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A disabling osteomalacic syndrome seen only during regular hemodialysis is described. Its features include skeletal fractures, pain, suppression of pre-existing hyperparathyroidism, and failure to improve with any of the vitamin-D metabolites. Phosphate depletion may be an important etiological factor but this could not explain all cases. A trial with phosphate-enriched dialysate and 1alphaOHD3 resulted in sustained clinical improvement in 54% of the patients and healing of fractures in 33%. Other etiological factors independent of 1,25(OH)2D3 deficiency and phosphate depletion must be considered. Current, indirect evidence suggests that accumulation of water toxins including aluminium may be important.

Separate ultrafiltration followed by haemodialysis (U.F.-H.D.) using Gambro Major or Cordis-Dow hollow-fiber dialyzers were evaluated in 10 dialysis patients over a mean period of 4 1/2 months and 455 U.F.-H.D. procedures. Fluid control was facilitated in oedema-tous patients but the number of hypotensive episodes during the combined procedure requiring intravenous 57. saline did not significantly decrease. No significant improvement in hypertension was noted.Ultrafiltration (U.F.) alone for acutely water overloaded, azotaemic patients proved very useful. Two to five liters of oedema fluid could be removed asymptomatically in one to three hours using transmembrane pressures of 250 to 500 mmHg and U.F. rates of 10 to 42 ml/tnin. Two patients became acutely and symptomatically hypotensive. One was an insulin dependent diabetic in whom 3800 ml were removed in 75 minutes and the other a hypertensive patient undergoing treatment with Minoxidil and propranolol.

Marrow mast cells have been counted in iliac bone from patients with chronic renal failure treated by renal transplantation. Mast cell numbers were initially increased but returned to the normal range in many patients after renal transplantation. Improvement in osteitis fibrosa and osteomalacia after transplant was not clearly related to this diminution in the number of mast cells. The use of prednisone in renal transplant patients may have some effect in reducing the numbers of mast cells. There is no fully acceptable explanation for the increase in marrow mast cells which occurs in chronic renal failure.

Hemodialysis encephalopathy with osteomalacic fractures and muscle weakness. The hemodialysis unit at Columbia, South Carolina, opened in April, 1974. By June of 1977, 7 patients had died from dialysis encephalopathy, and 16 of the 51 surviving patients showed speech disorders, fits, and myoclonic jerks. Pathologic fractures were seen in 22 patients. Bone histomorphometry showed severe osteomalacia with minimal, if any, osteitis fibrosa, and serum alkaline phosphatase activity was normal. The mean serum aluminum concentration in 33 random patients was elevated at 83.5 µg/liter (control group, 13.9 µg/liter, P < 0.001). The mean bone aluminum concentration in 4 patients who died from this syndrome was 307ppm of bone ash (normal, < 10 ppm). Dialysis fluid aluminum was high at 140 µg/liter. Purification of the dialysis fluid with a water softener, reverse osmosis and a deionizer and abandoning extra-strength Basaljel® resulted in a notable clinical and EEG improvement. None of 81 new patients who started hemodialysis between July of 1977 and July of 1979 after the change in treatment have developed any such symptoms. A syndrome of hemodialysis encephalopathy accompanied by pathologic osteomalacic fractures is described. Recovery is possible. The syndrome was eradicated after purification of the dialysis fluid.Encéphalopathie de l'hémodialyse avec fractures ostéomalaciques et faiblesse musculaire. Le centre d'hémodialyse à Columbia, South Carolina, USA, a ouvert en Avril 1974. De cette date à Juin 1977, 7 malades étaient morts d'encéphalopathie de la dialyse et 16 des 51 malades survivants avaient des troubles du langage, des convulsions et des secousses myocloniques. Des fractures pathologiques ont été observées chez 22 malades. L'histomorphométrie osseuse a montré une ostéomalacie sévère avec peu ou pas d'ostéite fibreuse. Les phosphatases alcalines sériques étaient normales. La concentration moyenne d'aluminium dans le sérum chez 33 malades choisis au hasard était élevée à 83,5 µg/liter (groupe contrôle: 13,9 µg/liter, P < 0,001). La concentration osseuse moyenne chez 4 malades décédés de ce syndrome était de 307ppm de résidu sur de l'os (normal < 10 ppm). L'aluminium du liquide de dialyse était élvé, à 140 µg/liter. La purification du liquide de dialyse au moyen d'un adoucisseur, de l'osmose inverse et d'un désionisant et l'abandon du Basaljel® ont eu pour conséquence une amélioration importante, clinique et électromyographique. Aucun des 81 nouveaux malades dont G hémodialyse a commencé entre Juillet 1977 et Juillet 1979, après la modification de la stratégie, n'a développé de tels symptômes. Un syndrome d'encéphalopathie de l'hémodialyse associé à des fractures pathologiques ostéomalaciques est décrit. La récupération est possible. Ce syndrome a disparu après la purification du liquide de dialyse.

