Pharmacology and therapeutic use of vitamin D and its analogues.

The term vitamin D is generally used to describe a number of chemically related compounds with common antirachitic properties, but which have differences in the rapidity of their action, the way they are produced in the body, and the conditions under which their results are optimal. Ergocalciferol, cholecalciferol, 25-hydroxycholecalciferol (calcifediol), dihydrotachysterol, 1 alpha-hydroxycholecalciferol (alfacalcidol), and 1,25-dihydroxycholecalciferol (calcitriol) are currently the most commonly used vitamin D metabolites. In man, cholecalciferol produced on the skin and the fraction obtained from the diet in the gastrointestinal tract are converted in the liver to 25-hydroxycholecalciferol and then in the kidney to 1,25-dihydroxycholecalciferol. The demonstration of these metabolic pathways has helped to elucidate the aetiology of such conditions a hepatobiliary osteodystrophy, drug-induced anticonvulsant osteomalacia, the hypocalcaemia of hypoparathyroidism and above all azotaemic osteodystrophy. In the therapy of azotaemic osteodystrophy, the period of 'vitamin D resistance' when large doses of vitamin D2 and D3 had to be used is now over, and these patients can be efficiently and successfully treated with almost physiological doses of 1 alpha-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol. Attention to diet, calcium supplements and oral phosphate binders are also important. During repetitive haemodialysis, the above principles still hold true, but in some of these patients an osteomalacic syndrome resistant to 1,25-dihydroxycholecalciferol has been recognised. These patients readily become hypercalcaemic when given 1,25-dihydroxycholecalciferol and their fractures and osteomalacia do not improve. Aluminium intoxication, possibly related to the use of impure dialysis fluid, is currently thought to be the most likely explanation of this dialysis osteomalacic syndrome.

Renal transplantation in Alport's syndrome: anti-glomerular basement membrane glomerulonephritis in the allograft.

Eleven patients with Alport's syndrome had renal transplantation between 1963 and 1980. The mean follow-up is 6 years (6 months to 14 years). All 11 patients are currently alive. Ten have functioning grafts, and in nine the serum creatinine concentration is less than 2 mg/dl. Three patients received a second allograft. Histologic study of the allografts that were lost revealed a diffuse crescentic glomerulonephritis with strongly positive linear IgG staining of the glomerular basement membrane in the allografts of two of the three patients; circulating antiglomerular basement membrane antibodies were present in one patient. These two patients had successful retransplantation and they remain well 1 1/2 and 4 1/2 years later. Renal transplantation in patients with Alport's syndrome is a worthwhile and very satisfactory procedure.

Comparative studies of total and ionized serum calcium values in normal subjects and patients with renal disorders.

One hundred fourteen nondialyzed azotemic adult patients (creatinine connentration 1.2 to 17.6 mg/dl), 78 stable renal transplant recipients (creatinine less than 1.9 mg/dl), 50 patients with idiopathic nephrolithiasis, 36 patients with surgically proven primary hyperparathyroidism, and 62 normal volunteers were studied with simultaneous serum ionized calcium, total calcium, parathyroid hormone (PTH), phosphorus, and creatinine measurements. Ionized calcium could not be reliably predicted from total calcium. Although in all patient groups values for serum ionized calcium correlated significantly with those for total calcium, the scatter around the regression line was such that a direct interpretation was not precise. With respect to reference values, significant differnces were found between ionized and total calcium in 26% of all studied patients. When compared with total serum calcium, ionized calcium appeared to be a more sensitive index of calcium metabolism. All correlations with ionized calcium had a higher r value compared with those with total serum calcium. Two findings were particularly rewarding. In patients with chronic renal failure, serum PTH showed a negative correlation with serum ionized calcium, indicating that the latter may have been largely responsible for the secondary increase in PTH; in patients after a successful transplant, serum PTH showed a positive correlation with serum ionized calcium, indicating that in the presence of normal kidney function the previously hypertrophied parathyroid glands may be largely responsible for the daily study of a large number of specimens, determinations of serum ionized calcium should be encouraged in all patients suspected of having abnormalities of renal calcium metabolism.

Reversible nonoliguric acute renal failure associated with zomepirac therapy.

