Metabolic studies in kidney stone disease.

Patients with kidney stones (n = 59) and healthy controls (n = 31) collected a 24-hour urine sample and later underwent a 6-hour 'fast and load' test in which an oral calcium load was taken after 2 hours. In the 24-hour urine sample, mean calcium excretion was higher in patients than controls, while mean urate, oxalate and citrate levels were similar. The patients had higher levels of fasting plasma calcium, serum calcitriol and fasting urinary calcium, and lower levels of plasma phosphate than did the controls. Following the calcium load, plasma and urinary calcium increased similarly in both groups. Serum parathyroid hormone (PTH) levels were similar in both groups and decreased similarly following the calcium load. Multiple linear regression, relating the presence or absence of stone formation to all variables, found the only variables significantly related to stone formation to be plasma levels of calcium (p less than 0.001) and phosphate (p = 0.001) and fasting urinary urea (p less than 0.001), and 24-hour urinary calcium excretion (p less than 0.05). Urinary oxalate and citrate were not related to stone formation. The data do not support the hypothesis that primary stimulation by calcitriol produces a normal fasting plasma calcium level, with an exaggerated increase after an oral calcium load. The findings instead suggest an abnormality of parathyroid cell 'set point', such that PTH secretion continues until the plasma calcium level is a little higher and the phosphate a little lower than in controls.     

Hyperparathyroidism, glucose tolerance and platelet intracellular free calcium in chronic renal failure

Disturbance in the vitamin D/parathyroid hormone (PTH) axismay be important in the pathogenesis of glucose intoleranceand insulin resistance in uraemia. To investigate possible relationshipsbetween hyperparathyroidism, intracellular free calcium ([Ca²⁺]₁),and glucose tolerance in chronic renal failure, we measuredserum intact PTH (l-PTH) by two-site immunometric assay, platelet[Ca²⁺]₁ using the fluorescent indicator fura-2, and plasma glucoseand insulin after 14 h overnight fast and at 30, 60 and 120min following a 75 g oral glucose load, in 18 chronic haemodialysispatients with elevated serum l-PTH. Calcitriol (1 µg)was administered parenterally at the end of each dialysis sessionfor four weeks. This significantly decreased serum l-PTH (p<0.001)and platelet [Ca²⁺], (p<0.01). Uraemic patients initiallyshowed marked glucose intolerance, with increased area belowthe glucose curve compared to healthy controls, but after 4weeks of calcitriol treatment, this effect was significantlydecreased, and there was a significant rise in the area underthe insulin curve after glucose load. The insulinogenic indexalso increased significantly after calcitriol treatment. These data suggest that calcitriol treatment of haemodialysispatient with secondary hyperparathyroidism is associated withincreased insulin secretion in response to glucose challenge,and that this change is linked to the decrease in intracellularfree calcium.     

Failure of Dietary Protein and Phosphate Restriction to Retard the Rate of Progression of Chronic Renal Failure: A Prospective, Randomized, Controlled Trial