Ten uraemic patients on regular haemodialysis were treated with 1alpha-hydroxycholecalciferol (1alpha-H.C.C.) for 5 to 14 months. Five patients who had histological osteitis fibrosa with or without osteomalacia responded well, with resolution of musculoskeletal pain, return of raised serum-alkaline-phosphatase concentrations to normal, resolution of radiological subperiosteal erosions, and improvement in histological signs of osteitis fibrosa and osteomalacia. In these patients 1alpha-H.C.C. proved a safe and effective drug. Five other patients did not improve. Characteristically these patients started with moderately severe histological osteomalacia and minimal, if any, osteitis fibrosa. Proximal myopathy was a prominent symptom and serum-alkaline-phosphatase was normal in four of them. Treatment with 1alpha-H.C.C. resulted in early troublesome hypercalcaemia, and repeat bone histology 5--11 months later showed no improvement. It is suggested that in these patients lack of 1,25-dihydroxycholecalciferol may not have been wholly responsible for the observed osteomalacia, hence 1alpha-H.C.C. alone was ineffective. Phosphate depeltion may have been an important contributing factor.

Elimination kinetics of captopril in patients with renal failure. Captopril kinetics were determined after a 100-mg oral dose of14C-captopril in 21 patients with various degrees of renal impairment. Elimination kinetics of captopril were evaluated by model-independent methods. The body clearance (ClB) of captopril decreased steadily with decreasing creatinine clearance (ClCr) from 5.2 ml/min/kg for mild renal failure patients to 1.6 ml/min/kg for hemodialysis patients during an interdialytic period. In patients with mild renal impairment, renal and nonrenal clearances of captopril averaged 2.2 and 3.0 ml/min/kg, respectively, and fell (P < 0.001) to 0.2 and 1.5 ml/min/kg in patients with severe renal impairment. There were no significant differences in the extent of total cumulative excretion (fecal plus urinary) of radioactivity over a 96- to 120-hr period between the patients with mild, moderate, and severe renal impairment. The 48-hr renal excretion of captopril averaged 29, 21, and 8% of the dose in the mild, moderate, and severe renally impaired groups. In five additional hemodialysis patients, the mean dialyzer clearance of captopril averaged 120ml/min. Approximately 35% of the dose was recovered in the 4-hr dialysate. Based on the above findings, a reduction in the dose of captopril is necessary in patients with renal failure.Cinétique d'élimination du captopril chez les malades en insuffisance rénale. La cinétique du captopril a été déterminée après une dose orale de 100mg del4C-captopril chez 21 malades atteints d'insuffisance rénale à des degrés divers. La cinétique d'élimination du captopril a été évaluée par des méthodes indépendants du modèle. La clearance corporelle (ClB) du captopril diminuait progressivement avec la baisse de la clearance de la créatinine (ClCr) de 5,2 mg/min/kg chez les malades en insuffisance rénale modérée à 1,6 ml/min/kg chez les malades en hémodialyse lors d'une période interdialytique. Chez les malades en insuffisance rénale modérée, les clearances rénales et non rénales du captopril étaient en moyenne de 2,2 et 3,0 ml/min/kg, respectivement, et chutaient (P < 0,001) à 0,2 et 1,5 ml/min/kg chez les malades avec une altération rénale sévère. Il n'y avait pas de différences significatives dans l'importance de l'excrétion cumulative totale (fécale et urinaire) de radioactivité sur une période de 96 à 120 heures entre les malades atteints d'une altération rénale modérée, moyenne ou sévère. L'excrétion rénale de 48 heures du captopril était en moyenne 29, 21, et 8% de la dose dans les groupes avec des altérations rénales modérées, moyennes ou sévères. Chez cinq malades hémodialysés supplémentaires, la clearance dialytique moyenne du captopril était de 120ml/min. Environ 35% de la dose était retrouvée dans un dialysat de 4 heures. D'après ces résultats, une diminution de la dose de captopril est nécessaire chez les malades en insuffisance rénale.

Measurement of serum lipids in 75 patients on regular haemodialysis showed that they had a higher mean serum triglyceride level than normal subjects. Cholesterol levels were not significantly different. Amongst haemodialysis patients men had higher serum triglycerides than women and women had higher cholesterol levels than men, a situation analogous to that found in normal subjects. In men, serum triglycerides correlated with percent body fat and treatment with Sustanon 250(R) intramuscularly weekly caused a significant rise.

Two regular hemodialysis patients were assessed before, during and after therapy for 8 1/2 months with 1alpha-hydroxycholecalciferol (1alphaOHD3). The first patient (F.S.), treated with 2 mug daily, improved considerably with complete resolution of histological osteomalacia (O.M.), reduction in osteitis fibrosa (O.F.) and healing of Looser zones. The second patient (T.Y.), who was treated at the same time with a combination of phenobarbitone and phenytoin, showed no improvement while taking 3 mug of 1alphaOHD3 daily. It is suggested that hepatic microsomal enzyme inducing drugs antagonize the action of 1alphaOHD3 by interfering with its subsequent hepatic 25-hydroxylation.

