Z. Varghese

LIPID NEPHROTOXICITY IN CHRONIC PROGRESSIVE GLOMERULAR AND TUBULO-INTERSTITIAL DISEASE

It is hypothesised that chronic progressive kidney disease may be mediated by abnormalities of lipid metabolism. A series of self-perpetuating secondary events follows an initial glomerular injury. Increased glomerular basement membrane permeability leads to loss of lipoprotein lipase activators, resulting in hyperlipidaemia. Circulating low-density lipoprotein binds with glycosaminoglycans in the glomerular basement membrane and increases its permeability. Filtered lipoprotein accumulates in mesangial cells and stimulates them to proliferate and produce excess basement membrane material. The proximal tubular cells metabolise some of the filtered lipoprotein and the remainder are altered on passage down the nephron. Luminal apoprotein precipitates, initiating or aggravating tubulo-interstitial disease, if the intraluminal pH is close to the isoelectric point of the apoprotein. The hypothesis offers new approaches to the study of chronic progressive kidney disease by proposing a major pathogenetic role for lipid abnormalities.

Insulin Resistance and Iron Overload

Glucose tolerance tests performed in 15 patients (10 males and 5 females, age range 6–34 years, mean 16 years) with transfusional iron overload revealed fasting and subsequent blood glucose concentrations within the normal range in all except one patient who was overtly diabetic. However, in all patients except one, blood glucose concentration at 2 hours was higher than the respective fasting glucose concentration. All but two of the patients (one of whom was diabetic) showed fasting and post glucose hyperinsulinism. All the patients had hepatic dysfunction of varying severity. It is hence suggested that the initial disturbance of carbohydrate metabolism in transfusional siderosis is insulin resistance, similar to that found in chronic liver disease. Overt diabetes is probably a later event, occurring when sufficient damage to pancreatic cells has occurred and appropriate hyperinsulinaemia cannot be sustained.

HYPOPHOSPHATAEMIC OSTEOMALACIA AFTER CADAVERIC RENAL TRANSPLANTATION

Abstract Seven patients with functioning renal transplants were found to have serum-inorganic-phosphate levels below normal, and five of them had X-ray evidence of osteomalacia Evidence for a phosphate leak came from abnormal high values for phosphate clearance and correspondingly low values for tubular reabsorption of phosphate. There was a slight metabolic acidosis. The cause of the phosphate leak is uncertain, but it could be that in these patients the proximal tubule is unduly sensitive to normal levels of parathyroid hormone.

Nephrotoxicity of ionic and non-ionic contrast material in digital vascular imaging and selective renal arteriography.

We assessed the nephrotoxicity of ionic and non-ionic radiocontrast material (CM) in two groups of patients in a prospective study. One group of 25 potential live kidney donors was studied following conventional renal angiography, carried out as part of the routine pre-operative assessment. The other group of 49 renal transplant patients with varying degrees of renal impairment was studied following digital vascular imaging carried out for investigation of hypertension. Plasma creatine, urinary N-acetyl-D-glucosaminidase (NAG), urinary microglobulin (B2M) and urinary protein excretion were measured before and after the imaging procedure. There were no significant changes in these parameters following digital vascular imaging, but there were increases in plasma creatinine (p less than 0.005) and urinary NAG creatinine ratio (p less than 0.002) in the conventional angiography group following the procedure. Substantial proteinuria developed in 35% of patients following conventional angiography. The differences in nephrotoxicity of radiocontrast agents during the two procedures could not be accounted for by the dose of material used, but probably reflect the effect of differences in the route of administration on the maximal concentration of the material reaching the kidney. Non-ionic radiocontrast material proved less toxic than ionic and may be preferable in conventional angiography.

Vitamin A toxicity and hypercalcaemia in chronic renal failure.

Serum vitamin A concentrations were measured in 38 patients undergoing haemodialysis, 24 of whom were taking multivitamin preparations containing vitamin A. Vitamin A concentrations were significantly higher in patients undergoing haemodialysis than in 28 normal controls (p less than 0.001). Patients taking vitamin A supplements had significantly higher vitamin A concentrations than those not taking them (p less than 0.05), and hypercalcaemic patients had higher concentrations than normocalcaemic patients (p less than 0.005). Withdrawal of vitamin A supplements in seven patients caused significant falls in serum vitamin A concentrations and plasma calcium concentrations (p less than 0.01 at two and three months in both cases) and in plasma alkaline phosphatase concentrations (p less than 0.01 at two months). Vitamin A toxicity can contribute to hypercalcaemia in patients undergoing haemodialysis, probably by an osteolytic effect. Multivitamin preparations containing vitamin A should therefore be prescribed with caution in these patients.

THREE YEARS' EXPERIENCE OF CONTINUOUS AMBULATORY PERITONEAL DIALYSIS

Patients on continuous ambulatory peritoneal dialysis (CAPD) were studied for three years. 29 of them who had been on CAPD for six months or more were compared with patients on intermittent peritoneal dialysis (IPD) and on haemodialysis (HD). CAPD patients had significantly higher levels of HDL-cholesterol than HD patients. Urea, potassium, phosphate, and urate levels were significantly lower, and haemoglobin levels significantly higher, than in the IPD and HD groups. 43 CAPD patients studied had a peritonitis rate of 2.22 episodes per patient-year. CAPD offers an alternative form of dialysis to those unsuitable for HD, but until peritonitis rates can be reduced CAPD cannot rival HD as a long-term treatment.

Parenteral 1,25-dihydroxycholecalciferol in hepatic osteomalacia.

