Assessing Posttransplant Renal Function

Assessing Posttransplant Renal Function The conventional reliance on serum creatinine as the primary tool for evaluation of renal allograft function is not justified, particularly for early detection of renal allograft impairment. journalArticle allograft dysfunction chronic,renal disease,transplants,renal,r,nephropathy,nephroapthy,nephorpathy,kidney disease, allograft pathology,transplan,nephrosis,graft, allograft,allograft,disorder,allogenic, kidney transplantation,dysfunction,transplant,o,neuphropathy,disorders,difficultly Akinlolu Ojo, MD Akinlolu Ojo, MD, Associate Professor, Internal Medicine, Nephrology, University of Michigan, Dearborn Disclosure: Akinlolu Ojo, MD, has no significant financial interests or relationships to disclose. Dr. Ojo has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity. Medscape Medscape Transplantation 11/01/2004 5 2 <H3>Introduction</H3>Laboratory evaluation of renal allograft function is an essential tool in the clinical management of kidney transplant recipients. Timely detection and investigation of renal allograft dysfunction and accurate dosing of pharmacologic agents to prevent nephrotoxicity and toxic accumulation of drugs and their metabolites depend critically on simple, rapid, and precise measurement of glomerular filtration rate (GFR). This article will describe the limitations attendant to the widespread use of serum creatinine (SCr) as a measure of renal allograft function. The potential value of serum cystatin C concentration as an alternative to SCr, and the biases engendered in the currently available predictive equations for estimating GFR in both clinical settings and for research purposes, will also be discussed. The scenarios where estimating equations can be of use will be considered along with recommendations for future strategies that may yield simple, widely applicable, and more precise tools for estimating renal allograft function.<H3>Overview of Methods</H3>Measurement of SCr is the most commonly utilized method for assessing renal allograft function; however, this measurement is plagued by significant limitations, including inability to detect functional impairment less than 50%, error-prone variability in assay techniques, interference by endogenous chromogens, tendency for tubular secretion, and the impact of age, gender, and nutritional status on creatinine generation.[1,2] These limitations conspire to make SCr concentration an imprecise index of renal allograft function and diminish its value as a sensitive and reliable tool in the clinical management of kidney transplant recipients. Furthermore, erroneous results and conclusions may derive from clinical research studies in which renal allograft function is an end point or important covariate and is measured by SCr.Inulin clearance, first described in 1937, is considered the gold standard for GFR determination, but in the last 2 decades, relatively simpler methods have been developed using serum and/or urinary sampling of injected radiolabeled isotopes (51Cr ethylenediaminetetraacetic acid [51CR-EDTA], 99mtechnetium pentetic acid [99mDTPA], or 125I-iothalamate) and nonradioactive contrast agents (iothlamate or iohexol). The isotopic GFR techniques are generally considered to accurately reflect inulin clearance, but their use is often limited to research studies with rare use in clinical practice because of the labor intensity, injections of radioisotopes, multiple serum and urinary samplings, and time needed to complete the studies (3-5 hours). For these and the additional reason of radiation exposure, isotopic GFR determinations have been relegated by GFR estimation techniques based on regression equations incorporating single SCr determination.The GFR-estimating equations offer a rapid, simple, inexpensive, and easily reproducible measure of renal function in chronic renal disease and in kidney transplant recipients.[3-9] Some of the predictive equations or formulae were derived to estimate GFR,[3,5,7] while others[4,6]were primarily developed to estimate 24-hour creatinine clearance (CrCl). Only the Nankivell formula was originally derived in kidney transplant recipients. As is commonly done, when the GFR-estimating equations are used comparatively or interchangeably with the equations for estimating CrCl, significant bias may result, as CrCl will consistently overestimate the true GFR consequent to the tubular secretion of creatinine, which increases in direction proportion to the decline of native renal or allograft function.Compared with other medical providers, kidney transplant physicians rely heavily on frequent assessment of renal function because the ability to obtain a quick index of renal allograft function is critical to nearly all aspects of posttransplant care. Among the numerous options for assessing renal allograft function, choice of the appropriate measurement should depend on the intended purpose or use of the result of functional graft assessment, the degree of measurement bias that is tolerable for the specific objective, the threshold of sensitivity required for a particular clinical/research situation, and characteristics of the population of kidney transplant recipients in which the allograft function is being evaluated. The 2 most common reasons for estimating renal allograft function are: (1) clinical assessment of the degree of acute or chronic graft impairment or to obtain a baseline against which future measurement will be compared in order to detect the onset of allograft dysfunction; and (2) in clinical research as an end point of an immunosuppressive drug trial, or assessment of regimen-associated nephrotoxicity or renoprotective effect of specific drugs. A summary of the characteristics and utility of each measurement technique available for estimating GFR in the renal allograft follows.