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Evaluation of Renal Function

Assessment of kidney function using both qualitative and quantitative methods is an important part of the evaluation of patients and an essential characterization of individuals who participate in clinical research investigations. Estimating of creatinine clearance has been considered the clinical standard for assessment of kidney function for nearly 50 years, and continues to be used as the primary method of stratifying kidney function in drug pharmacokinetic studies submitted to the United States Food and Drug Administration (FDA). New equations to estimate glomerular filtration rate (GFR) are now used in many clinical settings to identify patients with CKD, and in large epidemiology studies to evaluate risks of mortality and progression to stage 5 CKD, that is , ESKD. Other tests, such as urinalysis, radiographic procedures, and biopsy, are also valuable tools in the assessment of kidney disease, and these qualitative assessments are useful for determining the pathology and etiology of kidney disease.

Quantitative indices of GFR or Clcr are considered the most useful diagnostic tools for identify the presence and monitoring the progression of CKD. These measures can also be used to quantify changes in function that may occur as a result of disease progression, therapeutic intervention, or a toxic insult. It is important to note that the term kidney function includes the combined processes of glomerular filtration, tubular secretion, and reabsorption, as well as endocrine and metabolic functions. This thread critically evaluates the various methods that can be used for the quantitative assessment of kidney function in individuals with normal kidney function, as well as in those with CKD and acute kidney injury (AKI). Where appropriate, discussion regarding the qualitative assessment of the kidney function is also presented, including the role of imaging procedures and invasive tests such as kidney biopsy.

Excretory Function

The kidney is largely responsible for the maintenance of body homeostasis via its role in regulating urinary excretion of water, electrolytes, endogenous substances such as urea, medications, and environmental toxins. It accomplishes this through the combined processes of glomerular filtration, tubular secretion, and reabsorption.

The “intact nephron hypothesis” described by Bricker, more than 40 years ago, proposes that “kidney function” of patients with renal disease is the net result of a reduced number of appropriately functioning nephrons. As the number of nephrons is reduced from the initial complement of 2 million, those that are unaffected compensate; that is, they hyper function. The cornerstone of this hypothesis is that glomerulotubular balance is maintained, such that those nephrons capable of functioning will continue to perform in an appropriate fashion. Extensive studies have indeed shown that single-nephron GFR increases in the unaffected nephrons; thus, the whole-kidney GFR, which represents the sum of the single-nephron GFRs of the remaining functional nephrons, may remain close to normal until there is extensive injury. Based on this, one would presume that a measure of one component of nephron function could be used as an estimate of all renal functions. This, indeed, has been and remains our clinical approach. We estimate GFR and assume secretion and reabsorption remain proportionally intact.

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Filtration

GFR is dependent on numerous factors, one of which is protein load. Bosch suggested that an appropriate comprehensive evaluation of kidney function should include the measurement of “filtration capacity.” Recently, the concept of renal function reserve (RFR) has been defined as the capacity of the kidney to increase GFR in response to physiological or pathologic conditions. This is similar in context to a cardiac stress test. The patient may have no hypoxic symptoms, for example, angina while resting, but it may become quite evident when the patient begins to exercise. Subjects with normal renal function administered an oral or intravenous (IV) protein load prior to measurement of GFR have been noted to increase their GFR by as much as 50%. As renal function declines, the kidneys usually compensate by increasing the single-nephron GFR. The RFR will be reduced in those individuals whose kidneys are already functioning at higher-than-normal levels because of preexisting kidney injury or subclinical loss of kidney mass. Thus, RFR ma be a complementary, insightful index of renal function for many individual with as yet unidentified CKD.

Quantification of renal function (excretory) is not only an important component of a diagnostic evaluation, but it also serves as an important parameter for monitoring therapy directed at the etiology of the diminished function itself, thereby allowing for objective measurement of the success of treatment. Measurement of renal function also serves as a useful indicator of the ability to the kidneys to eliminate drugs from the body. Furthermore, alterations of drug distribution and metabolism have been associated with the degree of renal function. Although several indices have been used for the quantification of GFR in the research setting, estimation of Clcr and GFR are the primary approaches used in the clinical arena.

