Oliguria as predictive biomarker of acute kidney injury in critically ill patients.

INTRODUCTION: During critical illness, oliguria is often used as a biomarker of acute kidney injury (AKI). However, its relationship with the subsequent development of AKI has not been prospectively evaluated. METHODS: We documented urine output and daily serum creatinine concentration in patients admitted for more than 24 hours in seven intensive care units (ICUs) from six countries over a period of two to four weeks. Oliguria was defined by a urine output < 0.5 ml/kg/hr. Data were collected until the occurrence of creatinine-defined AKI (AKI-Cr), designated by RIFLE-Injury class or greater using creatinine criteria (RIFLE-I[Cr]), or until ICU discharge. Episodes of oliguria were classified by longest duration of consecutive oliguria during each day were correlated with new AKI-Cr the next day, examining cut-offs for oliguria of greater than 1,2,3,4,5,6, or 12 hr duration, RESULTS: We studied 239 patients during 723 days. Overall, 32 patients had AKI on ICU admission, while in 23, AKI-Cr developed in ICU. Oliguria of greater than one hour was significantly associated with AKI-Cr the next day. On receiver-operator characteristic area under the curve (ROCAUC) analysis, oliguria showed fair predictive ability for AKI-Cr (ROCAUC = 0.75; CI:0.64-0.85). The presence of 4 hrs or more oliguria provided the best discrimination (sensitivity 52% (0.31-0.73%), specificity 86% (0.84-0.89%), positive likelihood ratio 3.8 (2.2-5.6), P < 0.0001) with negative predictive value of 98% (0.97-0.99). Oliguria preceding AKI-Cr was more likely to be associated with lower blood pressure, higher heart rate and use of vasopressors or inotropes and was more likely to prompt clinical intervention. However, only 30 of 487 individual episodes of oliguria preceded the new occurrence of AKI-Cr the next day. CONCLUSIONS: Oliguria was significantly associated with the occurrence of new AKI-Cr, however oliguria occurred frequently compared to the small number of patients (~10%) developing AKI-Cr in the ICU, so that most episodes of oliguria were not followed by renal injury. Consequently, the occurrence of short periods (1-6 hr) of oliguria lacked utility in discriminating patients with incipient AKI-Cr (positive likelihood ratios of 2-4, with > 10 considered indicative of a useful screening test). However, oliguria accompanied by hemodynamic compromise or increasing vasopressor dose may represent a clinically useful trigger for other early biomarkers of renal injury.

Higher extracellular water to total body water ratio was associated with chronic kidney disease progression in type 2 diabetes.

AIM: We studied the association between extracellular volume status and chronic kidney disease (CKD) progression; and the role of extracellular volume excess as a potential mediator in the relationship between matrix metalloproteinases (MMP)-2 and CKD progression in Type 2 diabetes mellitus (T2DM). METHODS: We conducted a prospective cohort study of 1079 T2DM patients. Bioelectrical impedance analysis (BIA) was performed to assess body fluid status. RESULTS: After up to 8.6 years of follow-up, 471 (43.7%) patients experienced CKD progression. In the fully adjusted model, extracellular water (ECW)/ total body water (TBW)ratios 0.39-0.40 and > 0.40 were associated with 45% and 78% higher risk of CKD progression respectively. Patients with an increase in ECW/TBW ratio had 40% higher risk of CKD progression compared to those with no change or reduction of ECW/TBW ratio. Higher ECW/TBW ratio accounted for 17.4% of the relationship between MMP-2 and CKD progression in T2DM (p = 0.026). CONCLUSIONS: Extracellular volume excess was independently associated with CKD progression in T2DM. Higher ECW/TBW ratio mediated the positive association between MMP-2 and CKD progression. Further studies are needed to elucidate the role of extracellular volume excess in deterioration of renal function.

