The tale of parathyroid function in idiopathic hypercalciuria

At the origin, idiopathic hypercalciuria has been described as a syndrome consisting of normocalcemia, low plasma phosphate levels and abnormally high urinary calcium excretion. The cause of this syndrome was subject to many investigations throughout the years. Two main pathophysiologic hypotheses have been proposed: a) primary intestinal hyperabsorption of calcium, leading to depression of parathyroid hormone (PTH) secretion ("absorptive" hypercalciuria); and b) primary renal tubular leak of calcium which stimulates PTH secretion (secondary hyperparathyroidism). Most of the published studies indicate that intestinal hyperabsorption of calcium with subsequent relative hypoparathyroidism is the primary event causing idiopathic hypercalciuria, and that this occurs as a consequence of increased production of 1,25(OH)2-vitamin D3 (calcitriol). Fasting hypercalciuria, originally taken as evidence for a "renal leak" of calcium, appears to be, at least in part, the consequence of relative hypoparathyroidism.     

Idiopathic hypercalciuria in childhood

This review describes the supposed mechanisms leading to idiopathic hypercalciuria (IHU) in childhood, further the diagnostic criteria and the proposed treatment modalities are discussed. IHU is not only one of the main causes of renal stone disease in children but it's also at the origin of the postglomerular haematuria and the frequency-dysuria syndrome. Its role in the development of osteoporosis in adults is also documented. The diagnosis of raised calcium excretion is based on age specific values during early infancy. In older children and adults a urinary calcium/creatinine ratio exceeding 0.6 mmol/mmol is regarded as elevated. Dietary calcium restriction can no longer be recommended for the treatment of IHU because it results in secondary hyperoxaluria and on the long-term causes decreased bone mineral density. Patients should be kept on dietary sodium restriction and high fluid intake. In cases IHU associated with recurrent episodes of macroscopic haematuria or recurrent stone disease a therapeutic trial with hydrochlorothiazide in the dose of 0.5-1 mg/kg/day with potassium-citrate supplementation and possibly magnesium citrate should be started. In some special forms of hypercalciuria such as the X-linked recessive nephrolithiasis syndrome or Bartter syndrome the localization and in some cases even the molecular mechanism of the events leading to increased calcium excretion are elucidated. In IHU enhanced Ca(++)-ATPase, and Na-Li countertransport activity and decreased Na+/K+ ATPase activity were described in the erythrocyte membrane model. It is expected that with the molecular genetic development the clinical classification of the hypercalciuric syndromes will become a rational genome-based one.     

Oxalate: its role in lithogenesis and composition of calcium oxalate lithiasis

A prospective study was conducted on 374 patients with urinary lithiasis, aiming to analyze the participation of oxalate in the lithogenesis and composition of the calcium oxalate calculi, alone or associated to other factors. METHODOLOGY: Metabolic urinary study of the patient and analysis of calculi with infrared spectrography and optical microscopy. RESULTS: 26.3% patients had hyperoxaluria and 77.5% of the calculi contain calcium oxalate; these are 167 cases of calcium oxalate, 110 of oxalate and calcium phosphate and 13 cases of mixed calcium oxalate and uric acid lithiasis. 43.4% patients with pure monohydrate calcium oxalate calculi have hypercalciuria, 22.6% hyperoxaluria and 19% hyperuricosuria. Dihydrated calcium oxalate calculi are related to high hypercalciuria in 65% cases and to significant hyperoxaluria in 35% cases. 45% patients present a single lithogenic factor, either hypercalciuria (49.6%), hyperoxaluria (20.6%), hyperuricosuria (13.74%), hypocitraturia (9%), urinary infection (1.5%), A.T.R. (2.25%) or acid oliguria (3%).     