Secretion

Secretion is an active process that predominantly takes place in the proximal tubule and facilitates the elimination of compounds from the renal circulation into the tubular lumen. Several highly efficient transport pathways exist for a wide range of endogenous and exogenous substances, resulting in renal clearances of these actively secreted entities that often greatly exceed GFR and in some cases approximate renal blood flow. These transporters are typically found among the solute-linked carrier (SLC) and ATB-binding cassette (ABC) super families. Overall, the net process of tubular secretion for drugs is likely a result of multiple secretory pathways acting simultaneously.

Reabsorption

Reabsorption of water and solutes occurs throughout the nephron, whereas the reabsorption of most medications occurs predominantly along the distal tubule and collecting duct. Urine flow rate and physicochemical characteristics of the molecule influence these processes: highly ionized compounds are not reabsorbed unless pH changes within the urine increase the fraction unionized, so that reabsorption may be facilitated.

Endocrine Function

The kidney synthesizes and secretes many hormones involved in maintaining fluid and electrolyte homeostasis. Secretion of renin by the cells of the juxtaglomerular apparatus and production and metabolism of prostaglandins and kinins are among the kidney’s endocrine functions. In addition in response to decreased oxygen tension in the blood, which is sensed by the kidney, erythropoietin is produced and secreted by peritubular fibroblasts. Because these functions are related to renal mass, decreased endocrine activity is associated with the loss of viable kidney cells.

Metabolic Function

The kidney perform a wide variety of metabolic functions, including the activation of vitamin D, gluconeogenesis, and metabolism of endogenous compounds such as insulin, steroids, and xenobiotics. It is common for patients with diabetes and stages 4 to 5 CKD to have reduced requirements for exogenous insulin, and require supplemental therapy with activated vitamin D3 or other vitamin D analogs to avert the bone loss and pain associated with CKD-associated metabolic bone disease. Cytochrome P450, N-acetyltransferase, glutathione transferase, renal peptidases, and other enzymes responsible for the degradation and activation of selected endogenous and exogenous substances have been identified in the kidney. The CYP enzymes in the kidneys are as active as those in the liver, when corrected for organ mass. In vitro and in vivo studies have shown that CYP-mediated metabolism is impaired in the presence of renal failure or uremia. In clinical studies using CYP3A probes in ESRD patients receiving hemodialysis, hepatic CYP3A activity was reported to be reduced by 28% from values observed in age-matched controls; partial correction was noted following the hemodialysis procedure.

Measurement of Kidney Function

The gold standard quantitative index of kidney function is a mGFR. A variety of methods may be used to measure and estimate kidney function in the acute care and ambulatory settings. Measurement of GFR is important for early recognition and monitoring of patients with CKD and as a guide for drug-dose adjustment.

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It is important to recognize conditions that may alter renal function independent of underlying renal pathology. For example, protein intake, such as oral protein loading or an infusion of amino acid solution, may increase GFR. As a result, inter- and intrasubject variability must be considered when it is used as a longitudinal marker of renal function. Dietary protein intake has been demonstrated to correlate with GFR in healthy subjects. The increased GFR following a protein load is the result of renal vasodilation accompanied by an increased renal plasma flow. The exact mechanism of the renal response to protein is unknown, but may be related to extra renal factors such as glucagon, prostaglandins, and angiotensin II, or intra renal mechanisms, such as alterations in tubular transport and tubuloglomerular feedback. Despite the evidence of a “renal reserve,” standardized evaluation techniques have not been developed. Therefore, assessment of a mGFR must consider the dietary protein status of the patient at the time of the study.

Measurement of Glomerular Filtration Rate

  • Measurement of the GFR is most accurate when performed following the exogenous administration of iohexol, iothalamate, or radioisotopes such as technetium-99m diethylenetriamine pentaacetic acid (99mTc-DTPA).

A mGFR remains the single best index of kidney function. As renal mass declines in the presence of age-related loss of nephrons or disease states such as hypertension or diabetes, there is a progressive decline in GFR. The rate of decline in GFR can be used to predict the time to onset of stage 5 CKD, as well as the risk of complications of CKD. Accurate measurement of GFR in clinical practice is a critical variable for individualization of the dosage regimens of renal excreted medications so that one can maximize their therapeutic efficacy and avoid potential toxicity.

