[Hypocomplementemic urticarial vasculitis syndrome]. / Hypokomplementämisches Urtikaria-Vaskulitis-Syndrom.

HISTORY AND ADMISSION FINDINGS: A 40-year-old woman was admitted with recurrent membranoproliferative glomerulonephritis. For many years she had been suffering from joint pains and attacks of angio-oedema of the upper and lower lip. Physical examination was unremarkable except for marked oedema and urticaria of the trunk and limbs. INVESTIGATIONS: Skin biopsy revealed urticaria with vasculitis. Complement fractions C3, C4 and C1q were reduced, and C1q antibodies were demonstrated. DIAGNOSIS, TREATMENT AND COURSE: The findings of urticaria with vasculitis and reduced complement levels as cardinal symptoms together with joint pains, glomerulonephritis and C1q antibodies as minor symptoms were diagnostic of hypocomplementaemic vasculitic urticaria syndrome. The urticaria disappeared immediately when immunosuppressive treatment with prednisolone and cyclophosphamide was started, and the nephritic signs regressed. CONCLUSION: Differentiation of a vasculitic and a non-vasculitic form of chronic urticaria provides an initial step in delineating the underlying disease. Severe systemic disease such as collagen disease or vasculitis is not rare in vasculitic urticaria and requires long-term immunosuppression.

Oxidant stress in hyperlipidemia-induced renal damage.

Hyperlipoproteinemia can aggravate glomerulosclerosis and chronic tubulointerstitial (ti) damage in kidneys without primary immunologic disease. We evaluated whether the effect of hyperlipidemia on progression of renal damage differed between kidneys without preexisting glomerular disease and kidneys with mesangioproliferative glomerulonephritis and whether the renal actions of hyperlipidemia were dependent on oxidant-antioxidant balance. Hyperlipidemia was induced by high-fat and high-cholesterol diet in uninephrectomized rats. In rats without glomerulonephritis, hyperlipidemia led to a rise in glomerular and ti generation of reactive oxygen species (ROS). Oxygen radicals were mainly generated by enhanced xanthine oxidoreductase (XO), which rose with protein concentration and activity during hyperlipidemia; concurrently, glomerulosclerosis and chronic ti injury were noticed during hyperlipidemia [ti damage (% of total tubulointerstitium (TI) after 150 days): normolipidemia 0.1 +/- 0% vs. hyperlipidemia 3.4 +/- 0. 9%; P < 0.05]. In mesangioproliferative Thy-1 nephritis, ti injury was significantly accelerated by hyperlipidemia (ti damage after 150 days: normolipidemic Thy-1 nephritis 2.5 +/- 0.6% vs. hyperlipidemic Thy-1 nephritis 12.5 +/- 3.1%; P < 0.05). Antioxidant enzyme activities decreased and XO activity rose markedly in the TI (XO activity in TI after 150 days: normolipidemic Thy-1 nephritis 2.2 +/- 0.5 vs. hyperlipidemic Thy-1 nephritis 4.5 +/- 0.7 cpm/microg protein; P < 0.05). In hyperlipidemic Thy-1 nephritis rats, which had a higher urinary protein excretion than normolipidemic rats, hypochlorite-modified proteins, an indirect measure for enhanced myeloperoxidase activity, were detected in renal tissue and in urine, respectively. During hyperlipidemia, chronic damage increased in renal TI. Enhanced generation of ROS, rise in oxidant enzyme activity, and generation of hypochlorite-modified proteins in renal tissue and urine were noticed. These data suggest that oxidant stress contributed to the deleterious effects of hyperlipidemia on the renal TI.

Simvastatin in nephrotic syndrome. Simvastatin in Nephrotic Syndrome Study Group.

