K. M. Koch

Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study.

OBJECTIVE There is growing concern about the toxic side effects of daily oral cyclophosphamide (CYC) treatment. Intravenous (i.v.) pulse administration of CYC has been shown to be effective in patients with systemic lupus erythematosus, but contradictory results have been reported in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS The efficacy and toxicity of i.v. pulse administration of CYC (0.75 gm/m2) versus daily oral CYC treatment (2 mg/kg body weight) were investigated in a prospective, randomized, multicenter study in patients with ANCA-associated vasculitis and renal involvement. RESULTS The cumulative CYC dose was reduced by 57% in patients with i.v. pulse treatment (n = 22) compared with patients treated with daily oral therapy (n = 25). Patient survival, remission rate, time of remission, relapse rate, and outcome of renal function were not different between the 2 treatment groups. However, the rate of leukopenia (P < 0.01) and severe infections (P < 0.05 by 1-tailed test) was significantly reduced in the i.v. pulse group compared with the group receiving daily oral treatment. Moreover, gonadal toxicity was reduced in the i.v. pulse group, as indicated by significantly lower levels of follicle-stimulating hormone. CONCLUSION This randomized study shows that i.v. CYC administration is an effective therapeutic tool with low toxicity in patients with ANCA-associated vasculitis and renal involvement.

Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibody‐associated vasculitis) and invasive bacterial infection

OBJECTIVE To investigate whether the determination of serum procalcitonin (PCT) in systemic autoimmune disease will help to discriminate invasive infection from highly active underlying disease. METHODS Three hundred ninety-seven serum samples, from 18 patients with systemic lupus erythematosus (SLE) and 35 patients with systemic antineutrophil cytoplasmic antibody-associated vasculitis (AAV), were analyzed. Clinical disease activity was assessed by the Systemic Lupus Activity Measure in SLE patients and by the Birmingham Vasculitis Activity Score in AAV patients. Procalcitonin concentrations were determined in parallel with concentrations of neopterin, interleukin-6 (IL-6), and C-reactive protein (CRP). Additionally, serum creatinine values were obtained. RESULTS In 321 of the 324 samples from the 42 patients with autoimmune disease but without systemic infection, serum PCT levels were within the normal range (i.e., <0.5 ng/ml), whereas the values for neopterin, IL-6, and CRP were elevated in patients with active underlying disease. All 16 systemic infections occurred in 11 patients with AAV, and were associated with PCT levels that were markedly elevated, to a mean +/- SD of 1.93 +/- 1.19 ng/ml. No correlation between the degree of renal impairment and PCT concentrations was seen. CONCLUSION PCT may serve as a useful marker for the detection of systemic bacterial infection in patients with systemic autoimmune disease.

Recurrent immunoglobulin A nephropathy after renal transplantation: a significant contributor to graft loss.

BACKGROUND Although most transplanted patients with underlying IgA nephropathy (IgAN) develop histological recurrence, its clinical relevance is considered low. METHODS We performed a single-center analysis of 61 renal transplant patients with IgAN. RESULTS Forty-four percent of the patients showed a stable graft function. Progressive graft dysfunction apparently due to recurrent IgAN occurred in 23% of the patients (16% required dialysis). Five patients were retransplanted, and three again developed dialysis-dependent renal failure apparently due to recurrent IgAN. In 20% of the patients, chronic transplant dysfunction was due to other reasons, whereas no reason was identified in 13% of the patients. Neither findings before transplantation, the ACE genotype, the type of immunosuppression, nor the course after transplantation predicted transplant dysfunction due to recurrent IgAN. Follow-up after transplantation was longer in the group with dysfunction due to recurrent disease than in the group with dysfunction due to chronic rejection or in the stable group. CONCLUSION Recurrent IgAN is a clinically relevant problem in renal transplant patients. Its importance may have been underestimated in the past due to inadequate lengths of follow-up.

