Uric Acid Nephropathy Research Articles

Acute Uric Acid Nephropathy

Uric acid, as the end-product of purine metabolism in humans, presents a clinical problem because of its relative insolubility, particularly in the acid environment of the distal nephron of the kidney. As a result, states of enhanced purine catabolism increase the urate load on the kidney, leading to intrarenal precipitation. Major causes of increased purine metabolism are malignancies with rapid cell turnover, such as leukemias and lymphomas, and the added acceleration of cell lysis that occurs with chemotherapy and radiation. Serum urate levels rise rapidly, and acute renal failure occurs as a consequence of tubular deposition of urate and uric acid. The keys to the diagnosis of acute uric acid nephropathy are the appropriate clinical setting of increased cell lysis, oliguria, marked hyperuricemia, and hyperuricosuria. A urinary uric acid-to-creatinine ratio greater than 1 helps to distinguish acute uric acid nephropathy from other catabolic forms of acute renal failure in which serum urate is elevated. Preventive treatment involves pharmacologic xanthine oxidase inhibition with allopurinol and alkaline diuresis. Occasionally, acute renal failure occurs despite allopurinol because of the tubular precipitation of the precursor metabolites, such as xanthine, which accumulate with xanthine oxidase inhibition. Dialysis therapy may be required both to correct azotemia and to reduce the body burden of urate. Hemodialysis is preferred because it can achieve greater clearance than other dialysis modes.

Acute Urate Nephropathy Due to Partial Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency

Acute Urate Nephropathy Due to Partial Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency

Reaction of MDCK cells to crystals of monosodium urate monohydrate and uric acid

Madin-Darby canine kidney (MDCK) cells exhibit many of the characteristics of cells of the cortical collecting tubule. Since hypotheses concerning the development of gouty and uric acid nephropathy involve a reaction between such cells and crystals, either of monosodium urate monohydrate (MSUM) or uric acid, the reaction between MDCK cells in culture and the above crystals was studied, both morphologically and functionally. In monolayer cultures, reaction sites developed within four hours of exposure to urate crystals. These increased in number for up to 72 hours and subsided gradually after removal of the crystals. At these reaction sites, crystals were observed to have passed beneath the cell surface and could be demonstrated both within intra-cellular lysosomes as well as within the inter-cellular spaces. When the MDCK cells were maintained as single cells in suspension, phagocytosis of crystals by the majority of the cells could be observed, but the response was much more rapid than in monolayers. During the cell/crystal reaction, significant amounts of lysosomal enzymes and prostaglandin E2 were released and, to a less significant degree, cytosolic enzymes, presumably due to cell lysis. This enzyme release did not occur in MDCK cells grown in protein-free medium, and protein coating of the crystals was necessary for reactivity with cells. In this regard, coating with IgG or lysozyme was more effective than albumin. The reaction with uric acid crystals revealed a reactivity which was lesser in degree but qualitatively similar to that of urate crystals.(ABSTRACT TRUNCATED AT 250 WORDS)

A model of gout nephropathy.

It is generally accepted that many factors, such as hypertension, vascular disease, renal calculi and infection, may contribute to renal disease in patients with gout. However, these are usually regarded as secondary phenomena which are often superimposed on a primary nephropathy. Most studies of the gouty kidney, however, have found evidence of a primary nephropathy with deposits of urate and uric acid crystals (1, 2, 3); Talbott and Terplan (4), in a study of almost two hundred kidneys, concluded that “the only distinct pathological feature of the gouty kidney is the presence of urate crystals”. Crystallographic studies indicated that these crystals were either acicular crystals of monosodium urate monohydrate (urate or MSUM) or deposits of uric acid (UA) (5). Subsequent studies of urinary urate over-excretion, either following chemotherapy of malignancy (6) or due to HPRT deficiency (7, 8), have established the importance of intratubular uric acid deposition in the development of an acute uric acid nephropathy. Interstitial micro-tophi containing urate crystals have also been demonstrated in gouty kidneys and there is suggestive evidence that these might develop not only due to local formation, but also by the passage of uric acid crystals through the lining epithelium of the distal nephron into the interstitial tissues. This has been demonstrated with other crystals in animals (9). Indeed, urate crystals have been demonstrated by electron microscopy within the tubular lining cells of patients with leukemia (10). Thus, there is support for the hypothesis that, at least in some cases, renal damage from uric acid begins by a reaction between intraluminal uric acid crystals and tubular lining cells of the distal nephron. For this reason, a study was planned of the reaction between cultured renal tubular cells and crystals of urate and uric acid.