SUMMARY Ninety-five patients (63 male, 32 female), age 45±2 years(mean±SEM) with chronic renal failure of varied aetiologywere randomized to receive either a conventional low proteindiet (0.6 g/kg/day protein, 800 mg phosphate; n=33), a low phosphatediet (providing approximately 1000 mg phosphate plus an orallyadministered phosphate binder, minimum protein intake 0.8 g/kg/day;n=30) or to control (minimum protein intake 0.8 g/kg/day, nophosphate restriction; n=32). Patients were reviewed for a minimumof 6 months before randomization and were withdrawn from thestudy if plasma creatinine exceeded 900 µmol/1, plasmaphosphate was > 2.0 mmol/1 or at the onset of uraemic symptoms. Following randomization patients were studied for an averageof 19±3 months. Mean plasma creatinine rose from 398±33to 600±50 µmol/1. Dietary protein intake was estimatedat 0.69±0.02 g/kg/day in the low protein group, 1.02±0.05in the low phosphate and 1.14±0.05 in the controls, phosphateintake was 815±43, 1000± 47, and 1315±57mg/day, respectively. Urinary urea excretion and protein catabolicrates were significantly reduced (p<0.01) only in those onprotein restriction, at 213±9 mmol/24 hours and 0.71g/kg/day, respectively. Phosphate excretion was significantlylower (p<0.05) in both the low protein group (17.9±0.8mmol/24 hours) and the low phosphate group (18.6±1.0mmol/24 hours) compared to controls. Changes in body weight,muscle mass and serum transferrin, albumin and immunoglobulinswere comparable between the groups. Mean blood pressure followingrandomization was 150/89±3/1 (low protein), 148/87±3/1(low phosphate) and 146/87±3/1 (controls). Progression of renal failure was analysed by rate of fall ofcreatinine clearance (ml/min/ 1.73 m²/month), by rate of deteriorationderived from reciprocal plasma creatinine against time plots(1/mmol/year) and to assess individual patient's response totreatment by two phase linear regression (‘breakpoint’)analysis of reciprocal plasma creatinine/time plots. Progressionwas analysed only in patients seen for at least 3 months followingrandomization. The rate of fall of creatinine clearance was not significantlydifferent between the groups (ANOVA): 0.56±0.08 ml/min/1.73m2/month (low protein, n=28), 0.44±0.07 (low phosphate,n=23) and 0.69±0.11 (control, n=27). In 50 patients (18low protein, 16 low phosphate and 16 control) whose rate ofprogression could be calculated before and after randomization,there was a fall in rate of progression averaging 0.18 ml/min/1.73m2/month in those on low protein diet and those on low phosphatediet, but a rise of 0.08 in the controls. These differenceswere, however, not statistically significant. Similar resultswere obtained when the rates of deterioration were calculatedfrom plasma creatinine. Significant individual improvements(p<0.01) in rates of progression by ‘breakpoint’analysis occurred in 17 patients: six on low protein, sevenon low phosphate and in four controls. Sixty-one (72 per cent)of the patients examined by this method showed no significantchange in the rate of progression while seven patients had acceleratedprogression. There was no difference in the requirement formaintenance dialysis facilities between groups. No significant benefit of protein and phosphate restrictionwas therefore demonstrated.     

Insulin and C-peptide secretion in non-insulin-dependent diabetes mellitus and its response to dietary therapy

We studied insulin and C-peptide levels in patients with non-insulin-dependentdiabetes mellitus (NIDDM) during standard oral or intravenousglucose tolerance tests (GTT) at the time of diagnosis and after3 months dietary therapy. On the second occasion they also hadan ‘augmented’ GTT, in which slow intravenous infusionof glucose raised basal plasma glucose to a level similar tothat at the time of diagnosis. Eight patients had oral tests,and seven patients intravenous tests. In both groups, dietarytherapy significantly reduced fasting and peak plasma glucose(p<0.05 for oral; p<0.01 for intravenous GTT). Serum insulinlevels during conventional oral GTT were not significantly differentafter dietary therapy compared to diagnosis, but were significantlyhigher during the ‘augmented’ oral GTT (p<0.05).In those patients who underwent intravenous GTT, there was asignificant increase in both the total amount of insulin secreted(0–60 min) and in first-phase insulin secretion (0–10min) during the ‘augmented’ test compared to diagnosis(p<0.01), but first-phase insulin secretion during the conventionalintravenous GTT was unchanged. Serum C-peptide responses werealso greater during ‘augmented’ tests (p<0.05),similar in pattern to serum insulin. There is a relative deficiencyin insulin secretion in untreated NIDDM, which can be reversedby dietary therapy. It is essential to study insulin and C-peptidesecretion in controlled ‘fasting’ glucose conditions.     

Insulin resistance and low urinary citrate excretion in calcium stone formers.

