Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. β2-Microglobulin (B2M) and β-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.

Study of diagnostic test accuracy.

Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants.

Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race.

GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [51Cr]EDTA.

Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m2, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1 - P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1 - P30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.

No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.

The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Since 1957, over 70 equations based on creatinine and/or cystatin C levels have been developed to estimate glomerular filtration rate (GFR). However, whether these equations accurately reflect renal function is debated. In this Perspectives article, we discuss >70 studies that compared estimated GFR (eGFR) with measured GFR (mGFR), involving ~40,000 renal transplant recipients and patients with chronic kidney disease (CKD), type 2 diabetes mellitus or polycystic kidney disease. Their results show that eGFR often differed from mGFR by ±30% or more, that eGFR values incorrectly staged CKD in 30-60% of patients, and that eGFR and mGFR gave different rates of GFR decline. Errors were unpredictable, and comparable for equations based on creatinine and/or cystatin C. We argue, therefore, that the persistence of these errors (despite intensive research) suggests that the problem lies with using creatinine and/or cystatin C as markers of renal function, rather than with the mathematical methods used for GFR estimation.

The role that sex plays in the development and progression of chronic kidney disease remains a subject of controversy. The lack of clarity in this important area reflects complex interactions between biological factors and cultural and socioeconomic influences that impact the relationship between sex and renal disease. Certainly, additional observational studies are indicated; however, innovative approaches are required to isolate biological processes from cultural influences. Despite these limitations, available data suggest that the progression of renal disease is slower in women than in men and that this sexual dimorphism is primarily due to direct actions of sex hormones on cellular metabolism. The extent to which differences in lifestyle factors between the sexes influence sexual dimorphism in the progression of chronic kidney disease remains to be elucidated.

In February 2002, the United Network for Organ Sharing implemented a system for prioritizing candidates for liver transplantation that was based on the risk of 90-day mortality as determined by the Model for End-Stage Liver Disease (MELD) score. As the MELD score is driven in part by serum creatinine as a marker of kidney function, the prevalence of kidney dysfunction and failure in patients with end-stage liver disease at the time of listing and at transplantation has steadily risen. In this review, we discuss current practices in liver transplantation in patients with kidney dysfunction focusing briefly on the decision to perform simultaneous liver-kidney transplantation. We then discuss pitfalls to the current practices of liver transplantation in patients with kidney dysfunction. We conclude by discussing potential improvements to current practices including the use of the MELD-Na score, alternatives to creatinine and creatinine-based equation for estimating kidney function, and the use of intraoperative kidney replacement therapy during liver transplantation.

Kidney transplantation is the treatment of choice for end-stage renal disease. The evaluation of graft function is mandatory in the management of renal transplant recipients. Glomerular filtration rate (GFR), is generally considered the best index of graft function and also a predictor of graft and patient survival. However GFR measurement using inulin clearance, the gold standard for its measurement and exogenous markers such as radiolabeled isotopes ((51)Cr EDTA, (99m)Tc DTPA or (125)I Iothalamate) and non-radioactive contrast agents (Iothalamate or Iohexol), is laborious as well as expensive, being rarely used in clinical practice. Therefore, endogenous markers, such as serum creatinine or cystatin C, are used to estimate kidney function, and equations using these markers adjusted to other variables, mainly demographic, are an attempt to improve accuracy in estimation of GFR (eGFR). Nevertheless, there is some concern about the inability of the available eGFR equations to accurately identify changes in GFR, in kidney transplant recipients. This article will review and discuss the performance and limitations of these endogenous markers and their equations as estimators of GFR in the kidney transplant recipients, and their ability in predicting significant clinical outcomes.

Estimation of glomerular filtration rate (eGFR) after renal transplantation is performed with the use of methods that are standardized for a population of nontransplantation patients with chronic kidney disease. The aim of the study was to compare the performance of GFR estimation formulas in renal transplant recipients.

The Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were compared with measured creatinine clearance or clearance estimated by the Cockroft-Gault (C-G) formula. The influence of age, body mass index, and eGFR on the relative performance of these formulas also was studied by subgroups analysis.