<h4>SCr</h4>The blood concentration of SCr is affected by age, gender, race, muscle mass, and nutritional status.[2,10] Furthermore, the SCr assay may be affected by endogenous noncreatinine chromogens and commonly used drugs.[2] Assay methodologies vary across laboratories, which may introduce up to 20% variability in measurements.[11] Because of the nonlinear relationship between SCr and GFR (Figure), a clinically detectable increase in SCr may not be detected until the GFR has declined by 25% or more.[12] The reciprocal of SCr has been touted as a more accurate means of predicting the course of renal function decline over time, but this approach has not been found to be adequate in kidney transplant recipients.[13-15] In the aggregate, SCr is a relatively insensitive measure for detection of early functional renal allograft impairment. In most clinical trials, a 10 mL/min difference in GFR between treatment groups is considered to be clinically significant, yet this magnitude of difference is virtually undetectable by SCr measurement alone until renal allograft function is severely impaired. The appeal of SCr lies in its simplicity, low cost, and ready availability, but these advantages do not compensate for the gross limitations inherent to its use in most clinical and research settings following kidney transplantation.<center><img src="art-mt491513.fig.jpg" width="436" height="275" BORDER="1"></center><blockquote>Figure. Relationship between serum creatinine and glomerular filtration rates.</blockquote> <h4>Serum Cystatin C</h4>Cystatin C is a 122-amino acid basic protein synthesized by all nucleated cells.[16,17] This low-molecular-weight (13-kDa) product of the cystatin gene superfamily of cystein proteinase inhibitors is an ideal marker of GFR because its endogenous production occurs at a constant rate throughout most of life (4 months-70 years), and it is freely filtered by the glomerulus with no degradration or tubular secretion, although it is reabsorbed and catabolized by tubular epithelial cells.[17,18] Cystatin C production is not affected by age, gender, or inflammatory processes.[16,17] Cystatin C is measured in the serum by 1 of 2 United States Food and Drug Administration-approved methods: particle-enhanced turbidimetric immunoassay (PETIA) and particle-enhanced nephalometric immunoassay (PENIA). The reference interval is 0.51-0.98 mg/L, and there are no significant differences in the reference values for black and white adults.[19,20]Cystatin C has been studied in kidney transplant recipients and found to be superior to SCr, and similar in accuracy to CrCl and better than SCr in its ability to detect temporary and mild changes in GFR. Thus, cystatin C is more suitable for early detection of renal allograft rejection and other functional impairments.[21,22] A meta-analysis of 24 clinical studies of cystatin C, including studies conducted in adult and pediatric kidney transplant recipients, also confirmed that cystatin C is superior to SCr for detecting impaired GFR in the renal allograft.[18,23] However, other studies have shown that cystatin C values were significantly higher in kidney transplant recipients compared with nontransplant recipients with similar GFRs. A possible explanation is that cystatin C values may be affected by back leak of intact molecule into the systemic circulation as a result of tubulo-interstitial damage from calcineurin inhibitors and assay interference by other immunosuppressants.It has been shown in kidney transplant recipients that glucocorticoid therapy leads to a dose-dependent increased serum concentration of cystatin C.[24,25] Another study suggested that cystatin C values may be decreased by cyclosporine.[21] Despite these limitations, serum cystatin C concentration was a more accurate measure of allograft function in adult kidney transplant recipients.[24] Perhaps the greatest appeal of cystatin C is its ability to detect early impairment in GFR.[26] In studies of kidney transplant recipients, cystatin C levels rose several days before biopsy-proven rejection was confirmed and declined 4-5 days faster than SCr in recipients recovering from delayed graft function,[26,27] although the early sensitivity of cystatin C could not be confirmed in a study of 24 pediatric kidney transplant recipients.[28]Large clinical studies of transplant recipients under various immunosuppressive regimens are needed to validate the utility of cystatin C as an alternative to SCr in kidney transplant recipients. Meanwhile, it could be used concurrently with SCr to enhance the clinical experience of this potentially useful and more sensitive alternative.<h4>CrCl</h4>Estimation of GFR by 24-hour urinary CrCl is an excellent measure of GFR in normal subjects, but tends to grossly overestimate the level of renal function in patients with chronic renal dysfunction because of tubular secretion of creatinine, which increases proportionally with loss of renal function.[29-31] CrCl is of limited clinical utility in kidney transplant recipients because of compliance problems with collection instructions. Timed urine collection for shorter intervals (4-12 hours) has been used to extrapolate the 24-hour value, but compliance and completeness of collection also remain a source of error with this method. Other approaches to improve the accuracy of CrCl include pre-collection oral or intravenous cimetidine loading to block tubular creatinine secretion.[31-33] However, this improvisation is laborious and not practical for repeated renal function assessment in the clinical arena.