The role of pulse pressure in navigating the paradigm of chronic kidney disease progression in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Arterial stiffness is a risk factor for chronic kidney disease progression (CKD). Pulse pressure is a surrogate marker of arterial stiffness. It is unclear if pulse pressure predicts CKD progression in type 2 diabetes mellitus. METHODS: This was prospective study involving 1494 patients with estimated glomerular filtration rate (eGFR) ≥ 15 ml/min/1.73 m2. Carotid-femoral pulse wave velocity was measured using applanation tonometry. Pulse pressure was calculated as difference between systolic and diastolic blood pressures. CKD progression was defined as worsening of eGFR categories (stage 1, ≥ 90 ml/min/1.73 m2; stage 2, 60-89 ml/min/1.73 m2; stage 3a, 45-59 ml/min/1.73 m2; stage 3b, 30-44 ml/min/1.73 m2; stage 4; 15-29 ml/min/1.73 m2; and stage 5, < 15 ml/min/1.73 m2) with ≥ 25% decrease in eGFR from baseline. RESULTS: After follow-up of up to 6 years, CKD progression occurred in 33.5% of subjects. Subjects in 2nd, 3rd and 4th quartiles of peripheral pulse pressure experienced higher risk of CKD progression with unadjusted hazard ratios (HRs) 1.55 [95% confidence interval (CI) 1.13-2.11; p = 0.006], 2.58 (1.93-3.45; p < 0.001) and 3.41 (2.58-4.52; p < 0.001). In the fully adjusted model, the association for 2nd, 3rd and 4th quartiles remained with HRs 1.40 (1.02-1.93; p = 0.038), 1.87 (1.37-2.56; p < 0.001) and 1.75 (1.25-2.44; p = 0.001) respectively. Similarly, 2nd, 3rd and 4th quartiles of aortic pulse pressure were associated with higher hazards of CKD progression with HRs 1.73 (1.25-2.40; p = 0.001), 1.65 (1.18-2.29; p = 0.003) and 1.81 (1.26-2.60; p = 0.001). Increasing urinary albumin-to-creatinine ratio accounted for 44.0% of the association between peripheral pulse pressure and CKD progression. CONCLUSIONS: Individuals with high pulse pressure were more susceptible to deterioration of renal function. Pulse pressure could potentially be incorporated in clinical practice as an inexpensive and readily available biomarker of renal decline in type 2 diabetes mellitus. Graphic abstract.

Medical Costs Associated with Severity of Chronic Kidney Disease in Type 2 Diabetes Mellitus in Singapore.

INTRODUCTION: This was a retrospective cross-sectional study to assess the impact of chronic kidney disease (CKD) and its severity in Type 2 diabetes mellitus (T2DM) on direct medical costs, and the effects of economic burden on CKD related complications in T2DM in Singapore. METHODS: A total of 1,275 T2DM patients were recruited by the diabetes centre at Khoo Teck Puat Hospital from 2011-2014. CKD stages were classified based on improving global outcome (KDIGO) categories, namely the estimated glomerular filtration rate (eGFR) and albuminuria kidney disease. Medical costs were extracted from the hospital administrative database. RESULTS: CKD occurred in 57.3% of patients. The total mean cost ratio for CKD relative to non-CKD was 2.2 (P<0.001). Mean (median) baseline annual unadjusted costs were significantly higher with increasing CKD severity-S$1,523 (S$949), S$2,065 (S$1,198), S$3,502 (S$1,613), and S$5,328 (S$2,556) for low, moderate, high, and very high risk respectively (P<0.001). CKD (P<0.001), age at study entry (P=0.001), Malay ethnicity (P=0.035), duration of diabetes mellitus (DM; P<0.001), use of statins/fibrates (P=0.021), and modified Diabetes Complications Severity Index (DCSI) (P<0.001) were positively associated with mean annual direct medical costs in the univariate analysis. In the fully adjusted model, association with mean annual total costs persisted for CKD, CKD severity and modified DCSI. CONCLUSION: The presence and increased severity of CKD is significantly associated with higher direct medical costs in T2DM patients. Actively preventing the occurrence and progression in DM-induced CKD may significantly reduce healthcare resource consumption and healthcare costs.

Changes in blood pressure before the development of nosocomial acute kidney injury.

BACKGROUND: Blood pressure is an important determinant of renal perfusion and acute kidney injury (AKI) is common in hospital patients. However, there is limited knowledge concerning the incidence of relative hypotension prior to its development in general wards. METHODS: We compared blood pressure recordings in a cohort of consecutive patients with no change in renal function to a cohort of patients with acute changes in renal function according to RIFLE classes R, I and F for AKI. We assessed blood pressure over a 3-day period before the development of AKI in index patients and a similar 3-day period in controls. We excluded patients with absolute hypotension [systolic blood pressure (SBP) <90 mmHg]. RESULTS: Patients were old (mean age 76.1 +/- 15.1) and mostly female (57.1%). Those who developed AKI had a lower diastolic blood pressure (P = 0.01), a trend towards lower mean arterial pressure (P = 0.077) and a greater decrease in mean systolic (P < 0.0001), mean diastolic (P < 0.0001) and mean arterial pressure (P < 0.0001) compared to controls. On multivariate logistic regression analysis, a decrease in SBP relative to pre-morbid value was a significant independent predictor of the development of AKI and of RIFLE classes I and F (odds ratio 1.084 for every -1 mmHg change in SBP). CONCLUSIONS: Relative hypotension is more common in ward patients who develop nosocomial AKI than in controls. In these patients, a decrease in SBP relative to pre-morbid value is a significant independent predictor of the development of severe AKI.

