Ikp Cheng

Cholesterol-lowering therapy may retard the progression of diabetic nephropathy

There is experimental evidence to suggest that hypercholesterolaemia may play a pathogenetic role in progressive glomerular injury. We investigated the effect of cholesterol-lowering therapy on the progression of diabetic nephropathy in 34 patients with non-insulin-dependent diabetes mellitus. Patients were randomly assigned in a single-blind fashion to treatment with either lovastatin, an HMG CoA reductase inhibitor (n = 16; mean dose 30.0 +/- 12.6 mg/day) or placebo (n = 18) for 2 years. Renal function was assessed by serially measuring the serum creatinine, glomerular filtration rate (using Cr51-EDTA), and 24-h urinary protein excretion. Lovastatin treatment was associated with significant reductions in total cholesterol (p < 0.001), LDL-cholesterol (p < 0.001) and apo B (p < 0.01), the reductions at 24 months being 26, 30 and 18%, respectively. Beneficial effects on serum triglyceride, HDL-cholesterol and apo A1 levels were also observed. Lp(a) showed no significant change in both groups. Glomerular filtration rate deteriorated significantly in the placebo group after 24 months (p < 0.025) but showed no significant change in the lovastatin-treated patients. The increase in serum creatinine was statistically significant (p < 0.02) in placebo-treated patients at 12 and 24 months, and in the lovastatin group after 24 months. Twenty-four hour urinary protein excretion increased in both groups (p < 0.05). Lovastatin treatment was not associated with significant elevations in liver or muscle enzymes. We conclude that effective normalisation of hypercholesterolaemia may retard the progression of diabetic nephropathy.

Endothelial cell binding by human polyclonal anti‐DNA antibodies: relationship to disease activity and endothelial functional alterations

Polyclonal anti‐dsDNA and anti‐ssDNA antibodies (PoAb) that showed significant binding to human umbilical vein endothelial cells (HUVEC) were isolated from eight patients with systemic lupus erythematosus (SLE). Anti‐dsDNA PoAbs from five patients and anti‐ssDNA PoAbs from seven patients demonstrated enhanced binding to HUVEC during active disease, compared with PoAbs obtained from corresponding patients during remission. Reduction of the DNA content in the PoAb preparations by DNase treatment was associated with enhanced binding to HUVEC in 20 of 32 PoAbs tested, which included 75%‘active disease’ PoAbs, and with reduced binding to HUVEC in three of 32 PoAbs tested, all obtained during remission. Such altered endothelial cell binding was reversed with DNA reconstitution. Binding of the remaining nine PoAbs to HUVEC was not altered by variations in their DNA content. Induced plasma membrane expression of E‐selectin, but reduced expression of vascular cell adhesion molecule‐1 (VCAM‐1) by HUVEC, was observed following incubation of HUVEC with ‘active disease’ PoAbs from three and two of the eight patients, respectively. PoAbs and serum samples from two of the eight patients during active disease induced von Willebrand factor release from HUVEC, which was not observed during remission. We conclude that anti‐DNA antibodies from selected patients with SLE can bind to endothelial cells. Correlation between cellular binding and disease activity suggests that such binding of anti‐DNA antibodies to endothelial cells could be of pathogenic significance. Preliminary data also suggest that the expression of adhesion molecules and haemostatic factor(s) by endothelial cells may be modified following their binding by anti‐DNA antibodies.

Optimal treatment and long-term outcome of tuberculous peritonitis complicating continuous ambulatory peritoneal dialysis

A retrospective study of the treatment and short- and long-term outcomes of tuberculous peritonitis (TBP) complicating continuous ambulatory peritoneal dialysis (CAPD) among our dialysis patients over a 6-year period was performed. Ten cases of TBP complicating CAPD were identified among 601 dialysis patients between January 1988 and December 1994. There were four male and six female patients. The most common clinical features were abdominal pain, fever, and cloudy peritoneal fluid (PDF). Two patients had concurrent bacterial peritonitis. Extraperitoneal tuberculosis was not observed. The majority of the patients showed neutrophil predominance in the PDF. Only one patient had a positive acid-fast bacilli smear of the PDF. The acid-fast bacilli culture of the PDF was positive in all patients. The patients were treated with isoniazid, rifampicin, and pyrazinamide for 9 to 12 months (mean, 11 months). Continuous ambulatory peritoneal dialysis was continued in all patients. Two patients died, one from multiorgan failure at 2 months and the other from sudden cardiac death at 9 months. Two patients were converted to hemodialysis at 3 months. Six patients continued to receive CAPD after completion of the antituberculous treatment. Four of these six patients were still alive 5 years after the TBP. Three patients were still undergoing CAPD with satisfactory ultrafiltration and solute clearance. None of the patients developed relapse of TBP. We concluded that (1) TBP is a rare but important complication of CAPD, (2) removal of the Tenckhoff catheter is not mandatory in the management of TBP complicating CAPD, and (3) long-term continuation of CAPD is possible after TBP.

CD5-positive and CD5-negative rheumatoid factor-secreting B cells in IgA nephropathy, rheumatoid arthritis and Graves' disease.