Epidemiological data suggest an association between kidney stones and some features of metabolic syndrome such as an overweight condition, arterial hypertension or glucose intolerance. However, mechanisms remain to be elucidated. This study aimed to evaluate insulin resistance, as assessed by homeostasis model assessment (HOMA-IR), and urine composition analysis in patients affected by calcium nephrolithiasis. A cohort of 61 (38 male, 29-57 years of age) non-diabetic calcium stone formers was studied. Data about body mass index, arterial blood pressure, serum biochemistry including parathyroid hormone and calcitriol were recorded in all the patients; fasting glucose and insulin were determined to calculate HOMA-IR value and accordingly the patients were grouped into tertiles. Urine pH and urinary excretion of calcium, citrate, phosphate, oxalate, uric acid, urea and creatinine were measured on 24h urine samples. Patients of the highest HOMA-IR tertile showed lower urine citrate levels than patients of the lowest HOMA-IR tertile (475+/-243 vs. 630+/-187 mg/24h, p<0.05), whereas no difference was detected as far as urinary oxalate, calcium, uric acid, phosphate, and urine pH and urine volume output were concerned. HOMA-IR values were positively related to uric acid serum levels (r=0.31, p<0.05) and negatively to urinary citrate excretion (r=-0.26, p<0.05). Hypocitraturic patients showed higher levels of HOMA-IR than normocitraturic ones (3.03+/-0.92 vs. 2.25+/-1.19, p<0.05). This study shows that a higher level of insulin resistance is associated with lower urinary citrate excretion, and that hypocitraturic patients show a greater insulin resistance than normocitraturic calcium stone formers. This may be related to changes in citrate, Na(+)-K(+) and H(+) renal tubule transports, which have been described in insulin resistance. In conclusion, insulin resistance may contribute to an increased risk of calcium stone formation by lowering urinary citrate excretion. This finding suggests the need for a careful metabolic assessment in patients known to form calcium stones in order to ensure stone recurrence prevention and cardiovascular protection.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.     

Thirst in Diabetes Insipidus: Clinical Relevance of Quantitative Assessment

Patients with cranial diabetes insipidus are unable to concentrateurine, and depend on thirst and water intake to prevent hypertonicdehydration. Using a visual analogue scale (0-10 cm) we studiedosmotically stimulated thirst induced by hypertonic saline infusionin 15 patients with diabetes insipidus and 15 healthy controls.Plasma osmolality in the patients rose from 292 ±1 to316±1 mOsm/kg (p<0.001), and 13 patients showed aprogressive rise in thirst ratings (1.4 ±0.4 to 8.1 ±0.3cm, p<0.001) with abolition of thirst by drinking, in a similarfashion to controls. Water intake following infusion was greaterin patients than controls (p<0. 001). Linear regression analysisof thirst and plasma osmolality showed no difference in theosmotic threshold for thirst onset, or the sensitivity of thirstosmoreceptors, between 13 of the patients and the control group.One patient was shown to be hypodipsic and compulsive waterdrinking was demonstrated in another: abnormal thirst perceptioncaused abnormalities of salt and water balance in these twopatients. Most patients with cranial diabetes insipidus have normal thirstmechanisms, though clinically significant hypodipsia or hyperdipsiamay co-exist with vasopressin deficiency.     

Study of potassium citrate treatment of crystalluric nephrolithiasis

Patients with crystalluric nephrolithiasis were treated orally with aqueous potassium citrate solution three times a day with a large quantity of water. After administration of potassium citrate, citric acid (P < 0.001) and potassium (P < 0.001) excretion was significantly increased. Increase in protein (P < 0.05) and uric acid (P < 0.05) excretion in urine revealed their association with the crystallization process. Crystals were absent in 12 (71%) out of 17 patients. Calcium excretion in urine was significantly decreased (P < 0.05). A decrease of calcium ions availability to oxalate ions to form calcium oxalate crystals may result in the prevention of calcium oxalate stone formation.     

Patterns of Insulin Dependence in an African Diabetic Clinic

SUMMARY Analysis of the age of onset of diabetes amongst insulin-treatedpatients in a large African diabetic clinic revealed a bimodaltype of distribution, 23 per cent having an age of onset before30 years and 77 per cent with onset at 30 years of age. All66 of the young insulin-treated group (21.7±4.8 years(mean±1 SD)), and a random selection of 50 older insulin-treatedpatients (49.7±10 years), were studied. The older groupwere better controlled (HbA₁ 8.4±1.7 per cent vs. 10.8±2.6per cent, p<0.001), on lower doses of insulin (49±23vs. 71±23 u/day, p<0.001) and had higher body massindex (26.0±5.6 vs. 21.8±3.5, p<0.001). SerumC-peptide (0.24±0.15 vs. 0.07±0.10 nmol/l, p<0.0001),and C-peptide/glucose ratio (2.57±2.65 vs. 0.56+0.98nmol/mmolx 10², p<0.001) were very significantly higher inolder patients. Patients with later onset disease thus had betterpreservation of pancreatic function, higher body mass indexand better glycaemic control on lower doses of insulin. Thesefeatures suggest that older insulin-treated patients could infact be ‘Type 2’ or non-insulin dependent patients,and the condition may be controllable with diet and/or oralhypoglycaemic agents, at least in some.     

