Long-term treatment of lupus nephritis with cyclosporin A

We evaluated the efficacy and safety of long-term treatment with cyclosporin A (CSA) in type IV lupus nephritis. Seventeen patients with biopsy-proven WHO type IV lupus nephritis were enrolled in a prospective, open study. Twelve of the 17 completed 48 months of treatment with CSA and prednisolone. Three patients required the addition of azathioprine, at 12, 38 and 47 months, respectively, for cutaneous disease flare with refractory rashes. One patient was lost to follow-up at 40 months. The mean +/- SD duration of treatment was 43.2 +/- 10.1 months (range 15.7-48 months). A significant reduction of proteinuria and a significant rise in serum albumin were noted 1 month after initiation of treatment. Improvement was maintained throughout the study except for three patients who relapsed with recurrence of nephrotic syndrome. There were no significant changes in serum creatinine level or creatinine clearances throughout the study. Repeat renal biopsy at 12 months following treatment with CSA showed histological improvement, with WHO type II changes in all 17 patients accompanying significant reduction in activity indices. Patients with baseline haemoglobin (Hgb) levels < 12 g/dl showed significant improvement. Serum C3 and C4 levels were not changed significantly. Corticosteroid-sparing effects were noted. Side-effects included hypertension, gum hypertrophy and mild hirsuitism, but were not serious. Combination therapy using CSA and prednisone is effective and safe for long-term treatment in lupus patients with WHO type IV nephritis.      

Regulatory mechanisms in cell-mediated immune responses. VI. Interaction of H-2 and non-H-2 genes in elaboration of mixed leukocyte reaction suppressor factor

Previous studies have shown that alloantigen-activated spleen T cells produce a soluble factor which suppresses mixed lymphocyte reaction proliferative responses, and that the interaction between suppressor and responder cells is controlled by genes of the H-2 complex. However a defect in the expression of suppressor activity was identified in the mouse strain C57BL/6J. Factor prepared from alloactivated B6 spleen cells failed to suppress MLR responses of syngeneic or H-2 compatible responder cells. Unimpaired suppressor factor production by other H-2 (b) strains and failure of suppressor factor production by a B6 congenic strain, B6.C-H-2(d) isolated the defective gene to the non-H-2 portion of the genome. In addition, the defect appeared to be related specifically to inability to produce an active factor, while the capacity to respond to suppressor molecules was unimpaired. The genetic character of the non-H-2 gene action was identified in F1 hybrid studies. Initially F(1) hybrids of the nondefective histoincompatible strains were studied. Suppressor factor from F1 cells suppressed the responses of both parental strains, and parental factors each suppressed the response of F(1) cells. Adsorption of F(1) factor with Con A-activated thymocytes of either parental strain removed suppressor activity specific for that strain, leaving activity against the other parental strain intact. The data support cedominant expression and production of distinct, parental H-2 haplotype-specific suppressor molecules by F(1) suppressor cells. An F(1) hybrid of the defective B6 strain with nondefective BALB/c produced suppressor factor which was also capable of suppressing both parental strains. Production of a suppressive B6-reactive factor by F(1) cells was verified by adsorption studies. Thus it appears that non-H-2 genes of the BALB/c parent acted in a genetically dominant fashion to provide the function required for expression of B6 suppressor molecules. We conclude that multiple genes control the expression of alloactivated suppressor cell activity, with at least one gene mapped to the I-C subregion of the murine major histocompatibility complex and one or more genes mapped to the non-H-2 gene complement.     

Effect of dialysate calcium concentrations on intradialytic blood pressure course in cardiac-compromised patients

To prevent hypercalcemia in the treatment of secondary hyperparathyroidism, low calcium (L-Ca) dialysate is advocated. However, changes in ionized calcium (i-Ca) levels have a pivotal role in myocardial contraction and could influence blood pressure stability during dialysis. Recently, our group found in patients with normal cardiac function a significant decrease in blood pressure (decrease in systolic blood pressure [DSBP]: -13 mm Hg and decrease in mean arterial pressure [DMAP]: -7 mm Hg) during dialysis with L-Ca dialysate compared with high calcium (H-Ca) dialysate, and this was mainly related to a decreased left ventricular contractility with use of L-Ca dialysate. On the basis of these data, it could be expected that changes in i-Ca levels during dialysis are of more clinical importance in cardiac-compromised patients (CCpts), New York Heart Association classifications III and IV. In this study, the effects of L-Ca dialysate (1.25 mmol/L) and H-Ca dialysate (1.75 mmol/L) on arterial blood pressure parameters (systolic [SBP], diastolic [DBP], and mean arterial blood pressure [MAP]), heart rate, stroke distance (SDist), and minute distance (MDist) during 3 hours of a standardized ultrafiltration/hemodialysis (UF+HD) in nine CCpts was investigated. i-Ca levels increased significantly with H-Ca dialysate UF+HD, whereas there was no change with L-Ca dialysate. SBP, DBP, and MAP decreased statistically and clinically significantly during UF+HD with L-Ca dialysate and were significantly lower with the use of L-Ca dialysate compared with H-Ca dialysate. SDist and MDist decreased significantly with L-Ca dialysate, whereas there were no changes in SDist and MDist with H-Ca dialysate. The predialysis and postdialysis index of systemic vascular resistance (SVRI) was similar between L-Ca dialysate and H-Ca dialysate use. Between the two groups, there were no significant differences in changes in SVRI. From this study, we can conclude that changes in i-Ca levels are a very important determinant of the blood pressure response during UF+HD in CCpts, and this response is mediated by changes in myocardial contractility.