Mean measured or estimated creatinine clearance overestimates the values of GFR calculated using the MDRD or CKD-EPI equation. This was statistically significant (P < .05) in whole-study population and in subgroups of patients at age above 25 years, with body mass index above 25, and in a subgroup with eGFR-MDRD <50 mL/min/m(2). The mean bias from creatinine clearance was 7.46 mL/min for MDRD, 4.4 mL/min for CKD-EPI and -1.65 mL/min for C-G formula. There was a statistically significant (P < .05) negative correlation between eGFR value and bias from creatinine clearance for all 3 methods of estimation. The correlation coefficient was -0.4 for MDRD, -0.36 for CKD-EPI, and -0.46 for C-G clearance.

Measured and estimated creatinine clearance overestimate values of eGFR calculated by the MDRD or CKD-EPI formula in a population of kidney transplant recipients, especially in subjects with obesity and worse renal function. Accuracy of analyzed GFR estimation formulas decreases with deterioration of renal graft function.

Weight excess and/or central body fat distribution are associated with increased long-term renal risk, not only in subjects with renal disease or renal transplant recipients, but also in the general population. As the prevalence of weight excess is rising worldwide, this may become a main renal risk factor on a population basis, even more so because the risk extends to the overweight range. Understanding the mechanisms of this detrimental effect of weight excess on the kidneys is needed in order to design preventive treatment strategies. The increased risk associated with weight excess is partly attributed to associated comorbid conditions, such as hypertension, dyslipidaemia, insulin resistance and diabetes; however, current evidence supports a direct pathogenetic role for renal haemodynamics as well. Weight excess is associated with an altered renal haemodynamic profile, i.e. an increased glomerular filtration rate relative to effective renal plasma flow, resulting in an increased filtration fraction (FF). This renal haemodynamic profile is considered to reflect glomerular hyperfiltration and glomerular hypertension, resulting from a dysbalance between afferent and efferent arterial vasomotor balance. This unfavorable renal haemodynamic profile was found to be associated with renal outcome in experimental models and in human renal transplant recipients, and is associated with a blunted sodium excretion, and reversible by weight loss, renin-angiotensin-aldosterone system blockade or by dietary sodium restriction. More recent evidence showed that a central body fat distribution is also associated with an increased FF, even independent of overall weight excess. In this review, we provide an overview on current literature on the impact of weight excess and central body fat distribution on the renal haemodynamic profile in humans, and its possible role in progressive renal damage.

Urinary tract infection (UTI) is the most common infectious complication after kidney transplantation. We aim to determine its impact on allograft function as indicated by several measures such as iothalamate glomerular filtration rate (iGFR), estimated glomerular filtration rate (eGFR), and creatinine value.

We performed a single-center retrospective cohort study to determine the impact of UTI on kidney allograft outcome.

The study population consisted of 301 kidney transplant recipients; 84% were living donor transplants. One hundred and one patients (34%) developed at least one episode of UTI and the incidence of UTI during the first year after transplantation was 25%. At the end of the follow-up, the iGFR was lower among patients who had developed at least one UTI (p = 0.044). However, eGFR and creatinine values were not significantly different between UTI and non-UTI groups.

When kidney function was measured by eGFR and creatinine, there was no significant difference in allograft function between kidney recipients with or without UTI. However, when kidney function was measured by nuclear studies, there was a tendency toward impairment in allograft function among patients who developed atleast one UTI after transplantation.

National transplant registries routinely focus on centre-specific patient and graft survival rates following renal transplantation. However other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important quality of care indicators.

Renal transplant activity, incident graft survival data and donor information were obtained from NHS Blood and Transplant. Laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients.

The numbers of live and deceased kidney donors increased in 2010. The death-censored graft failure rate fell slightly to 2.4% and the transplant patient death rates remained stable at 2.5 per 100 patient years. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year post-transplant patients. Analysis of prevalent transplants by chronic kidney disease stage showed 13.7% with an eGFR <30 ml/min/1.73 m(2) and 1.5% with an eGFR <15 ml/min/1.73 m(2). Of those with CKD stage 5 T, 36.1% had haemoglobin concentrations <10.5 g/dl, 22.9% phosphate concentrations ≥ 1.8 mmol/L and 6.2% adjusted calcium concentrations ≥ 2.6 mmol/L. Malignancy (23%) and infection (22%) remained the commonest two causes of death in prevalent transplant patients.