BACKGROUND: Hyperlipidemia of the nephrotic syndrome is a risk factor for the development of systemic atherosclerosis, but it also may aggravate glomerulosclerosis and enhance the progression of glomerular disease. HMG-CoA reductase inhibitors are effective in reducing cardiovascular morbidity and mortality. Whether they may influence the progression of glomerular disease is not clear. The Simvastatin in Nephrotic Syndrome Study addressed the question of whether or not cholesterol lowering by the HMG-CoA reductase inhibitor simvastatin was superior to placebo treatment in limiting the decline of GFR and reducing proteinuria in nephrotic patients with primary glomerulonephritis. METHODS: This was a prospective, two-year, double-blind trial that included 56 patients with primary glomerulonephritis, hypercholesterolemia due to the nephrotic syndrome (proteinuria > 3 g/24 hr), and a creatinine clearance > 40 ml/min/1.73 m2. They were randomly assigned to treatment with simvastatin or placebo targeted to achieve low density lipoprotein (LDL) cholesterol levels below 120 mg/dl. The objectives were to determine the efficacy and safety of simvastatin, the rate of GFR decline as measured by inulin clearance, and the change in proteinuria over a two-year treatment period. RESULTS: Simvastatin produced a mean change in cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides of -39% -47%, +1%, and -30%, respectively. Serum lipoprotein(a) [Lp(a)] was not affected. No major simvastatin related events occurred. Minor events included elevations in serum creatine kinase without clinical symptoms. The course of renal function and of proteinuria during the study are still under evaluation and are not given here. CONCLUSIONS: Long-term treatment with simvastatin in nephrotic patients with hypercholesterolemia is effective and safe.

Role of xanthine oxidase in passive Heymann nephritis in rats.

Passive Heymann nephritis (PHN) in rats is a model of human membranous nephropathy characterized by formation of subepithelial immune deposits in the glomerular capillary wall and complement activation. Oxygen radicals have been implicated in the subsequent glomerular damage which leads to proteinuria. This study examines the involvement of xanthine oxidase in this process. Xanthine oxidase activity was increased nearly twofold in glomeruli isolated 1 and 12 d after induction of PHN, and this was associated with increased glomerular superoxide anion generation. Analysis of glomerular samples by Northern and Western blotting revealed no quantitative changes in xanthine oxidoreductase expression in PHN, suggesting conversion of xanthine dehydrogenase to the oxidase form as the cause of increased activity. Treatment of rats with tungsten, an inhibitor of xanthine oxidase, before induction of PHN resulted in a marked decrease in glomerular xanthine oxidase activity and superoxide anion generation, and decreased proteinuria by 80% (day 12: 423+/-245 mg/d in PHN versus 78+/-53 mg/d in tungsten-treated PHN animals, P < 0.01). These findings point to a pivotal role of xanthine oxidase in the pathophysiology of PHN and could be of importance in the therapy of human membranous nephropathy.

Metabolic rates of 4-hydroxynonenal in tubular and mesangial cells of the kidney.

The degradation of the lipid peroxidation product 4-hydroxynonenal (HNE) in primary cultures of kidney tubular and mesangial cells was determined. Using various initial concentrations of the aldehyde a decline of cellular viability was found. Mesangial cells were more susceptible to the toxic effects of HNE. In consumption studies of HNE the decline of the exogenously added aldehyde was comparable in both cell types after addition of 10 and 1 micromol HNE/l. After addition of 100 micromol/l aldehyde a drastically lower HNE degrading capacity was found in mesangial cells as compared to tubular cells. The loss in the HNE degrading capacity was accompanied by an increased formation of HNE-protein aggregates as demonstrated by immunoblots. Therefore, we concluded that the low ability of mesangial cells to degrade HNE may be a factor of the toxicity of free radicals on the kidney.

[New kidney, but a sick heart. Why many patients with renal failure and kidney transplant patients die of cardiovascular disease]. / Neue Niere, aber krankes Herz. Warum viele Niereninsuffiziente und Nierentransplantierte an einer kardiovaskulären Erkrankung sterben.

Renal insufficiency and dialysis is associated with hypertriglyceridemia caused by a decreased activity of the enzyme lipoprotein lipase. Peritoneal dialysis is further complicated by hypercholesterolemia due to an increase in the synthesis of VLDL by the liver, stimulated by a rise in glucose absorption from the peritoneal dialysate. The treatment of choice is a lipid lowering diet. If necessary, fibrates should be given in a dose adjusted to the renal failure. Hypercholesterolemia should be treated with HMG-CoA reductase inhibitors. Serum cholesterol is elevated in more than one-half of the patients with glomerular disease and protein-urea. The consequences are high rate of cardiovascular disease and accelerated progression of the glomerular disease, which can also be slowed by HMG-CoA reductase inhibitors. In 60 to 80% of the patients undergoing kidney transplantation, a cholesterol level of more than 250 mg/dl induced by corticosteroids and immunosuppressants is observed. Cardiovascular mortality is high (> 50%), with hypercholesterolemia being a major risk factor. There is evidence to show that increased cholesterol levels can shorten the survival time of transplanted kidneys. The treatment of choice is HMG-CoA reductase inhibitors which, to avoid the development of rhabdomyolysis should be used at a reduced dose when given together with cyclosporine or tacrolimus.

