Lithogenic risk factors for renal stones in patients with Crohn's disease.

OBJECTIVES: Calcium oxalate kidney stones are more common in patients with Crohn's disease (CD). The aims of this study were to verify the prevalence of the main risk factors for calcium oxalate nephrolithiasis in patients with CD and to evaluate the degree of urinary relative supersaturation for calcium oxalate (CaOx), dihydrogen uric acid (DHUA) and monohydrogen calcium phosphate (MHCaP). SUBJECTS AND STUDY PROTOCOL: 42 patients with CD (22 male and 20 female, aged 15-72 years) and 18 controls (8 male and 10 female, aged 26-65) were studied. Nine patients were evaluated during an active episode and 33 in a quiescent phase. All patients had normal glomerular filtration rate. All subjects collected a 24-hr urine sample and fasting venous blood was drawn. Good compliance of urine collection was assessed by the Cockcroft and Gault formula. In urine pH and oxalate (Ox), calcium (Ca), phosphate (P), uric acid (UA), citrate (Cit), magnesium (Mg), sulphate (Sulph), sodium, potassium and chloride concentrations were measured and their excretions calculated. Urinary RS index was obtained using the software EQUIL93. RESULTS: A decreased urinary volume (61.9%) was the most frequent finding. A decreased excretion of Cit, Mg and Sulph (38.1%, 31.0% and 31.0%, respectively) and increased excretion of P, Ox, UA and Ca (33.3%, 23.8%, 16.7% and 14.3%, respectively) were found. Thirty four patients (81.0%) showed at least 2 lithogenic risk factors and only 2 patients showed none. Urine of patients had a higher urinary CaOx and DHUA relative super saturation. Patients studied in an active episode showed a higher urinary CaOx and MHCaP RS than those studied in the quiescent period. CONCLUSIONS: The majority of patients with CD have a multifactorial high risk for calcium oxalate and a single patient usually has several metabolic disturbances which are more evident in an active episode.

[Biochemical, enzymatic and genetic study of hypoxanthine guanine phosphoribosyl transferase (HPRT) deficiency]. / Estudio bioquímico, enzimático y genético de la deficiencia de hipoxantina guanina fosforribosiltransferasa (HPRT).

OBJECTIVE: The objective of this study was to analyze the diagnosis of HPRT deficiency, perform a thorough purine metabolism study and to establish the carrier and prenatal diagnosis in 16 HPRT deficient families. PATIENTS AND METHODS: Plasma and urinary concentrations of uric acid, creatinine and oxypurines, APRT and HPRT activities in hemolysates and HPRT in intact erythrocytes and adenine 8-C14 urinary excretion were analyzed. Carrier diagnosis was made by hair root enzyme analysis and genetic studies. RESULTS: These studies allowed the diagnosis of HPRT deficiency in 20 patients. Carrier diagnosis could be performed in 23 women at risk and in a 9 week old female fetus. CONCLUSIONS: The study results suggest that HPRT deficiency accounts for increased purine nucleotide degradation. This increase results in elevated urinary and plasma concentrations of hypoxanthine, xanthine and uric acid. The clinical severity of the disease is not related to the degree of urinary or plasma concentrations of oxypurines. Hair root analysis generally allows the diagnosis of carrier status, but the carrier state cannot be fully excluded in women at risk. When the familial mutation causing the defect in HPRT is known, analysis of the differences in the restriction pattern of the HPRT gene (natural or due to directed mutagenesis) allow a rapid and reliable diagnosis of carrier status and HPRT deficiency.

[Physiopathology of neurological signs of hypoxanthine-guanine phosphoribosyltransferase deficiency]. / Fisiopatología de las manifestaciones neurológicas en la deficiencia de hipoxantina-guanina fosforribosiltransferasa.

OBJECTIVE: Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is characterized by an increase in renal uric acid excretion, usually with hyperuricemia and may be associated with more or less important neurological symptoms. Based on a series of 20 patients from 16 Spanish families we propose that HPRT deficiency could be clinically classified in four different groups. In the more severe form (classic Lesch-Nyhan syndrome) HPRT deficiency is characterized by choreoathetosis, spasticity, mental retardation and compulsive self-mutilation behavior. The pathophysiology of the neurological symptoms remains unclear and there is no effective therapy. This review is intended to provide a research strategy for a better knowledge of the neurological pathophysiology of HPRT deficiency. DEVELOPMENT: We have analyzed the knowledge on the neurological symptoms of HPRT deficiency. This knowledge comes from histopathological studies of the brains from Lesch-Nyhan patients, chemical studies of the cerebrospinal fluid, experimental animal models (pharmacologic and lesioning and genetic approaches), and human in vivo studies with positron-emission tomography. CONCLUSIONS: The observed findings suggest that the neurological symptoms of Lesch-Nyhan syndrome could be related with the neonatal neuronal and/or dopaminergic terminations damage. This damage could be due to lost or reorganization of dopaminergic system, and is associated with a reduced dopamine levels and with hypersensitivity of the D1 subclass dopamine receptors.

