Mycophenolate mofetil reduces deterioration of renal function in patients with chronic allograft nephropathy. A follow-up study by the Spanish Cooperative Study Group of Chronic Allograft Nephropathy

BACKGROUND: Although studies have shown that mycophenolate mofetil (MMF) with cyclosporine (CsA) and prednisone can reduce the incidence of acute rejection and increase the half-life of the graft, the effects of MMF on established chronic allograft nephropathy (CAN) are controversial. METHODS: We studied 121 patients with biopsy-proven CAN, 59 treated with CsA and prednisone and 62 treated with triple-drug therapy with azathioprine. At inclusion, each group received 2 g per day of MMF and azathioprine was stopped. Renal function was measured by the glomerular filtration rate (GFR) obtained by creatinine clearance (Cockcroft-Gault) and monitored by the slope of the GFR, adjusted using linear regression. RESULTS: The median follow-up, after incorporation of MMF, was 36 (13-36) months, with 103 (85.1%) having a full 3-year follow-up. Before the introduction of MMF, there was progressive deterioration in renal function (GFR: 54.8+/-20.9 vs. 39.7+/-14.0 mL/min, P<0.001). After introduction of MMF, renal function remained stable (GFR: 39.7+/-14.0 vs. 41.3+/-10.8 mL/min, P=NS), with a significant change in the slope of the GFR (-0.0144 vs. +0.00045, P<0.001). In 65 patients in whom CsA blood levels remained unchanged during follow-up (148.0+/-65.6 vs. 154.1+/-58.2, P=NS), the slope of the GFR showed a reduction in loss of renal function (-0.0147 vs. -0.0001, P<0.001). CONCLUSIONS: Treatment with MMF reduced the progressive deterioration of renal function in patients with CAN, independently of the blood levels of CsA.     

Mycophenolate mofetil-induced reversal of glomerular filtration loss in children with chronic allograft nephropathy

BACKGROUND: Mycophenolate mofetil (MMF) has been used for the treatment of chronic allograft nephropathy (CAN) in adults with inconsistent results, but data in children are rare. To evaluate its impact on advanced CAN, we studied changes in glomerular filtration rate (GFR) and the correlation of GFR changes to histology. METHODS: Thirty-six children (13.1+/-3.6 years) with a progressive decline in GFR of 16.9+/-12.4 mL/min per 1.73 m2/year and biopsy confirmed CAN 4.3+/-2.9 years after transplantation were studied. MMF was added to conventional immunosuppression (IS) consisting of cyclosporine (CsA) and prednisolone (n=26) or tacrolimus (n=1) or replaced azathioprine in triple IS (n=9). Alterations of GFR were correlated to histologic guidelines according to the Banff chronic score (BCS). RESULTS: One year after conversion, 22 (61%) children showed a rise in GFR (7.5+/-6 mL/min per 1.73 m2), 8 (22%) remained stable, and 6 (17%) showed a further decline of GFR (7.4+/-2 mL/min per 1.73 m2). Mean CsA trough levels were 114 ng/mL before and 98 ng/mL 1 year after conversion. MMF side effects required dose reduction in 14 children. Children responding to MMF with increasing GFR showed a trend toward less fibrosis, less incidence of vasculopathy, and transplant glomerulopathy in the initial biopsy but had a similar incidence of borderline tubulitis compared with the other groups. CONCLUSIONS: Cotreatment with MMF reversed the progressive loss of GFR in approximately two thirds of children with CAN for at least 1 year. Less chronicity signs in histology seem to indicate a more favorable response to treatment.     

Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients

BACKGROUND: There is limited data on the potential nephrotoxicity of sirolimus (SRL) and tacrolimus (TAC) in combination. METHODS: We reviewed the course of 97 kidney transplant patients treated with SRL and reduced-dose TAC. Conversion from SRL to mycophenolate mofetil (MMF) was prescribed in a minority (n = 19) for various nonrenal side effects. We compared outcomes of converted patients to those remaining on TAC/SRL (n = 78). RESULTS: TAC levels were increased in converters (P = 0.009). Rejection rates were similar between groups over 18 months (21% vs. 16%, p = ns). Serum creatinine (Cr) and MDRD glomerular filtration rate (GFR) were similar between groups at nadir and six-months, but at 18 months the percent change from six-month Cr was +17% in non-converters vs. -10% in converters (P = 0.004 for the difference). The difference in GFR between groups at 18 months was also significant (P = 0.01). By multivariate analysis, only conversion to MMF was associated with a greater percent change in Cr from 6 to 18 months (P = 0.015). Conversion to MMF also correlated with higher GFR at 18 months independent of rejection, delayed graft function, and ethnicity. CONCLUSIONS: Conversion from TAC/SRL to TAC/MMF led to improved renal function despite increased TAC exposure after conversion.     

