Time as a risk factor in diabetic nephropathy.

Eighteen individuals with IDDM (type I) and diabetic nephropathy in whom the initial glomerular filtration rate (GFR) was reduced but not below 60 ml/min per 1.73 m2 were observed for an average of 3 yr. The rate of further decline of GFR was found to range between -2 and 21 ml/min/yr. The duration of diabetes until the GFR was first found to be reduced varied between 14 and 33 yr and was not correlated to the ensuing rate of decline in GFR (r = -0.13). In 10 individuals who developed uremia 40 yr or more after onset of IDDM, the development of persistent proteinuria was followed by hypertension and increased serum creatinine 2 yr later and by terminal uremia after an average of 8 yr. This is also the normal time span for individuals who develop terminal uremia after shorter duration of diabetes. We conclude that the course of clinical diabetic nephropathy is not more favorable in individuals with late onset of this complication and that there is no point at which a person with diabetes can be considered to be spared from developing diabetic nephropathy.

Body composition during long-term treatment of uremia with amino acid supplemented low-protein diet.

The influence on body composition of prolonged treatment with low-protein diet (20 g/day) supplemented with the essential amino acids and histidine was studied in 49 patients with chronic renal failure and uremic symptoms. Total body potassium (TBK) was measured with 40K in a whole-body counter. Total body water was determined with dilution of tritiated water. Predicted values for TBK and total body water were obtained from a reference population of 476 healthy subjects. In 38 patients investigated before treatment body weight was normal while mean TBK was 91% of predicted in men and 100% in women. Mean total body water was 104% of predicted in both men and women. Thirty-one patients were investigated at 3-month intervals during treatment for up to 12 months. No significant changes in mean body weight, TBK, or total body water were found. However, in 10/13 patients TBK decreased significantly, presumably due to increased catabolism in connection with intercurrent disease or insufficient energy intake. In the absence of complications long-term treatment with a low-protein diet and essential amino acids in renal failure seems to maintain body cell mass reflected in unchanged TBK.

Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function.

The pharmacokinetics of metoprolol have been studied in a group of patients with varying degrees of renal impairment and in healthy subjects after administration of 20 mg of metoprolol tartrate intravenously and 50 mg orally in a single dose and during steady-state conditions. There were no significant differences in the extent of bioavailability or rate of elimination of the drug between the 2 groups. The fraction of the oral dose systemically available during steady-state was 59 +/- 9% in the renal patients and 55 +/- 7% in the control group. Total body clearance in the patients with renal failure was 1.0 +/- 0.1 L/min and in the healthy subjects it was 0.8 +/- 0.1 L/min. The corresponding values for the elimination half-life were 4.6 +/- 1.2h and 4.1 +/- 1.0h, respectively. The beta-adrenoceptor blocking effect of metoprolol (determined as percent reduction of exercise heart rate) did not differ significantly between the 2 groups during steady-state conditions. The effect on exercise heart rate was linearly related to the log of the plasma concentration of metoprolol. The relationship was identical for the single dose and during steady-state conditions, indicating that accumulation of metabolites in patients with renal failure does not influence the beta-blocking properties of metoprolol.

Cadmium, mercury, and lead in kidney cortex of the general Swedish population: a study of biopsies from living kidney donors.

Cadmium, mercury, and lead concentrations were determined in deep-frozen kidney cortex biopsies taken from 36 living, healthy Swedish kidney donors (18 males and 18 females), who were 30-71 (mean 53) years of age. Information about occupation, smoking, the presence of dental amalgam, and fish consumption could be obtained for 27 of the donors. The samples (median dry weight 0.74 mg) were analyzed using inductively coupled plasma mass spectrometry, and the results were transformed to wet-weight concentrations. The median kidney Cd was 17 micrograms/g (95% confidence interval, 14-23 micrograms/g), which was similar in males and females. In 10 active smokers, the median kidney Cd was 24 micrograms/g, and in 12 who never smoked, it was 17 micrograms/g. The median kidney Hg was 0.29 micrograms/g, with higher levels in females (median 0.54 micrograms/g) than in males (median 0.16 micrograms/g). Subjects with amalgam fillings had higher kidney Hg (median 0.47 micrograms/g, n = 20) than those without dental amalgam (median 0.15 micrograms;g/g, n = 6), but kidney Hg was below the detection limit in some samples. Nearly half of the samples had kidney Pb below the detection limit. The median kidney Pb was estimated as 0. 14 micrograms/g. This is the first study of heavy metals in kidney cortex of living, healthy subjects, and the results are relatively similar to those of a few previous autopsy studies, indicating that results from autopsy cases are not seriously biased in relation to kidney metal concentrations in the general population. Cd concentrations in those who never smoked were relatively high, indicating considerable Cd intake from the diet in Sweden. The effect of dental amalgam on kidney Hg was as expected, although the reason for the difference in Hg levels between males and females is unclear.

