Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial.

Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2 , respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09-3.76; p = 0.03) and 2.56 (1.35-4.88; p = 0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p < 0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.

The risk of recurrent IgA nephropathy in a steroid-free protocol and other modifying immunosuppression.

Recurrent glomerulonephritis is an important cause of kidney allograft failure. The effect of immunosuppression on recurrent IgA nephropathy (IgAN) is unclear. We analyzed the impact of steroids and other immunosuppression on the risk of recurrent IgAN post-kidney transplantation. Between June 1989 and November 2008, 3311 kidney transplants were performed at our center. IgAN was the primary disease in 124 patients; of these, 75 (60.5%) patients received steroid-based immunosuppression (15 undergoing late steroid withdrawal), and 49 (39.5%) were maintained on steroid-free immunosuppression. Recurrent IgAN was diagnosed in 27 of 124 (22%) patients in clinically indicated kidney allograft biopsies over a median follow-up of 6.86 ± 5.4 yr. On cox proportional hazards model multivariate analysis, the hazard risk (HR) of IgAN recurrence was significantly higher in patients managed with steroid-free (HR 8.59: 3.03, 24.38, p < 0.001) and sirolimus-based (HR = 3.00:1.16, 7.75, p = 0.024) immunosuppression without antilymphocyte globulin induction (HR = 4.5: 1.77, 11.73, p = 0.002). Mycophenolate use was associated with a lower risk (HR = 0.42: 0.19, 0.95, p = 0.036), whereas cyclosporine did not have a significant impact on the risk of IgAN recurrence (p = 0.61). These results warrant future prospective studies regarding the role of steroids and other immunosuppression drugs in reducing recurrence of IgAN and other glomerulonephritis post-transplant.

The pathogenesis of acute allograft dysfunction in desensitized renal transplant recipients.

BACKGROUND: Acute allograft rejection after HLA desensitization is common early post-transplant but the sequence of histopathologic changes leading to graft dysfunction has not been well defined. METHODS: We evaluated the early pathogenesis and sequence of antibody-mediated graft damage of 35 desensitized living donor kidney recipients by studying the course of biopsies taken in the very early post-transplant period (<1 month). RESULTS: A total of 14 of the 35 patients met criteria for acute antibody-mediated rejection (AMR). In these patients, the chronologic sequence of pathologic changes was C4d peritubular capillary deposition, acute tubular injury, and peritubular capillaritis, followed by glomerulitis and interstitial inflammation. Classic AMR lesions occurred early, followed by mononuclear cellular infiltration, which comprised CD4 and CD8 T cells and monocytes. Development of graft dysfunction in most patients occurred concurrently with the emergence of graft cellular infiltration, rather than at the earlier time of antibody deposition as detected via C4d deposition. CONCLUSION: These data provide novel insight into the sequence of pathologic changes in patients with AMR post-transplant after HLA desensitization.

Monitoring infection with Epstein-Barr virus among seromismatch adult renal transplant recipients.

Patients who undergo Epstein-Barr virus (EBV) seromismatch (D+/R-) transplants have a higher risk for the development of post-transplant lymphoproliferative disorder (PTLD). Adult renal transplant recipients at a single institution were prospectively monitored for EBV during the first year post-transplant. Over a 2-year period, 34 patients (7.78%) were identified as being EBV D+/R-recipients. Patients who developed symptoms or had persistent viremia were pre-emptively administered rituximab. Six recipients were discharged without monitoring on the protocol. Of those six, three (50%) developed PTLD and all three lost their grafts. Twenty (60.6%) of the 34 recipients developed viremia during the first year post-transplant. Of the recipients who became viremic, six (30%) received rituximab. None of the six who received rituximab-developed PTLD. We found that recipients who were not monitored on the protocol were more likely to have PTLD and graft loss compared to those who were (p = 0.008). Post-transplant monitoring of adults who undergo EBV D+/R-kidney transplants for viremia and symptoms associated with EBV infection may prompt intervention which reduces the incidence of PTLD within the first year. Use of rituximab in preventing PTLD among patients with primary EBV infection requires further prospective study to determine its overall safety and efficacy.