Antioxidant-oxidant balance in the glomerulus and proximal tubule of the rat kidney.

1. Antioxidant and oxidative enzymes were examined in renal glomeruli and proximal tubules of healthy young rats (10-12 weeks old), and results were related to the superoxide anion generation of these tissues. 2. Activities of superoxide dismutases, catalase, and glutathione peroxidase were 3- to 6-fold higher in proximal tubules than in glomeruli. Similarly, enzyme levels and mRNA levels of superoxide dismutases and catalase were significantly higher in proximal tubules. 3. NADH- and NADPH-dependent oxidase activity and xanthine oxidase activity were not different in glomeruli and proximal tubules. 4. Measurements with lucigenin-enhanced chemiluminescence in vital tissues indicated 10-fold higher rates of superoxide anion in glomeruli than in tubules. 5. Compared with the young rats, tubules of 8-month-old rats had significantly higher superoxide anion rates and lower superoxide dismutase activity, whereas NADH- and NADPH-dependent oxidase activities were unchanged. 6. We conclude that considerable differences in the antioxidant-oxidant balance exist between the glomerulus and proximal tubule. Results from experiments using chemiluminescence in vital tissues suggest that changes in the antioxidant-oxidant balance have an effect on oxygen radical levels. The relevance of the observed differences to glomerular and tubulo-interstitial disease remains to be determined, but a greater susceptibility of the glomerulus to oxidant stress might be anticipated.

Reactive oxygen species and antioxidant defense in puromycin aminonucleoside glomerulopathy.

Results from several radical scavenger studies indirectly suggested an involvement of reactive oxygen species in the pathogenesis of puromycin aminonucleoside glomerulopathy. In this study, generation of reactive oxygen species was examined directly in glomeruli isolated from rats in the acute phase of puromycin aminonucleoside nephrosis and related to the changes in the glomerular antioxidant defense. Five and nine days after puromycin aminonucleoside injection, gross proteinuria, reduced creatinine clearances, and typical changes of glomerular morphology were present. Levels of reactive oxygen species were increased eightfold in glomeruli isolated 15 min after puromycin aminonucleoside injection, returned to baseline levels on days 1 and 5 after injection, and rose again to 14-fold on day 9 after injection, as determined by chemiluminescence with luminol. Further analysis of increased glomerular radical generation, using the chemiluminescence enhancer lucigenin and different radical scavengers, suggested a predominant involvement of hydroxyl radical and hydrogen peroxide in the initial increase in reactive oxygen species 15 min after puromycin aminonucleoside. Nine days after induction of nephrosis, primarily superoxide anion and hydroxyl radical were found to contribute to increased reactive oxygen species. Despite oxidative stress, antioxidant enzymes were not induced in the course of nephrosis. On the contrary, catalase and glutathione peroxidase activities declined 9 d after puromycin aminonucleoside injection. The results indicate that a transient increase in glomerular reactive oxygen species is sufficient to induce the oxidative glomerular injury observed in this model and that the glomerulus may not necessarily respond to oxidative stress with an induction of antioxidant enzymes.

Low-density lipoprotein apheresis for prevention and regression of atherosclerosis: clinical results.

Hypercholesterolemia can be adequately controlled by appropriate diet and maximum lipid lowering drug therapy in most patients. Nevertheless, there exists a group of patients, including those with familial hypercholesterolemia (FH), who remain at high risk for the development or progression of premature coronary heart disease (CHD). For these patients additional measures such as surgery and low-density lipoprotein (LDL) apheresis have to be considered. The objective of this multicenter trial, which included 30 clinical centers (28 in Germany and one each in Scotland and Luxembourg), was to determine if repeated LDL apheresis using the Liposorber LA-15 system (Kaneka Corporation, Osaka, Japan) could lead to an additional acute and time averaged lowering of total cholesterol (TC) and LDL-cholesterol (LDL-C) in severely hypercholesterolemic patients whose cholesterol levels could not be controlled by appropriate diet and maximum drug therapy. A total of 6,798 treatments were performed on 120 patients, including 8 with homozygous FH, 75 with heterozygous FH, and 37 with unclassified FH or other hyperlipidemias from 1988 through 1994. The mean TC and mean LDL-C levels at baseline were 410.0 mg/dl and 333.9 mg/dl, respectively. LDL apheresis was performed once a week or at least once every 2 weeks in all patients. During treatment with the Liposorber system the mean acute percentage reduction was 52.6% for TC and 63.1% for LDL-C. Very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) were also substantially reduced to 60.6% and 47.5%, respectively. Fibrinogen, a potential risk factor for CHD, was reduced by 26.2%. In contrast, the mean acute reduction of high density lipoprotein (HDL) was only 3.4%. During the course of the treatment, the time averaged levels of TC and LDL-C were reduced by approximately 39% and 50%, respectively, compared to baseline levels. The adverse events (AEs) were those generally associated with extracorporeal treatments. The most common AE was hypotension, with 69 episodes corresponding to 1% of all treatments reported in 44 of the 120 patients treated. All other kinds of AEs occurred in less than 0.2% of the treatments. The treatment with the Liposorber LA-15 system was overall well tolerated. It should be noted, however, that a more severe type of hypotensive reaction associated with flush, bradycardia, and dyspnea was reported in patients taking concomitant angiotensin converting enzyme (ACE) inhibitor medication. Except for such anaphylactoid-like reactions associated with the intake of ACE inhibitors, the Liposorber LA-15 system represents a safe and effective therapeutic option for patients suffering from severe hypercholesterolemia that could not be adequately controlled by diet and maximum drug therapy.

