The recurrence of focal segmental glomerulosclerosis in kidney transplant patients treated with cyclosporine.

To evaluate the rate of recurrence of focal segmental glomerulosclerosis (FSGS) in renal transplant patients treated with cyclosporine, we reviewed the outcome of 25 renal Tx performed in 24 patients who had FSGS as their original renal disease. After Tx, 6 patients were treated with steroids and azathioprine (follow-up: 42 +/- 34 months) and 19 with CsA (follow-up: 30 +/- 31 months). Two of 6 Aza treated patients (33%) developed recurrence of FSGS and nephrotic syndrome (NS). Both patients lost their graft because of FSGS 24 and 25 months after Tx. Ten of 19 patients (55%) given CsA showed recurrence of FSGS; one of them had had recurrence in the first graft treated with Aza. One patient lost his graft a few weeks after Tx because of acute rejection and 3 lost their graft because of FSGS 4-28 months after NS developed. One patient with NS died from pneumonia 14 months after Tx when his plasma creatinine was 2.7 mg/dl. Three other patients now have NS and plasma creatinine between 1.9 and 2.4 mg/dl 15-37 months after Tx. The last two patients have NS and normal renal function 10 and 31 months after Tx. In both groups, most patients developed NS within the first week after Tx. The patients with recurrence, given Aza or CsA, tended to be younger at the onset of the disease and to have a shorter duration of the disease, when compared with those without recurrence, but the differences were not statistically significant. In our experience neither CsA nor Aza showed any effect on the outcome of FSGS recurring in the graft.

The impact of azathioprine and cyclosporine on long-term function in kidney transplantation.

To assess the impact of cyclosporine on long-term kidney function in transplant patients, we retrospectively analyzed 273 patients on azathioprine and 308 on CsA with graft functioning at 1 year. To balance the length of follow-ups, the observation of patients was cut at 5 years. Actual graft survival rate at 5 years was similar in Aza and CsA (88% vs. 90%). Multivariate analysis in Aza pts showed that proteinuria (P = 0.006) and hypertension at 1 year (P = 0.002) increased the probability of irreversible graft failure by 2.47 and 2.85, respectively. In CsA patients, proteinuria (P = 0.007) and plasma creatinine higher than 2.5 mg/dl (P = 0.006) increased the probability of graft failure by 5.12 and 6.48, respectively. In both Aza and CsA patients with a follow-up of at least 5 years, plasma creatinine levels were significantly worse at 5 years vs. 1 year (P = 0.004). The slopes of plasma creatinine values plotted vs time were not different between the two groups. Chronic graft dysfunction (CGD) was defined as a stable increase of plasma creatinine of at least 50% above stable values at 1 year. The probability of remaining without CGD at 5 years was 75% for CsA and 80% for Aza patients (P = N.S.). Multivariate analysis of factors influencing the development of CGD showed that hypertension (P = 0.003) and proteinuria at 1 year (P = 0.081) increased the probability of developing CGD by 2.19 and 1.76, respectively, in Aza, while in CsA patients proteinuria only (P = 0.063) increased the probability of developing CGD by 2.29. Graft survival at 5 years after development of CGD was 34% in Aza and 53% in CsA-treated patients. These data confirm that in the long-term CsA does not cause a higher prevalence of CGD and show that, in the presence of CGD, CsA has a superior protective effect than Aza.

Calcium-PTH relationship in dialysis patients: the pitfalls of using a constant dialysate calcium concentration during the dynamic tests.

The calcium-PTH relationship in uremic patients has been often studied during dialysis sessions with high or low dialysate calcium concentration (CaD). This method has been used because it is less complex and invasive than i.v. infusion of calcium salts and calcium chelating agents. However, the constancy of CaD during the tests does not allow for the control of the serum calcium profile and, given that the blood calcium concentration is only one factor of a more complex calcium-related mechanism of the PTH release, the calcium-PTH curve may become dependent on the unpredictable rate at which the ionized calcium changes. Dynamic testing of the parathyroid gland was performed in 9 dialysis patients comparing constant CaD of 1.0 and 2.0 mmol/l (A) with a linear change in CaD (B). The rate of serum calcium change remained constant over time only in experiment B. The total decrease in calcemia (0-0.38 +/- 0.03 vs -0.14 +/- 0.1 mmol/l) and PTHmax (748.25 +/- 124.76 vs 374.89 +/- 53.03 pg/ml) were significantly higher in B, whereas the total increase in calcemia (+0.26 +/- 0.03 vs +0.28 +/- 0.02 mmol/l) and the minimum value of PTH (59.15 +/- 9.53 vs 55.64 +/- 9.08 pg/ml) were similar in both experiments. The calcium-PTH curves were clearly different in A and B. The setpoint and the slope were significantly higher in A (1.196 +/- 0.01 vs 1.142 +/- 0.02 mmol/l; 840.54 +/- 96.85 vs 542.43 +/- 112.26%/mmol). For similar serum calcium values (1.084 +/- 0.01 vs 1.059 +/- 0.02 in the stimulation test and 1.325 +/- 0.02 vs 1.336 +/- 0.02 mmol/l in the inhibition test) the PTH secretion was significantly different (335.86 +/- 44.36 vs 647.65 +/- 104.09 in the stimulation test and 76.35 +/- 12.57 vs 105.03 +/- 20.59 pg/ml in the inhibition test). In conclusion, the way of inducing serum calcium change affected the calcium-PTH curve and the value of the set point and the slope was a function of the way in which the blood calcium changes were achieved. The modulated CaD dialysis was shown to be a more correct method of studying the calcium-PTH relationship in dialysis patients, as well as an alternative to the more complex and invasive infusional methodology.