Among 39 patients treated by regular haemodialysis for four years or more pathological fractures and histological evidence of osteomalacia were significantly more common in those taking barbiturates. Out of 58 transplant recipients surveyed after one year, seven had osteomalacia; four of these had been taking phenobarbitone and phenytoin and one had taken barbiturates alone. Sedatives and other drugs such as phenobarbitone and phenytoin that induce hepatic microsomal enzymes should probably be avoided when possible in patients with chronic renal failure and after transplantation.

One hundren seventy-eight azotemic patients, 114 on hemodialysis, had measurements of total serum ALP, and definition of isoenzyme patterns on acrylamide gel electrophoresis. In addition, bone histomorphometry was defined in all of the patients by means of transiliac bone biopsies. Serial estimations over 2 years were carried out on several patients, including some being treated with vitamin D2, 1alphaOHD3, and 1,25(OH)2D3. (1) In both nondialyzed and dialyzed patients, serum ALP showed a significant positive correlation with osteitis fibrosa due to secondary hyperparathyroidism irrespective of the presence or absence of concurrent osteomalacia. Increases in the bone isoenzyme were largely responsible for the rise in total ALP. (2) A higher incidence of osteomalacia (p less than 0.001) was observed in patients on hemodialysis in Newcastle Upon Tyne. In hemodialyzed patients where osteomalacia was accompanied by either no secondary hyperparathyroidism (21 patients) or minimal secondary hyperparathyroidism (14 patients), serum ALP remained within normal limits, giving no indication of the existing osteomalacic bone disease. Isoenzyme studies revealed a high prevalence of the intestinal type and also varied combinations of hepatic, intestinal, and bone types. (3) Good response to vitamin D depended on the presence of significant amounts of the bone isoenzyme. Azotemic osteodystrophy characterized by a raised serum ALP and a prominent bone isoenzyme predicted a good response to vitamin D, and the decrease in serum ALP following vitamin D was the result of a reduction in the bone isoenzyme. Patients with symptomatic dialysis osteomalacic bone disease, accompanied by normal total serum ALP and no elevation of the bone isoenzyme, responded less well.

(1) The bone histology of 233 non-dialysed and 276 haemodialysed patients with chronic renal failure is reviewed. In non-dialysed patients osteitis fibrosa occurred in 83.7% and osteomalacia in 23.6% of patients. Osteomalacia was not found in the absence of osteitis fibrosa. In haemodialysed patients there was a more variable bone histology, sometimes resembling non-dialysed bone disease, but in general with a greater incidence of osteomalacia, especially with increasing time on dialysis. In some patients there was a predominance of osteomalacia accompanied by no or only mild osteitis fibrosa and the serum alkaline phosphatase was normal. (2) The results of treating twenty-six haemodialysed patients with 1alpha-hydroxyvitamin D3 (1alpha-OHD3) are described. Patients with osteomalacia and minimal or no osteitis fibrosa and a normal serum alkaline phosphatase (Group I) in general failed to respond and it is suggested that 1,25-dihydroxyvitamin D3 deficiency is not the sole factor responsible for the osteomalacia in these patients. In contrast, 1alpha-OHD3 therapy was effective in improving osteitis fibrosa and osteomalacia in some patients with moderate to severe degrees of osteitis fibrosa and osteomalacia (Group IIa) and in improving osteitis fibrosa where this occurred alone (Group IIb).

The inter-relationships between serum ferritin, hemoglobin, serum iron and total body iron stores were studied in 20 patients with chronic renal failure treated conservatively and in 20 patients on regular hemodialysis. There was no relationship between serum iron or transferrin and bone marrow iron deposits, but serum ferritin concentration was a good indicator of increased marrow iron stores. All patients with serum ferritin levels above 300 microgram/l had increased iron stores. Serum ferritin assay is a useful non-invasive technique for detecting iron overload in uremic and hemodialyzed patients.

Using a 2-hour 47Ca absorption test, significant depression of active calcium absorption was demonstrated in 48 vitamin D untreated haemodialysis patients. This malabsorption of calcium could be corrected by the daily oral administration of 1--2 microgram of 1alphaOHD3 and 1--1.5 microgram of 1,25(OH)2D3. 5 microgram daily for 2 weeks of 3-deoxy-1alphaOHD3 AND 16 and 64 microgram daily for 1 week of 24R,25(OH)2D3 proved ineffective. In 32 successfully transplanted patients, restoration of normal or near normal renal function (serum creatinine less than 1.9 mg/100 ml) was not always followed by an immediate improvement in active calcium absorption. Calcium absorption, especially in female patients, was adversely affected by the required immunosuppressive prednisone therapy and improvement was slow.