Long-term graft function with tacrolimus and cyclosporine in renal transplantation: paired kidney analysis.

AIM: The first prospective, randomized trial with paired kidney analysis was conducted to compare the efficacy and safety of tacrolimus with cyclosporine-based immunosuppressive therapy in renal transplant recipients. This paper reports the long-term follow-up results of the authors' previously published study, with the main focus on graft survival and renal function. METHODS: Chinese patients transplanted in our centre between June 1998 and June 2005 with their first deceased renal transplant were included. Patients were included if both kidneys were received by the authors' centre, thus allowing a paired analysis. Patients were randomized to receive triple immunosuppressive therapy with either tacrolimus or Neoral cyclosporine, concomitantly with prednisolone and azathioprine therapy. RESULTS: Seventy-six patients received cadaveric kidneys from 38 donors. Each pair of kidneys was randomly assigned to a separate group (38 subjects/group). The mean follow-up duration was 6.1 +/- 1.8 years. The mean calculated creatinine clearance was significantly higher in patients receiving tacrolimus-based therapy. The rate of biopsy-proven acute rejection was lower in the tacrolimus group (18.4% vs 42.1%, P = 0.03). The patient and graft survival were comparable in both treatment arms. Significantly fewer patients on tacrolimus-based therapy developed hypercholesterolaemia (P = 0.05). However, there was no significant difference in the development of post-transplant diabetes mellitus, hypertension, opportunistic infection and malignancy between both groups. CONCLUSION: Using the immunosuppressive regimen, tacrolimus-based therapy provided adequate immunosuppression with better renal function and less acute rejection, as compared with cyclosporine-based therapy.

Prevalence of abnormal glucose metabolism in Chinese renal transplant recipients: a single centre study.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) after renal transplantation is associated with adverse outcome on patient and graft survival. Fasting blood glucose alone will underestimate diabetes and also ignores diagnosis of impaired glucose tolerance (IGT). IGT has a strong correlation with diabetes and cardiovascular risk. METHODS: In this cross-sectional study, we estimate the prevalence of abnormal glucose metabolism (AGM) using oral glucose tolerance test (OGTT) and identify its predictive factors. Patients who received kidney transplantation in our centre without pre-transplant diabetes were recruited. OGTT was performed in patients with fasting glucose levels between 5.6 and 6.9 mmol/L for at least two occasions 6 months post-transplantation. RESULTS: Of 119 patients recruited, 31 had OGTT performed. The prevalence of PTDM, IGT and IFG was 21.8 (26/119)%, 6.7 (8/119)% and 3.4 (4/119)% respectively. Thus the overall prevalence of AGM was 31.9%. Age (P = 0.003), body mass index (P = 0.032), hepatitis B seropositivity status (P = 0.01), CMV infection (P = 0.02) and acute rejection (P = 0.002) were all associated with development of AGM. Using multivariate analysis, only older age at transplant (OR 1.09), history of acute rejection (OR 3.40) and hepatitis B seropositivity (OR 3.13) were significantly associated with the development of AGM. CONCLUSION: AGM is common in our renal transplant recipients.

Can daclizumab reduce acute rejection and improve long-term renal function in tacrolimus-based primary renal transplant recipients?

AIMS: To evaluate the efficacy and safety of a tacrolimus-based immunosuppressive regimen with and without induction therapy using daclizumab in first cadaveric renal transplant recipients. METHODS: Since January 2001, we studied the effect of daclizumab in a non-randomized and prospective study of 36 sequential first cadaveric renal transplant recipients. They were compared with a historical control group of 21 sequential first cadaveric renal transplant recipients without induction therapy. All patients received tacrolimus, azathioprine and corticosteroids as concomitant immunosuppressive therapy. Daclizumab was given at 1 mg/kg infusion 2 h before transplantation and then every 14 days for four more doses. Outcomes measured included incidence of acute rejection, patient survival, graft survival, annualized change in creatinine clearance (CrCl), cardiovascular risk profile, infection and malignancy. RESULTS: Fewer biopsy proven acute rejections were observed in the induction treatment group: 11.1% (4/36) versus 19% (4/21) but the rejection free survival was similar (P = 0.37). The patient survival and graft survival were comparable. The renal function was similar in both groups. There were also no significant difference in infection, malignancy and cardiovascular risk profile in both groups. CONCLUSION: Adding daclizumab to a tacrolimus-based therapy is safe but cannot further improve clinical efficacy.