De novo thrombotic microangiopathy in renal allograft biopsies-role of antibody-mediated rejection.

The most common cause of thrombotic microangiopathy (TMA) in renal allografts is thought to be calcineurin inhibitor toxicity. Antibody-mediated rejection (AMR) can also cause TMA, but its true impact on de novo TMA is unknown. In a retrospective review of renal allograft biopsies from January 2003 to December 2008 at our institution, we determined the prevalence of TMA in patients with C4d positive (n = 243) and C4d negative (n = 715) biopsies. Over 90% of patients received cyclosporine in both groups. De novo TMA was seen in 59 (6.1%) patients; most of them (55%) with C4d positive biopsy. Among patients with C4d positive biopsies, 13.6% had TMA, as compared to only 3.6% patients with C4d negative biopsies (p < 0.0001). Incidence of graft loss between C4d positive and C4d negative TMA groups was not significantly different, but 70% of patients with C4d positive TMA who received plasmapheresis had slightly lower graft loss rate. In biopsies with AMR-associated TMA, glomerulitis and peritubular capillaritis were significantly more prominent. AMR is the most common cause of TMA in renal allografts in our patient population. It is important to recognize AMR-related TMA because plasmapheresis treatment may be beneficial.

Elevated blood pressure predicts the risk of acute rejection in renal allograft recipients.

BACKGROUND: Acute rejection (AR) is a strong predictor of renal allograft survival. Recent advances in immunosuppression have reduced considerably the incidence of AR. Still, approximately 25% of patients have AR early post-transplant, and the factors that predispose to AR have not been fully clarified. METHODS: The study includes 1641 adults, recipients of first cadaveric (CAD, N = 1195) or living related renal grafts (LRD, N = 446), transplanted in one institution. The variables associated with the occurrence of AR during the first year post-transplant were identified. RESULTS: By univariate analyses, AR was associated with the following variables: younger (P < 0.001); heavier (P = 0.003); and African American recipients (P = 0.002); CAD transplants (P = 0.001); higher number of HLA mismatches (P = 0.001); delayed graft function (DGF, P = 0.001); higher levels of serum creatinine post-transplant (P = 0.003); and higher levels of systolic and/or diastolic blood pressure (BP) post-transplant (P < 0.001). Higher BP levels were also associated with earlier AR episodes (P < 0.0001). By multivariable analysis AR was significantly associated with recipient age, number of HLA mismatches, DGF, pre-PRA and systolic BP. Analysis of BP measured weekly post-transplant indicated that elevated BP levels, even three weeks prior to the AR episode, were significantly associated with AR. For every level of BP, the use of BP medications was associated with a lower incidence of AR (P < 0.0001). Furthermore, the use of calcium channel blockers was also associated with lower incidence of AR (P = 0.001). Of note, 81% of recipients whose BP increased after the transplant had AR. In contrast, 22% of patients whose BP declined post-transplant had AR. CONCLUSIONS: Elevated BP levels post-transplant identify patients at high risk of AR independently of graft function. Treatment of BP and reduction of BP levels appears to be associated with a decreased risk of AR. We hypothesize that high BP may be an indicator of a particular type of allograft damage, perhaps ischemic, that may predispose to AR.

Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a serious complication of transplantation caused by immunosuppressive drugs. In this study, we assessed the incidence of PTDM and the factors that are associated with the development of this complication. METHODS: The study population included 2078 non-DM renal allograft recipients, transplanted since 1983 in one institution. PTDM was diagnosed by the requirement of hypoglycemic medications, starting more than 30 days after transplantation. Post-transplant, all patients received cyclosporine (CsA) and prednisone, but none of these patients received tacrolimus. RESULTS: At 1, 3, 5, and 10 years after transplantation, 7, 10, 13, and 21% of patients developed PTDM. By multivariate Cox, the following variables correlated with a more rapid increase in the number of PTDM cases: (1) older age (RR = 2.2 comparing patients younger or older than 45 years, P < 0.0001), (2) transplant done after 1995 (RR = 1.7, P = 0.003), (3) African American race (RR = 1.6, P = 0.003), and (4) higher body weight at transplant (RR = 1.4, P < 0.0001). Compared with before 1995, since 1995, the percentage of patients with PTDM has increased from 5.9 to 10.5% at one year and from 8.8 to 16.9% at three years. This increase was statistically independent from all other variables tested. However, since 1995, recipients have become significantly heavier (P < 0.0001) and older (P < 0.0001), and the average CsA level has increased significantly (P < 0.0001). Also, since 1995, the cumulative dose of corticosteroids has declined (P < 0.0001); patients received a newer, better absorbed preparation of CsA and received mycophenolate mofetil. CONCLUSIONS: The risk of PTDM increases continuously with time post-transplant. There has been an increase in the incidence of PTDM in patients transplanted recently, and that increase can be explained only partially by changes in the recipients' characteristics. We postulate that this increase may be due to the introduction of better absorbed CsA formulations that result in higher blood levels and higher cumulative exposure to this diabetogenic drug.

Obese living kidney donors: short-term results and possible implications.

BACKGROUND: Living kidney donation has increased recently as the shortage of cadaveric organs continues. This increase has occurred in part, due to expanded donor criteria, including obese patients. This is a potential concern because obesity is associated with surgical complications, possibly death, and chronic medical problems. To address this concern, we examined the outcome of a large group of obese (ObD) and nonobese living kidney donors (NObD). METHODS: A total of 107 obese (body mass index> or =27 kg/m2) and 116 nonobese (body mass index<27 kg/m2) living kidney donors donating at a single institution between 1990 and 1996 were studied. Surgical complications, operative duration, and hospital length of stay were assessed. Preoperative blood pressure, serum creatinine, creatinine clearance, protein excretion, fasting glucose, and hemoglobin A1C were measured and first degree relatives with diabetes were identified. RESULTS: Overall complications were significantly more common in ObD, 16.8 vs. 3.4% (P=0.0012). The majority of complications in the entire cohort, 56%, were wound related and were significantly more common in ObD (P=0.016). There was no significant increase in nonwound-related infections, bleeding, or cardiopulmonary events. There were no deaths or major complications. Operative time was significantly longer in ObD 151+/-30 vs. 141+/-29 min (P<0.05) but hospital duration was no different. Predonation, blood pressure in ObD was significantly higher, (P<0.05) and they more often had a family history of diabetes, 46 vs. 30% (P<0.05) than nonobese donors. Renal function, proteinuria, fasting glucose, or hemoglobin A1C were no different. CONCLUSION: With prudent selection, the use of obese living kidney donors appears safe in the short term. They experience more minor complications, usually wound related, and slightly longer operations. Given a higher baseline blood pressure and family history of diabetes, the long-term effect on the remaining solitary kidney in ObD needs to be examined.

Renal allograft survival following acute rejection correlates with blood pressure levels and histopathology.

BACKGROUND: Acute rejection (AR) is a strong predictor of renal graft survival, but the negative impact of AR on survival is variable, suggesting that other factors modulate this relationship. In this study, we examined the variables that correlate with graft survival after AR, particularly the impact of blood pressure (BP), graft function, and histopathology. METHODS: The study population included patients with no AR (N = 942) and patients with one (N = 407) or two (N = 156) AR during the first year post-transplant. Patients were adults who were recipients of living related (LRD, N = 410) or cadaveric grafts (CAD, N = 1095) and who were transplanted in a single institution and followed for 5.8 +/- 4 years. RESULTS: Compared with patients without AR, those with AR were significantly younger, had more human lymphocyte antigen mismatches, and included more CAD recipients. Graft survival was analyzed beyond six-months post-transplant. In patients with AR, reduced survival correlated (multivariate) with (a) younger recipients (P = 0.01), (b) AR occurring later during the first-year post-transplant (P = 0.0006), (c) elevated serum creatinine (Cr) before (P = 0.05), at the time (P = 0.0001) of, or after AR (P = 0.0004), and (d) average BP levels after AR [systolic BP (P = 0.003 logistic, P < 0.0001 by Cox), diastolic BP (P = 0.007), mean arterial pressure (P < 0.0001)]. This latter correlation was independent of graft function and recipient race. Thus, post-AR BP levels correlated with graft survival in patients with post-AR creatinine

Focal segmental glomerulosclerosis in renal allografts with chronic nephropathy: implications for graft survival.

