The pathogenesis of secondary hyperparathyroidism of renal failure. Is there a controversy?
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Biomedical subjects
Publications and source records attributed to E Ritz.
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Osteocyte ultrastructure was studied in the cortical bone of the tibia of rats after acute or chronic administration of supraphysiological doses of PTH. Confirming previous reports, an increase in the width of the cytoplasm with the appearance of numerous thin cytoplasmic processes, an increase in rough ergastoplasmic reticulum and Golgi apparatus, an increase in lacunar width and lysis of the lacunar wall ("brush border" after Bonucci) were observed. Particularly striking was the appearance of numerous microfilaments and microtubules in the cytoplasm of activated osteocytes. The appearance of microfilaments, often densely packed in cytoplasmic processes or running parallel to the plasma membrane, points to a role of the cytoskeleton in mediating the effects of PTH on conformational changes of the plasma membrane (and possible on cell motility); microtubules were particularly prominent in the Golgi field and are presumably involved in the exocytosis of lysosomes. Another striking feature was the non-random distribution of periosteocytic osteolysis along the lacunar perimeter. Osteolysis was particularly pronounced at the cell pole opposite to the cell nucleus. After chronic administration of PTH, autolysis of osteocytes, associated with signs of excessive periosteocytic osteolysis, was frequently encountered.
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Lipid metabolism was studied in experimental uremia. Uremic (U) rats were compared with sham-operated, pair-fed (PF) controls and with ad-lib-fed (AL) controls. In U animals, fasting glucose concentrations were normal, immunoreactive serum insulin (IRI) levels were decreased, and immunoreactive glucagon levels were increased. A significant increase in the serum concentration of all lipid classes was observed: triglycerides were elevated 10-fold above the values in PF and AL controls; phospholipids, twofold; total cholesterol, threefold; and free cholesterol, sixfold. Cholesterol concentration was increased in beta- and pre-beta-lipoproteins and even more so in alpha- and pre-alpha-lipoproteins. There was an increase in the ratio of free cholesterol/total cholesterol. The fatty acid composition of serum lipoproteins was unchanged. Concomitantly, in liver tissue, there was no change in lipid content (triglyceride, cholesterol) and fatty acid composition. These findings argue against glucose- or insulin-mediated changes in hepatic de novo fatty acid synthesis, chain elongation, or poly-desaturation. In U animals, the HMG-CoA-reductase activity of liver microsomes was slightly, but not significantly, reduced as was tritiated water incorporation into cholesterol in isolated perfused liver preparations. In adipose tissue, there was a decrease in triglyceride content. The results provide evidence against insulin-mediated hepatic overproduction as a major cause of hyperlipoproteinemia in this model of experimental renal insufficiency and point to peripheral under-utilization of lipoproteins.
X-ray films of the hand skeleton (mammography technique), serum chemistry, and quantitative bone histology (micromorphometry of undecalcified sections, iliac crest spongiosa) were compared in 25 patients on maintenance hemodialysis. The X-ray findings correlated better with serum PTH levels than with bone histology. Of all radiological signs of renal osteodystrophy, pronounced subperiosteal resorption (radial aspect, second finger, middle phalanx) and periosteal new bone formation (middle phalanx) correlated best with histological indicators of osteitis fibrosa. These signs were never seen in control patients. Acroosteolysis (endphalanx) and intracortical or endosteal resorption (middle phalanx) were less specific (i.e., seen even in the absence of metabolic bone disease) and correlated less with bone histology. Osteosclerosis in iliac cancellous bone was paralleled by abnormal texture of spongy bone in the proximal metaphysis of the middle phalanx (second finger).
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Acceleration of growth of uremic children after administration of vitamin D has been demonstrated by various authors. This has been attributed to healing of skeletal lesions. Clinical observations suggest that vitamin D has also an effect on food intake perhaps associated with improvement of vitality. This could be confirmed in an experimental study in which uremic rats (subtotal nephrectomy) with and without vitamin D supplementation were compared with sham-operated pair-fed control rats with and without vitamin D supplementation. In uremic animals supplemented with vitamin D, weight gain and growth were significantly greater than in uremic animals on the control diet. Both with and without vitamin D supplements, weight gain and growth rate were greater in sham-operated pair-fed control than in the corresponding uremic animals. Histological abnormalities in the growth zone of uremic rats were markedly reduced by vitamin D. Since food intake was greater in vitamin D-treated uremic animals than in nonvitamin D-treated uremic animals, the increase in growth rate under vitamin D cannot be attributed exclusively to the skeletal effects of vitamin D. This study demonstrates important extraskeletal actions of vitamin D which may be associated with or causally related to the improvement of growth.
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Protein-restricted diets are widely used in the dietary management of uremia. These diets are undoubtedly effective in ameliorating many aspects of the uremic syndrome. However, there is no consensus as to whether diets providing less than 0.6 g/kg per day of protein are nutritionally adequate and capable of preventing the wasting syndrome. Wasting is common in the adult patient with renal insufficiency as is growth failure in the uremic child. There is some evidence that wasted patients do less well on hemodialysis and are more prone to infection. Experimental studies in uremic animals point ot diminihsed efficiency of utilization of protein, increased gluconeogenesis from animo acids, and increased catabolism of protein in the fasting state; in addition, the metabolism of a number of individual amino acids is altered in uremia. In view of these multiple abnormalities, it would seem unwise to routinely provide less than the Recommended Daily Allowances of protein. More recent developments, i.e., supplementation of essential amino acids and perhaps alpha keto acids, may provide useful alternatives. One important aspect of dietary management, i.e. prevention of hyperlipidemia, has attracted surprisingly little attention so far. Therapy with protein restricted diets in nondialyzed uremic patients has to compete with other modalities of treatment currently available, i.e., hemodialysis and transplantation, in providing optimal medical rehabilitaiton of the patient.
24 patients with renal transplants were studied beyond the immediate postoperative period (greater than 8 weeks p.o.) for a period of 6 months in three weekly intervals. Quantitative bacteriology (dip slide method) and immunofluorescence microscopy (antibody coating of urinary bacteria) of the urine were regularly performed. Urinary tract infection was found in 13 of 24 patients, being permanent in 9 and episodic in 4 of the patients. There was no correlation between presence of urinary tract infection and deterioration of renal function. Mixed infection was found in 7 of the 13 patients and monoinfection in the others. In 7 out of these 13 patients, antibody coating of urinary bacteria could be demonstrated by immunofluorescence microscopy. In 3 of the 7 cases with antibody coating, this was permanently positive, in the other 4 it was intermittently positive. In only 1 case could conversion to positive antibody coating be attributed to urological complications (pyelostomy). Both IGG and IGA were demonstrable in 6 of 7 cases with positive antibody coating and IGG exclusively was demonstrable in 1 more case. IGM was questionably positive in 1 case and complement (beta1C) could not be demonstrated in any of the patients. This investigation shows that despite immunosuppression patients with renal transplants are able to mount an immune response against urinary tract infections.
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