Hyperoxaluria or hypercalciuria in nephrolithiasis: the importance of renal tubular functions

The role of the kidney in states of hyperoxaluria and hypercalciuria was investigated in seven patients with hyperoxaluria after jejunoileal bypass (JIB) and six patients with idiopathic hypercalciuria (IHC). Eight apparently healthy persons formed a control group. Besides hyperoxaluria, the patients with JIB displayed an elevated plasma concentration of oxalate and the oxalate clearance was increased and higher than creatinine clearance, indicating a net tubular secretion of oxalate. The JIB patients had lower 24-h urinary excretions of calcium, phosphate, magnesium and citrate and higher serum parathyroid hormone (PTH) than controls, indicating increased secretion of PTH to compensate for calcium malabsorption. IHC patients exhibited increased fasting urinary calcium even though their serum values were similar to those in the controls. These results indicate a reduced tubular calcium reabsorption, which was most pronounced in patients with highest PTH values. We conclude that hyperoxaluria in JIB patients is associated both with intestinal hyperabsorption and with enhanced tubular secretion of oxalate, and that in some patients with IHC hypercalciuria is due to reduced tubular reabsorption of calcium.     

Percutaneous Transluminal Angioplasty for Atheromatous Renal Artery Stenosis - Blood Pressure Response and Discriminant Analysis of Outcome Predictors

Percutaneous transluminal angioplasty was performed in 39 consectivepatients with atheromatous renal artery stenosis associatedwith hypertension. The mean blood pressure before angioplastywas 191/107 mm Hg and this had dropped to a mean of 167/90 mmHG at the patient's most recent visit, representing a significantfall in both systolic (p<0.01) and diastolic pressures (p<0.001).The mean serum creatinine was 166.7 µmol/l before percutaneoustransluminal angioplasty and 155.3 µmol/1 at the mostrecent visit (not statistically significant. The mean numberof anti-hypertensive drugs fell from 2.4 to1.9 after percutaneoustransluminal angioplasty (p<0.05). Three patients (eightper cent) were ‘cured’ (diastolic blood pressure<90 mm Hg without medication), 25 (64 per cent) had ‘improved’(diastolic blood pressure <109 mmHg, with a fall of morethan 15 per cent) and 11 (28 per cent) had not improved. Logisticdiscriminant analysis showed that pre-percutaneous transluminalangioplasty diastolic blood pressure, age, serum creatinineand smoking habit together correctly predicted the outcome ofpercutaneous transluminal angioplasty in 90 per cent of patients,with four ‘false positives’ and no ‘falsenegatives’. Ten patients suffered, a total of 12 seriouscomplications related to the procedure: one death in acute renalfailure, one myocardial infarction, one severe hypotension,just after the procedure, one deep vein thrombosis, one episodeof transient ischaemia of the toes and seven groin haematomas.Thus percutaneous transluminal angioplasty for atheromatousrenal artery stenosis rarely ‘cures’ hypertension,but improved blood pressure control is often achieved, albeitat the expense of troublesome complications. A prospective,randomized trial is needed to establish whether or not the improvementis due directly to percutaneous transluminal angioplasty.     

A Comparative Study of the Relative Effects of Anticonvulsant Drugs and Dietary Folate on the Red Cell Folate Status of Patients with Epilepsy

In a survey of the red cell folate status of 200 patients withepilepsy, compared to 72 controls, we found that median redcell folate levels were reduced significantly in patients treatedwith phenytoin (p<0.01) or carbamazepine (p<0.001) alone.Patients taking more than one drug had reduced levels also (p<0.001),but in patients treated with sodium valproate alone there wasno significant decrease in red cell folate levels compared tocontrols. Twenty-two per cent of patients in the group takingmore than one drug had reduced levels of red cell folate comparedwith 17 per cent of those taking carbamazepine alone, 13 percent of those taking phenytoin only, and 9 per cent of thosetaking sodium valproate only. Dietary folate intake was significantlyreduced in all the patient groups compared with controls (p<0.001for the carbamazepine and phenytoin groups, p<0.01 for thepolypharmacy and sodium valproate groups); a significant correlation,between red cell folate levels and dietary folate was not established. Significant negative relationships were established betweencarbamazepine dose (r=0.35, p<0.01) or serum level (r=-0.27,p<0.05) and red cell folate level in patients on one drugonly. The correlation between dose or serum level-of phenytoinand red cell folate level was also negative but did not reachsignificance. Our findings show that all anticonvulsant drugs interfere withfolate metabolism. While the effect is greatest with drugs whichinduce microsomal liver enzymes, low levels of folate also occurredin patients taking the non-enzyme inducer sodium valproate.Although a significant relationship between diet and red cellfolate was not established, dietary folate could be a furthercontributory factor.     