De novo focal segmental glomerulosclerosis (FSGS) in renal allografts most often is diagnosed in association with chronic allograft nephropathy (CN). In this study, we assessed the clinical and pathological variables that correlate with the presence of de novo FSGS and the implications of FSGS for the survival of grafts with CN. The study population included 293 renal allograft recipients (52 living related donor, 241 cadaveric donor) diagnosed with CN by biopsy more than 6 months after transplantation. Patients with recurrent FSGS or FSGS associated with other glomerulopathies were excluded. FSGS was present in 87 patients with CN (30%). FSGS was diagnosed more commonly in the following groups of patients: young (P = 0.04), black (P = 0.02), and those with elevated serum cholesterol levels (P = 0.002) and/or high-grade proteinuria (P < 0. 0001, all univariate analysis). FSGS was diagnosed later after transplantation than CN without FSGS (P < 0.0001), and FSGS correlated with the presence of arteriolar hyalinosis in the biopsy specimen (P = 0.04). Compared with CN without FSGS, FSGS was associated with significantly worse death-censored graft survival (P = 0.008, univariate Cox). In addition, when we analyzed all patients with CN, graft survival correlated by multivariate analysis with the following parameters: serum creatinine level (P < 0.0001) and proteinuria (P = 0.004) at the time of diagnosis, presence of FSGS (P = 0.03), and degree of interstitial fibrosis and tubular atrophy (CN score; P < 0.0001, Cox). Of interest, the use of lipid-reducing agents was also associated with improved graft survival in patients with CN (P = 0.0002, univariate Cox), although total lipid levels were not significantly less in patients receiving these drugs. In conclusion, de novo FSGS presents late after transplantation and in association with arteriolar hyalinosis, suggesting these lesions may be related to chronic cyclosporine toxicity. In CN, the presence of FSGS and the severity of interstitial fibrosis are negative independent predictors of graft survival. The possible relationship between lipid-reducing agents and graft survival clearly needs to be examined carefully in future studies.

Patient survival after renal transplantation: II. The impact of smoking.

Renal transplant recipients have significantly higher mortality than individuals without kidney disease and the excess mortality is mainly due to cardiovascular causes. In this study, we sought to determine the impact of smoking, a major cardiovascular risk factor, on patient and renal graft survival. The study population included all adult recipients of first cadaveric kidney transplants done in our institution from 1984 to 1991. By selection, all patients were alive and had a functioning graft for at least 1 yr after transplantation. Smoking history was gathered prior to transplantation. The follow-up period was 84.3 + 41 months and during this time 28%, of the patients died and 21%, lost their graft. By univariate and multivariate analysis, patient survival, censored at the time of graft loss, correlated with these pre-transplant variables: age (p < 0.0001); diabetes (p = 0.0002); history of cigarette smoking (p = 0.004); time on dialysis prior to the transplant (p = 0.0005); and cardiomegaly by chest X-ray (p = 0.0005). Post-transplant variables did not correlate with patient mortality. By Cox regression, patient survival time was significantly shorter in diabetics (p < 0.0001), smokers (p = 0.0005), and recipients older than 40 yr. However, there were no significant differences between the survival of smokers, non-diabetics, diabetics, and older recipients. Patient death was the most common cause of renal transplant failure in smokers, in patients older than 40 yr, and in diabetics, but these patient characteristics did not correlate with graft survival. The prevalence of different causes of death was not significantly different between smokers and non-smokers. In conclusion, a history of cigarette smoking correlates with decreased patient survival after transplantation, and the magnitude of the negative impact of smoking in renal transplant recipients is quantitatively similar to that of diabetes.