Significant variations in clinical outcomes (unadjusted for patient-specific variables) amongst kidney transplant recipients continued to exist in the UK and may reflect differences in healthcare delivery between renal centres.

The management of kidney transplant recipients requires accurate estimate of glomerular filtration rate (GFR). This study aims at evaluating the performance of four creatinine-based formulas for estimating the GFR (estimated GFR) in this population.

Performances of Cockcroft and Gault formula, Modification of Diet in Renal Disease (MDRD) simplified formula, Chronic Kidney Disease Epidemiology Collaboration formula, and Nankivell formula were assessed compared with inulin clearance taken as the gold standard for measuring GFR (measured GFR). Performances were assessed using the first measurements of GFR obtained in 1249 subjects. How estimated GFR tracks changes in measured GFR over time since transplantation in those patients with repeated measures was also assessed.

The MDRD formula provided the best estimate of GFR with a mean bias of -0.5 mL/min/1.73 m, a standard deviation of bias of 12 mL/min/1.73 m, and a 30% accuracy at 85%. The MDRD formula also seemed to provide the best performance for estimating GFR, irrespective of age, stage of renal failure, and in people whose body mass index was more than 18.5 kg/m. This robustness is important in clinical practice. The performance of the four formulas was not modified by the posttransplant period.

Even if 30% accuracy was suboptimal in the Kidney Disease Outcomes Quality Initiative guidelines, our results, obtained in a large number of patients, lead us to recommend using the MDRD formula to monitor GFR in kidney transplant recipients.

The aim was to evaluate the accuracy of Cockcroft-Gault, Jelliffe, Wright and Modification of Diet in Renal Disease (MDRD) formulae as a substitute for the gold standard measure of glomerular filtration rate (GFR) using chromium 51 EDTA.

Retrospective analysis of GFR measurements in oncology patients from a University Teaching Hospital over 3 years was carried out. Bias and precision of estimates of GFR were compared with measured GFR.

Six hundred and sixty patients with measured GFR (median 90 ml/min, range 23-179 ml/min) were identified. Cockcroft-Gault produced the smallest bias (median percentage error -1.4%) and highest precision (median absolute percentage error 14.0%) and was the most accurate for carboplatin dosing. For patients>30% over their ideal body weight (IBW), using IBW+30% in the Cockcroft-Gault formula was more precise than using actual body weight or IBW. The Wright formula was most accurate for patients aged 70+years and patients with a body mass index (BMI)≥30 but overestimated GFR when GFR<50 ml/min.

When measured GFR is unavailable, we advise estimating GFR using the Cockcroft-Gault formula and using IBW+30% for patients weighing>30% over their IBW. If the GFR is ≥50 ml/min and the patient is >70 years and/or BMI≥30, the Wright formula gives the best estimate of GFR.

The calcimimetic cinacalcet is approved for treating secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Biochemical profiles and clinical outcomes in patients discontinuing cinacalcet at the time of transplantation are scarce.

We performed a prospective observational cohort study, including 303 incident renal transplant recipients, of whom 21 were on cinacalcet treatment at the time of transplantation. Parameters of mineral metabolism and incidence of parathyroidectomy and nephrocalcinosis in patients discontinuing cinacalcet at the time of transplantation patients ("cinacalcet +") were compared to cinacalcet-naïve patients ("cinacalcet -"). Mean follow-up was 35.6 ± 15.8 months.

At the time of transplantation, parameters of mineral metabolism were similar in both groups. Conversely, at month 3, serum ionized calcium (p = 0.0007), calcitriol (p = 0.02), biointact parathyroid hormone (p = 0.06) levels and urinary fractional excretion of phosphorus (p = 0.06) were higher, while serum phosphorus levels (p = 0.06) were lower in "cinacalcet +." Analysis based on matching at the time of initiation showed that the course of post-transplant mineral metabolism in cinacalcet-treated patients (median treatment period 12.5 months) vs. cinacalcet-naïve patients was identical. "Cinacalcet +" patients are characterized by a high-incidence proportion of both post-transplant nephrocalcinosis (45% at month 3) and parathyroidectomy (28.6%). No difference in renal function was observed between "cinacalcet +" and "cinacalcet-" patients.