Rate dependence of acute PTH release and association between basal plasma calcium and set point of calcium-PTH curve in dialysis patients.

BACKGROUND: In vivo, the control of calcium-mediated acute PTH release during induced hypo- or hypercalcaemia is linked not only to plasma calcium concentration per se but also to the rate and direction of calcium change. In fact, during induced hypocalcaemia, the predominant mechanism that causes PTH to be released is the reduction of plasma Ca(2+) irrespective of the absolute starting concentration of ionized calcium. This mechanism, which is rate-dependent and even activated in conditions of hypercalcaemia, may be involved in the association, reported in several papers, between the basal Ca(2+) and the set point of the calcium-PTH curve. METHODS: The calcium-PTH relationship was studied in 12 dialysis patients under conditions of induced low and high predialysis plasma Ca(2+). At each level of basal Ca(2+), dynamic tests were conducted using two methodological approaches. In method A patients underwent low (0.5 mmol/l) calcium dialysis in the stimulation test and high (2 mmol/l) calcium dialysis in the inhibition test, while the dialysate calcium (CaD) was kept constant during each test. In this way a higher but variable rate of change in plasma Ca(2+) was achieved. In method B, CaD was progressively decreased (stimulation test) and increased (inhibition test) during the tests in order to obtain a lower but more constant rate of change in plasma Ca(2+). Consequently, for each patient, four calcium-PTH curves were produced: low basal Ca(2+) with methods A and B, and high basal Ca(2+) with methods A and B. RESULTS: Basal plasma Ca(2+) was similar in A and B at low (1.16+/-0.02 vs 1.15+/-0.02 mmol/l) and high (1.25+/-0.02 vs 1.26+/-0.02 mmol/l) basal plasma Ca(2+). The set point was higher in A than in B both at low (1.12+/-0.02 vs 1.10+/-0.02 mmol/l, P=0.01) and high (1.20+/-0.02 vs 1.16+/-0.02 mmol/l, P=0.03) basal Ca(2+) as was the slope (542+/-41 vs 426+/-44%/mmol, P=0.02; 615+/-73 vs 389+/-25%/mmol, P=0.01). No significant difference was found between A and B as regards minimal PTH and plasma Ca(2+) at minimal PTH (Camin) in both calcaemic states. Maximal PTH was slightly higher in B at low (510+/-97 vs 548+/-107 pg/ml, P=NS) and high basal plasma Ca(2+) (410+/-97 vs 464+/-108 pg/ml, P=0.02). Plasma calcium at maximal PTH (Camax) was significantly higher in A (1.1+/-0.03 vs 0.99+/-0.02 mmol/l, P=0.001) at high basal plasma Ca(2+). The set point was strictly related to basal plasma Ca(2+) in both methods, but the slope of the linear regression was significantly steeper with method A. The set point was predicted to increase by 0.881 (CI 0.772-0.990) mmol/l for each mmol/l of increase in basal plasma Ca(2+) with method A and by 0.641 (CI 0.546-0.737) mmol/l for each mmol/l of increase in basal plasma Ca(2+) with method B. CONCLUSIONS: (i) Higher and variable rates of change in plasma Ca(2+) produce a higher set point value and a steeper slope of the calcium-PTH curve when compared to lower and more constant rates of calcium change. (ii) The different slope of the linear correlations between basal plasma Ca(2+) and set point in the two methods suggests that the rate-dependent mechanism of acute PTH release plays a significant role in the association between set point and basal plasma Ca(2+). (iii) The significance of the set point is questionable when the calcium-PTH curve is carried out in vivo.