Prospective cross-over comparisons of three low-density lipoprotein (LDL)-apheresis methods in patients with familial hypercholesterolaemia.

We prospectively compared effectiveness, selectivity and biocompatibility of three LDL-apheresis methods, immunoadsorption (IMAL), dextran sulphate adsorption (DSAL) and heparin-induced extracorporeal LDL precipitation (HELP). Seven patients with familial hypercholesterolaemia were treated twice with each method in random sequence. Reduction in atherogenic lipoproteins was without significant difference: LDL -60% to -75%, VLDL -20% to -30%, triglycerides -20% to -42%. High-density lipoprotein (HDL)-cholesterol was reduced by IMAL only (-27%, P < 0.05); DSAL and HELP did not decrease HDL. Total plasma protein reduction was 13-15% with each method, indicating unselectivity. Albumin was significantly decreased by IMAL (-15%, P < 0.05) but not by the other methods. DSAL and HELP reduced fibrinogen (-40%, -58%, P < 0.0001) and other clotting factors. IMAL had almost no effect on coagulation. The white blood cell count did not change. C3 and C4 complement were decreased (-20% to -46%) by all methods. C5a complement did not increase in systemic blood, but was increased in the extracorporeal circulation of IMAL (+200%) and HELP (+150%). Plasma PMN elastase rose in all methods (+200%) indicating neutrophile degranulation. In conclusion, in this short-term study of a small patient population, effectiveness of the three LDL-apheresis methods was similar, but selectivity and biocompatibility were different. The therapeutic relevance of these differences for long-term treatment remains to be elucidated.

Extracorporeal removal of lipids by dextran sulfate cellulose adsorption.

Extracorporeal removal of low-density lipoprotein (LDL) cholesterol by dextran sulfate adsorption is indicated in patients with diet and drug resistant hyper-cholesterolemia to prevent or to regress coronary heart disease. Plasma separation is the first step in the process, followed by adsorption of LDL cholesterol and lipoprotein (a) (Lp[a]) to negatively charged dextran sulfate covalently bound to cellulose beads. The reduction per treatment in LDL cholesterol is 65-75% and in Lp(a) 40-60%. In most patients one treatment per week is sufficient to reduce mean LDL to 100-150 mg/dl. Minor side effects occur in 2-6% of treatments. Major side effects are rare. In uncontrolled studies long-term treatment was associated with inhibition of progression and induction of regression of coronary artery disease. LDL apheresis by dextran sulfate may increase blood perfusion of some tissues, and preliminary results indicate a beneficial effect on therapy resistant nephrotic syndrome with hypercholesterolemia.

Long-term performance of hemofilters in continuous hemofiltration.

We measured the filter performance of six polyamide hemofilters with a running time exceeding 72 h applied for continuous hemofiltration in intensive care patients. The sieving coefficients for urea and creatinine were close to unity and remained constant. The sieving coefficient of polyfructosan (mean molecular weight 3 kD) was around 0.75 and did not change with running time. The hydraulic permeability remained also unchanged. The relationships between blood pressure and blood flow and between blood flow and filtration rate remained linear, and the gradient did not change with time. We conclude that a daily routine change of polyamide hemofilters applied in continuous arteriovenous hemofiltration and presumably in continuous venovenous hemofiltration is not necessary within the first 72 h of treatment, unless a major decrease in the filtration rate occurs.