Chronic allograft nephropathy score before sirolimus rescue predicts allograft function in renal transplant patients

Chronic allograft nephropathy (CAN) is a major indication for initiation of sirolimus (SRL) in renal transplantation (TX) to prevent deterioration of renal function. We evaluated whether the CAN score at time of sirolimus rescue (SRL-R) predicts renal allograft function. CAN score is the sum of the following 4 categories: glomerulopathy (cg, 0-3), interstitial fibrosis (ci, 0-3), tubular atrophy (ct, 0-3), and vasculopathy (cv, 0-3). This is a retrospective cohort study of renal transplant recipients from July 2001 to March 2004. Immunosuppression consisted of preconditioning with rabbit anti-thymocyte globulin or alemtuzumab and maintenance with tacrolimus (TAC) monotherapy with spaced weaning, if applicable, SRL-R was achieved by conversion from TAC, or by addition to reduced doses of TAC. Ninety patients received SRL. Thirty-three of these patients met the inclusion criteria of the following: (1) receipt of SRL for >6 months, and (2) follow-up of > or =6 months. There were 16 patients in the low-CAN (0-4) group and 17 patients in the high-CAN (>4) group. Cockcroft-Gault (C-G) glomerular filtration rate (GFR) was calculated at SRL-R and at 1, 3, 6, and 12 months. The DeltaGFR was significantly better in the low-CAN group at 1, 3, and 6 months. A trend toward an improved DeltaGFR was present at 12 months in the low-CAN group (P = .16). CAN scoring at the time of SRL-R predicts recovery of renal allograft function (as measured using DeltaGFR), and should be used in preference to biochemical markers (Cr and C-G GFR), which may not be reliable predictors.     

Marked erythrocyte microcytosis under primary immunosuppression with sirolimus

The preliminary observation of marked erythrocyte microcytosis in patients treated with sirolimus (SRL) and mycophenolate mofetil (MMF) has been evaluated as part of a prospective study comparing SRL and cyclosporin A (CsA) as a primary immunosuppressant. Normal risk de novo kidney recipients were randomized either to SRL or to CsA. Additional immunosuppressants consisted of MMF and prednisone. In patients with erythrocyte microcytosis, iron deficiency was excluded by measuring serum ferritin and transferrin saturation rate. Fifty-nine patients (30 in SRL and 29 in CsA) were included. Mean corpuscular volume (MCV) (fl) on day 7 was 91.7 +/- 4.8 in SRL group versus 91.4 +/- 4.2 in CsA group (P = 0.77), whereas mean MCV on day 183 post-transplant was 78.5 +/- 3.8 in SRL group versus 88.4 +/- 3.4 in CsA group (P < 0.0001). Hemoglobin concentration (g/dl) was not significantly different. Only two patients in SRL group presented decreased transferrin saturation rate. Marked erythrocyte microcytosis without persistent anemia was observed in patients treated with SRL and MMF.     

Characteristics of population with normal serum creatinine impaired renal function and: the validation of a MDRD formula in a healthy general population