Long-term prospective observation suggests that glomerular hyperfiltration is associated with rapid decline in renal filtration function: A multiethnic study.

AIM: Glomerular hyperfiltration usually occurs early in development of kidney complications in diabetes. To understand hyperfiltration as a marker of renal disease progression in type 2 diabetes mellitus, we aimed to examine association between glomerular hyperfiltration (estimated glomerular filtration rate ⩾ 120 mL/min/1.73 m2) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/min/1.73 m2). METHODS: This was a prospective cohort comprising 1014 patients with type 2 diabetes mellitus attending a Diabetes Centre of a regional hospital in 2002-2014. A separate prospective cohort, comprising 491 patients who attended Diabetes Centre or primary-care polyclinics, was used for validation. We performed binary mediation analysis to examine role of hyperfiltration on relationship between baseline haemoglobin A1c and rapid renal decline. RESULTS: Among patients in discovery cohort, 5.2% had baseline hyperfiltration. Over mean follow-up of 6 years, 22.9% had rapid glomerular filtration rate decline. Baseline hyperfiltration was significantly associated with greater odds of rapid renal decline after adjusting for demographics, diabetes duration and clinical covariates (odds ratio: 2.57; 95% confidence interval: 1.21-5.46; p = 0.014). Similar finding was found in validation cohort (odds ratio: 2.98; 95% confidence interval: 1.06-8.42; p = 0.034). Hyperfiltration significantly accounted for 35.3% of association between increasing baseline haemoglobin A1c and rapid renal decline. CONCLUSION: Glomerular hyperfiltration is an independent risk factor of rapid renal decline. It mediates the association between increasing haemoglobin A1c and rapid renal decline.

Discovery and validation of serum creatinine variability as novel biomarker for predicting onset of albuminuria in Type 2 diabetes mellitus.

AIM: We aim to study association serum creatinine(cr) variability and albuminuria progression. METHODS: We conducted a retrospective cohort study on patients with Type 2 Diabetes Mellitus at a Diabetes Centre in Singapore ("discovery cohort"). Outcome is worsening of urinary albumin-to-creatinine(ACR) across stages. Cr variability was expressed as adjusted cr-intrapersonal standard deviation(SD) and coefficient-of-variation(cr-CV). A separate cohort was used for validating association between cr variability and albuminuria progression ("validation cohort"). RESULTS: Over median follow-up of 4.2 years, 38.4% of 636 patients had albuminuria progression in the discovery cohort. Increasing log-transformed adjusted cr-intrapersonal SD and cr-CV were significantly associated with albuminuria progression: HRs 1.43 (95%CI 1.11-1.85) and 1.44 (1.11-1.87) respectively in the discovery cohort, and HRs 1.94 (1.09-3.45) and 1.91 (1.05-3.45) respectively in the validation cohort. When stratified by baseline urinary ACR, higher cr variability was significantly associated with albuminuria progression in patients with normoalbuminuria but not microalbuminuria. CONCLUSIONS: Cr variability independently predicts albuminuria onset. This is evident in patients with normoalbuminuria, suggesting that higher cr variability could herald albuminuria onset.

Long-term outcomes of patients with type 2 diabetes attending a multidisciplinary diabetes kidney disease clinic.