The relative contributions of CD5+ and CD5– B–cells in production of rheumatoid factors (RF) was evaluated in polyclonally activated B–cells from patients with IgA nephropathy (IgAN), rheumatoid arthritis (RA) and Graves’ disease (GD). In IgAN and RA, diseases in which RFs are believed to be involved in pathogenesis, there were 10– and 4–fold decreases respectively in CD5+ IgG–RF–secreting B–cells compared with controls. Furthermore, the number of CD5– IgG–RF– and IgA–RF–secreting B–cells were increased 12– and 14–fold in IgAN and 9– and 4–fold in RA. Such abnormalities were not apparent in GD, in which RFs have not been implicated in pathogenesis. These findings are compatible with the concept of CD5+ RF–secreting B–cells normally acting to prevent production of potentially pathogenic RFs by CD5– B–cells. When IgAN or RA patients’ B–cells were activated in the presence of control instead of autologous CD4+ cells, numbers of RF– secreting CD5– B–cells were reduced to the levels seen with control B–cells plus control T–helper cells. Presumably lymphokine secretion profiles of T–helper cells would be important in determining whether CD5+ or CD5– B–cells are activated to secrete RFs, and perhaps therapeutic manipulation of these profiles could restore normal activity of CD5+ B–cells in IgAN and RA.

Aberrant T‐regulation in rheumatoid arthritis and IgA nephropathy affects CD5+ and CD5– B lymphocytes equally

T‐suppressor function and T‐helper function in healthy adults, elderly patients with non‐immune diseases, and patients with rheumatoid arthritis (RA) and IgA nephropathy (IgAN) were titrated by adding graded concentrations of CDS+ cells to autologous CD8‐depleted peripheral blood mononuclear cells (PBMC), or CD4+ cells to CDX– 4– PBMC, respectively. Following culture with pokeweed mitogen (PWM), numbers of CD5+ and CD5– immunoglobulin‐secreting cells were determined using a combination of rosetting with anti‐CD5‐coated Dynabeads and reverse haemolytic plaque formation (Jones, 1990). Of 11 RA patients studied, eight had slightly reduced suppressor activity for CD5+ and CD5– IgM‐secreting cells, and three with active disease and high serum levels of C‐reactive protein, could not suppress IgG, IgA or IgM secretion by either B subset. Helper activity for both CD5+ and CD5– B cells was slightly but significantly increased in RA patients, One of eight patients with IgAN could not suppress IgG, IgA or IgM production by CD5+ or CD5– B cells, and all IgAN patients required strikingly fewer CD4+ cells for PWM‐induced activation or CD5+ and CD5– B cells than controls. It was concluded that in two immunologically mediated diseases in which some patients have raised numbers of circulating CD5+ B cells, aberrant T‐regulation affects CD5+ and conventional CD5– B cells equally.

Clinicopathologic features of antineutrophil cytoplasm autoantibody (ANCA)-associated acute renal failure in Chinese patients

Summary: The clinical course and renal pathologic features of anti‐neutrophil cytoplasm auto‐antibody (ANCA)‐associated renal disease were studied among Chinese patients from a single centre. Eight ANCA positive patients with acute renal impairment were studied, four of whom required dialysis shortly after presentation. Their mean age at presentation was 61.6 ± 4.2 years. Renal histology, obtained in seven patients, showed paucummune crescentic glomerulonephritis in five patients, interstitial nephritis in two patients, and small vessel vasculitis in one patient. Pulmonary baemorrhage was the other common disease manifestation, present in four of the eight patients, necessitating ventilatory support in three patients. Neurologic, cutaneous, and gastrointestinal involvement were also observed. Seven of the eight patients tested positive for pANCA and anti‐myeloperoxidase, while cANCA was detected in one patient of the eight patients, six (75%) responded to therapy, consisting of prednisolone and cyclophosphamide in five patients, and antibacterial therapy alone in one patient, who had interstitial nephritis but no evidence of vasculitis. Two patients died from sepsis and severe debilitation one month after presentation. of the other six patients, five had significant improvement of renal function, while one became dialysis‐dependent. the levels of ANCA and C‐reactive protein remained normal, and disease reactivation was not observed during follow‐up for 32.4 ± 6.1 months. Patient and renal survival rates at one year were 75% and 62.5%, respectively. It was concluded that the clinical and pathologic features of ANCA‐associated renal disease in Chinese patients are, in general, similar to those described in Caucasians. Nevertheless, cANCA‐positivity is distinctly uncommon. the demonstration of interstitial nephritis in two of the eight patients underlines the importance of renal biopsy for correct histologic diagnosis. Early institution of aggressive immunosuppression and supportive therapies are essential for the achievement of favourable outcome in patients with vasculitis.

Immunosuppression in renal transplantation long-term clinical trial of a double versus triple therapy regimen

Summary: Sixty‐nine renal allograft recipients were randomized to two immunosuppressive regimens: 35 patients received cyclosporine A and prednisolone (PC) while 34 patients received low dose cyclosporine A, prednisolone and short term azathioprine (PCA). the data of 66 patients (34 in PC and 32 in PCA groups) were analysed. the median follow‐up periods were 62 months for the PC group and 60 months for the PCA group. There was no difference in graft survival between the two groups but five patients died in the PC group compared to none in the PCA group (graft survival: 88 vs 90% at 1 year and 82 vs 82% at 5 years, P= not significant at any time point; patient survival: 90 vs 100% at 1 year and 88 vs 100% at 5 years, P= 0.05 at 5 years). There was a trend for patients in the PCA group to develop earlier and more frequent rejections (not significant; P= 0.106 and P= 0.062, respectively). There were also more episodes of acute cyclosporine A nephrotoxicity and cytomegalovirus (CMV) infection in the PC group. the mean serum creatinine at 5 years was significantly higher in the PCA group when compared to the PC group (179.8 ± 76.5 μmol/L vs 154.7 ± 41.0 μmol/L; P=0.05). We found that both therapeutic regimens were effective in preventing renal allograft rejections. However, double therapy was associated with higher patient mortality secondary to infection. Patients on triple therapy, on the other hand, were more prone to develop rejections in the early post‐transplant period and were associated with less favourable renal function in the long run.