Progression of renal failure: role of apolipoprotein B-containing lipoproteins.

Plasma lipoproteins (LP) may be identified on the basis of density properties or apolipoprotein (apo) composition. ApoB-containing LP occur in VLDL, IDL and LDL. There are several types of apoB-containing LP characterized by specific composition of minor apolipoproteins (apoC, apoE etc.) and lipid constituents (triglycerides and cholesterol), metabolic properties and relative atherogenicity. The alterations of lipoprotein metabolism in renal disease resulting in elevated levels of apoB-containing LP may be reflected in hyperlipidemia. Whereas nephrotic syndrome and heavy proteinuria are associated with increased formation of cholesterol-rich apoB-containing LP in LDL and VLDL, the characteristic feature in renal failure is the accumulation of intact or partially metabolised triglyceride-rich LP in IDL and VLDL. The potentially atherogenic apoB-containing LP have been linked to the pathogenic processes that result in progressive glomerular and interstitial lesions and ultimate loss of renal function. The mechanisms of injury are not fully understood. Receptor- and non-receptor mediated uptake of LP by mesangial cells may induce or accelerate proliferative and sclerotic processes in the glomerular mesangium that are analogous to atherosclerosis in the arterial wall. Changes in glomerular permeability can result in increased filtration of LP that may be internalized by tubular cells and elicit corresponding lesions in the interstitial tissues. The negative impact of proteinuria on the prognosis of renal disease could be mediated in part through an increased filtration of lipoproteins. Induction of hyperlipidemia accelerates glomerular and interstitial damage in experimental renal failure. This can be attenuated by treatment with hypolipemic agents. In patients, increased concentrations of apoB-containing LP are associated with more rapid progression of renal insufficiency in both primary renal disease and diabetic nephropathy. It is, however, presently not known to what extent treatment of the renal dyslipidemia can modify the progression of chronic renal failure. Experimental and clinical evidence suggest that apoB-containing LP may play a pathogenetic role in the progression of renal disease.

Lipoprotein abnormalities as a risk factor for progressive nondiabetic renal disease.

Renal disease is accompanied by characteristic alterations of lipoprotein metabolism, which appear as a consequence of nephrotic syndrome or renal insufficiency and are primarily reflected in an altered apolipoprotein profile rather than elevated plasma lipid levels. Their full characterization requires identification of discrete lipoprotein particles. While nephrotic syndrome results in increased concentrations of both cholesterol- and triglyceride-rich apoB-containing lipoproteins, renal insufficiency is characterized by an accumulation of intact or partially metabolised triglyceride-rich apoB-containing lipoproteins. The dyslipidemia has been discussed as a contributory factor for the progression of renal insufficiency through development of glomerulosclerosis and tubulointerstitial lesions together with accelerated atherosclerosis. Several experimental studies have shown that hyperlipidemia accelerates renal damage. Lipid-lowering treatment can reduce renal lesions and preserve renal function. The documentation in human nondiabetic progressive renal insufficiency is more limited. We have found that increased concentrations of triglyceride-rich, but not cholesterol-rich, apoB-containing lipoproteins are, associated with a more rapid loss of renal function. The underlying pathophysiological mechanisms for the relation between triglyceride-rich apoB-containing lipoproteins and progression of renal insufficiency are not fully understood. Treatment with hypolipemic drugs may attenuate the renal dyslipidemia, but thus far there have been no reports about controlled clinical trials testing the possible effect of such treatment on the progression of renal insufficiency. In summary, there is evidence to suggest that some specific lipoprotein abnormalities are a risk factor for the progression of renal dysfunction, but the final test of such assumptions still rests on the results of urgently needed controlled intervention studies.

Lipid and carbohydrate metabolism in uremia. Influence of treatment with protein-reduced diet and essential amino acids.

The effects of low protein diet on lipid and carbohydrate metabolism in uremia were investigated in 22 patients treated during a period of 3--18 months (mean 9.5 months). Before treatment, the patients showed elevated serum triglycerides, low alpha-lipoprotein cholesterol and reduced glucose elimination rate. There were no major changes in mean serum lipid or carbohydrate metabolism variables during treatment. The arachidonic acid content of lecithin decreased while linoleic acid increased during treatment. While the dietary treatment was effective in ameliorating uremic symptoms, it did evidently not influence the deranged lipid/carbohydrate metabolism.

