Therefore, we would like to consider each assumption and the data relevant to it. 

The functional interrelationships of reabsorption of the various glomerular solutes are becoming increasingly apparent (i ). It is probable that these factors are important aw well as the morphological immaturities in the newborn kidney to explain their increased uric acid excretion. 

Most of the low molecular substances that are flushed into the primary urine during ultrafiltration are reabsorbed to a large extent. This is true even for such typical excretion products as urea and uric acid, but especially for free amino acids and glucose, which are reabsorbed completely so long as the blood sugar level stays normal. If the level exceeds 0.16%, some of the sugar is excreted in the urine. Reabsorption is active transport (Chapt. XXI-3) and the enzymic apparatus of active transport can no longer cope with the amounts delivered by the blood. Similar conditions prevail for other substances the capacity for reabsorption (formerly called kidney threshold ) differs widely for various substances. 

The kidney is also sensitive to lead exposure, with kidney failure resulting from long-term exposure to toxic levels of lead. Furthermore, toxic levels of lead inhibit other functions of the kidney aside from the primary function of urine production. The nephron of a kidney, which is that portion where blood filtering and urine production takes place, is sensitive to lead. It is well known that the active form of vitamin is produced in the proximal tubules of the nephron. Decreased levels of vitamin D3 in the body results in decreased calcium absorption by the gut, and ultimately affect the strength of bones in a lead-exposed body. Increased levels of lead in blood can lead to protein-lead complexes in the nephron tubules. Gout may be a symptom of such toxicity due to increased reabsorption of uric acid into the bloodstream. Typical measures of renal failure (e.g., blood urea nitrogen, creatine) are elevated as a consequence of lead-induced renal failure. 

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