[The genetic diagnosis of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency. A study of 12 cases]. / Diagnóstico genético de la deficiencia de hipoxantina-guanina fosforribosiltransferasa (HGPRT). Estudio de 12 casos.

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency is transmitted as an X-linked recessive trait. Female carriers are asymptomatic and the carrier diagnosis is usually performed by determining HGPRT activity in hair roots. This technique does not allow a non-carrier state diagnosis with absolute certainty and has other limitations such as obtaining non-viable hair roots. The knowledge of the genetic mutation in three Spanish families with HGPRT deficiency, enabled us to perform the genetic diagnosis of the carrier state in 10 female subjects at risk and one female fetus. The genetic diagnosis has been performed by analyzing the differences between the mutant and the normal allele with respect to the restriction pattern. When the restriction pattern showed no differences, this has been created by directed mutagenesis. With this methodology we confirmed that a newborn of a known carrier female of HGPRT deficiency was healthy. In all cases the diagnosis could be established with great fiability in a mean time of 24 to 48 hours. We report the first genetic diagnosis of the carrier state for the HGPRT deficiency performed in Spain.

[Hyperoxaluria and renal calculi]. / Hiperoxaluria y litiasis renal.

Urolithiasis is one of the most frequent causes of morbidity in developed countries and its incidence is close to 5%. In our experience, 67.4% of urinary stones contain calcium oxalate as the main component, and hyperoxaluria plays an important role in the pathophysiology of this type of stone. The mechanisms responsible for the increment in urinary excretion of oxalate could involve oxalic acid synthesis. This increase could be due either to an increment of its endogenous formation or to an exogenous load of its precursors. Furthermore, an increased intestinal oxalate absorption is a frequent cause of hyperoxaluria and urolithiasis. Ingestion of oxalate rich foods, imbalance in the supply of other nutrients that influence oxalic acid absorption and GI disorders with malabsorption and/or decreased degradation of intraluminal oxalate can increase intestinal oxalate transport and cause hyperoxaluria. In this article we review the physiological mechanisms that control the oxalate pool: endogenous synthesis, exogenous supply, intestinal absorption and renal excretion of oxalic acid. We analyze the causes and the pathophysiological mechanisms that increase urinary oxalate excretion. We describe a protocol for the biochemical study of patients with hyperoxaluria and the therapeutic measures to reduce urinary oxalate are reviewed. Finally, possible research that may provide further insight into oxalate metabolism in patients with hyperoxaluria are discussed.

[Incidence of the different types of hypercalciuria in Spain]. / Incidencia de los diferentes tipos de hipercalciuria en España.

OBJECTIVE: To carry out a comparative biochemical study of primary hyperparathyroidism, the different types of hypercalciuria and a healthy population. METHODS: Fourteen patients with primary hyperparathyroidism and 103 patients with idiopathic hypercalciuria were studied under conditions of restricted calcium intake and following a calcium load; the results were compared to those of 18 healthy controls. RESULTS: The patients with hyperparathyroidism showed high parathormone concentrations. Sixty-nine patients with idiopathic hypercalciuria had normal parathormone levels and were considered suffering from absorptive hypercalciuria. Those patients with high urinary calcium excretion under restricted calcium intake and normal urinary phosphate threshold were considered as being absorptive hypercalciuria type I, those with normal urinary calcium as absorptive hypercalciuria type II, and those with low urinary phosphate threshold constituted a renal phosphate leakage group. Thirty-four patients had normal serum calcium, elevated parathormone, hypophosphatemia and high calcium excretion under all dietary conditions, and were considered undergoing renal hypercalciuria. Patients with renal hypercalciuria had increased urine hydroxyproline and low serum calcium compared with the controls after an oral calcium load. This biochemical behaviour is compatible with secondary hyperparathyroidism caused by renal calcium leakage. CONCLUSIONS: In summary, the biochemical parameters: parathormone, urinary phosphate threshold and urinary calcium excretion, measured in fasting conditions, allowed classification of patients with idiopathic hypercalciuria.

[Physiopathology and treatment of acute gouty arthritis]. / Fisiopatología y tratamiento de la artritis gotosa aguda.

Severe gouty arthritis is a clinical expression of a very intense inflammatory process. The initial pathogenic event which sets off the chain process is the intraarticular deposit of monosodium urate crystals. However, urate crystals do not always promote an inflammatory process (e.g., dormant tophus), and only a minority of patients with hyperuricemia develop gout. The therapeutic bases for gout should be based on the knowledge surrounding the physiopathology of the inflammatory process. In this study, we present the physiopathology of severe gouty arthritis in order to improve understanding of its treatment.

