No abstract

Objective. To examine the relationship between changes in anti-double-stranded DNA (anti-dsDNA) antibody levels and the risk of renal flare in patients with systemic lupus erythematosus (SLE), using data from 2 randomized, controlled trials.Methods. Analyses were based on 487 patients with SLE and a history of lupus nephritis who had an anti-dsDNA antibody titer >15 IU/ml at baseline, as measured by Farr assay. Results are presented for the combined population of patients, the placebo arms, and the drug treatment arms in which a dsDNA-based bioconjugate (abetimus sodium; LJP 394) was used.Results. Changes in anti-dsDNA antibody levels were inversely correlated with changes in the C3 level (P < 0.0001 in both trials). Cox proportional hazards regression models showed that changes in anti-dsDNA antibody levels correlated with the risk of renal flare. The models predicted that a point estimate of a 50% reduction in anti-dsDNA antibody levels is associated with a 52% reduction (95% confidence interval [95% CI] 26-68%, nominal P ‫؍‬ 0.0007) and a 53% reduction (95% CI 33-69%, nominal P < 0.0001) in the risk of renal flare in the 2 trials, respectively. In the 2 trials, the incidence of renal flare was lower in patients with sustained reductions in anti-dsDNA antibodies (3.0% and 4.1%, respectively) than in patients with stable or increasing antibody levels (21.3% and 20.3%, respectively).Conclusion. Changes in anti-dsDNA antibody levels were directly correlated with the risk of renal flare and inversely correlated with changes in the C3 level. Reducing anti-dsDNA antibody levels may represent a therapeutic objective in SLE patients with lupus nephritis, because it is associated with a reduced risk of renal flare.Anti-double-stranded DNA (anti-dsDNA) antibodies are diagnostic for systemic lupus erythematosus (SLE) (1) and have been implicated in the underlying pathogenesis of SLE renal disease and other disease manifestations (2-7). Immune complexes containing anti-

We studied renal function in 13 patients with obstructive uropathy and hyperkalemic metabolic acidosis to characterize the pathogenesis of this disorder. Base-line fractional potassium excretion was lower in all patients than in controls with similar glomerular filtration rates. Acetazolamide was given to 11 patients but failed to increase fractional potassium excretion to normal. In five patients, impaired potassium excretion was associated with decreased ammonium excretion, a urinary pH below 5.5 (5.18 +/- 0.07, mean +/- S.E.M.), and aldosterone deficiency. In the remaining eight patients, the urinary pH did not fall below 5.5 (6.4 +/- 0.2) with acidosis, and we failed to lower the urinary pH and increase fractional potassium excretion to normal by administering a mineralocorticoid and sodium sulfate. A syndrome of hyperkalemic distal renal tubular acidosis may occur in patients with obstructive uropathy. In some patients, this syndrome results from a defect in hydrogen and potassium secretion in the distal nephron rather than from aldosterone deficiency. Obstructive uropathy should be included in the differential diagnosis of hyperkalemic acidosis and renal insufficiency.

The utility of bicarbonate administration to patients with severe metabolic acidosis remains controversial. Chronic bicarbonate replacement is obviously indicated for patients who continue to lose bicarbonate in the ambulatory setting, particularly patients with renal tubular acidosis syndromes or diarrhea. In patients with acute lactic acidosis and ketoacidosis, lactate and ketone bodies can be converted back to bicarbonate if the clinical situation improves. For these patients, therapy must be individualized. In general, bicarbonate should be given at an arterial blood pH of < or =7.0. The amount given should be what is calculated to bring the pH up to 7.2. The urge to give bicarbonate to a patient with severe acidemia is apt to be all but irresistible. Intervention should be restrained, however, unless the clinical situation clearly suggests benefit. Here we discuss the pros and cons of bicarbonate therapy for patients with severe metabolic acidosis.