Cinacalcet does not affect the course of secondary hyperparathyroidism in patients awaiting kidney transplantation. Biochemical profiles and a high parathyroidectomy rate suggest rebound hyperparathyroidism in renal transplant recipients discontinuing cinacalcet at the time of transplantation, which may be related to the short exposure time specific to this population. Risk/benefit studies are urgently required to define the role of continued calcimimetic treatment in renal transplant recipients and to determine the optimal treatment of secondary hyperparathyroidism in patients listed for transplantation.

The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.

Despite the advances in immunosuppression, renal allograft attrition over time remains unabated due to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA). We aimed to evaluate microRNA (miRNA) signatures in CAD with IF/TA and appraise correlation with paired urine samples and potential utility in prospective evaluation of graft function. MiRNA signatures were established between CAD with IF/TA versus normal allografts by microarray. Validation of the microarray results and prospective evaluation of urine samples was performed using real-time quantitative-PCR (RT-qPCR). Fifty-six miRNAs were identified in samples with CAD-IF/TA. Five miRNAs were selected for further validation based on array fold change, p-value and in silico predicted mRNA targets. We confirmed the differential expression of these five miRNAs by RT-qPCR using an independent set of samples. Differential expression was detected for miR-142-3p, miR-204, miR-107 and miR-211 (p < 0.001) and miR-32 (p < 0.05). Furthermore, differential expression of miR-142-3p (p < 0.01), miR-204 (p < 0.01) and miR-211 (p < 0.05) was also observed between patient groups in urine samples. A characteristic miRNA signature for IF/TA that correlates with paired urine samples was identified. These results support the potential use of miRNAs as noninvasive markers of IF/TA and for monitoring graft function.

Proteinuria is an established marker of decreased kidney function after kidney transplant. It recently has been suggested that albuminuria might be a more reliable marker. Although albuminuria often is regarded as a marker of glomerular damage, because chronic renal allograft damage is believed to be predominantly an interstitial process, albuminuria in this case might reflect tubular damage. Accordingly, we investigated the value of albuminuria, proteinuria, and tubular damage markers (KIM-1 [kidney injury molecule 1], NAG [N-acetyl-β-d-glucosaminidase], NGAL [neutrophil gelatinase-associated lipocalin], and H-FABP [heart fatty acid binding protein]) in predicting graft outcome in kidney transplant recipients.

Prospective observational cohort study.

606 patients visiting our outpatient kidney transplant clinic in 2001-2003 were included and used in the analysis for death-censored graft failure. Median follow-up was 4.7 (25th-75th percentile, 3.8-5.2) years. 577 patients had follow-up longer than 1 year and were included in the analysis for estimated glomerular filtration rate (eGFR) decrease. Median follow-up was 3.2 (25th-75th percentile, 2.7-3.7) years.

Urine protein, albumin, and tubular damage markers in 24-hour urine samples.

Death-censored graft failure and decrease in eGFR.

There were 42 patients with graft failure; mean eGFR change was -0.46 ± 3.7 (standard deviation) mL/min/1.73 m(2)/y. The area under the receiver operating characteristic curve for death-censored graft failure showed that albuminuria (0.78; 95% CI, 0.59-0.76) was significantly higher than proteinuria (0.67; 95% CI, 0.59-0.76; P = 0.001), NGAL (0.63; 95% CI, 0.52-0.74; P = 0.02), and H-FABP (0.62; 95% CI, 0.53-0.73; P = 0.005) and not significantly different from KIM-1 (0.74; 95% CI, 0.66-0.82) and NAG (0.75; 95% CI, 0.67-0.83). Results were similar for the eGFR decrease outcome.

Single-center observational study.

Measuring albuminuria may provide superior predictions for long-term renal outcomes after kidney transplant than total proteinuria. Additional assessment of urinary excretion of tubular damage markers may have limited value.

Accurate glomerular filtration rate (GFR) measurement in normal to high range is important for epidemiological studies and workup for kidney donation. Creatinine-based equations perform poorly in this GFR range. Creatinine clearance (CrCl) provides a substitute, provided urine is collected accurately and tubular creatinine handling can be accounted for. The latter is poorly characterized in the normal GFR range.