[Physiopathology and treatment of metabolic changes in transintestinal urinary diversions]. / Fisiopatología y tratamiento de las alteraciones metabólicas en las derivaciones urinarias transintestinales.

The use of intestinal segments in the urinary tract can cause metabolic changes that depend on the intestinal segment utilized. The severity of these changes basically depends on the area of the intestinal mucosa in contact with urine, the duration of exposure to urine and renal function. The length of time the intestinal mucosa is in contact with urine largely depends on the surgical technique employed. It is longer for the reservoirs, intestinal neobladders and ureterosigmoidostomies than for the intestinal conduits with cutaneous urinary diversion and therefore carry a higher incidence of metabolic changes. Jejunal urinary diversion causes metabolic acidosis with hypochloremia, hyponatremia, hyperpotassemia, azotemia and dehydration in at least 50% of the cases. Ileal and colonic urinary diversion can cause metabolic acidosis, although the incidence is significantly less. Acidosis presents with hyperchloremia, hyperammonemia, hypersulfatemia, increased osmolality and uremia with normal creatininemia and a tendency to develop hypocalcemia, hypophosphoremia and hypomagnesemia. Recent studies performed in our service show that acidosis is basically due to the secretion of sodium bicarbonate by the intestinal segment used in the urinary tract, which causes water-salt depletion that is compensated by secondary hyperaldosteronism. Mild chronic acidosis is neutralized via the respiratory system and by the bone buffers, which leads to bone remodelling manifested by the significant increase of serum alkaline phosphatase levels and increased calciuria. These calcium phosphate changes, although statistically significant, do not appear to be important since they were not accompanied by changes of serum PTH levels, 25 and 1-25-cholecalciferol. Nicotinic acid as inhibitor of cyclic AMP synthesis failed to correct metabolic acidosis in the patients with transileal diversion.

[Prenatal diagnosis of Lesch-Nyhan syndrome]. / Diagnóstico prenatal del síndrome de Lesch-Nyhan.

A pregnant woman with Lesch-Nyhan's syndrome (hypoxanthine-guanine-phosphoribosyltransferase, or HGPRT deficiency) requested antenatal diagnosis. HGPRT and adenine phosphoribosyltransferase (APRT) activities were measured in fetal erythrocytes by funiculocentesis in the 21st gestational week. HGPRT activity was lower than 0.01 mmol/h/Hb g (normal value 87.0 +/- 16.05 mmol/h/Hb g). APRT activity was increased (44.0 mmol/h/Hb g) as compared with that from 50 normal individuals (28.1 +/- 6.9 mmol/h/Hb g). Pregnancy was interrupted and the antenatal diagnosis of Lesch-Nyhan's syndrome was confirmed after delivery. In the 20th gestational week, amniotic fluid showed a marked increase if oxypurines (hypoxanthine, xanthine and uric acid) as compared with the values in 14 amniotic fluids from normal pregnancies and gestational age within 15-22 weeks. The present study illustrates the possibility to make the antenatal diagnosis of Lesch-Nyhan's syndrome by funiculocentesis . The previously unreported finding of a marked abnormality of oxypurine concentration in amniotic fluid represents a new outlook for the diagnosis of enzymatic defects of synthesis and degradation of purine nucleotides.

[Metabolism of purine nucleotides in the central nervous system in patients with phosphoribosylpyrophosphate synthetase hyperactivity and neurosensory deafness]. / Metabolismo de nucleótidos purínicos en el sistema nervioso central de pacientes con sobreactividad de fosforribosilpirofosfato (PRPP) sintetasa y sordera neurosensorial.

The overactivity of PRPP synthetase is transmitted as a sex-linked abnormality, being characterized by uric acid overproduction and, in some patients, by muscular hypotonia, neurosensitive deafness and/or ataxia. The pathogenesis of these neurologic abnormalities is not yet known. The CSF concentrations of end products of the neuronal metabolism of purines--hypoxanthine for the adenine nucleotides and xanthine for guanine nucleotides--have not been previously studied in patients with overactivity of PRPP synthetase. We have evaluated the plasma and CSF levels of hypoxanthine and xanthine in a 8-year-old male with tophaceous gout and neurosensitive deafness and in his mother, who had gout without neurological involvement. PRPP synthetase overactivity was demonstrated in fibroblast culture; the male was hemizygote and his mother was heterozygotic. In 4 normal individuals, the plasma levels of hypoxanthine and xanthine were 1.7 +/- 0.4 microM and 0.9 +/- 0.2 microM (mean +/- SEM), respectively, while in in CSF they were 3.3 +/- 1.1 microM and 2.0 +/- 0.2 microM. The hemizygote male showed a considerable increase in hypoxanthine level (5.6 microM in plasma and 22.1 microM in CSF); the plasma and CSF xanthine levels were 1.8 and 4.5 microM, respectively. The heterozygotic female showed moderately increased plasma hypoxanthine levels (3.9 and 10.6 microM) and normal xanthine levels (1.3 and 1.8 microM). These results suggest an increase in the degradation of purine nucleotides in the central nervous system of patients with PRPP synthetase overactivity and neurological symptoms. The predominance of hypoxanthine over xanthine may indicate a greater increase of the degradation of adenine rather than guanine nucleotides.