Clinical implications of the diagnosis of renal allograft infarction by percutaneous biopsy.

BACKGROUND: Herein we investigated the relationships between acute rejection (AR), infection, and renal allograft infarcts, particularly those infarcts that occur beyond the immediate posttransplant period and that affect functioning grafts. METHODS: Infarcts (n=59) were classified as: (1) early (EI; <2 months after transplant; n=32); or (2) late (LI; >2 months; n=27). Controls included patients with severe AR but without infarction (n=84). RESULTS: There were not significant differences in donor or recipient characteristics between infarcts and controls. At diagnosis, patients with infarcts were more likely to be infected (30%) than controls (14%, P=0.01); 15% of infarcts and 1% of controls had disseminated cytomegalovirus (P=0.04). Infarct and AR coexisted in the biopsy specimens of 66% of patients with EI and 62% of patients with LI, but the AR severity ranged from borderline to severe. Furthermore, 30% of patients with EI/LI had a history of severe AR. Graft survival was 47% in patients with EI, 22% in patients with LI (NS), and 71% in controls (P<0.0001, chi-square and Cox regression). Correlates of better graft survival in infarcts included: older recipient (P=0.03); smaller area of infarction in the biopsy specimen (P=0.04); and use of anti-AR therapy (P=0.03). Therapy was effective in patients with EI (treated, 71% survival; untreated, 29%, P=0.02) but not in patients with LI (25% vs. 23%). CONCLUSIONS: Allograft infarcts are associated with AR in 64% of patients, but the AR may be mild. Infarcts are associated with infections. Graft survival is worse in patients with infarcts than in patients with severe AR, consequently these two pathologic diagnoses should not be considered as a single entity.

Patient survival after renal transplantation: I. The impact of dialysis pre-transplant.

Patients on dialysis and recipients of renal transplants have higher mortality than individuals without kidney disease. In this study we evaluated the possible impact of dialysis therapy before transplantation on patient survival after the transplant. This analysis includes all of the patients who received a cadaveric renal transplant at The Ohio State University from 1984 to 1991 and who remained alive with functioning grafts for at least six months after the transplant (N = 523). After a follow-up of 84 +/- 14 months, 28% of the patients died and 23% lost their grafts. By multivariate analysis, reduced patient survival (censored at the time of graft loss) correlated with these pre-transplant variables: Older age (P < 0.0001), the presence of diabetes (P = 0.0002), smoking (P = 0.009), and the length of time on dialysis (P = 0.0002). Thus, 7% of patients who were never dialyzed, 23% of those dialyzed for less than three years, and 44% of patients dialyzed for > or = three years died post-transplant. By Cox regression, patient survival months correlated with time on dialysis pre-transplant (P = 0.0003). The type of dialysis (CAPD vs. hemodialysis) did not correlate with patient survival. Graft survival, censored for patient death, did not correlate with any of these pre-transplant variables. The relationship between time on dialysis and patient mortality is due to at least two factors: (1) transplant recipients who had dialysis for > or = 3 years had higher mortality due to infections (22%) than those who had dialysis for < 3 years (3%, P = 0.01 by X2); and (2) increasing time on dialysis increases the prevalence of both left ventricular hypertrophy (P = 0.008) and cardiomegaly (P = 0.004), and these relationships are statistically independent of other factors that also correlate with the prevalence of cardiovascular disease. In conclusion, increased time on dialysis prior to renal transplantation is associated with decreased survival of transplant recipients.

Function and survival of renal allografts from the same donor transplanted into kidney-only or kidney-pancreas recipients.