Zomepirac sodium (Zomax) is a nonsteroidal anti-inflammatory agent with analgesic properties which was recently released for clinical use in this country. We report here a case of nonoliguric acute renal failure associated with zomepirac sodium therapy. This acute renal failure improved upon cessation of zomepirac treatment. Renal biopsy disclosed the presence of a tubulointerstitial nephritis, which was thought to have been responsible for the acute renal failure in this patient. Clinicians should be aware of the potential nephrotoxicity of zomepirac sodium and use caution in its administration, especially in patients with compromised intravascular volume status, hypertension, or preexistent chronic renal disease.

Effect of renal transplantation on marrow mast cell hyperplasia of chronic renal failure.

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.

Serum alkaline phosphatase isoenzyme patterns in patients with chronic renal failure.

1. Using acrylamide gel electrophoresis the serum alkaline phosphatase (ALP) isoenzyme patterns of 204 patients with chronic renal failure have been examined for periods up to 18 months in length. 2. Of those with elevated serum ALP activity the bone isoenzyme was largely responsible. The presence of increasing amounts of the bone isoenzyme even if the total serum ALP activity remains within the normal reference range should also indicate bone pathology. 3. Intestinal alkaline phosphatase was the major serum alkaline phosphatase in 15% of patients on regular haemodialysis and 10% of uraemic patients not on dialysis. The overall incidence of detectable intestinal alkaline phosphatase in those with normal serum ALP activity was 36%. 4. With those patients whose serum ALP activity changed significantly during the investigation this usually reflected changes in the amount of the bone isoenzyme. Patients with abnormal amounts of the intestinal isoenzymes in their serum usually showed little variation in serum ALP activity over the period of the study.

Serum gamma-glutamyl transferase activity in chronic renal failure during regular hemodialysis and after successful renal transplantation.

Serum gamma-glutamyl transferase activity (gamma-GT) was measured in 108 uraemic patients, 110 patients on regular haemodialysis and 71 sucessfully transplanted patients. The incidence of abnormal results was 11, 14 and 28%, respectively. The results in the non-dialyzed and dialyzed patients indicate that in uraemia serum gamma-GT activity remains normal and as such, significant hepatic microsomal enzyme induction does not appear to occur. Raised serum gamma-GT in uraemic patients and after renal transplantation should suggest concurrent, added, pathology such as hepatobiliary disease or the administration of hepatic microsomal enzyme inducing drugs.

Serum gamma glutamyl transferase and alkaline phosphatase activities in epileptics receiving anticonvulsant therapy.

1. Serum gamma glutamyl transferase (gammaGT) and alkaline phosphatase (ALP) activities have been estimated in 49 epileptic patients taking anticonvulsant drugs. 2. Serum gammaGT activity was clearly elevated in 12 of the patients and borderline in 8, giving a 40% frequency of abnormal values. 3. Total serum ALP activity was elevated in 7 out of 33 adult patients and 2 of 16 juveniles. 4. Electrophoresis on polyacrylamide gel showed that the bone isoenzyme was responsible for most of the increased serum ALP activity and that even when the total was not elevated, the contribution of the bone isoenzyme was greater than normal. 5. There was no correlation between total serum ALP and gammaGT activities but elevations of serum gammaGT were often accompanied by an increase in the proportion of the bone enzyme in the total serum ALP activity.

Seasonal variation of serum 25-hydroxyvitamin D in patients with chronic renal failure treated by regular haemodialysis.

Serum 25-hydroxyvitamin D was measured by a competitive protein-binding assay in 44 normal subjects, 60 uraemic patients on regular haemodialysis at different times of the year and in 13 non-dialyzed uraemic patients. The results obtained indicate that uraemic patients on regular haemodialysis have a mean serum 25-hydroxyvitamin D concentration comparable to controls and that they also exhibit a seasonal variation with a significant reduction during the winter months. However, serum 25-hydroxyvitamin D concentration remained essentially within the normal range and did not reflect the increased incidence of osteomalacia in these patients. In the 13 non-dialyzed uraemic patients, serum 25-hydroxyvitamin D concentrations were lower than in the dialyzed patients, but the explanation is not yet clear. This reduction in serum 25-hydroxyvitamin D was not accompanied by any osteomalacia. The results indicate that deficiency of 25-hydroxyvitamin D in our patients on regular haemodialysis is uncommon and clearly not the explanation of dialysis osteomalacia.

Quadriceps tendon ruptures in uremia. Treatment with surgery and 1alpha-hydroxycholecalciferol.