2 URATE NEPHROPATHY: A RARE BUT NOT VANISHED ENTITY

Chronic urate nephropathy in the past decades was a frequent cause of renal failure in gouty patients but this entity has become very rare in the recent years and in many centers of hemodialysis the registries of chronic renal failure populations do not list gouty nephropathy as a cause. Some authors even discuss the existence of gouty nephropathy (1). In our series of 140 patients with primary gout (128 M, 12 F) including 20 patinets with late onset (over 65 years) of the disease (15 M, 5 F) we never observed renal insufficiency with serum creatinine over 1.5 mg/dl; but the urate nephropathy exist also as a rare familial form, inherited in a autosomal dominant manner and, more rarely, as an idiopathic form, without clinical evidence of gouty arthritis. Recently we observed an idiopathic form of this disease in a male patient, 51 years old, who presented a middle renal insufficiency (serum creatinine over 2.0 mg/dl and albuminuria). Ultrasonic kidney study and C.A.T. have shown numerous microcysts in the cortical of the kidney, but only the needle biopsy has confirmed the urate nature of the interstitial chronic nephropathy. 1- L.H. Beck Kidney Int. 30 (1986) 280-286.

Suprofen-Induced Uricosuria

Suprofen, a nonsteroidal anti-inflammatory drug, has been associated with the onset of acute flank pain, hematuria, and transient renal dysfunction after the ingestion of one or two doses, particularly in young males. Potential mechanisms of this nephropathy were evaluated in normal males following ingestion of suprofen (200 mg) on two occasions: the first with ad libitum fluid intake and the second during forced water diuresis. On the first study occasion, creatinine clearance, the fractional excretions of uric acid (FEUA) and sodium (FENa), the urinary concentration of undissociated uric acid, and the urinary excretions of prostaglandins and glomerular and tubular proteins were assessed. On the second occasion, inulin and PAH clearances and FEUA and FENa were determined. Within 90 min after suprofen administration, the FEUA increased from 8.8 +/- 2.6 to 35.5 +/- 9.6% (p less than 0.05). Urine became supersaturated for uric acid during ad libitum fluid intake. Glomerular filtration rate, renal plasma flow, and FENa decreased significantly, while prostaglandin and protein excretions did not change. The findings are consistent with acute uric acid nephropathy as a mechanism of suprofen-induced renal dysfunction.

Uric acid nephrolithiasis and acute renal failure secondary to streptozotocin nephrotoxicity

Uric acid nephrolithiasis developed in a 75-year-old man who had received a large cumulative dose of streptozotocin for treatment of metastatic islet cell carcinoma of the pancreas. Oligoanuric renal failure mediated by massive intraureteral uric acid deposits occurred despite normal serum concentrations of uric acid. This case implicates the uricosuric effects of streptozotocin in the pathogenesis of uric acid nephropathy and suggests that renal uric acid excretion should be monitored routinely in patients receiving large cumulative doses of this drug.

Renal disease from excess uric acid.

Excess uric acid or urate deposition is a common element in three different forms of renal disease: acute uric acid nephropathy, chronic urate nephropathy, and uric acid nephrolithiasis. Clinical features vary with each form. Therapy is directed at decreasing production of uric acid, increasing its solubility, or both. When possible, preventive measures are taken.