Characteristics of renal tubular atrophy in experimental renovascular hypertension: a model of kidney hibernation.

The inability to separate irreversible lesions of tubular epithelia from reversible tubular atrophy constitutes a major problem in histopathology and in decisions for revascularization of shrunken kidneys with renal artery stenosis. In order to characterize reversible tubular atrophy ('kidney hibernation') we studied the physiological and biochemical parameters and morphology including histochemistry in rat kidneys made atrophic by renal artery stenosis and treatment with the angiotensin-converting enzyme inhibitor, enalapril. Renal artery stenosis was induced by a 0.2-mm clip around the left renal artery. Following 7 weeks of clipping and 2 concomitant weeks of enalapril treatment, the kidney length decreased from 17.8 +/- 0.3 to 13.7 +/- 0.7 mm (mean +/- SEM). Renal blood flow and glomerular filtration rate decreased to 39 +/- 3% and to approximately 3% of control values, respectively. The activities of the intracellular proteolytic enzymes cathepsin B and L and of Na-K-ATPase in microdissected proximal tubular segments decreased to values below 50 and 10%, respectively. All changes were significant (p < 0.05). Histochemical staining for ATPase activity in the distal tubule segments remained unchanged. Tubular cells were atrophic but not necrotic. Histochemical staining of alkaline phosphatase in the tubular brush border and of acid phosphatase and peroxidase in lysosomes was greatly reduced. All observed changes were reversible within 2-3 weeks following removal of the clip and withdrawal of enalapril either with or without contralateral nephrectomy. Thus, a form of kidney hibernation with readily reversible tubular atrophy has been described. Based on this description it may be possible in consecutive experiments to differentiate between reversible and irreversible tubular atrophy.

Removal of clodronate by haemodialysis in end-stage renal disease patients.

BACKGROUND: Clodronate is a potent calcium-lowering drug. The effect of haemodialysis on clodronate pharmacokinetics is unknown. METHODS: The removal of clodronate by haemodialysis was determined in 10 end-stage renal disease patients (ESRD). A 2-h infusion of 300 mg of clodronate was followed immediately by a 4-h haemodialysis. Vascular access was by AV fistula. A 1.5-m2 cuprophane hollow-fibre dialyser was applied. Blood flow was 205 +/- 15 ml/min, dialysate flow 523 +/- 29 ml/min. Clodronate was determined by high-performance liquid chromatography in total collected dialysate, and in blood before and after the dialyser at initiation, 2 h, and 4 h of HD. RESULTS: The initial predialyser serum concentration of clodronate was 13.6 +/- 4 micrograms/ml. It decreased to 4.9 +/- 0.5 micrograms/ml and 2.6 +/- 0.5 micrograms/ml at 2 h and 4 h respectively. The clearance of clodronate (86 +/- 10 ml/min) remained unchanged during HD. Clodronate in total collected dialysate per single 4-h HD was 105 +/- 16 mg (35% of injected dose). CONCLUSION: We conclude that clodronate is effectively removed from plasma by HD. The present data together with information provided by previous studies suggest that 300 mg of clodronate given as an 2-h infusion immediately prior to haemodialysis is an adequate dosage for ESRD patients.

Minimally invasive diagnosis of renal artery stenosis by spiral computed tomography angiography.

We prospectively compared in a blinded fashion spiral computed tomography angiography (CTA) with arteriography in 62 consecutive patients with suspected renal artery stenosis (RAS). For CTA 150 ml of contrast material were injected intravenously. Arteriography was performed by DSA technique with selective catheterization of renal arteries. Of the 157 visualized renal arteries 155 could be evaluated with DSA and a total of 157 with CTA. Sensitivity of CTA for RAS > or = 50% was 98% and the specificity was 94%. Comparison of the grade of stenosis as evaluated by DSA versus CTA showed: identical gradation in 59 arteries (DSA > or = 50%/CTA > or = 50%), underestimation by CTA in one artery (DSA 50 to 75%/CTA < 50%), and overestimation by CTA in six arteries (DSA < 50%/CTA 50 to 75%). Factors that may contribute to these differences include impaired renal function and possibly "underestimation" of ostial RAS by arteriography. One artery not evaluable by arteriography showed a 70% stenosis by CTA. CTA showed no major side effects. We conclude that CTA has the same accuracy for the diagnosis of RAS > or = 50% as arteriography. However, CTA is only minimally invasive, safe, and causes less discomfort to patients.