Protein-reduced diet in diabetic renal failure.

The effect of treatment with a protein-reduced diet (20-30 g/day) and essential amino acids was studied in 21 patients with diabetes mellitus and renal failure. The mean treatment time was 5.0 (0.5-14) months. Most patients experienced considerable amelioration of their uremic symptoms and the mean serum value was reduced by 50% of the initial value during treatment. Residual renal function continued to decrease during treatment. Vigorous treatment of fluid retention and hypertension was a prerequisite for a successful course and may also have decreased the rate of progression towards dialysis. Compliance with the diet was not different from that found in non-diabetic uremic patients. Satisfactory control of blood glucose levels was obtained with no or only minor adjustments of the insulin dosage. It is concluded that dietary therapy should be considered in diabetic patients with renal failure for treatment of uremic symptoms.

Growth during treatment with low-protein diet in children with renal failure.

Fourteen children, 10 boys and 4 girls, with chronic progressive renal failure were treated with a low-protein (0.4-2 g/kg body wt and maximum 20 g/day), high-energy diet (55-130 kcal/kg body wt) and supplemented with essential amino acids and histidine (0.21-0.5 g/kg body wt). The mean age at the onset of treatment was 9.9 years (5.5 months - 15.3 years), mean serum creatinine 461 mumoles/1 (167-1110) and mean BUN 60.2 mmoles/1 (20-83). Indications for treatment were incipient or manifest growth retardation. A 50% reduction of BUN was found after about 2 weeks of treatment while serum creatinine remained unchanged. BUN remained decreased during therapy despite further increase of serum creatinine. The mean duration of treatment was 21 months (range 4-48). Increasing appetite and vitality were found after introduction of the diet, which was well accepted by most of the children while their general condition remained satisfactory. The earlier decrease of growth rate was interrupted and a linear or almost linear growth within the SD-scores at onset of treatment was seen in 10 of the 14 children. Three children had a reduced growth rate and one child did not grow at all during treatment. Signs of osteodystrophy did not improve during the diet. It is speculated that the protein restriction has a detoxifying effect, which together with supplementation of amino acids and a high energy supply could in part correct the metabolic disturbances and provide an opportunity for anabolism and growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Dyslipidemia in peritoneal dialysis--relation to dialytic variables.

OBJECTIVE: To investigate whether the specific lipoprotein (LP) abnormalities of peritoneal dialysis (PD) are associated with functional variables of this mode of dialysis. DESIGN: A survey of the LP profile in relation to peritoneal dialysis capacity (PDC) variables. The LP profile was compared to that of a group of age- and sex-matched controls. SETTING: The Peritoneal Dialysis Unit at Sahlgrenska University Hospital in Gothenburg, Sweden. PATIENTS: Twenty-two nondiabetic PD patients (5 women, 17 men) who had been on PD for at least 6 months. MAIN OUTCOME MEASURES: The LP profile included plasma lipids, apolipoproteins (Apo), and individual ApoA- and ApoB-containing LP. The PDC measurement determined peritoneal glucose uptake, protein losses, effective peritoneal surface area, and total weekly creatinine clearance. RESULTS: The patients had been on PD for 6 to 48 months (mean 15.3 months) and had a total weekly creatinine clearance of 69.7+/-13.3 L/1.73 m2 body surface area, an average peritoneal glucose uptake corresponding to 446+/-162 kcal/24 hour, and a protein loss of 8.1+/-2.5 g/24 hr. The patients had significantly higher total cholesterol (7.1 mmol/L),VLDL-cholesterol (1.0 mmol/L), LDL-cholesterol (4.7 mmol/L), and triglyceride levels (2.5 mmol/L); whereas the HDL-cholesterol level (1.2 mmol/L) was significantly lower than in controls. The PD patients had increased levels of ApoB-containing LPs, both of the cholesterol-rich LP-B and of the triglyceride-rich LP-B complex, reflected in higher plasma concentrations of ApoB, ApoC-III, and ApoE. Furthermore, they had significantly lower levels of LP-A-I:A-II, as well as of ApoA-I and ApoA-II. The LP-A-I:A-II and ApoA-II levels correlated inversely with the duration of PD treatment (r = 0.54, p < 0.01 and r = 0.52, p < 0.05, respectively). The ApoA-II level was inversely correlated with the peritoneal surface area (r = 0.53, p < 0.05). There were no other correlations between LP variables and PDC variables, nor did any of the LP variables correlate with peritoneal glucose uptake or protein losses. CONCLUSION: The proatherogenic lipoprotein profile of patients on PD is characterized by increased concentrations of cholesterol-rich and triglyceride-rich ApoB-containing LPs. While the duration of treatment appears to have some influence on the development of this type of dyslipidemia, the pathophysiological links to the dialysis mode must be further explored.