BACKGROUND AND AIMS: Glomerular filtration rate (GFR) provides the most accurate estimation of renal function. This study investigated the clinical characteristics of patients with impaired renal function having a normal serum creatinine level. We also validated whether the new Modification of Diet in Renal Disease (MDRD) formula can be applied in a healthy general population. MATERIAL AND METHODS: A total 393 participants who had serum creatinine concentration below 132.6 micromol/L without underlying diseases were randomly selected on an address basis in Ansan City. According to the level of GFR, they were divided into 3 groups and we analyzed their clinical characteristics. In 75 subjects, who were randomly selected 25 cases in each group based on GFR estimated by Cockcroft-Gault (C-G) formula, true GFR was measured using the 99mTc-DTPA renal clearance method. RESULTS: A total 393 (male: 106, female: 287) participants were as follows: GFR < 60 ml/min/1.73 m2; 4% (n = 25); 60 < or = GFR < 90 ml/min/1.73 m2; 26.2% (n = 103); GFR > or = 90 ml/min/1.73 m2; 67.4% (n = 265). In the group of decreased GFR, the mean age was older (67.4+/-10.7 vs. 48.7+/-12.8 vs. 39.4+/-8.2 years, p < 0.001), the gender was male (90.33+/-28.77 vs. 110.55+/-31.64, p < 0.001), and amount of proteinuria more increased (0.61 (0.56) vs. 0.33 (0.34) vs. 0.38 (0.33) gm/day, p = 0.007). The accuracy and precision of each formula were assessed by the difference in GFR measured by the 99mTc-DTPA renal clearance method--estimated GFR by each formula (deltaGFR), and the coefficient of determination (r2) of different predictive equations. The results were as follows: deltaGFR = -14.78+/-46.03, r2 = 0.79 (24-hour urinary creatinine clearance), deltaGFR=-16.79+/-57.32, r2 = 0.66 (100/serum creatinine), deltaGFR = 9.54+/-39.18, r2 = 0.87 (C-G formula), deltaGFR = -12.30+/-54.31, r2 = 0.66 (AASK formula), deltaGFR = 8.70+/-37.62, r2 = 0.79 (MDRD formula). Multiple linear regression analysis and logistic regression analysis showed that age, serum creatinine, total cholesterol and 24-hour urinary protein excretion were independently related to GFR and associated with a significant increase in the risk of decrement of GFR. CONCLUSIONS: From these results, a more accurate assessment of renal function should be required in a population characterized by older age, male gender and more proteinuria. The MDRD study formula and Cockcroft-Gault formula have greater accuracy and precision with true GFR, and this equation can be applied in subjects with healthy general population.     

Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patients.

Sirolimus (SRL) has been proposed to replace calcineurin inhibitors (CNI) in case of CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of conversion from CNI to SRL in maintenance liver transplantation (LT) patients. Between 2002 and 2006, conversion was performed in 48 patients (17 female, 31 male; mean age 57 +/- 10 yr) after a median delay of 19.4 months (range 0.2-173 months) after LT. Indication for conversion was renal impairment (RI) (78%), CNI neurotoxicity (13%), or post-LT cancer (9%). Median follow-up was 22.6 +/- 11 months. Median SRL dosage and trough levels were 2.4 +/- 1.3 mg and 8.1 +/- 2.7 microg/L. Immunosuppression consisted of SRL alone (33%), or SRL + mycophenolate mofetil (MMF) (39%), SRL + prednisone (15%), SRL + CNI (4%), or SRL + MMF + prednisone (8%). Mean glomerular filtration rate (GFR) improved from 33 to 48 mL/minute in patients with severe RI (P = 0.022) and from 56 to 74 mL/minute in patients with moderate RI (P = 0.0001). After conversion, main complications were albuminuria (36%), hyperlipidemia (49%), dermatitis (14%), edema (14%), oral ulcers (12%), joint pain (4%), infection (2%), and pneumonia (2%). Acute rejection (AR) occurred in 17% of the patients. SRL was withdrawn in 17% of the patients. In conclusion, conversion from CNI to SRL is safe and is associated with significant renal function improvement.     

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients

BACKGROUND: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. METHOD: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. RESULTS: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004). CONCLUSION: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.     

Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients

BACKGROUND: Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. METHODS: CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR < or =50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. RESULTS: In the SRL group, GFR increased from 47.0+/-18.0 to 61.2+/-22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5+/-12.7 to 53.9+/-19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2+/-15.8 to 83.5+/-27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5+/-14.0 mL/min to 36.4+/-12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299+/-622 mg/day to 517+/-795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637+/-806 vs. 514+/-744 mg/day, P=0.39). Uric acid decreased from 7.6+/-2.4 to 6.2+/-1.9 mg/dL (P=0.0007) in the SRL group. CONCLUSIONS: Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.     

Can modifications of the MDRD formula improve the estimation of glomerular filtration rate in renal allograft recipients?