Hyperuricemia and Uric Acid Nephropathy

DOUGLAS D. Dykman, MD, Senior Assistant Resident in Medicine, the Jewish Hospital of St Louis: A 76-year-old woman presented with fever and mental status changes. Her medical history was notable for hypertension, diabetes, atherosclerotic peripheral vascular disease, and polymyalgia rheumatica. She had been admitted to the Jewish Hospital three weeks previously for incision and drainage of a sterile hematoma of the right foot. At that time, a uric acid level of 870 μmol/L (14.6 mg/dL) was noted. There was no prior history of gout or renal stones; her serum creatinine level was 150 μmol/L (1.7 mg/dL). Allopurinol therapy was initiated at the time of discharge at a dose of 300 mg/d. She did well until two days prior to admission, when she developed weakness, nausea, vomiting, and low-back pain. Her family also noted a progressively increasing lethargy and confusion and brought her to the emergency room. Her medical history was

Hyperuricemia and uric acid nephropathy

Hyperuricemia and uric acid nephropathy

Nonsteroidal Anti-Inflammatory Drugs as Risk Factor for Renal Failure from Acute Uric Acid Nephropathy

Nonsteroidal Anti-Inflammatory Drugs as Risk Factor for Renal Failure from Acute Uric Acid Nephropathy

Allopurinol in renal failure and the tumour lysis syndrome

This paper illustrates several important points relating to the use of allopurinol in renal failure, or situations of purine overproduction: 1. It is very easy to give too much allopurinol. 2. Most of the side effects (bone marrow depression, exfoliative dermatitis, etc) are the result of overdosage due to the retention of oxipurinol, an effect exaggerated by thiazide diuretics. 3. Monitoring of plasma oxipurinol levels (ideally < 100 μmol/l) by high-pressure liquid chromatography is helpful for adjusting dosage in renal failure. 4. Some estimate of the anticipated purine excess is equally vital in deciding dosage during tumour lysis if the risk of urate nephropathy is not to be substituted for the certainty of xanthine nephropathy. In this situation the use of allopurinol may even be questioned. 5. Patients with HGPRT deficiency are exquisitely sensitive to allopurinol, and careful monitoring of the effect on urinary purine levels is essential if xanthine colic is to be avoided.

Hyperuricemia and Gout

Gout is a clinical syndrome encompassing a group of metabolic diseases that are all characterized by abnormal uric acid metabolism. In its fullest form, gout is defined by: an increase in the serum urate concentration; characteristic, recurrent, acute arthritic attacks, with monosodium urate monohydrate crystals demonstrable in synovial fluid leukocytes; tophi, usually in and around joints of the extremities, composed of monosodium urate monohydrate deposits; renal disease, often accompanied by hypertension with glomerular, tubular, interstitial, and vascular involvement; and uric acid nephrolithiasis. Any combination of these manifestations may occur, although tophi and urate nephropathy rarely antedate gouty arthritis.

Role of alcohol in clinical nephrology.

Different nephrological derangements are observed in severe alcoholics. Until now the direct toxicity of ethanol is only shown in the fetal alcohol syndrome with various malformations of the genitourinary tract. In the adult the kidney is often involved in the development, maintenance and counterregulation of complex electrolyte disturbances like phosphate and potassium hypoglycemia etc. The alcohol associated retention of urate, induced by hyperlactatemia and/or increased beta-hydroxybutyrate concentration is only rarely complicated by urate nephropathy. Alcohol intoxication (acute and chronic) predisposes to rhabdomyolysis with the risk of acute renal failure. There are some hints that chronic alcoholism with myopathy increases the vulnerability of the kidney for further toxic agents. In rats glycerol induced renal failure is enhanced by alcohol pretreatment. Finally, regular alcohol consumption raises the blood pressure, which per se is a risk factor for renal damage.

Early deaths in acute lymphoblastic leukemia (ALL): results of the Italian Pediatric Cooperative Group for Therapy of Acute Leukemia (AIL-AIEOP).

In this retrospective multicentric study, we report on early deaths (ie, those that occurred during the first month of treatment) in a total of 943 newly diagnosed ALL pediatric patients registered from 1976 to 1981 at 21 centers of the AIL- AIEOP . Objectives of this study were as follows: (1) to verify the incidence and the cause of early death in a wide population of children with ALL and (2) to elucidate factors associated with early death and therefore to identify "high-risk" groups of patients. Out of the 943 ALL patients, 39 (4.1%) early deaths were registered. Main causes were infection, 20 patients (51.3%); hemorrhage, 11 patients (28.3%); uric acid nephropathy, 2 patients (5.1%); cardiac failure, 3 patients (7.6%); syndrome of inappropriate antidiuretic hormone secretion, 1 patient. Two patients died during the first week of unknown cause. Thirteen factors measured at diagnosis and possibly influencing the early death rate were analyzed. Using the chi-square test, only three of these factors (age, mediastinum status, surface markers) appear to have any significant influence on the early death rate. We also tried to determine how therapy influences this process by analyzing variations in the early death rate, other factors being equal. Significant differences in the early death rates were encountered in AIEOP protocols using different induction regimens.