[Plasma hypoxanthine and intraerythrocytic ATP in umbilical cord blood as markers of perinatal hypoxia]. / La hipoxantina plasmática y el ATP intraeritrocitario en sangre de cordón umbilical como marcadores de hipoxia perinatal.

We determined blood pH, plasma hypoxanthine (Hx) and intraerythrocyte ATP (iATP) concentrations in umbilical cord blood from 20 normal newborn infants (10 delivered by the vaginal route and 10 by caesarean section) and in 18 newborns with clinical signs of perinatal asphyxia (9 with meconium stained amniotic fluid and 9 with fetal bradycardia). Blood pH was significantly lower in infants with clinical signs of perinatal asphyxia (p less than 0.01). Four newborns with meconium or bradycardia had pH values within normal control levels. Hx concentrations were lower in infants delivered by caesarean section with respect to normal infants born by the vaginal route (p less than 0.05). Newborns with meconium or fetal bradycardia showed Hx concentrations higher than normal newborns (p less than 0.01), but 2 infants with signs of perinatal hypoxia had Hx levels within the normal newborn range. All babies with meconium or bradycardia had an iATP concentration lower than control infants (p less than 0.01). These results indicate that: the pH and Hx determinations in the newborn may underestimate hypoxia and, that measurement of iATP may be useful parameters to asses perinatal hypoxia.

[Degradation of purine nucleotides in patients with chronic obstruction to airflow]. / Degradación de los nucleótidos purínicos en pacientes con obstrucción crónica al flujo aéreo.

The increase in hypoxanthine (Hx), xanthine (X), uric acid (VA) and total purines (TP) that may be found in several clinical conditions associated with tissue hypoxia has been attributed to an increase in adenine nucleotides degradation by a reduced ATP synthesis caused by oxygen deprivation. To test this hypothesis we have investigated the urinary excretion of Hx, X, VA, TP and radioactivity elimination after labeling the adenine nucleotides with adenine (8-14C) in 5 patients with chronic airflow obstruction (CAFO), in the basal state and after oxygen therapy (FiO2, 24%). The results were compared with those from 4 normal individuals. Patients with COFA showed an increase of the renal elimination of Hx, X, VA, TP and radioactivity, which was significantly different from the control group (p less than 0.05). Oxygen administration was associated with a significant reduction in the excretion of purines and radioactivity (p less than 0.01), which decreased to values similar to those found in normal individuals. These findings suggest that in patients with COFA and severe hypoxemia there is a marked increase in the degradation of adenine nucleotides. The normalization of the purine and radioactivity excretion after oxygen therapy points to a basic role of oxygen in the catabolism of adenine nucleotides.

[Purine transport through the blood-brain barrier in hypoxanthine phosphoribosyltransferase deficiency]. / Transporte de purinas a través de la barrera hematoencefálica en la deficiencia de hipoxantina fosforribosiltransferasa.

The transfer of purines through the hematoencephalic barrier is poorly understood. Allopurinol inhibits the enzyme xanthine oxidase and increases xanthine and hypoxanthine plasma levels, but it should not increase the cerebrospinal fluid (CSF) levels of these purines owing to the absence of xanthine oxidase in the central nervous system (CNS). In the present study we evaluated the plasma and CSF concentrations of uric acid, hypoxanthine, xanthine and inosine in the baseline state and after 7 days of allopurinol administration (5-10 mg/kg/24 h) in 4 patients with hypoxanthine phosphoribosyltransferase (HPRT) deficiency. The CSF uric acid level was positively correlated with its plasma level (r = 0.93, p less than 0.01). The CSF hypoxanthine and xanthine concentrations were, as a mean, 5 and 2 times higher, respectively, in patients with HPRT deficiency than in 4 control individuals. As hypoxanthine basically comes from adenine nucleotides, while xanthine comes from guanine nucleotides, this finding suggests that in the CNS of patients with HPRT deficiency there is a higher degradation level of adenine nucleotides than of guanine nucleotides. Allopurinol increased plasma concentration of hypoxanthine, xanthine and inosine 4, 10 and 3 times, respectively, in relation to baseline values. In CSF, the mean increase of hypoxanthine and xanthine concentration was 17.5 mumol and 7.7 mumol, respectively, whereas inosine level was unchanged. These results suggest that in HPRT deficiency hypoxanthine and xanthine may be transferred to the brain.