Is calcium oxalate nucleation in postprandial urine of males with idiopathic recurrent calcium urolithiasis related to calcium phosphate nucleation and the intensity of stone formation? Studies allowing insight into a possible role of urinary free citrate and protein.

In idiopathic recurrent urolithiasis (IRCU) calcium oxalate and calcium phosphate are components of stones. It is not sufficiently known whether in urine the nucleation (liquid-solid transition) of each salt requires a different environment, if so which environment, and whether there is an impact on stone formation. Nucleation was induced by in vitro addition of oxalate or calcium to post-test meal load whole urine of male stone patients (n=48), showing normal daily and baseline fasting oxaluria. The maximally tolerated (until visible precipitates occur) concentration of oxalate (T-Ox) or calcium (T-Ca) was determined; additionally evaluated were other variables in urine, including total, complexed and free citrate (F-Cit), protein (albumin, non-albumin protein) and the clinical intensity (synonymous metabolic activity; MA) of IRCU. In the first of three trials the accumulation of substances in stone-forming urine was verified (trial-V); in the second (clinical trial 1) two strata of T-Ox (Low, High) were compared; in the third (clinical trial 2) IRCU patients (n=27) and a control group (n=13) were included to clarify whether in stone-forming urine the first crystal formed was calcium oxalate or calcium phosphate, and to identify the state of F-Cit. T-Ox was studied at the original pH (average < 6.0), T-Ca at prefixed pH 6.0; the precipitates were subjected to electron microscopy and element analysis. Trial-V: Among the urinary substances accumulating at the indicated pHs were calcium, oxalate and phosphate, and the crystal-urine ratios were compatible with the nucleation of calcium oxalate, calcium-poor and calcium-rich calcium phosphate; citrate, protein and potassium also accumulated. Clinical trial 1: the two strata exhibited an inverse change of T-Ox and T-Ca, the ratio T-Ox/T-Ca and MA. The initial (before induction of Ox or Ca excess) supersaturation of calcium oxalate and brushite were unchanged, with the difference of proteinuria being borderline. Several correlations were significant (p < or = 0.05): urine pH with citrate and volume, protein with volume and MA, T-Ox with T-Ca and MA. Clinical trial 2: in patients with reduced urine volume and moderate urine calcium excess, the first precipitate appeared to be calcium oxalate, followed by amorphous calcium phosphate. Conversely, when the calcium excess was extreme, calcium-rich hydroxyapatite developed, followed by calcium oxalate; F-Cit, not total and complexed citrate, was decreased in IRCU vs. male controls; F-Cit rose pH-dependently, and the ratio F-Cit at original pH vs. F-Cit at pH 6.0 correlated inversely with the nucleation index T-Ox/T-Ca; MA correlated inversely with the ratio F-Cit at pH 6.0, respectively, original pH, but directly with the urinary albumin/non-albumin protein ratio. In summary 1) to study calcium oxalate and calcium phosphate nucleation in whole urine of IRCU patients is feasible; 2) at this crystallization stage the two substances, dominant in calcium stones, appear intimately linked, 3) in stone-forming urine, calcium phosphate may be ubiquitously present, likely as particles < 0.22 microm; 4) together with co-precipitation of calcium oxalate and calcium phosphate, low F-Cit and alteration of proteinuria may act in concert and accelerate stones.     