<H3>Prediction Equations for GFR and CrCl</H3>Numerous prediction equations have been developed to estimate renal function(<a href="491513_tab.html#Table 1." target="Tables" onclick="resizeWin('Tables',500,650)">Table 1</a>). Except for the Nankivell formula, all were developed in the nontransplant populations. These predictive equations incorporate clinical and demographic variables to compensate for the limitations of SCr measurement. Since the equations were developed in steady-state conditions, they are of questionable applicability to rapidly changing posttransplant situations during which accurate and sensitive determination of renal allograft function is often critically needed. Most of the predictive equations have been tested or validated in the kidney transplant populations that were deemed to be in a steady state. In a nutshell, the Modification of Diet in Renal Disease equations yielded the least bias in most studies comparing predicted GFR measurement with isotopic GFR determinations.[34-38] It is notable, however, even with the best available predictive equations, that the predicted GFR differs from measured GFR by >/= 10 mL/min/1.73m2 34% to 53% of the time (<a href="491513_tab.html#Table 2." target="Tables" onclick="resizeWin('Tables',500,650)">Table 2</a>). Thus, these predictive equations harbor unacceptably large biases that make them only modestly useful for clinical management, and completely inadequate for clinical research in transplantation.<H3>Summary</H3>In summary, the essential points of this discussion are as follows:<table border="0" cellpadding="0" cellspacing="0"><tr><td><ul><li>The conventional reliance on SCr as the primary tool for evaluation of renal allograft function cannot be justified, particularly when early detection of renal allograft impairment is the objective of the measurement. Moreover, errors due to assay interference and assay technique can be large, leading to potentially wrong clinical decisions.</li><li>Serum concentration of cystatin C is superior to SCr as an index of GFR in terms of sensitivity and limited potential sources of spurious measurement. Because immunosuppressive drugs used in kidney transplant recipients could be a unique source of error in cystatin C measurements, large validation studies are needed in the kidney transplant population before cystatin C can supplant SCr as the primary clinical index of renal allograft function.</li><li>Predictive equations incorporating clinical and demographic variables can be used to correct for the inherent limitation of SCr measurement alone, but these equations harbor relatively large biases that make them unsuitable for clinical research studies. Nonetheless, some of the predictive equations are useful for clinical management (ie, the 24-hour urinary CrCl performs well in the normal range of GFR before severe impairment ensues).</li><li>There appears to be no suitable substitute for isotopic GFR determination of renal allograft function in clinical research involving kidney transplant recipients.</li></ul></td></tr></table> <a name="Table 1."><h3>Table 1. Predictive Equations for Clinical Estimation of Glomerular Filtration Rate and Creatinine Clearance</h3></a> <blockquote><table border="1" cellpadding="3" cellspacing="1" width="400"><tr valign="top"><td>Cockcroft-Gault[4] CrCl = (140 age) (body weight in kg)/72 × SCr × 0.85 (if female)</td></tr><tr valign="top"><td>MDRD[8] GFR = 170 × SCr−0.999 × age−0.176 × 0.762 (if female) X 1.180 (if black) × BUN−0.170 × serum albumin−0.318 MDRD (4-variable equation)[9] GFR = 170 × SCr−0.999 × age−0.176 × BUN−0.170 × 0.762 (if female) × 1.180 (if black)</td></tr><tr valign="top"><td>Schwartz[5] GFR = K × height (cm)/SCr mg/dL) where K = 0.55 for children aged 2-12 years, 0.55 for girls 13-21 years, and 0.70 for boys 13-21 years</td></tr><tr valign="top"><td>Walser[6] CrCl (for male) = 7.57 × (SCr in mmol/L)−1 0.103 × age + 0096 × weight-6.66 CrCl (for female) = 6.05 × (SCr in mmol/L)−1 0.08 × age + 0.08 × weight(kg) 4.81</td></tr><tr valign="top"><td>Jelliffe[3] CrCl = 98 16 × [(age 20)/20] × 0.90 (if female) SCr (mg/dL)</td></tr><tr valign="top"><td>Nankivell[7] GFR = 6.7/SCr (mmol/L) + 0.25 × weight (kg) 0.5 × urea 0.01 × height2 (meters) + 35 (or 25 if female)</td></tr></table>CrCl = creatinine clearance; GFR = glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; SCr = serum creatinine</blockquote> <a name="Table 2."><h3>Table 2. Percentage of Absolute Differences over 20, 15, and 10 mL/min /1.73m2 Between Glomerular Filtration Rate Tests and Inulin Clearance[38]</h3></a> <blockquote><table border="1" cellpadding="3" cellspacing="1"><tr valign="bottom"><th valign="bottom" align="left">Absolute Difference (mL/min/1.73m2)</th><th valign="bottom">Creatinine Clearance</th><th valign="bottom">Cockcroft-Gault[4]</th><th valign="bottom">Walser[6]</th><th valign="bottom">Jelliffee[3]</th><th valign="bottom">Nankivell[7]</th><th valign="bottom">MDRD[34-38]</th></tr><tr valign="top"><td>>20</td><td align="center">21%</td><td align="center">21%</td><td align="center">16%</td><td align="center">13%</td><td align="center">23%</td><td align="center">15%</td></tr><tr valign="top"><td>>15</td><td align="center">34%</td><td align="center">33%</td><td align="center">27%</td><td align="center">22%</td><td align="center">37%</td><td align="center">24%</td></tr><tr valign="top"><td>>10</td><td align="center">44%</td><td align="center">48%</td><td align="center">48%</td><td align="center">34%</td><td align="center">53%</td><td align="center">41%</td></tr></table>MDRD = Modification of Diet in Renal Disease</blockquote> <ol><li>Levey AS, Berg RL, Gassman JJ, Hall PM, Walker WG. 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