BACKGROUND: The best model of care to retard diabetic kidney disease (DKD) in the clinic is underexplored. In this study we investigated the long-term renal outcomes of a joint endocrinologist-nephrologist clinic. METHODS: The present study was a nested case-control study derived from a cohort of patients with type 2 diabetes mellitus (T2DM) seen prospectively at a secondary care diabetes center (DC). Cases ("DKD clinic group") were patients seen at the CKD clinic after being referred by physicians in DCs for management of DKD. Controls ("non-DKD clinic group") were patients from the same DC (i.e. same source population) with the same inclusion criteria of Stages 3-4 chronic kidney disease (CKD) at baseline but not seen at the DKD clinic. The outcome was Stage 5 CKD, defined as an estimated glomerular filtration rate <15 mL/min per 1.73 m2 . RESULTS: During the median follow-up period of 3.0 years (interquartile range 1.2-5.1 years), 240 patients (28.7%) reached Stage 5 CKD, with 45.8% and 54.2% of those reaching Stage 5 CKD in the DKD and non-DKD clinic groups, respectively. Multivariable Cox regression revealed that the DKD clinic group had a lower risk of progressing to Stage 5 CKD (hazard ratio 0.55; 95% confidence interval 0.36-0.83; P = 0.004) compared with the non-DKD clinic group. CONCLUSIONS: Multidisciplinary endocrinology and nephrology care in the DKD clinic is associated with a lower risk of end-stage renal disease. These findings may inform future management strategies targeted at patients with T2DM and CKD, especially with regard to joint specialist management involving endocrinologists and nephrologists.

Development and validation of a predictive model for Chronic Kidney Disease progression in Type 2 Diabetes Mellitus based on a 13-year study in Singapore.

AIMS: This study aims to develop and validate a predictive model for Chronic Kidney Disease (CKD) progression in Type 2 Diabetes Mellitus (T2DM). METHODS: We conducted a prospective study on 1582 patients with T2DM from a Diabetes Centre in regional hospital in 2002-2014. CKD progression was defined as deterioration across eGFR categories with ⩾25% drop from baseline. The dataset was randomly split into development (70%) and validation (30%) datasets. Stepwise multivariable logistic regression was used to identify baseline predictors for model development. Model performance in the two datasets was assessed. RESULTS: During median follow-up of 5.5years, 679 (42.9%) had CKD progression. Progression occurred in 467 (42.2%) and 212 patients (44.6%) in development and validation datasets respectively. Systolic blood pressure, HbA1c, estimated glomerular filtration rate and urinary albumin-to-creatinine ratio were associated with progression. Areas under receiving-operating-characteristics curve for the training and test datasets were 0.80 (95%CI, 0.77-0.83) and 0.83 (95%CI, 0.79-0.87). Observed and predicted probabilities by quintiles were not statistically different with Hosmer-Lemeshow χ2 0.65 (p=0.986) and 1.36 (p=0.928) in the two datasets. Sensitivity and specificity were 71.4% and 72.2% in development dataset, and 75.6% and 72.3% in the validation dataset. CONCLUSIONS: A model using routinely available clinical measurements can accurately predict CKD progression in T2DM.

Onset and progression of kidney disease in type 2 diabetes among multi-ethnic Asian population.

AIM: To elucidate the natural history of chronic kidney disease(CKD), which is defined as estimated glomerular filtration rate(eGFR)<60ml/min/1.73m(2) and/or increase of urinary albumin-to-creatinine ratio (uACR)≥30mg/g), and to identify factors associated with its onset and progression. METHODS: Prospective cohort study on individuals with T2DM attending Diabetes Centre in a regional hospital in Singapore from 2002. There were 553 patients with no pre-existing CKD for "onset" analysis and 967 patients with pre-existing CKD for "progression" analysis. Multivariable logistic regression was performed to determine risk factors of the outcomes. RESULTS: The mean follow-up period was 5.8years (4.5-7.1) and 5.3years (3.9-6.9) for the onset and progression cohorts respectively. About 45% of individuals developed CKD and 41% had progression. Among subjects with CKD onset, albuminuria-only occurred in 75% of them. Majority of the patients remained in the same CKD risk-category during follow-up. Progression and regression occurred across all CKD-categories. Transitions to adjacent risk-category were much more likely than transitions bypassing adjacent state. Risk factors for CKD onset included baseline albuminuria, eGFR, HbA1c variability, body mass index, triglycerides and age (all P<0.05). The predictors for CKD progression or rapid-progression included HbA1c variability, baseline albuminuria, systolic blood pressure, LDL-cholesterol, eGFR, HbA1c and ethnicity (all P<0.05). CONCLUSIONS: Albuminuria was the first manifestation of CKD in most T2DM patients. Transition across CKD-category occurred bi-directionally, but evolved largely in a stepwise fashion. The onset and progression of CKD were predicted by multiple risk factors, some of which were modifiable.

Dried blood spot measurement: application in tacrolimus monitoring using limited sampling strategy and abbreviated AUC estimation.