Renal calculus dissolution in immobilized patients

13 patients presenting with immobilization stones are reported. Young males with an infection of the urinary tract are most commonly affected. In the case of phosphate stones, the infection of the urinary tract with an alkaline shift of the pH and an idiopathic hyperuricosuria play a decisive part together with temporary hyperphosphaturia and hypercalciuria. The importance of urea splitting bacteria in the urine for stone formation is stressed. Applied in time increase of fluid intake, specific antibiotics and allopurinol can lead to litholysis. If the urine of immobilized patients were monitored closely from the beginning of the hospitalisation for the above factors, and treated appropriately, urine calculi should be largely prevented.     

Urolithiasis in childhood: surgery and lithotripsy

From 1982 through 1993, 174 interventions in 160 infants and children with urolithiasis were performed at our department. There were 101 boys and 59 girls, mean age 8.9 years. The main causes of the interventions were congenital malformations in 62, followed by recurrent urinary tract infections in 29, previous operations in 17, and hypercalciuria in 35 patients. In 17 children, the cause of urolithiasis remained unknown. As a therapeutic option, extracorporeal shock-wave lithotripsy (ESWL) has become available since 1988. The malformations and postoperative conditions are surgically corrected, and the calculi removed in the same act. For post-infectious, idiopathic or hypercalciuric calculi, ESWL has been used in the majority of patients since 1988. Thus, a total of 129 calculi were removed by operation and 47 by ESWL, whereas 18 calculi were endoscopically extracted. There were no complications after either ESWL or open surgery. Calculi in congenital malformations or as a result of operation are still removed by open surgery. In other cases, ESWL is the method of choice.     

Urinary calculi in children: contribution of anamnesis, biological exploration and physical analysis of calculi to the etiological diagnosis

BACKGROUND: It is always of importance to define the cause of urinary calculi disease in children to prevent recurrence and possible impairing of renal function. Nevertheless, etiology is not always easy to prove and must be deduced from both clinical and biological arguments. PATIENTS AND METHODS: The aim of this prospective study including 39 Tunisian children with urinary stones was to identify etiology and stone risk factors and detail the part of clinical and biological data and results of physical analysis of stones in determining the cause of the stone. RESULTS: In 31 cases among 39, clinical and biological data were not sufficient to identify clearly the stone etiology. When considering the structure and stone composition, the cause of the stone could be determined in 97.4% of the cases. An inherited disease was found responsible for the stone in 11 children, urinary tract infection in 13 cases, idiopathic hypercalciuria in nine cases and a nutritional deficiency disease in seven cases. In one case, polycystic kidney disease with metabolic risk factors could explain the stone process. No precise etiology was found in one case. Among infection stones, struvite stones could be related to urea-splitting bacteria while other calculi, containing whitlockite and protein matrix could be related to other micro-organisms. Earlier severe chronic diarrhoea episodes were noted in six among seven children presenting stones with a nucleus mainly composed of ammonium urate. CONCLUSION: Clinical data, biological data from both urine and blood of the patients and also the structure and composition of the stones are needed to identify the cause of urinary calculi. Such a procedure could provide the stone etiology in most cases.     

Evidence of absorptive hypercalciuria in tuberculosis patients

In patients with granulomatous diseases, disturbances in calcium metabolism have been described. The aim of the study was to evaluate alterations in calcium metabolism in patients with tuberculosis. Forty patients with tuberculosis (TB) were studied in a baseline state (calcium intake 1000 mg/day). Fourteen of these patients were also studied after restrictive calcium diet (400 mg/calcium/day) and after a load of oral calcium of 1000 mg. In all the studies, calcium and phosphorus were measured in serum and urine, and parathyroid hormone (PTH) in plasma. In addition, serum 25OHD and 1,25(OH)2D (calcitriol) levels were measured in the baseline state and after the restrictive diet. In the baseline state, 25OHD levels were lower and urinary calcium higher in TB patients than in the control group. No patients had hypercalcemia, but hypercalciuria was present in 10 patients (25%). The patients with tuberculosis were divided according to the presence or absence of hypercalciuria. In both groups, the 25OHD levels were lower than in controls. Hypercalciuric patients had lower plasma parathyroid hormone levels and higher serum calcitriol levels than the control group and the TB patients without hypercalciuria. Urinary calcium excretion after a calcium load was higher in TB patients with hypercalciuria than in controls. A positive correlation was found between the calcitriol levels and postcalcium load urinary calcium excretion in patients with calcium hyperabsorption. These data indicate that absorptive hypercalciuria is frequently observed in patients with TB and is possible due to inappropriately high serum calcitriol levels.     