First clinical experience with a new concentrate system for dialysis with dry sodium chloride.

Clinical investigation of a new concentrate system for preparing the acid concentrate in bicarbonate dialysis was performed to evaluate handling, safety aspects, and correct mixing of the final dialysis fluid. The system is characterized by an acid concentrate prepared from two components: a cartridge containing 1.1 kg dry sodium chloride and a concentrate bag with 500 ml of a highly concentrated solution of electrolytes (KCl, MgCl2, CaCl2) and acetic acid. The investigation comprised a total of 142 treatments. The concentrate system was well accepted by the clinical staff and considered safe and easy to handle. Marginal deviations in electrolyte concentration of the dialysis fluid relative to set values were observed, but were considered to lack biologic or clinical relevance. The new concentrate system will facilitate the handling of dialysis concentrates and provide a convenient means for individual tailoring of the dialysis fluid composition.

Do high-flux dialysis membranes affect renal dyslipidemia?

High-flux hemodialysis has been reported to attenuate renal dyslipidemia. To evaluate the contribution of dialysis membrane composition per se, we compared the impact on the lipoprotein profile of hemodialysis (HD) with a conventional cellulose dialysis membrane with that of a synthetic high-flux dialysis membrane in standard hemodialysis mode. Forty-two patients (24 men, 18 women; mean age, 69 years; range, 39-85 years) on maintenance HD with cellulosic dialysis membranes were randomized and stratified for diabetes mellitus to 12 weeks of HD treatment with either a cellulose acetate (CA; n = 23) or polyacrylonitrile (AN69; n = 19) membrane. HD was performed in a conventional low-flux standard HD mode 4-6 hours/session. Plasma levels of lipids (TC, TG), apolipoproteins (A-I, B, C-III, E), lipoprotein (a) (Ip(a)), and individual apoA and apoB containing lipoproteins (LP-A-I, LP-A-I:A-II, LP-B, LP-Bc) were determined. At baseline, the AN69 group had slightly higher plasma concentrations of apoC-III and C-III/HS, but there were no other differences at entry in study variables between the treatment groups. Twelve week treatment with an AN69 membrane did not result in any significant changes in lipoprotein profile compared with treatment with a cellulose acetate membrane. HD with AN69 dialysis membranes in the conventional low-flux standard hemodialysis mode does not affect the lipoprotein profile.

Proteinuria and renal function in kidney transplant donors 10-18 years after donor uninephrectomy.

Ten to eighteen years after donor uninephrectomy (UN) the compensatory increase in renal function is maintained. Albuminuria was slightly increased in a few donors compared to the controls. We found no evidence for donor uninephrectomy to carry a risk for progressive renal failure. Further studies 2-3 decades after UN will provide additional insight in how UN affects the development of proteinuria and renal function.

Dual PPAR α / γ Agonism Normalizes Lipoprotein Profile of Renal Dyslipidemia.

Chronic kidney disease (CKD) is characterised by specific lipoprotein abnormalities and insulin resistance. Dual activation of the peroxisome proliferators-activated receptors (PPAR) α and γ can significantly improve insulin sensitivity. The aim of the study was to investigate the effects of a dual PPAR α / γ agonist on lipoprotein abnormalities in patients with CKD. One mg of the dual PPAR α / γ agonist tesaglitazar was given once daily during six weeks to CKD patients, and to healthy subjects. Plasma lipids, apolipoproteins (apo) and discrete lipoprotein subclasses were measured at baseline and end of treatment. In the CKD patients apoA-I increased significantly by 9%, and apoB decreased by 18%. There was an increase of apoC-III in HDL by 30%, and a parallel decrease of apoC-III in VLDL + LDL by 13%. Both the apoB-containing cholesterol-rich and the triglyceride-rich subclasses decreased significantly. With the exception of ApoC-III,all plasma lipids apolipoproteins and lipoprotein subclasses were reduced by treatment down to similar levels as the baseline levels of a healthy group of reference subjects. This study suggests that by improving insulin sensitivity a dual PPAR α / γ agonist has the potential to normalise most of the lipoprotein abnormalities in patients with CKD.