AB STR A CT The ability of the kidney to reabsorb bicarbonate is held to be a function of plasma C02 tension, carbonic anhydrase activity, and potassium stores. The effects of alterations of extracellular volume on bicarbonate reabsorption were studied in dogs whose arterial Pco2 was kept constant at 40 mm Hg (range 35-45 mm Hg).The effect of extracellular volume expansion was studied in dogs receiving hypertonic bicarbonate and isotonic saline, isotonic saline alone (two of the animals in this group received HCO to lower the plasma bicarbonate concentration), and isotonic bicarbonate. The results were similar in each group. Extracellular volume expansion depressed bicarbonate reabsorption. This depression was related not to changes in -glomerular filtration rate (GFR) or bicarbonate concentration, but to the increase of fractional sodium excretion. In addition, volume expansion with bicarbonate increased chloride excretion.Bicarbonate loading was performed in tvo groups of dogs in which effective expansion of extracellular volume was minimized by hemorrhage or acute constriction of the thoracic vena cava. Both groups demonstrated enhanced bicarbonate reabsorption relative to that seen in the volume-expanded groups. Release of the caval ligature promptly decreased bicarbonate reabsorption.Plasma potassium decreased in all animals studied, but the changes in bicarbonate reabsorption noted could not be related to the decrease.This study demonstrates that the state of effective extracellular volume is a major determinant of bicarbonate reabsorption by the kidney.

, 5 and the LJP 394-90-09 Investigator ConsortiumObjective. To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-doublestranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare.Methods. We conducted a randomized, placebocontrolled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat ( Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced >50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P ‫؍‬ 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated.Conclusion. Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.There is a substantial body of evidence implicating anti-double-stranded DNA (anti-dsDNA) antibodies in the pathogenesis of lupus nephritis. Anti-dsDNA antibodies are rarely found in individuals without SLE (1-4), and their presence is diagnostic for SLE and prognostic for development of lupus nephritis. The presence of anti-dsDNA antibodies often correlates with active renal disease (5-8). Anti-dsDNA antibodies are concentrated in the kidneys of SLE patients and often have a much higher avidity for dsDNA than do antibodies in the circulation (9,10). Well-controlled studies have demonstrated a strong correlation between rises in anti-dsDNA antibody levels and subsequent exacerbations of . Similarly, reductions in antiClinicalTrials.gov identifier: NCT00035308.

Maleic acid administration is known to produce the Fanconi syndrome, although the biochemical mechanism is incompletely understood. In this study the effect of a single injection of maleic acid (50 mg/kg body wt, i.v.) on the rat renal ATPases was examined. Maleic acid rapidly caused bicarbonaturia, natriuresis, and kaliuresis. When nephron segments were microdissected, there was an 81 +/- 2% reduction in proximal convoluted tubule (PCT) Na-K-ATPase activity (P < 0.005) and a 48 +/- 4% reduction in PCT H-ATPase activity (P < 0.01). Enzyme activity (Na-K-ATPase, H-ATPase, H-K-ATPase) in the medullary thick ascending limb of Henle's loop and distal nephron segments was normal. In vitro, maleic acid (1 and 10 mM) inhibited Na-K-ATPase in PCT, but it had no effect on H-ATPase in PCT. Prior phosphate infusion to maleic acid-treated rats attenuated urinary bicarbonate wastage by 50% (P < 0.05); activity of proximal tubule Na-K-ATPase and H-ATPase activities were partially protected as compared to the animals given maleic acid alone (P < 0.05). Renal cortical ATP levels were not altered at the concentration of maleic acid used in this study (that is, 50 mg/kg body wt), but higher doses of maleic acid (that is, 500 and 1000 mg/kg body wt) caused ATP levels to fall. Maleic acid did not affect cortical medullary total phosphate concentration, however, P32 turnover (1 and 24 hr) was altered by prior phosphate infusion. A protective effect of prior phosphate loading on the membrane bound Pi pool (insoluble) was seen while the cytosolic Pi pool (soluble) was not different from control. Thus, maleic acid-induced "Fanconi" syndrome likely results from both direct inhibition of proximal tubule Na-K-ATPase activity and membrane-bound phosphorus depletion. The former mechanism would reduce activity of the sodium-dependent transporters (that is, Na/H antiporter), while the latter would inhibit the electrogenic proton pump (H-ATPase). The combination of reduced proximal tubule Na-H exchange and H-ATPase activities would markedly inhibit bicarbonate reabsorption and result in the metabolic acidosis universally seen in the Fanconi syndrome.

No abstract