Safety and efficacy of increasing wintertime vitamin D and calcium intake by milk fortification

We studied the safety and efficacy of milk fortified with vitaminD₃ and calcium. Over the winter, we conducted a double-blind,placebo-controlled trial of fortified milk (12µg vitaminD₃ and 1525 mg calcium per litre) compared to unfortified milk(0.3µg vitamin D₃ and 1270 mg calcium per litre) in 102adults (aged 17–54 years). Serum 25-hydroxyvitamin D [25(OH)D],ionized calcium, and creatinine were measured at baseline andafter intervention. Fortification reduced the seasonal declinein serum 25(OH)D concentrations by >50%. In the fortifiedgroup, serum 25(OH)D decreased by 15nmol/l from 77±35nmol/l to 62±26 nmol/l (p<0.001). In the control group,serum 25(OH)D fell by 31 nmol/l from 85±39 nmol/l to54±25 nmol/l (p<0.001). We suggest that milk enrichedwith vitamin D be provided in high-latitude European countriesto diminish the wintertime fall in serum 25(OH)D.     

Radioiodine therapy compared in patients with toxic nodular or Graves' hyperthyroidism

In view of uncertainty regarding the most appropriate radioiodinedose for patients with hyperthyroidism due to toxic nodulardisease or Graves' disease, we prospectively studied outcomein patients with these disorders given a single 5 mCi (185 MBq)dose of radioiodine. We studied 103 patients receiving theirfirst radioiodine dose; 44 with toxic nodular hyperthyroidismand 59 with Graves' hyperthyroidism. Thyroid status (off anti-thyroiddrug therapy) at 6 and 12 months after radioiodine was relatedto diagnosis, use of carbimazole before or after radioiodine,and physical and biochemical findings. At 6 months, persistenthyperthyroidism was less frequent in toxic nodular disease thanin Graves' disease (34.1 % vs. 55.9%, p<0.05); hypothyroidismwas also less frequent (11.4% vs. 27.1%, p<0.05). Those withpersistent hyperthyroidism at 6 months were given a second (10mCi, 370 MBq) dose of radioiodine. At 12 months after the firstdose, 80.6% of the group with toxic nodular hyperthyroidismwere either euthyroid or hypothyroid, and 74.5% of those withGraves' disease were euthyroid or hypothyroid, the rate of hypothyroidismagain being less in toxic nodular disease (19.4% vs. 58.8%,p<0.05). Logistic regression and stepwise discriminant analysisdemonstrated that ‘cure’ (euthyroidism or hypothyroidism)at 6 months was related to serum free T4 at presentation (p<0.001) and administration of carbimazole before or after radioiodine(p<0.001) (severe hyperthyroidism and carbimazole increasingthe likelihood of persistent hyperthyroidism) but was not relatedto the diagnosis of toxic nodular or Graves' hyperthyroidism.These results argue in favour of a ‘low dose’ ratherthan a 'high dose' radioiodine regimen in patients with toxicnodular hyperthyroidism, at least in those with mild diseaseand without complications. The marked influence upon outcomeof both carbimazole treatment before or after radioiodine, andthe degree of hyperthyroidism at presentation, suggests thatdoses of radioiodine of > 5 mCi should be administered tohyperthyroid patients requiring adjunctive antithyroid drugsand those with marked biochemical hyperthyroidism.     

Calcium and Phosphorus Metabolism in Nephrotic Syndrome

Calcium and phosphorus balance studies were performed on 13nephrotic patients and eight patients during clinical remissionof the nephrotic syndrome. Marked impairment of intestinal absorptionof calcium was found among nephrotic patients, in eight of whomfaecal calcium equalled or exceeded dietary calcium. The meanfaecal :dietary calcium ratio of nephrotic patients, 1·06±0·23(SD), was significantly higher (p<0·005) than thatof patients in remission, 0·58±0·21 (SD).The mean 24-hour urinary excretion of calcium of nephrotic patients,0·68±0·68 (SD) mmol, was significantlylower (p<0·005) than that of patients in remission,3·02±1·91 (SD) mmol. Calciferol administeredto three nephrotic patients in the dosage of 1.25 mg per daydid not significantly influence intestinal absorption or renalexcretion of calcium. There was no difference between the two groups of patients inintestinal absorption or renal excretion of phosphorus; therewas net intestinal absorption in all subjects. Quantitative bone histology was studied in seven of the nephroticpatients. None had osteomalacia or osteitis fibrosa, while onlyone had evidence of mild osteoporosis.     