Despite regular long-term parenteral vitamin D2 treatment, four patients with biliary cirrhosis had multiple symptoms of bone disease and bone biopsy specimens showed osteomalacia without osteoporosis. Three patients also had a proximal myopathy. Plasma calcium values (after correction for albumin), phosphorus, magnesium, and serum 25-hydroxy-vitamin D were within normal limits. Treatment with 1,25-dihydroxy-cholecalciferol (1,25-(OH)2D3) relieved symptoms in three of the four patients and improved those in the fourth. Histological examination of bone showed improvement in all four patients, but serum and urinary biochemical changes were not pronounced. We conclude that 1,25-(0H)2D3 treatment has a beneficial effect on bone and muscle in hepatic osteomalacia, either because vitamin D 1-hydroxylation fails in biliary cirrhosis or because hepatic osteomalacia is resistant to vitamin D2 metabolites.

PERSISTENT HYPOPHOSPHATÆMIA AND OSTEOMALACIA IN DIALYSIS PATIENTS NOT ON ORAL PHOSPHATE-BINDERS: RESPONSE TO DIHYDROTACHYSTEROL THERAPY

Four patients who had been on regular haemodialysis for periods of 3 1/2 to 7 years became hypophosphataemic with plasma-phosphate concentrations of 2.5 mg/dl or less before dialysis. None of them had been taking oral phosphate-binders for 2 years or more. Histologically all the patients had an excess of osteoid on bone biopsy. Intestinal absorption of phosphate and calcium was impaired, despite normal or high serum-25-hydroxycholecaliferol concentrations. Treatment with oral dihydrotachysterol resulted in corrections of the phosphate malabsorption and increases in plasma-phosphate concentration. The initial low plasma-phosphate values in these patients before dialysis probably reflected a state of phosphate depletion caused by the combination of malabsorption, loss during dialysis, and a low dietary intake.

Plasma hydroxyproline fractions in patients with dialysis osteodystrophy

Plasma hydroxyproline fractions were measured in 17 normal subjects and in 54 patients on maintenance haemodialysis therapy (MHT) with various degrees of dialysis osteodystrophy. On the basis of both radiological and histological findings these patients were divided into three groups: radiologically normal, histologically normal and those with osteitis fibrosa. The mean total plasma hydroxyproline concentrations were significantly elevated in all groups of MHT patients. However, these increases were mainly due to peptide-bound and free hydroxyproline fractions. The highest values for these two fractions were found in patients with osteitis fibrosa. The free to peptide-bound hydroxyproline ratio was not significantly altered in the majority of patients on dialysis; the mean ratio was significantly lower in patients with osteitis fibrosa when compared with patients with no histological evidence of bone disease. This finding would suggest that there is no inhibition of hydroxyproline catabolism in patients on haemodialysis and the measurements of both free and peptide-bound hydroxyproline were equally sensitive in identifying patients with osteitis fibrosa.

In Vitro Cyclosporine Toxicity: The Effect Of Verapamil

The epithelial cell line LLC-PK1, which expresses many proximal tubular characteristics, was used to investigate the relationship between calcium, the calcium channel blocker verapamil, and cyclosporine toxicity. The LLC-PK1 cells took up cyclosporine when this was added in a concentration of 2 micrograms/ml, and this uptake was maximal at 30 min (112 +/- 3 ng cyclosporine/mg cell protein). At 12 micrograms/ml it inhibited the sodium glucose cotransporter, as assessed by phlorizin-inhibitable 14C-alpha-methyl glucopyranoside (alpha-MG) uptake (control 37.2 +/- 6.3, 12 micrograms/ml 21.2 +/- 1.1 mumol/hr/mg protein). Cyclosporine at 2 micrograms/ml did not affect cell growth after 5 days (control 945 +/- 60 micrograms cell protein per 25 cm2 flask, 2 micrograms/ml cyclosporine/ml 1046 +/- 32 micrograms protein/flask), even in the presence of 7.6 mM ionized calcium (862 +/- 37 micrograms protein/flask). Cyclosporine at 12 micrograms/ml inhibited cell growth (286 +/- 27 micrograms protein/flask), and raising the ambient ionized calcium concentration to 7.6 mM reduced cell growth further (91 +/- 6 micrograms protein/flask). Cyclosporine at concentrations of 2 and 12 micrograms/ml produced increasing cell vacuolation, as seen in vivo. Short-term uptake of 2 micrograms/ml cyclosporine could be inhibited by 1.0 mM and 0.5 mM verapamil (49 +/- 9.5 and 71 +/- 6.4 ng cyclosporine/mg cell protein, respectively, at 30 min). However, in the presence of 2 micrograms/ml cyclosporine 0.1 mM verapamil was toxic to the cells grown over five days (44 +/- 5 micrograms protein/flask). At 0.01 mM verapamil was not toxic to cell growth (921 +/- 29 micrograms protein/flask), but raising the medium calcium to 7.6 mM reduced cell growth (652 +/- 96 micrograms/ml). Inhibition of cyclosporine uptake did not occur with 0.01 mm verapamil (control 145.6 +/- 12.3 vs. 0.01 mM verapamil 150.4 +/- 3.8 ng cyclosporine/mg cell protein). The LLC-PK1 cell line represents a good in vitro model for cyclosporine renal tubular toxicity, as the in vivo observation of glycosuria and proximal tubular cell vacuolation in cyclosporine nephrotoxicity can be reproduced. In vitro this is shown to be associated with inhibition of sodium-dependent glucose cotransport. Verapamil inhibited cyclosporine uptake, but only at concentrations that were toxic to the cells. Verapamil potentiated rather than reduced the increased cyclosporine toxicity produced by increasing the medium calcium concentration. The suggested protective effect of verapamil against cyclosporine nephrotoxicity is therefore unlikely to be due to inhibition of cyclosporine uptake or of calcium entry into proximal tubular cells.