Therefore, we studied performance of CrCl, fractional creatinine excretion (FE(creat)) and its determinants in 226 potential kidney donors (47% males, mean 53 ± 10 years). GFR was assessed as (125)I-iothalamate clearance, simultaneously with 2-h CrCl and 24-h CrCl.

Mean GFR was 101 ± 18, 2-h CrCl 110 ± 20 and 24-h CrCl 106 ± 29 mL/min/1.73 m(2). Mean bias of 24 h CrCl was 7.4 [inter-quartile range -6.7 to 20.0] mL/min/1.73 m(2), precision (R(2)) 0.39 and 30% accuracy 82%. Mean FE(creat) was 110 ± 11%. FE(creat) correlated with body mass index (BMI) (r = 0.34, P < 0.001). Consequently, bias of 24-h CrCl increased from 2.7 (inter-quartile range -6.5 to 16.7) to 8.6 (inter-quartile range -5.8 to 20.5) and 12.6 (inter-quartile range 7.0 to 25.4) mL/min in subjects with BMI <25, 25-30 and >30 kg/m(2), respectively (P < 0.05). On multivariate analysis, BMI and gender were predictors of FE(creat).

CrCl systematically overestimates GFR in healthy subjects. The overestimation significantly correlates with BMI, with higher FE(creat) in subjects with higher BMI. The impact of BMI on tubular creatinine secretion can be accounted for, when using CrCl for GFR assessment in the normal to high range, by the following formula: GFR = 24-h CrCl - (22.75 + 0.76 × BMI - 0.29 × mean arterial pressure (-6.11 if female).

There is a critical need for biomarkers for early diagnosis, treatment response, and surrogate end point and outcome prediction in organ transplantation, leading to a tailored and individualized treatment. Genomic and proteomic platforms have provided multiple promising new biomarkers during the last few years. However, there is still no routine application of any of these markers in clinical transplantation. This article will discuss the existing gap between biomarker discovery and clinical application in the kidney transplant setting. Approaches to implementing biomarker monitoring into clinical practice will also be discussed.

An equation from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) provides more accurate estimates of the glomerular filtration rate (eGFR) than that from the modification of diet in renal disease (MDRD) Study, although both include a two-level variable for race (Black and White and other). Since creatinine generation differs among ethnic groups, it is possible that a multilevel ethnic variable would allow more accurate estimates across all groups. To evaluate this, we developed an equation to calculate eGFR that includes a four-level race variable (Black, Asian, Native American and Hispanic, and White and other) using a database of 8254 patients pooled from 10 studies. This equation was then validated in 4014 patients using 17 additional studies from the United States and Europe (validation database), and in 1022 patients from China (675), Japan (248), and South Africa (99). Coefficients for the Black, Asian, and Native American and Hispanic groups resulted in 15, 5, and 1% higher levels of eGFR, respectively, compared with the White and other group. In the validation database, the two-level race equation had minimal bias in Black, Native American and Hispanic, and White and other cohorts. The four-level ethnicity equation significantly improved bias in Asians of the validation data set and in Chinese. Both equations had a large bias in Japanese and South African patients. Thus, heterogeneity in performance among the ethnic and geographic groups precludes use of the four-level race equation. The CKD-EPI two-level race equation can be used in the United States and Europe across a wide range of ethnicity.

The critical importance of donor organ quality, i.e., number of surviving nephrons, ability to withstand injury, and capacity for repair in determining short- and long-term outcomes is becoming increasingly clear. This review provides an overview of studies to assess donor kidney quality and subsequent transplant outcomes based on clinical pathology and transcriptome-based variables available at time of transplantation. Prediction scores using clinical variables function when applied to large data sets but perform poorly for the individual patient. Histopathology findings in pre-implantation or post-reperfusion biopsies help to assess structural integrity of the donor kidney, provide information on pre-existing donor disease, and can serve as a baseline for tracking changes over time. However, more validated approaches of analysis and prospective studies are needed to reduce the number of discarded organs, improve allocation, and allow prediction of outcomes. Molecular profiling detects changes not seen by morphology or captured by clinical markers. In particular, molecular profiles provide a quantitative measurement of inflammatory burden or immune activation and reflect coordinated changes in pathways associated with injury and repair. However, description of transcriptome patterns is not an end in itself. The identification of predictive gene sets and the application to an individualized patient management needs the integration of clinical and pathology-based variables, as well as more objective reference markers of transplant function, post-transplant events, and long-term outcomes.