The Effect of Ultrafiltered Dialysate on the Cellular Content of lnterleukin-1 Receptor Antagonist in Patients on Chronic Hemodialysis

We investigated the effect of dialysate ultrafiltration on the content of IL-1 receptor antagonist (IL-1Ra) in mononuclear cells (PBMC) as a marker of the inflammatory response. 11 patients on Cuprophan dialyzers were randomly assigned to treatment with standard bicarbonate dialysate first and then to ultrafiltered dialysate or the reverse order in a crossover design. In each treatment period (at least 4 weeks) weekly separations of PBMC were performed before the start of dialysis. Cellular content of IL-1Ra was determined in PBMC that were frozen immediately after separation; all values of IL-1Ra in each treatment period were averaged. The dialysate contained a median of 148 (range, 61-400) colony-forming units without dialysate filter; no bacterial growth was detected in ultrafiltered dialysate. The median endotoxin content was 80 pg/ml in nonfiltered dialysate; endotoxin was below 5 pg/ml in all ultrafiltered dialysate samples. Cellular content of IL-1Ra decreased in all but 1 patient with the use of ultrafiltered dialysate (mean +/- SEM: 1,467 +/- 113 pg/ml without dialysate filter vs. 1,166 +/- 104 pg/ml with filter, p = 0.016). The present study demonstrates that the bacterial contamination of the dialysate induces a systemic inflammatory response in hemodialysis patients.

Comparison of Intermittent and Continuous Oral Administration of Calcitriol in Dialysis Patients: A Randomized Prospective Trial

Intermittent bolus administration of calcitriol--i.e., 1,25-dihydroxycholecalciferol or 1,25-(OH)2D3--is highly efficacious in dialysis patients. In experimental studies, intermittent administration of calcitriol is superior to continuous administration in suppressing preproparathyroid hormone (PTH) mRNA and circulating PTH concentrations. In a randomized, prospective, open multicenter trial 45 dialysis patients with elevated 1,84-iPTH (> or = 20 pmol/l, normal 1-6 pmol/l) levels were randomly allocated to daily administration of 0.75 microgram calcitriol (continuous) or twice weekly administration (intermittent); the two protocols provided an identical total weekly doses of 5.25 micrograms calcitriol. Patients were dialyzed with a dialysate Ca concentration of 1.75 mmol/l and had oral CaCO3 or Ca acetate. 1,84-iPTH (immunoradiometric assay) and serum Ca and Pi levels were measured weekly. At the beginning of the study, the median 1,84-iPTH value was 37 pmol/l (range 20-115) in the intermittent versus 36 pmol/l (range 21-72) in the continuous calcitriol group. After 2 weeks, the median 1,84-iPTH level was 18.5 pmol/l (range 1.4-106) versus 18 pmol/l (range 1.2-48). After 12 weeks, 11 of 21 of the patients in the intermittent and 18 of 24 patients in the continuous group had reached the treatment goal, i.e., 1,84-iPTH < or = 10 pmol/l without hypercalcemia or hyperphosphatemia. There were seven episodes of hypercalcemia (> 2.7 mmol/l) in the intermittent versus two in the continuous group; the mean peak Ca level was 2.8 mmol/l (range 2.76-3.0) versus 2.9 mmol/l (range 2.74-3.06). There were 21 versus 17 episodes, respectively, of hyperphosphatemia (> 2.2 mmol/l).

Effect of Treatment with Recombinant Human Erythropoietin on Peripheral Hemodynamics and Oxygenation

Slow progressive improvement of renal anemia from 21 up to 33% hematocrit by rhEPO treatment results in an increase of tissue oxygenation as indicated by a rise of the transcutaneous oxygen pressure. In normotensive patients this was accompanied by an increase in MAP (delta 6 mm Hg) within the normal range and a significant fall of the regional blood flow. These hemodynamic changes are caused by increases of the regional and presumably also of the total peripheral vascular resistance. Most likely the increase in total peripheral vascular resistance represents an autoregulatory event triggered by the rising tissue oxygenation. From the present data it is difficult to estimate to what extent the observed rise in hematocrit affects peripheral vascular resistance also via an increase of blood viscosity.

Renal transplantation for patients with autoimmune diseases: single-center experience with 42 patients.

BACKGROUND In patients with autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE), end-stage renal disease develops in a high percentage of patients, and kidney transplantation has become a therapeutic option. However, only limited data about the prognosis and outcome after kidney transplantation are available. METHODS Long-term graft survival and graft function of renal transplant recipients with SLE, Wegeners granulomatosis, microscopic polyangiitis, Goodpastures syndrome, and Henoch-Schonlein purpura were evaluated in a single center. In addition, the incidence of renal and extrarenal relapses and the impact of the immunosuppressive therapy on the course of the autoimmune disease were studied. RESULTS Renal transplant recipients with autoimmune diseases such as vasculitis and SLE had a patient survival rate (94% after 5 years) and a graft survival rate (65% after 5 years) comparable to those of patients with other causes of end-stage renal disease (patient survival 88% and graft survival 71% after 5 years). Graft losses due to the underlying disease were rare. Extrarenal relapses occurred in three patients with Wegeners granulomatosis, one patient with microscopic polyangiitis, and three patients with SLE, but were less frequent compared with the period with chronic dialysis therapy. Autoantibody levels in patients with SLE, Wegeners granulomatosis, or microscopic polyangiitis did not seem to influence the outcome. CONCLUSIONS Renal transplantation should be offered to patients with autoimmune diseases. Follow-up should include the short-term control of renal and extrarenal disease activity.