Androgenic Status and Sexual Function in Males with Rheumatoid Arthritis and Ankylosing Spondylitis

The pituitary-testicular axis was investigated in 31 males withrheumatoid arthritis (age range 19–60 years, median 55years) and 33 males with ankylosing spondylitis (age range 22–55years, median 37 years) and compared with a control group of95 normal male volunteers. Using analysis of covariance, patientswith rheumatoid arthritis showed significantly lower serum testosterone(p<0.05) and derived free testosterone (p<0.01) concentrationsand significantly higher serum LH and FSH concentrations (p<0.05)compared with controls. All patients had normal serum prolactinand cortisol concentrations. Serum testosterone correlated withESR, haemoglobln concentrations and rheumatoid factor titres(r<–0.448, p<0.02; r=0.440, p<0.02; r<–0.360,p<0.05 respectively) in the rheumatoid patients. Althoughthere was a significant negative correlation between ESR andhaemoglobin concentrations (p<0.005) in the patients withankylosing spondylitis, neither variable correlated with serumtestosterone concentrations. There was no association betweentesticular dysfunction and the presence of extraarticular featuresof rheumatoid arthritis. Ten patients (33 per cent) with rheumatoidarthritis and four (13 per cent) with ankylosing spondylitisadmitted to periods of impotence while 15 (50 per cent) of theformer and 12 (39 per cent) of the latter had periods of decreasedlibido. There was no evidence for increased rates of infertilityin either group.     

Mixed expired nitric oxide in primary pulmonary hypertension in relation to lung diffusion capacity

The mixed expired nitric oxide (NO) production of the lungsof patients with primary pulmonary hypertension (PPH) and normalsubjects was measured to determine the relationship betweenNO production and the diffusion capacity of the lung (KCO).Expired air was collected from eight patients with PPH and 20healthy volunteers for analysis by a chemluminescent analyser.Mean pulmonary artery pressure in the PPH patients was 59.5± 6.45 mmHg and their mean cardiac output was 2.95 ±0.35 l/min. All patients and subjects underwent measurementsof FEV1, VC and KCO. The rate of production of NO in mixed exhaledair was lower in the PPH group compared to the controls (2.85± 0.7 vs. 4.69 ± 0.35 nM/min; p<0.05). Therewas a good correlation of expired NO with the KCO (r=0.7; n=30;p<0.001). When corrected, KCO differences in exhaled NO werenot significant (p=0.09). We conclude that the low exhaled NOobserved in PPH patients is a reflection of the reduced bloodcapillary volume in these patients rather than a decreased basalproduction of NO.     

Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease

In a multi-centre retrospective study, we compared clinicaland laboratory data in 913 patients with cryoglobulinaemias,divided as: (i) essential cryoglobulinaemias; (ii) cryoglobulinaemiassecondary to connective tissue diseases (CTD), lymphoproliferativeor other haematological diseases (LPD), chronic liver diseases(CLD), and ‘other diseases’. Purpura was the commonestpresenting feature in all groups and was more common in essentialcryoglobulinaemias (p<0.0001). Meltzer's triad (purpura,arthralgia, weakness) was less frequent, but similarly distributed.Renal involvement was randomly distributed. Neurological impairmentwas less frequent in cryoglobulinaemias secondary to CLD (p<0.002).Raynaud's phenomenon, arthritis and sicca syndrome were morefrequent in cryoglobulinaemias secondary to CTD. Essential cryoglobulinaemiashad a significantly higher percentage of serum complement C4<8mg/dl (p<0.004), of detectable rheumatoid factor activity(p<0.0002), and of type II cryoglobulins (p<0.0001). Liverinvolvement was evident at presentation in 32.6% of essentialcryoglobulinaemias, 27.1% of cryoglobulinaemias secondary toLPD and 12.2% of cryoglobulinaemias secondary to CTD. Antibodiesto hepatitis B surface (HBsAg) and core (HBc) antigens weremore frequent in cryoglobulinaemias secondary to CLD; anti-HBsantibodies were randomly distributed. Antibodies to hepatitisC (HCV) were tested for in 224 patients, and prevalence washigh in all the groups, but lower in cryoglobulinaemias secondaryto CTD (p<0.0001). Type II and type III essential cryoglobulinaemiasdiffered significantly in renal involvement (p<0.0001), cryocrit< 3 % (p<0.0001), C4 <15 mg/dl (p<0.001), HBsAgprevalence (p<0.01) and purpura (p<0.05). Despite thehigh prevalence of HCV markers in all groups, the role of HCVin essential cryoglobulinaemia is not well defined; HBV seemsto play only a marginal role.