BACKGROUND: Two modifications of the MDRD equation [the Mayo Clinic (MC) equation and Rule's refitted (RR) MDRD formula] were proposed to overcome disadvantages of the original MDRD formula to calculate glomerular filtration rate (GFR). Additionally, a correction factor for the original MDRD formula has been introduced to adapt this formula to creatinine values measured by the isotope-dilution mass spectrometry (IDMS) method. Although precise determination of GFR is of central importance in renal transplant recipients, these equations have not been tested in these patients so far. METHODS: Considering the impact of different creatinine calibrations, we analysed the MC equation and the RR-MDRD formula in comparison with the old as well as the re-expressed (IDMS traceable) MDRD equation and the Cockcroft-Gault (C-G) formula in 126 consecutive patients after kidney transplantation with respect to correlation, bias, precision, accuracy and ROC analysis. GFR was determined as technetium-diethylenetriamine pentaacetic acid ((99m)Tc-DTPA-clearance). RESULTS: After adjustment to IDMS creatinine determination, the performance of the re-expressed MDRD formula improved considerably in comparison to the original MDRD equation. In comparison with the re-expressed MDRD formula bias of the MC formula and the RR-MDRD formula were significantly smaller (2.31 and -0.35 vs 3.82 ml/min/1.73 m(2)). However, precision and correlation of these formulae did not differ significantly from one another, but all equations showed a higher precision than the C-G formula (P < or = 0.006 each). The accuracies within 30% of true GFR of the MC (79.4%) and the RR-MDRD equation (84.9%) were significantly higher than those of the re-expressed MDRD formula (72.2%; P < 0.03). CONCLUSION: In comparison to the original and the re-expressed MDRD formula, calculation of GFR by the MC equation and the RR-MDRD formula led to improved diagnostic performance in renal transplant recipients after adjustment of creatinine. In quotidian work both formulae can be applied to these patients. Nonetheless, to determine GFR exactly, gold standard techniques are mandatory.     

Assessment of glomerular filtration rate in transplant recipients with severe renal insufficiency by Nankivell,Modification of Diet in Renal Disease (MDRD), and Cockroft-Gault equations

Measurement of glomerular filtration rate (GFR) is time consuming and cumbersome. Several formulas have been developed to predict creatinine clearance (CrCl) or GFR using serum creatinine (Cr) concentrations and demographic characteristics. However, few studies have been performed to discern the best formula to estimate GFR in kidney transplantation. In this study, Cockroft-Gault (CG), Nankivell, and Levey (MDRD) formulas were tested to predict GFR in 125 cadaveric renal transplant patients with severe renal insufficiency (GFR less than 30 mL/min per 1.73 m2). The GFR was estimated as the average Cr and urea clearances. The mean GFR estimated by averaged Cr and urea clearances (22.18+/-5.23 mL/min per 1.73 m2) was significantly different from the mean values yielded by the MDRD formula (20.42+/-6.65 mL/min per 1.73 m2, P=.000), the Nankivell formula (30.14+/-11.98 mL/min per 1.73 m2, P=.000), and the CG formula (29.42+/-8.64 mL/min per 1.73 m2, P=.000). The MDRD formula showed a better correlation (R=0.741, P=.000) than the CG (R=0.698, P=.000) and the Nankivell formulas (R=0.685, P=.000). Analysis of differences using the Bland-Altmann method demonstrated that MDRD gave the lowest bias (MDRD: -1.65+/-4.4 mL/min per 1.73 m2; CG: 7.33+/-6.24 mL/min per 1.73 m2; Nankivell: 8.05+/-9.23 mL/min per 1.73 m2) and narrower limits of agreement (Nankivell: -10.41-26.51 mL/min per 1.73 m2; CG: -5.15-19.81 mL/min per 1.73 m2; MDRD: -10.61-7.31 mL/min per 1.73 m2). In transplant patients with severe renal insufficiency, the MDRD equation seems better than the other formulas to estimate GFR.     

Pharmacokinetics of mycophenolic acid in kidney transplant patients receiving sirolimus versus cyclosporine

INTRODUCTION: Mycophenolic acid (MPA) pharmacokinetics exhibit large variability in transplant recipients and may be altered due to concurrent immunosuppressants. Little is known about the influence of sirolimus (SRL) on MPA pharmacokinetics in kidney transplant patients. METHODS: We studied the areas under concentration-time curves (AUC) for MPA in 15 patients receiving immunosuppression combining SRL with mycophenolate mofetil (MMF). The pharmacokinetic measurements were performed in all patients using three MMF dosing regimens (0.5 g twice a day, 0.75 g twice a day, 1 g twice a day). Similar blood AUC profiles were also sampled from 12 patients treated with a fixed dose of MMF 1 g twice a day and cyclosporine (CsA). MPA was measured using HPLC; the AUC0-12 of MPA was determined by the trapezoidal method using four sampling time points: C0, C1, C3, C5. RESULTS: While patients on SRL were receiving 0.75 g MMF twice a day, mean AUC0-12 and C0 values of MPA were comparable to those of patients receiving CsA and 1 g MMF twice a day (54.1 +/- 17.6 and 3 +/- 1.87 vs 51.7 +/- 16.7 mg.h/L and 2.76 +/- 1.57 mg/L, respectively). On the other hand, 0.5 g MMF twice a day with SRL therapy resulted in AUC0-12 and C0 values of MPA of 32.3 +/- 12.6 mg.h/L and 2.32 +/- 1.72 mg/L, respectively, whereas, 1 g MMF twice a day with SRL resulted in AUC0-12 and C0 values of MPA of 70.9 +/- 19.3 mg.h/L and 4.7 +/- 2.44 mg/L, respectively. CONCLUSIONS: These findings demonstrate that MPA exposure in the presence of SRL is higher than that with CsA. It appears that the MMF dose should be reduced to 0.75 g twice a day in patients receiving SRL to obtain AUC0-12 of MPA levels comparable to that in patients treated with CsA and MMF 1 g twice a day.     