BACKGROUND: The aim of this study was to assess whether kidney-pancreas transplantation (KPT) compromises the prognosis of kidney transplantation (KT). METHODS: This study included 368 paired recipients who received grafts from the same donor (184 KPT/184 KT), i.e., renal grafts with the same pretransplant functional and pathologic characteristics. RESULTS: KPT recipients (KPR) were significantly younger and included fewer African-Americans (22% vs. 6%, P=0.0005) than recipients of kidney alone (KR). During year 1 after transplant surgery, KPR were re-admitted more often than KR (4.2+/-2 vs. 2.8+/-2, P < 0.0001). The number of acute rejections (AR) and the serum creatinine were not significantly different in KR and KPR up to 3 years after transplant. After 44+/-29 months, 13% of KR and 17% of KPR died (NS), and 17% of KR and 16% of KPR lost their kidneys (NS). In KPR, reduced renal graft survival did not correlate with AR (P=0.44), but it correlated with: older donors, younger recipients, elevated serum creatinine at 6 months, pancreas loss, and the number of episodes of acute graft dysfunction evaluated by biopsy (multivariate analysis). By Cox, graft and patient survival were not significantly different in KR and KPR. However, the patient survival of KPR < 40 years of age was lower than that of KR (P=0.02). Renal biopsies (n=165) in 40 paired recipients showed no significant differences in AR, interstitial fibrosis, or vascular pathology. CONCLUSIONS: Renal graft function, structure, and survival are not different in KPR and KR, but the correlates of renal graft survival are different in these two groups of recipients.

Relationships between arterial hypertension and renal allograft survival in African-American patients.

In previous studies, we showed that in African-American patients arterial hypertension during the first 6 months after transplantation is associated with a high risk of renal allograft loss. In this study, we sought to examine the relationships between pretransplant blood pressure (preBP), blood pressure early after transplantation (postBP), and allograft function and survival. The study included 116 African-American recipients of first cadaveric renal allografts followed for 64 +/- 40 months. Prior to transplantation, 78% of the patients required antihypertensive medications and 59% had poorly controlled BP (average mean arterial pressure, > or =107 mm Hg). Blood pressure levels increased significantly during the first month posttransplant, particularly in patients with poorly controlled preBP. During the first 6 months posttransplant, 95% of patients required antihypertensive drugs; after the transplant, patients required significantly more and higher doses of antihypertensives compared with pretransplant. In 38% of the patients, postBP remained high despite therapy. The level of postBP correlated with the patient's weight pretransplant and with the level of preBP. Pretransplant BP correlated with postBP 1 month after transplantation (r = 0.4, P < 0.0001), and 70% of the patients with poorly controlled postBP had uncontrolled preBP. Patients with poorly controlled preBP had worse graft survival than patients with well-controlled preBP (P = 0.03 by Cox regression). Furthermore, compared with patients with well-controlled postBP, patients with high postBP had higher serum creatinine at 10 days (P = 0.04) and at 6 months (P = 0.0004) posttransplant; these patients had reduced graft survival (P = 0.0006 by Cox). We found no objective evidence of differences in patient compliance between individuals with high postBP and those with well-controlled postBP. This study confirms the association between high postBP and reduced renal allograft survival in African-American patients. In addition, these results show that the level of preBP can be used to identify patients at high risk of developing severe hypertension immediately after transplantation and those at risk for renal allograft failure.

Amlodipine increases cyclosporine levels in hypertensive renal transplant patients: results of a prospective study.

Calcium channel blockers (CCB) are considered the agents of choice to treat hypertension in cyclosporine (CsA)-treated renal transplant patients. Verapamil, diltiazem, and nicardipine, but not nifedipine or isradipine, can significantly increase CsA levels. The effect of a new CCB, amlodipine, has not been established. However, some hospitals are routinely switching patients to amlodipine from other CCB for reasons of cost. A case of a man with stable CsA levels who developed significantly increased CsA levels after being changed to amlodipine is presented along with a prospective trial to formally examine this issue. Eleven hypertensive, CsA-treated renal transplant patients were placed on amlodipine for an average of 6.9 wk and later withdrawn. Three measurements of CsA trough level, blood pressure, serum creatinine concentration, and BUN were obtained at baseline, during treatment with amlodipine, and after withdrawal of amlodipine. CsA levels on amlodipine increased an average of 40% above baseline (P = 0.003) and decreased to baseline (P = 0.001) after amlodipine was withdrawn, despite no significant change in CsA dose. Additionally, there was no change in serum creatinine, BUN, or mean arterial pressure values. Amlodipine can increase CsA levels