Seasonal variations in urinary crystals

Individual urine samples from normal subjects and stone-formers with idiopathic hypercalciuria have been examined for crystals both qualitatively and quantitatively at 37 degrees C. The group as a whole showed a rise in incidence of urinary crystals in the summer months of June to August inclusive. This rise was seen most clearly in overnight urines, collected on rising in the morning, and the patients appeared to be at risk overnight during the summer. In the untreated patients the summer rise in incidence of phosphate crystals was quite dramatic but was only small in the cellulose phosphate treated group, who showed a rather constant and raised incidence of oxalate crystals right through the year. Seasonal crystal incidence has been compared with seasonal changes in urinary composition. The rise in crystal incidence during the summer was associated with increased creatinine concentration in the same urine samples and with increased oxalate concentration in 24-hour urine collections.     

Low calcium diet in hypercalciuric calcium nephrolithiasis: first do no harm

Many studies indicate that up-regulated production of 1,25(OH)2-vitamin D3 (calcitriol) with increased intestinal absorption of calcium is the primary event causing idiopathic hypercalciuria. Thus, a low calcium diet appears to be a straightforward strategy in calcium stone formers with hypercalciuria (HCSF). However, the efficacy of such a regimen has never been established, and lowering calcium intake from 1000 to 400 mg/day further enhances calcitriol production. On a diet chronically restricted in calcium, many stone formers increase their intake of animal flesh protein. The latter is known to increase renal mass, and calcitriol levels indeed are positively correlated with renal mass in animals as well as in HCSF. Thus, low calcium and high animal flesh protein consumption are independent stimuli for further up-regulation of calcitriol production. The rise in calcitriol suppresses parathyroid hormone synthesis thereby diminishing renal tubular calcium reabsorption, and increasing urinary calcium losses. Since calcitriol up-regulation also increases bone resorption, the combination of low calcium and high protein intake is particularly likely to induce negative calcium balance and thus osteopenia. Finally, low calcium intake carries the risk of insufficient intestinal binding of oxalate with subsequent increases in intestinal absorption and urinary excretion of oxalate. Indeed, most recent studies suggest that high amounts of calcium, when ingested simultaneously with oxalate-containing meals, are able to prevent hyperoxaluria during severe oral oxalate loading.     

Spectrum of hypereosinophilia syndrome based on 2 clinical case reports

BACKGROUND: Two severe cases of hypereosinophilic syndrome with cardiopulmonary symptoms, erythema nodosum, eosinophilic ileocolitis and paresthesia are reported. Definition, etiology, pathophysiological mechanisms, types, complications and therapeutic approaches of this relatively rare clinical disorder are discussed on the basis of these two cases. The distinction between eosinophilia and hypereosinophilic syndrome is clearly defined. DIFFERENTIAL DIAGNOSIS: The 2 cases of hypereosinophilic syndrome demonstrate the difficulty to decide whether they represent the idiopathic or the reactive type of hypereosinophilic syndrome. If the assumption is made in favor of the reactive type of hypereosinophilic syndrome the assumed prognosis could eventually be too promising. In case of an assumed idiopathic type of hypereosinophilic syndrome the search for causing factors like allergens could be left out. The decision concerning the type of hypereosinophilic syndrome of the 2 cases reported was made with high probability. In the case of idiopathic hypereosinophilic syndrome, eosinophilic leukemia was excluded by bone marrow biopsy. CONCLUSION: In order to be able to make a diagnosis it is necessary to search carefully for causing and influencing factors of the hypereosinophilic syndrome such as allergens or medicaments and to eliminate them. The hypereosinophilic syndrome must be put under frequent control in order to avoid complications or to start with therapeutic approaches in time.     