Cyclosporin withdrawal with concomitant conversion from azathioprine to mycophenolate mofetil in renal transplant recipients with chronic allograft nephropathy: a 2-year follow-up

Because recent large studies have demonstrated that mycophenolate mofetil (MMF) is superior to azathioprine (AZA) as a post-transplant immunosuppressant, it has been speculated that MMF could have a cyclosporin (CsA)-sparing effect in renal transplant recipients with chronic allograft dysfunction. Between April 1996 and October 1998, 31 patients with chronic allograft dysfunction were assigned to have conversion from AZA to MMF with concomitant CsA withdrawal. Patient and graft outcomes were analysed. Mean follow-up time after MMF conversion was 27+/-11 months. Serum creatinine concentration (sCt) significantly decreased after conversion and remained stable at the end of follow-up (227+/-31 micro mol/l vs. 185+/-50 micro mol/l; P<0.0005). Mean variation in sCt was -24% after conversion, whereas it was +20% in the year before conversion ( P<0.001). There was a significant inverse relationship between proteinuria at baseline and improvement in renal function (r=-0.35; P=0.01). Proteinuria increased during follow-up (0.79+/-0.6 vs. 1.79+/-1.08 g/day; P=0.04). Isolated CsA nephropathy was associated with the best outcome. Renal function significantly improved in patients with grade 1 chronic rejection and remained stable in patients with grade 2 chronic rejection. Two patients (6.5%) experienced late acute rejection, respectively 13 and 24 months after CsA withdrawal. Eight patients (29%) experienced systemic infections requiring hospitalization. Blood pressure control and lipid profile improved after conversion. CsA withdrawal with a concomitant switch from AZA to MMF allows a substantial and durable improvement in renal function. Both allograft histology and proteinuria at baseline are predictive of the evolution of renal function after conversion. Physicians should consider the risk of over-immunosuppression possibly associated with this therapeutic strategy.     

Predicting GFR in children and adults: a comparison of the Cockcroft-Gault,Schwartz, and modification of diet in renal disease formulas

BACKGROUND: A rapid prediction of glomerular filtration rate (GFR) is often needed in clinics. Formulas based on plasma creatinine level are being increasingly used, Schwartz for children, supposed to give GFR; Cockcroft-Gault for adults, supposed to indicate the creatinine clearance; and a recent formula introduced by the Modification of Diet in Renal Disease (MDRD) group. Our objective was to test whether one single formula could suffice and which one gives the best estimation of GFR. METHODS: In 198 children (with two kidneys, single kidney, or renal transplant) and 116 adults (single kidney and transplanted), we measured inulin clearance and creatinine clearance and calculated Cockcroft-Gault, MDRD and, in children only, Schwartz. Data were compared with analysis of variance (ANOVA), regression statistics, and concordance studies. RESULTS: In patients over 12 years of age, Cockcroft-Gault was almost similar to GFR corrected for body surface and creatinine clearance exceeded GFR by more than 20%; Schwartz was above creatinine clearance excepted for transplanted children. In younger children, no prediction approached GFR. Predictions were well correlated with GFR, but concordance studies showed Schwartz with dispersed results and GFR overestimated (20 mL/min/1.73 m2); Cockcroft-Gault was close to GFR and results were dispersed; MDRD in children gave a large overestimation and badly dispersed results; in transplanted adults its prediction was good. CONCLUSION: Cockcroft-Gault prediction could be used for children over 12 years of age and adults; it should not be considered as creatinine clearance but as GFR corrected for body surface, it is merely a prediction, 95% of the results are between +/-40 mL/min/1.73 m(2) in children and +/-30 mL/min/1.72 m(2) in adults. In younger children no formula is satisfying.     

Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury

BACKGROUND: In kidney transplant recipients with alemtuzumab induction maintained on mycophenolate mofetil (MMF) immunosuppression, sirolimus (SRL) promotes significant expansion of circulating CD4+CD25high regulatory T cells (Treg). This might translate into more effective protection against chronic graft injury compared to cyclosporin A (CsA), which, in the same clinical setting, does not affect Treg. METHODS: To assess this hypothesis, in the extension of a single-center, prospective, randomized, open, blind endpoint study aimed to assess the effect of low-dose SRL or CsA on circulating Treg, we compared the outcomes of renal transplant recipients on SRL (n=11) or CsA (n=10) by per-protocol biopsies and serial measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), and 24-hour proteinuria over 30 months posttransplant. RESULTS: Despite 4-fold higher CD4+CD25high Treg counts (22.1+/-12.2% vs. 5.7+/-4.2% of CD3+CD4+ T cells), SRL-treated patients, compared to CsA-treated patients, had a significantly higher tubular C4d staining score (1.1+/-0.6 vs. 0.2+/-0.3, P<0.01), with nonsignificant trends to higher chronic allograft damage index score (5.6+/-2.4 vs. 3.7+/-3.3), faster GFR (-2.92+/-0.33 vs. -0.28+/-0.44 ml/min/1.73 m2 per year), and RPF (-10.80+/-5.45 vs. -1.86+/-3.09 ml/min/1.73 m2 per year) decline, and more clinical proteinuria (n=6 vs. 4). There was no significant correlation between Treg counts and any considered outcome variable in the study group as a whole and within each cohort. CONCLUSIONS: These data suggest that, despite enhanced Treg expression, low-dose SRL combined to alemtuzumab induction and MMF-based steroid-free maintenance therapy, does not appreciably protect renal transplant recipients from chronic allograft injury and dysfunction.     

肾移植后不同免疫抑制方案的效果及不良反应的临床分析

目的 总结肾移植后使用不同免疫抑制方案的效果和不良反应,以提高人/肾的长期存活率.方法 对单中心3102例肾移植受者的临床资料进行回顾性分析,所采用的免疫抑制方案有环孢素A(CsA)+硫唑嘌呤(Aza)+泼尼松(Pred)、低剂量CsA+吗替麦考酚酯(MMF)+Pred、低剂量他克莫司(Tac)+MMF+Pred、低剂量CsA(或Tac)+西罗莫司(SRL)+Pred等方案,分析各方案的效果和不良反应.结果 低剂量CsA+MMF+Pred方案的人/肾1、5、10年存活率均高于CsA+Aza+Pred方案,而高血压、震颤、高尿酸、肝肾毒性、白细胞下降等的发生率显著低于CsA+Aza+Pred方案(P＜0.05),腹泻发生率显著高于CsA+Aza+Pred方案(P＜0.05).低剂量Tac+MMF+Pred方案的高血糖发生率显著高于低剂量CsA+MMF+Pred方案(P＜0.05),多毛症发生率显著低于低剂量CsA+MMF+Pred方案(P＜0.05);低剂量CsA(或Tac)+SRL+Pred方案的腹泻、高尿酸血症、肝肾毒性和多毛症等的发生率显著低于低剂量CsA(或Tac)+MMF+Pred方案(P＜0.05),但高血脂发生率显著高于后者(P＜0.05).以低剂量Tac为基础的方案者高血糖发生率显著应用低剂量CsA者.结论 低剂量CsA(或Tac)+MMF+Pred方案改善了肾移植受者和移植肾的存活,降低了不良反应发生率,尤以低剂量Tac+MMF+Pred方案为优;调整免疫抑制方案或剂量,改善饮食习惯,加强锻炼,优化降血压、降血脂、控制血糖的治疗措施对预防和控制不良反应尤为重要.