The Modification of Diet in Renal Disease (MDRD) study equation and the Cockcroft-Gault (CG) equation perform poorly in the (near-) normal range of GFR. Whether this is due to the level of GFR as such or to differences in individual characteristics between healthy individuals and patient with chronic kidney disease (CKD) is unknown.

We evaluated the performance of MDRD, CG per BSA (CG/(BSA)) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with measured GFR (mGFR; I-iothalamate) at 4 months before and 2 months after donation in 253 consecutive living kidney donors.

mGFR declined from 103 ± 15 to 66 ± 11 ml/min per 1.73 m(2) after donation. All equations underestimated mGFR at both time points. Arithmetic performance analysis showed improved performance after donation of all equations, with significant reduction of bias after donation. Expressed as percentage difference, mGFR-estimated GFR (eGFR) bias was reduced after donation only for CG/(BSA). Finally, in 295 unselected individuals who were screened for donation, mGFR was below the cutoff for donation of 80 ml/min per 1.73 m(2) in 19 individual but in 166, 98, and 74 for MDRD, CDK-EPI, and CG/(BSA), respectively.

A higher level of GFR as such is associated with larger absolute underestimation of true GFR by eGFR. For donor screening purposes, eGFR should be interpreted with great caution; when in doubt, true GFR should be performed to prevent unjustified decline of prospective kidney donors.

Clinical trials in kidney transplantation are beginning to include markers of kidney function as end points now that traditional outcomes, such as acute rejection, become increasingly rare events. The frequency and type of kidney function end points used are unknown.

Systematic review.

Randomized controlled trials in adult kidney transplant recipients reported in 5 major general medical journals and 5 major subspecialty journals in nephrology and transplantation between January 2003 and November 2008.

Inclusion of at least one kidney function end point at least 1 month posttransplant.

133 (79%) of 169 randomized trials identified used a kidney function end point. Of these, 37 (28%) used one or more measures of kidney function as the primary end point, and 81 (61%), as a secondary end point. For the primary end point, 21 (57%) trials used a creatinine-based estimated glomerular filtration rate (eGFR), 18 (49%) used serum creatinine level, and 7 (19%) used measured GFR. Overall, eGFR was an end point in 81 (61%) trials, and measured GFR, in 12 (9%) trials.

This review is limited by the poor quality of the included trials, with many not defining either primary or secondary end points.

Measures of kidney function are used commonly as surrogate end points in kidney transplant trials, with eGFR becoming more frequently used over time. Further data are needed to properly validate these surrogate end points and fully understand their limitations when designing and interpreting randomized trials.

Living kidney transplant donors generally have a favorable renal functional outcome postuninephrectomy, but concern remains that a reduced glomerular filtration rate (GFR) postuninephrectomy might have harmful effects. This study examines the short-term (3 months) effect of donor nephrectomy on GFR and the occurrence of stage 3 chronic kidney disease (CKD) postuninephrectomy.

The prevalence of stage 3 CKD (Kidney Disease Quality Outcome Initiative [GFR<60 mL/min/1.73 m]) was examined in 196 living donors by comparing preuninephrectomy and 3-month postuninephrectomy values of GFR using I-iothalamate GFR (iGFR), modification of diet in renal disease estimated GFR (eGFR), Cockcroft-Gault estimated creatinine clearance, and endogenous 24-hr creatinine clearance. The accuracy of GFR estimations for predicting iGFR was also studied.

The mean GFR before and after donation were iGFR, 105+/-18 and 68+/-13 mL/min/1.73 m; eGFR, 98+/-19 and 63+/-12 mL/min/1.73 m; Cockcroft-Gault estimated creatinine clearance, 125+/-33 and 85+/-22 mL/min/1.73 m, and endogenous 24-hr creatinine clearance, 133+/-38 and 86+/-24 mL/min/1.73 m, respectively. Stage 3 CKD was found postuninephrectomy in 53 donors (27%) by iGFR and in 73 donors (38%) by eGFR. The prevalence of stage 3 CKD was greater with older age. GFR estimation equations did not accurately predict iGFR, particularly postuninephrectomy.