Salt intake, urinary sodium, and hypercalciuria

Several studies have reported that high sodium (Na) intake increases not only urinary Na but also urinary calcium (Ca), suggesting that high Na intake could be involved in the pathogenesis of hypercalciuria. No research data are available on the relationship of Na intake to the prevalence of hypercalciuria within the general population. Moreover, it is not clear if Na intake relates only to urinary Ca or also to other indices of Ca homeostasis, including intestinal Ca absorption. In the present paper, two distinct studies addressed these points using 24-hour urinary Na as an index of salt intake in individuals on their habitual unrestricted free diet. Study 1 analyzed the relationship between 24-hour urinary Na and hypercalciuria (24-hour urinary Ca > or = 7.5 mmol in men, > or = 6.25 mmol in women) in a population sample of 203 men and women, aged 20-59 years. Study 2 analyzed the relationship between 24-hour urinary Na and intestinal strontium (Sr) absorption, used as an index of intestinal Ca absorption, urinary (24-hour and fasting) and plasma Ca, and plasma parathyroid hormone in 36 healthy men and women, aged 18-65 years. Within the population sample (study 1), 24-hour urinary Na was directly and significantly correlated with prevalence of hypercalciuria when controlling for gender, age, weight, and urinary creatinine: the relationship was continuous and linear for urinary Na ranging between 40 and 200 mmol/24 h. In the 36 volunteers (study 2), 24-hour urinary Na was related to 24-hour and fasting urinary Ca (p < 0.001) but not to intestinal Sr absorption: the relationship between 24-hour urinary Na and urinary Ca (both 24 h and fasting) was also significant, controlling for other variables. The results indicate that in adults on their habitual diet, urinary Na, which reflects dietary salt intake, correlates with the prevalence of hypercalciuria independently of intestinal Ca absorption and mainly via renal mechanisms.     

Effect of oral calcium loading on intact PTH and calcitriol in idiopathic renal calcium stone formers and healthy controls

The calciuric response after an oral calcium load (1000 mg elemental calcium together with a standard breakfast) was studied in 13 healthy male controls and 21 recurrent idiopathic renal calcium stone formers, 12 with hypercalciuria (UCa x V > 7.50 mmol/24 h) and nine with normocalciuria. In controls, serum 1,25(OH)2 vitamin D3 (calcitriol) remained unchanged 6 h after oral calcium load (50.6 +/- 5.1 versus 50.9 +/- 5.0 pg/ml), whereas it tended to increase in hypercalciuric (from 53.6 +/- 3.2 to 60.6 +/- 5.4 pg/ml, P = 0.182) and fell in normocalciuric stone formers (from 45.9 +/- 2.6 to 38.1 +/- 3.3 pg/ml, P = 0.011). The total amount of urinary calcium excreted after OCL was 2.50 +/- 0.20 mmol in controls, 2.27 +/- 0.27 mmol in normocalciuric and 3.62 +/- 0.32 mmol in hypercalciuric stone formers (P = 0.005 versus controls and normocalciuric stone formers respectively); it positively correlated with serum calcitriol 6 h after calcium load (r = 0.392, P = 0.024). Maximum increase in urinary calcium excretion rate, delta Ca-Emax, was inversely related to intact PTH levels in the first 4 h after calcium load, i.e. more pronounced PTH suppression predicted a steeper increase in urinary calcium excretion rate. Twenty-four-hour urine calcium excretion rate was inversely related to the ratio of delta calcitriol/deltaPTHmax after calcium load (r = -0.653, P = 0.0001), indicating that an abnormally up-regulated synthesis of calcitriol and consecutive relative PTH suppression induce hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphologic discrimination among healthy subjects and patients with progressive and nonprogressive adolescent idiopathic scoliosis