Three young patients with chronic renal failure, one on regular hemodialysis, suffered bilateral quadriceps tendon ruptures. All three had uncontrolled, severe osteitis fibrosa. In two, aluminium hydroxide failed to control secondary hyperparathyroidism, while 1alpha-hydroxycholecalciferol (1alphaOHD3) given after the injury resulted in rapid resolution of the hyperparathyroidism. Prevention of tendon ruptures in uremia depends on effective control of secondary hyperparathyroidism. Treatment should involve prompt surgical repair and reversal of the osteitis fibrosa with an effective vitamin D metabolite such as 1alphaOHD3.

Serum ferritin concentration: a reliable guide to iron overload in uremic and hemodialyzed patients.

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.

1 alpha-hydroxycholecalciferol in hemodialysis renal osteodystrophy. Adverse effects of anticonvulsant therapy.

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.

Photon absorptiometry of bone after successful renal transplantation.

Photon absorptiometric measurements of the right lower femur were carried out at regular intervals of one to three months in 58 recipients of renal transplant. (1) During the first six months after transplant 57% showed a significant and abnormal rate of loss of bone mineral (mean 11.7% per year. +/- 1.1% S.E.M.) while 30 months' after transplantation only 17% showed such a significant loss (p=0.025). (2) Eighteen months after transplantation both male and female recipients of transplants had a significantly lower mean bone mineral index than controls (p less than 0.001). (3) Male patients who developed new post-transplant fractures had a lower mean bone mineral content compared with age and sex-matched controls taken from transplant recipients without such fractures (p less than 0.01). Similarly male patients with post-transplant fractures had a significantly longer mean period on regular haemodialysis (p less than 0.05) compared with patients without such fractures. Regular photon absorptiometric measurements provide an accurate, informative and non-invasive technique for following changes of bone mineral content after successful renal transplantation.

Ultrafiltration followed by haemodialysis. A longterm trial and acute studies.

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 oedematous patients but the number of hypotensive episodes during the combined procedure requiring intravenous 5% 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/min. 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.

Familial homozygous hypercholesterolemia: effective long-term treatment with cascade double filtration plasmapheresis.

BACKGROUND: Homozygous familial hypercholesterolemia (FH) is a rare disease with an incidence of 1 in 1 million births. It is characterized by blood cholesterol levels over 600 mg/dl and the development of extensive cutaneous xanthomata before the age of 5. Severe premature coronary artery disease results in fatal myocardial infarctions within the first two decades of life. The absence of LDL receptors makes homozygous FH resistant to treatment with most HMG-CoA reductase inhibitors, and alternative methods of removing cholesterol have been employed. METHODS: We used the ASAHI plasauto-IQ double filtration cascade plasmapheresis to treat 2 young brothers aged 14 and 11 years and 6 months for 5 years and 1 month and 3 years and 10 months, respectively. The elder brother has received 136 double filtration treatments at 2-week intervals and the younger brother 100 such treatments without complications. RESULTS: During the period of treatment the average pretreatment total serum cholesterol level for patient 1 was 442 mg/dl. The average posttreatment value was 163 mg/dl. The average fall in total serum cholesterol with each treatment was 63.2%. The mean total serum cholesterol for all the periods of treatment was calculated at 303 mg/dl. For the 2nd patient, the average pretreatment value of total serum cholesterol was 435 mg/dl. The posttreatment value was 124 mg/dl and the average fall 71.5%. The calculated mean total serum cholesterol for all periods of treatment was 280 mg/dl. CONCLUSIONS: Double filtration cascade plasmapheresis at 2-week intervals provides an effective and safe long-term treatment for patients with homozygous FH. The achieved reduction in serum cholesterol allows complete resolution of cutaneous xanthomata, arrests previous atherosclerosis, and prolongs normal life.

Clofibrate-induced muscle damage in patients with chronic renal failure.

Muscle weakness and tenderness together with a rise in serum creatine kinase (C.K.) were noted in five uraemic patients treated with 1-2 g of clofibrate ('Atromid-S') daily. Excessive accumulation of both total and free serum chlorophenoxyisobutyric acid (C.P.I.B.), the active circulating metabolite after clofibrate therapy, was found in three patients in whom it was sought. It is suggested that chronic renal failure should be regarded as a contraindication to the use of clofibrate for the treatment of any coexisting hyperlipidaemia. If such therapy is contemplated it must be cautiously instituted at low dosage and the patient monitored by regular assessment of serum C.K. and levels of both total and free C.P.I.B.

Serum alkaline phosphatase in azotemic and hemodialysis osteodystrophy: a study of isoenzyme patterns, their correlation with bone histology, and their changes in response to treatment with 1alphaOHD3 and 1,25(OH)2D3.

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.