Stage 3 CKD is commonly observed after living kidney donation, particularly in older donors. The long-term impact of stage 3 CKD postuninephrectomy is poorly understood and may not have the same implications as stage 3 CKD in other conditions. eGFR is a poor predictor of true GFR in kidney donors.

Hypercalcemia is a common complication in renal transplant recipients and has been associated with nephrocalcinosis and poor graft outcome. The performance of total calcium (tCa) in the diagnosis of blood calcium disturbances in renal transplant recipients is unknown.

We compared the ability of total tCa concentration to identify low, normal, or high ionized calcium (iCa) concentration, i.e., the gold standard, in an unselected cohort of 268 renal transplant recipients. All patients were studied 3 and 12 months after successful engraftment.

Hypercalcemia, defined as a iCa >1.29 mmol/L, was present in 58.6 and 44.8% of the patients at months 3 and 12, respectively. tCa concentrations >10.3 mg/dl, conversely, were observed in only 13.1% of the patients. Measuring tCa had a low sensitivity (20.3 and 24.2% at months 3 and 12, respectively) for the diagnosis of hypercalcemia. The agreement (κ coefficient [95% confidence interval]) between tCa concentrations and iCa was poor (month 3: 0.11 [0.05 to 0.17]; month 12: 0.20 [0.11 to 0.30]). The risk for underestimating iCa was increased by a low total bicarbonate concentration. Metabolic acidosis was observed in 48.1 and 37.3% of the patients at months 3 and 12, respectively.

Total calcium greatly underestimates the diagnosis of hypercalcemia in incident renal transplant recipients. This is mainly explained by the high prevalence of metabolic acidosis in these patients.

The Modification of Diet in Renal Disease (MDRD) Study equation underestimates measured glomerular filtration rate (GFR) at levels>60 mL/min/1.73 m2, with variable accuracy among subgroups; consequently, estimated GFR (eGFR)>or=60 mL/min/1.73 m2 is not reported by clinical laboratories. Here, performance of a more accurate GFR-estimating equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, is reported by level of GFR and clinical characteristics.

Test of diagnostic accuracy.

Pooled data set of 3,896 people from 16 studies with measured GFR (not used for the development of either equation). Subgroups were defined by eGFR, age, sex, race, diabetes, prior solid-organ transplant, and body mass index.

eGFR from the CKD-EPI and MDRD Study equations and standardized serum creatinine.

Measured GFR using urinary or plasma clearance of exogenous filtration markers.

Mean measured GFR was 68+/-36 (SD) mL/min/1.73 m2. For eGFR<30 mL/min/1.73 m2, both equations have similar bias (median difference compared with measured GFR). For eGFR of 30-59 mL/min/1.73 m2, bias was decreased from 4.9 to 2.1 mL/min/1.73 m2 (57% improvement). For eGFR of 60-89 mL/min/1.73 m2, bias was decreased from 11.9 to 4.2 mL/min/1.73 m2 (61% improvement). For eGFR of 90-119 mL/min/1.73 m2, bias was decreased from 10.0 to 1.9 mL/min/1.73 m2 (75% improvement). Similar or improved performance was noted for most subgroups with eGFR<90 mL/min/1.73 m2, other than body mass index<20 kg/m2, with greater variation noted for some subgroups with eGFR>or=90 mL/min/1.73 m2.

Limited number of elderly people and racial and ethnic minorities with measured GFR.

The CKD-EPI equation is more accurate than the MDRD Study equation overall and across most subgroups. In contrast to the MDRD Study equation, eGFR>or=60 mL/min/1.73 m2 can be reported using the CKD-EPI equation.

Evaluation of kidney function is crucial in the care of kidney transplant recipients and in the design and interpretation of clinical trials in transplantation. Kidney function is most commonly assessed in both instances using serum creatinine concentration or an estimate of glomerular filtration rate (GFR) based on serum creatinine. These are inexpensive, widely available, and easily administered. Both have significant drawbacks, notably with respect to their inability to accurately identify changes in GFR. Novel markers of GFR such as cystatin C and beta-trace protein show promise as accurate and sensitive markers of GFR but have not yet been adequately evaluated in kidney transplantation. In addition, they are relatively expensive compared to creatinine and their assays are not available in most clinical laboratories. Glomerular filtration rate measurement using a variety of different available tracers and techniques is infrequently used in either clinical care or research protocols because of its cost and cumbersomeness. This review will discuss the merits and pitfalls of the various tools available to evaluate GFR in kidney transplantation.