STUDY DESIGN: A prospective and controlled comparative study. OBJECTIVES: To identify variables that would allow discrimination among patients with progressive adolescent idiopathic scoliosis, patients with nonprogressive adolescent idiopathic scoliosis, and control subjects. SUMMARY OF BACKGROUND DATA: In a previous study, the correlation was demonstrated between morphologic somatotypes and adolescent idiopathic scoliosis. METHODS: One hundred forty-six subjects were evaluated anthropometrically and were classified according to their morphologic somatotype. Of these subjects, 52 were adolescent girls with progressive idiopathic scoliosis, whereas 32 girls had nonprogressive idiopathic scoliosis. The control group was composed of 62 healthy adolescent girls. Somatotype values for ectomorphism, mesomorphism, and endomorphism were obtained according to a technique based on Sheldon's method, and 77 anthropometric measurements of segments of the thorax, head, and limbs were taken. RESULTS: The discriminant analysis realized on a subset of 18 variables allowed the correct identification of each subject's group in 84% of the cases. CONCLUSIONS: It is possible to differentiate healthy adolescent subjects, patients with nonprogressive adolescent idiopathic scoliosis, and patients with progressive idiopathic scoliosis by using anthropometric measurements and morphologic classification. These findings may be useful in the early detection of children at risk for progression of scoliosis and may allow earlier application of treatment methods without waiting for a significant increase in the curve.     

Osteoporosis in men. Pathogenesis and clinical classification of 254 cases

In a prospective study, 321 consecutive male patients, aged between 16 and 86 years, referred to the Department of Medicine of the Medical Centre at Leverkusen from many parts of Germany over a three-year period with the diagnosis of osteoporosis, underwent a standardized programme of clinical investigation: 254 (79%) were found to have the condition. The programme consisted of a detailed history, physical examination, a battery of laboratory tests, X-ray examination of the skeleton and osteodensitometry. Where, as a result, underlying disease or risk factors were suspected, further tests were performed. 98 patients (39%) were found by densitometric criteria to have preclinical, 156 (61%) manifest osteoporosis with one or more vertebral body fractures. There was no significant difference regarding bone density between the preclinical and manifest cases. 76 of the 254 (30%) patients had no detectable pathogenetic factors, i. e. their osteoporosis was classified as idiopathic (mean age 51 years), while as senile osteoporosis in 16 elderly patients (mean age 78 years). The remaining 162 patients had 286 risk factors within 24 different categories. Depending on duration, intensity and combination of these risk factors, the osteoporosis was classified as primary with few risk factors or as secondary osteoporosis of single or multiple aetiology (mean age of these three groups was 51, 56 and 52 years, respectively). The most important demonstrable risk factors were (in decreasing order of frequency) glucocorticoid treatment, alcohol consumption, smoking, hypogonadism, hypercalciuria, liver disease, Crohn's disease, low calcium nutrition, hyperthyroidism, physical inactivity, stomach operation and plasmacytoma.--This study indicates that if there is evidence of significant risk factors detailed bone densitometry should be performed so that any necessary treatment can be initiated early. If there is known osteoporosis, staging and exact analysis of risk factors is a precondition for any cause-oriented treatment.     

Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP

Based on past difficulties in clinically differentiating patients with idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans-organizing pneumonia (BOOP), and nonspecific interstitial pneumonia/fibrosis (NSIP), which all manifest clinically as interstitial lung disease, experience with pathologically confirmed examples of the three diseases was reviewed to compare clinical profiles and prognosis and to define NSIP more clearly. Thirty-one patients (15 males and 16 females) were pathologically identified as NSIP and subclassified into either the cellular (n=16) or fibrotic group (n=15). All 31 patients were clinically considered to be idiopathic NSIP cases. Patients with idiopathic BOOP (n=16) and IPF (n=64) were compared with the NSIP patients. Subacute presentation of interstitial lung disease characterized both idiopathic NSIP and idiopathic BOOP. NSIP patients showed volume loss on a chest radiograph (29.0%) and honeycombing on a computed tomography scan (25.8%); these features were not found in BOOP patients. Bronchoalveolar lavage lymphocytosis was characteristic of both BOOP and NSIP. Two subgroups of NSIP can be recognized histologically: patients in the fibrotic group had a less favourable outcome than those in the cellular group. BOOP and NSIP had a more favourable outcome than IPF. In conclusion, idiopathic nonspecific interstitial pneumonia can be differentiated from other types of idiopathic interstitial pneumonia, both pathologically and clinically.     

Observations on the Raynaud's disease

During the last 25 years, owing to the improvement of the diagnostic means, the cases of "Raynaud's phenomenon" with well known etiology have been increasing and according to some authors they should be considered clearly prevailing. Through a right prevention and a medical and surgical therapy it is possible to obtain significant results. Consequently it is important to carry out a diagnostic screening. A study concerns 68 cases have been carried out in the Institute of Vascular Surgery, University of Milan, during the period 1971-1974. The cases are divided in two groups: idiopathic forms (disease) and forms connected to identifiable etiologies (syndrome). Many of the clinical parameters studied are examined. The so-called idiopathic forms: 47 cases (69%) with an average age of 45 years and a clear female prevalence (33 against 14). The forms with an identifiable etiology: 21 (31%) with an average age of 31 years and a clear male prevalence (16 against 5). It is therefore observed that the idiopathic Raynaud's disease is still prevailing and particularly in women. In idiopathic forms brachial angiography shows in most of the cases X-ray evidence of digital artery occlusion.     

Atelectases as part of the convex-sided lungs in thoracic scoliosis (author's transl)

In 4 patients with juvenile idiopathic thoracic scoliosis an atelectasis as part of the convex-sided lungs was found. In all cases there was a small sagittal diameter of the chest; the atelectases were situated in the right lower and middle lobe and caused by the close topographical relation of large bronchi and scoliotic spine (sometimes compression of the bronchus) demonstrable by tomography, bronchoscopy and bronchography. The therapeutic approach of these atelectases is discussed. Thoracic casting either for conservative correction and treatment of scoliosis or as postoperative immobilisation after fusion was done. In all cases, it may influence the occurrence of an atelectasis.     

New aspects in the treatment of oxalate lithiasis (author's transl)

The causes of hypercalciuria and simple diagnostic criteria for the various forms of hypercalciuria are outlined. Indications, effectiveness, limitations, and side effects of cellulose phosphate are described. Emphasis is placed on the biochemical pathogenesis and classification of hyperoxaluria. The problems of measuring and controlling oxalate excretion in patients with hyperoxaluria and calcium oxalate stones are discussed. Succinimide offers a partly successful approach to the reduction of endogenous oxalate synthesis.     

The functional status of the parathyroid in adult spasmophilia patients estimated by plasma parathormone assay

In 25 cases of spasmophilia the parathyroid function was assessed by complete exploration of the P-Ca metabolism and radioimmunoassay (RIA) of parathormone (PTH). Concomitantly the bone mineralization status was assessed by induced hypercalciuria tests and administration of 30 mg vitamin D2. RIA of PTH revealed increased values in 50% of the cases. The values fall within the range of secondary hyperparathyroidism, but this percentage varies with the values of the parathyroid function obtained by P-Ca metabolism explorations. The increased PTH values do no correlate with the level of plasma total calcium, ionic calcium, and magnesemia. Nor do they correlate with the bone mineralization disorders or the duration of the disease and the age of the patients.