Gout and uric acid nephropathy: some new aspects in diagnosis and treatment.

It has been recognized that primary disorders of uric acid metabolism result from impaired renal excretion or increased endogenous production of uric acid. It has also been found that these two mechanisms do not comprise two distinct syndromes, but may each constitute a group of syndromes. Contrary to earlier as well as currently published reports we conclude from our clinical and experimental experience that the fraction of so-called over-producers is less than 1% of all patients with primary hyperuricaemia and gout. A procedure for the diagnosis of uric acid overproduction is suggested. The manifestation of hyperuricaemia and gout mainly depends on renal uric acid clearance and is greatly influenced by dietary habits in most of the patients. An impaired renal uric acid excretion results in an increased intestinal excretion; this partly compensates for the defect. Normalization of serum uric acid should be achieved by dietary regimens with or without additional drug treatment, but not by drug treatment alone. With drug treatment xanthine oxidase inhibitors are preferable to uricosurics; no other xanthine oxidase inhibitor besides Allopurinol has been in clinical trial, however. Due to the enhancement of uric acid clearance with uricosurics, there are groups of patients who should not be treated with these drugs. Fixed combinations of Allopurinol and uricosurics should not be used. Drugs which have uricosuric as well as other pharmacologic properties are under investigation. So far they have not reached general clinical application.

Renal uric acid clearance in human neonates

Renal clearance of uric acid was examined in 40 premature and term infants during the first 24 hours of life. Creatinine clearance and uric acid clearance increased with increasing gestational age. Serum uric acid concentration (r = -0.31, P less than 0.05) and fractional excretion of uric acid (r = -0.50, P less than 0.01) were inversely related to gestational age; FEUA was nearly 70% at 29 to 31 weeks gestational age, and decreased to a mean value of 39 +/- 14% (+/- SD) at 38 to 40 weeks gestational age. The decline in FEUA with advancing gestational age appears to represent alterations in net renal tubular transport of uric acid, because the filtered load of uric acid increased with gestational age. Postnatal clearance studies were performed in 18 premature infants of 29 to 35 weeks gestational age; FEUA also declined during early postnatal development (r = -0.44, P less than 0.01). In all studies, a relationship between FEUA and fractional excretion of sodium was observed. The high basal excretion of uric acid in infants may increase the risk of acute uric acid nephropathy when excretion demands are increased.

Uric acid nephropathy with phencyclidine abuse

Uric acid nephropathy with phencyclidine abuse

Acute renal insufficiency after change from chlorthalidone to tienilic acid

In an in-hospital study, 3 out of 5 patients with essential hypertension on continuous chlorthalidone treatment developed reversible renal insufficiency when chlorthalidone was replaced by tienilic acid. In a control group of 6 patients, tienilic acid after placebo was not followed by renal insufficiency. Since the urinary uric acid concentration and the uric acid/creatinine ratio was not higher in the patients who developed renal insufficiency than in the control group, the drug interaction probably cannot be explained by uric acid nephropathy.

Management of Asymptomatic Hyperuricemia

Although the incidence of gout, renal stones, or both is increased in patients with hyperuricemia, there is no evidence that long-term therapy offers any substantial long-term benefits. Recent data also suggest that no clear relationship exists between hyperuricemia and the development of interstitial nephritis (so-called urate nephropathy). Finally, the relationship between elevations in the serum concentration of uric acid and the risk of developing cardiovascular disease remains undefined. It is recommended that, in a patient with asymptomatic hyperuricemia, a conservative approach be taken and hypouricemic therapy not be instituted as a matter of routine.