Glomerular Oxidative and Antioxidative Systems in Experimental Mesangioproliferative Glomerulonephritis

Increased mesangial cell proliferation is a hallmark of many glomerulopathies in humans. Whereas the pathogenic role of reactive oxygen species (ROS) in the development of experimental mesangioproliferative glomerulonephritis (GN) is well established, very little is known about the mechanisms leading to increased ROS concentrations in the glomerulus. This study therefore examined glomerular ROS and the activities of oxidative and antioxidative enzymes during the early course of mesangioproliferative anti-Thy 1.1 GN. Anti-Thy 1.1 GN was induced in male Wistar rats, and glomeruli were isolated 2, 24, and 120 h after disease induction to examine ROS levels as well as oxidative and antioxidative enzyme expression in comparison to non-nephritic controls. At all time points, increased glomerular ROS levels, particularly of hydrogen peroxide and superoxide anions, were observed. Activities of NADH-dependent and NADPH-dependent oxidative enzymes were also increased during the course of GN, whereas no increased activity of xanthine oxidase, another potential source of ROS, was detectable. Despite glomerular oxidative stress, no compensatory increase of antioxidative enzyme activities occurred. On the contrary, catalase, superoxide dismutase, and glutathione peroxidase activities even decreased during the course of disease. In tubulointerstitial samples, no increase in oxidative activity was observed in the course of disease, thus confirming that detected ROS were of glomerular origin. Our data document for the first time a pronounced dysregulation of pro-oxidative and antioxidative enzymes in mesangioproliferative GN, leading to a net increase in glomerular ROS levels. Detailed knowledge of such pathways may lead to new therapeutic approaches for GN in humans.

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.

Plasma Levels Of Tumor Necrosis Factor (tnf) And Soluble Tnf Receptors In Kidney Transplant Recipients

Tumor necrosis factor-alpha is elevated in plasma during kidney transplant rejection. However, the measurement and biological activity of TNF alpha is influenced by inhibitory soluble TNF receptors. We therefore determined plasma levels of TNF alpha and the 2 soluble TNF receptors, the 55-kDa TNF receptor (TNF-sR55) and the 75-kDa TNF receptor (TNF-sR75), by immunoassays in 25 patients before and daily after kidney transplantation. Plasma samples were retrospectively assigned to 3 groups: (1) patients with well-functioning grafts (n = 14); (2) patients with biopsy-proven graft rejections (n = 7 patients with 10 rejections); and (3) patients with episodes of CsA nephrotoxicity (n = 4 patients with 9 samples). On the day of biopsy-proven graft rejection, TNF alpha increased from 8.6 +/- 0.9 pg/ml to 14.8 +/- 3.5 pg/ml (P < 0.02), TNF-sR55 from 6.6 +/- 1.3 ng/ml to 9.0 +/- 1.2 ng/ml (NS), and TNF-sR75 from 10.3 +/- 1.0 ng/ml to 15.3 +/- 2.0 ng/ml (P < 0.01). During episodes of CsA toxicity, TNF alpha levels did not change, TNF-sR55 increased from 5.2 +/- 0.5 ng/ml to 10.5 +/- 0.5 ng/ml (P < 0.01), and TNF-sR75 increased from 10.2 +/- 0.8 ng/ml to 17.5 +/- 0.9 ng/ml (P < 0.01). There was a strong correlation between serum creatinine and plasma TNF-sR55 (r = 0.7, P < 0.001) and TNF-sR75 (r = 0.7, P < 0.001), but not with TNF alpha. Therefore, levels of TNF-sR55 and TNF-sR75 were corrected for serum creatinine. An index expressing TNF alpha over actively released soluble receptors (index = TNF alpha/(corr.TNF-sR55 + corr.TNF-sR75)) detected rejection episodes with a sensitivity of 70-80% and a specificity of 89%. We conclude that the measurement of plasma TNF alpha in combination with its soluble receptors is superior to isolated TNF alpha determinations in discriminating acute graft rejection from episodes of CsA toxicity in kidney transplant recipients.