Dried blood spot (DBS) sampling and high-performance liquid chromatography tandem-mass spectrometry have been developed in monitoring tacrolimus levels. Our center favors the use of limited sampling strategy and abbreviated formula to estimate the area under concentration-time curve (AUC(0-12)). However, it is inconvenient for patients because they have to wait in the center for blood sampling. We investigated the application of DBS method in tacrolimus level monitoring using limited sampling strategy and abbreviated AUC estimation approach. Duplicate venous samples were obtained at each time point (C(0), C(2), and C(4)). To determine the stability of blood samples, one venous sample was sent to our laboratory immediately. The other duplicate venous samples, together with simultaneous fingerprick blood samples, were sent to the University of Maastricht in the Netherlands. Thirty six patients were recruited and 108 sets of blood samples were collected. There was a highly significant relationship between AUC(0-12), estimated from venous blood samples, and fingerprick blood samples (r(2) = 0.96, P < 0.0001). Moreover, there was an excellent correlation between whole blood venous tacrolimus levels in the two centers (r(2) = 0.97; P < 0.0001). The blood samples were stable after long-distance transport. DBS sampling can be used in centers using limited sampling and abbreviated AUC(0-12) strategy as drug monitoring.

Prevalence of chronic kidney disease in Chinese HIV-infected patients.

BACKGROUND: To evaluate the prevalence of chronic kidney disease (CKD) in Chinese HIV-infected population. METHODS: This was a cross-sectional point prevalence study. All Chinese HIV-infected patients who were followed up in a tertiary referral center in Hong Kong were recruited. Spot urine was saved for each patient to calculate urine protein-to-creatinine ratio (urine P/Cr). Those with urine P/Cr > 0.3 would have 24-h urine collection to determine the exact amount of proteinuria. Glomerular filtration rate (GFR) was estimated using MDRD formula. CKD was defined as GFR <60 ml/min/1.73 m2 and/or urine P/Cr > 0.3. Baseline demographic and clinical data were extracted from patients' records. RESULTS: In total 322 patients were recruited. The mean age was 45.2 +/- 11.7 years. The duration of follow up was 6.0 +/- 4.0 years. There were 264 male and 58 female patients. The prevalence of hypertension, diabetes mellitus and CKD were 7.4%, 10.6% and 16.8%, respectively. Eighteen patients (5.6%) had GFR < 60 ml/min/1.73 m2 while 44 patients (13.7%) had spot urine P/Cr > 0.3. Among those with urine P/Cr > 0.3, 38 patients had 24-h urine collection. Using univariate analysis, CKD was found to be significantly (P < 0.05) associated with age, hypertension, diabetes, use of indinavir, lower CD4 count and peak viral load. Multivariate logistic regression revealed older age (P < 0.001), lower CD4 count (P = 0.02) and use of indinavir therapy (P = 0.04) were associated with development of CKD. CONCLUSION: CKD is prevalent in Chinese HIV-infected patients. Patients with CKD were more likely to be older, associated with use of indinavir and CD4 nadir less than 100 cells/mul.

Paired kidney analysis of tacrolimus and cyclosporine microemulsion-based therapy in Chinese cadaveric renal transplant recipients.

Few studies used paired kidneys for comparison between tacrolimus and cyclosporine in renal transplantation. Most of the published data used whole blood trough levels for drug monitoring. However, the use of limited sampling strategy and abbreviated formula to estimate the 12-h area under concentration-time curve (AUC(0-12)) allowed better prediction of drug exposure. Sixty-six first cadaveric renal transplant recipients receiving paired kidneys were randomized to receive either tacrolimus-based (n = 33) or cyclosporine microemulsion (Neoral)-based therapies (n = 33). Abbreviated AUC(0-12) was used for drug monitoring and dose titration. Mean follow-up duration was 2.8 +/- 2 years. The patient and graft survival were comparable. Fewer incidence of acute rejection was observed in tacrolimus group (15% vs. 27.3%) though the difference was not significant (P = 0.23). The absolute value and the rate of decline of creatinine clearance were both significantly better in tacrolimus-treated patients. Prevalence of hypertension, post-transplant diabetes mellitus, infection, and malignancy were similar in both groups. Prevalence of hypercholesterolemia (11/33 vs. 4/33) and gum hypertrophy (6/33 vs. 1/33) was more common in cyclosporine-treated patients (P = 0.04 in both parameters). This was the first prospective, randomized study with paired kidney analysis showing the renal function was significantly better in tacrolimus-treated patients than in cyclosporine-treated patients.