Abstract：

Objective To summarize the incidence and treatment experience of the effectiveness and adverse reactions of the different immunosuppressive protocols and to increase the long-term survival rate in kidney recipients. Methods Single-center retrospective analysis was performed on 3102 cases of kidney transplant recipients in effectiveness and adverse reactions of different immunosuppressive protocols. The immunosuppressive protocols were as follows: CsA + Aza + Pred,low dose CsA + MMF + Pred, low dose Tac + MMF + Pred, low dose CsA + SRL + Pred, and low dose Tac+ SRL+ Pred. Results The 1-, 5-, 10-year survival rate of patients/kidney in low dose CsA + MMF + Pred protocol was higher than that in CsA + Aza + Pred protocol. The incidence of adverse reactions, such as hypertension, hyperuricemia, kidney and liver toxicity, and leukopenia was significantly lower, but the incidence of diarrhea was significantly higher in CsA + MMF + Pred protocol than in CsA + Aza + Pred protocol (all P＜0. 01). The incidence of hyperglycemia was significantly higher (P＜0. 05), and that of hairy and gingival hyperplsia was significantly lower (P＜0. 05) in low dose Tac+ MMF+ Pred than in low dose CsA+ MMF+ Pred protocol. The incidence of hyperlipidemia in low dose CsA (or Tac)+ SRL + Pred was significantly higher than in CsA (or Tac)+ MMF+ Pred protocol (P＜0. 05). The incidence of hirsutism in low dose Tac + SRL + Pred was significantly lower than that in CsA + SRL + Pred protocol (P ＜ 0. 05). The incidence of hyperglycemia in low dose Tac + SRL + Pred was significantly higher than that in low dose CsA + SRL + Pred protocol. Conclusion The triple drug protocol with a low dose of CsA (or Tac)+ MMF+ Pred significantly improved the survival of renal transplant recipients and graft, and reduced the incidence of adverse reactions, especially Tae + MMF + Pred protocol. Adjustment of the immunosuppressant dosage and protocol, improvement of eating habits, exercise, reduction of blood pressure, reduction of blood lipid, and control of blood glucose were particularly important in preventing and controlling adverse reactions during kidney transplantation.     

A modified Cockcroft-Gault formula taking into account the body surface area gives a more accurate estimation of the glomerular filtration rate

We sought to validate the improvement by adjustment for body surface area (BSA) of the accuracy of the original Cockcroft-Gault equation to estimate glomerular filtration rate (GFR), in a prospective cross-sectional study of 269 European patients with chronic kidney disease (CKD). We compared 3 methods: original Cockcroft-Gault equation, modified Cockcroft-Gault formula adjusted for BSA and abbreviated Modification of Diet in Renal Disease (MDRD) equation, using inulin clearance. Statistical analyses comprised repeated-measures analysis of variance (ANOVA), determination of the Pearson coefficient of correlation and a Bland-Altman concordance study. The ability of the GFR estimates to properly categorize patients in K/DOQI stages of CKD was also examined. Inulin clearance differed significantly from the standard Cockcroft-Gault method (ANOVA, p<0.001) and the abbreviated MDRD method (ANOVA, p<0.001) but not from the BSA-modified Cockcroft-Gault formula. Inulin clearance correlated better with the BSA-modified Cockcroft-Gault formula (r=0.88) and abbreviated MDRD equation (r=0.87) than with the standard Cockcroft-Gault equation (r=0.82). In concordance studies, bias was far smaller with the BSA-modified Cockcroft-Gault formula (mean bias -1.75 ml/min), than with the standard Cockcroft-Gault equation (mean bias -4.72 ml/min). The bias of the abbreviated MDRD was larger (mean bias +6.24 ml/min). Only patients with CKD stage 1 were better categorized with the BSA-modified Cockcroft-Gault formula and with the standard Cockcroft-Gault estimate than with the abbreviated MDRD equation. We conclude that adjustment for body surface area improves accuracy of the original Cockcroft-Gault equation.     

Comparison of prediction equations of glomerular filtration rate in Japanese adults

OBJECTIVE: Creatinine clearance (Ccr) is widely used for the evaluation of the glomerular filtration rate (GFR). Since the clearance method requires urine collection, formulae for predicting GFR without urine collection have been developed. In the guidelines of the Kidney Disease Outcomes Quality Initiative(K/ DOQI), the formulae developed from the Modification of Diet in Renal Disease Study (MDRD) are recommended for estimating GFR. The objective of the present study is to compare measured Ccr and Ccr estimated by the Cockcroft-Gault, Horio and MDRD equations in Japanese adults. MATERIALS AND METHODS: In 100 inpatients (67 men and 33 women) in this hospital, we evaluated the correlation between measured Ccr derived from 24-hour urinary collections and predicted Ccr or GFR calculated using the Cockcroft-Gault, Horio, and MDRD equations. RESULTS: The equation of linear regression is given as y = 0.8165x+2.1229 (r = 0.9415, p < 0.0001) by the Cockcroft-Gault formula, y = 0.7478x+1.6757 (r = 0.9458, p < 0.0001) by the Horio formula and y = 0.8335x+4.4261 (r = 0.9209, p < 0.0001) by the MDRD formula (y : measured Ccr, x : estimated Ccr or GFR). These predictive formulae demonstrated a strong correlation. CONCLUSION: Although the Cockcroft-Gault formula derived from Japanese patients demonstrated the highest correlation with Ccr, both the Horio formula and the MDRD formula also showed a high correlation. These predictive formulae could be useful for the prediction of Ccr in Japanese patients.     

Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: validity of a new (MDRD) prediction equation.

BACKGROUND: Based on the data derived from the Modification of Diet in Renal Disease (MDRD) study, a new equation was developed for the estimation of glomerular filtration rate (GFR). This equation, which takes into account body weight, age, sex, serum creatinine, race, serum urea, and serum albumin, provided a more accurate estimation of GFR in patients with renal insufficiency. However, this prediction equation has not been validated in subjects with normal or supra-normal GFR. METHODS: In a cross-sectional study, we measured GFR by inulin clearance in 46 healthy controls and 46 non-complicated type 1 diabetic patients. In this study population, GFR was predicted by measured creatinine clearance, the Cockcroft-Gault formula, and the MDRD equation. RESULTS: In the healthy subjects, mean GFR (+/-SD) was 107+/-11 as compared to 122+/-18 ml/min per 1.73 m(2) in the diabetic patients. This difference in GFR was reflected by a lower serum creatinine (76+/-8 vs 71+/-8 micro mol/l) in the diabetic patients. In the healthy controls, median absolute differences (and the 50th-75th-90th percentile of percentage absolute differences) between predicted and measured GFR were 5.2 ml/min per 1.73 m(2) (4.9-9.8-18.5%) for creatinine clearance, 9.0 ml/min per 1.73 m(2) (8.6-14.3-24.6%) for the Cockcroft-Gault formula, and 10.7 ml/min per 1.73 m(2) (10.9-16.3-25.5%) for the MDRD equation. In the diabetic patients, these differences were 8.3 ml/min per 1.73 m(2) (7.6-9.3-13.0%) for creatinine clearance; 11.8 ml/min per 1.73 m(2) (10.1-16.0-22.5%) for the Cockcroft-Gault formula, and 18.8 ml/min per 1.73 m(2) (16.0-24.2-31.9%) for the MDRD equation. CONCLUSIONS: In subjects with a normal or increased GFR, the new MDRD-prediction equation of GFR is less accurate than creatinine clearance or the Cockcroft-Gault formula, and offers no advantage.     

Estimating the prevalence of renal insufficiency in seniors requiring long-term care

BACKGROUND: Renal function declines with age, but little is known about the extent of renal insufficiency among the institutionalized elderly. The objective of this study was to estimate the prevalence of low glomerular filtration rate (GFR) in a large sample of elderly adults living in long-term care facilities, and to compare two commonly used methods for estimating GFR. METHODS: A total of 9931 residents aged 65 years and older participated in a retrospective cross-sectional study of 87 long-term care facilities in Ontario. GFR was estimated by the Cockcroft-Gault and Modification of Diet in Renal Disease Study (MDRD) equations. The prevalence of low GFR, using the Cockcroft-Gault equation (<30 mL/min), was compared with the MDRD equation (<30 mL/min/1.73 m2). RESULTS: A total of 17.0% (95% CI 15.6 to 18.5) of men and 14.4% (95% CI 13.6 to 15.3) of women had a serum creatinine concentration above the laboratory reported upper reference limit of normal. The prevalence of both elevated serum creatinine and low GFR were observed to increase with age (P < 0.0001). The Cockcroft-Gault equation produced a consistently lower estimate of GFR than did the MDRD equation, a discrepancy most pronounced in the oldest residents. Among all men, a low GFR was more prevalent using the Cockcroft-Gault (10.3%, 95% CI 9.2 to 11.5) than MDRD (3.5%, 95% CI 2.8 to 4.2) equation, with a similar difference also seen in women (23.3%, 95% CI 22.4 to 24.3 versus 4.0%, 95% CI 3.6 to 4.5, respectively). Of all residents whose Cockcroft-Gault estimated GFR was under 30 mL/min, 14.7% (95% CI 13.2 to 16.3) were found to have GFR greater than 60 mL/min/1.73 m2 according to the MDRD equation. CONCLUSION: Age-associated renal impairment is common among elderly long-term care residents, but there exists a clear discrepancy between the Cockcroft-Gault and MDRD equations in predicting GFR. Consideration should be given to medication dose adjustment, based on a practical estimate of GFR. However clarification is needed about which method, if either, is most valid among the frail elderly. Complex patient and societal issues surrounding advanced care directives, treatments associated with renal insufficiency, and, if and when to initiate dialysis, require further attention.