The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was developed to address the systematic underestimation of the glomerular filtration rate (GFR) by the Modification of Diet in Renal Disease (MDRD) Study equation in patients with a relatively well-preserved kidney function. The performance of the new equation for kidney transplant recipients (KTRs) is unknown.

We used the plasma clearance of (99m)Tc-diethylenetriamine pentaacetic acid to measure the GFR in a cohort of 207 stable KTRs and estimated the GFR with the new CKD-EPI equation.

The mean bias for the CKD-EPI equation of -4.5 mL x min(-1) x (1.73 m(2))(-1) was lower than that of the 4-variable MDRD Study equation; however, the 2 equations showed similar variation of individual biases around the mean or median bias, so that only modest improvement was seen in the overall percentage of GFR estimates within 30% of the measured GFR (84% vs 77% for the CKD-EPI vs MDRD Study equations, respectively). In the cohort with a GFR >60 mL x min(-1) x (1.73 m(2))(-1) (n = 98), the CKD-EPI bias was much less than that of the MDRD Study equation [-7.4 mL x min(-1) x (1.73 m(2))(-1) vs -14.3 mL x min(-1) x (1.73 m(2))(-1)], and an accuracy of + or - 30% was seen for 89% of GFR estimates, compared with 77% with the MDRD Study equation. The variation of the individual biases around the mean bias remained substantial [SD = 13.7 mL x min(-1) x (1.73 m(2))(-1)].

The CKD-EPI equation shows improved estimation ability, and we recommend that it replace the MDRD Study equation as the currently preferred creatinine-based estimating equation for KTRs. The precision of GFR estimates obtained with the CKD-EPI equation remains suboptimal, however, and we recommend that research on other markers of GFR, such as cystatin C and beta-trace protein, be pursued.

Hypercalcemia, hypophosphatemia and renal phosphate wasting are common after kidney transplantation. Animal data suggest that these alterations in mineral metabolism may contribute to calcium phosphate (CaPhos) deposition in the kidney and renal dysfunction. We tested the hypothesis that CaPhos deposition is highly prevalent in the early posttransplant period and is related to a disturbed mineral metabolism. For this purpose, biomarkers of mineral metabolism and renal calcium and phosphorus handling were prospectively assessed in 201 renal transplant recipients. CaPhos deposits were observed in 4.6, 30.4 and 24.7% of protocol biopsies obtained at the time of engraftment, and 3 and 12 months thereafter, respectively. In multivariate logistic regression analysis, high calcium and low serum phosphorus levels were independently associated with renal CaPhos deposition at month 3. The extent of CaPhos deposition correlated significantly with the severity of mineral metabolism disturbances. Renal function after a mean follow-up of 33 months was similar in patients with and without CaPhos deposition at month 3. In conclusion, our data demonstrate that CaPhos deposition is highly prevalent in the early posttransplant period and suggest that a disordered mineral metabolism is implicated in its pathogenesis. The clinical relevance of CaPhos deposition remains to be established.

Conversion from cyclosporine (CsA) to sirolimus at week 12 after kidney transplantation is associated with a significant improvement in renal function. The aim of this analysis was to investigate the effect of this conversion on interstitial fibrosis (IF), a hallmark of chronic allograft injury, in patients taking part in the CONCEPT trial. This multicenter, prospective, trial included 193 renal recipients randomized at week 12 to switch from CsA to sirolimus or to continue CsA, with mycophenolate mofetil. Routine biopsy with automated, quantified assessment of IF by a program of color segmentation was performed at 1 year in 121 patients. At 1 year, renal function was significantly improved in the conversion group as assessed by estimated GFR (MDRD) and measured GFR. Biopsy results, however, showed no between-group difference in percentage of IF. Calculated GFR at 1 year was significantly associated with the percentage of IF (p = 0.004, R(2)= 0.07). By multivariate analysis diabetic patients had more fibrosis than non-diabetic patients. In conclusion, although kidney transplant patients converted from CsA to sirolimus showed significant improvement in renal function, we found no difference of IF on 1-year biopsies.