The GFR is expressed as the volume of plasma filtered across the glomerulus per unit of time, based on total renal blood flow and capillary hemodynamics. The normal values for GFR are 127 +- 20 mL/min/1.73 m2 and 118 +- 20 mL/min/1.73 m2 in healthy men and women, respectively. These measured values closely approximate what one would predict if the normal renal blood flow were approximately 1.0 L/min/1.73 m2, plasma volume was 60% of blood volume, and filtration fraction across the glomerulus was 20%. In that situation the normal GFR would be expected to be approximately 120 mL/min/1.73 m2.

Optimal clinical measurement of GFR involves determining the renal clearance of a substance that is freely filtered without additional clearance because of tubular secretion or reduction as the result of reabsorption. Additionally, the substance should not be susceptible to metabolism within renal tissues and should not alter renal function. Given these conditions, the mGFR is equivalent to the renal clearance of the solute marker:

GFR = renal Cl = Ae / AUC 0>t

where renal Cl is renal clearance of the marker, Ae is the amount of marker excreted in the urine from time 0 to t, and AUC 0>t is the area under the plasma-concentration-versus-time curve of the marker.

Under steady-state conditions, for example during a continuous infusion of the marker, the expression simplifies to

GFR = renal Cl = Ae / (Css*t)

where Css is the steady-state plasma concentration of the marker achieved during continuous infusion. The continuous infusion method can also be employed without urine collection, where plasma clearance is calculated as Cl = infusion rate / Css. This method is dependent on the attainment of steady-state plasma concentrations and accurate measurement of infusatn concentrations. Plasma clearance can also be determined following a single-dose IV injection with the collection of multiple blood samples to estimate area under the curve (AUC 0>∞). Here, clearance is calculated as Cl = dose/AUC. These plasma clearance methods commonly yield clearance values 10% to 15% higher than GFR measured by urine collection methods.

Several markers have been used for the measurement of GFR and include both exogenous and endogenous compounds. Those administered as exogenous agents, such as inulin, sinistrin, iothalamate, iohexol, and radioisotopes, require specialized administration techniques and detection methods for the quantification of concentrations in serum and urine, but generally provide an accurate measure of GFR. Methods that employ endogenous compounds, such as creatinine or cyst, require less technical expertise, but produce results with greater variability. The GFR marker of choice depends on the purpose and cost of the compound which ranges from $2,000 per vial for radioactive for 125I-iothalamate to $6 per vial for nonradiolabeled iothalamate or iohexol.

Inulin and Sinistrin Clearance

Inulin is a large fructose polysaccharide, obtained from the Jerusalem artichoke, dahlia, and chicory plants. It is not bound to plasma proteins, is freely filtered at the glomerulus, is not secreted or reabsorbed, and is not metabolized by the kidney. The volume of distribution of inulin approximates extracellular volume, or 20% of ideal body weight. Because it is eliminated by glomerular filtration, its elimination half-life is dependent on renal function and is approximately 1.3 hours in subjects with normal renal function. Measurement of plasma and urine inulin concentrations can be performed using high-performance liquid chromatography. Sinistrin, another polyfructosan, has similar characteristics to inulin; it is filtered at the glomerulus and not secreted or reabsorbed to any significant extent. It is a naturally occurring substance derived from the root of the North African vegetable red squill, Urginea maritime, which has a much higher degree of water solubility than inulin. Assay methods for sinistrin have been described using enzymatic procedures, as well as high-performance liquid chromatography with electrochemical detection. Alternatives have been sought for inulin as a marker for GFR because of the problems of availability, high cost, sample preparation and assay variability.

Iothalamate Clearance

Iothalamate is an iodine-containing radio contrast agent that is available in both radiolabeled (125I) and nonradiolabeled forms. This agent is handled in a manner similar to that of inulin; it is freely filtered at the glomerulus and does not undergo substantial tubular secretion or reabsorption. The nonradiolabeled form is most widely used to measure GFR in ambulatory and research settings, and can safely be administered by IV bolus, continuous infusion, or subcutaneous injection. Plasma and urine iothalamate concentrations can be measured using high-performance liquid chromatography. Plasma clearance methods that do not require urine collections have been shown to be highly correlated with renal clearance, making them particularly well-suited for longitudinal evaluations of renal function. These plasma clearance methods require two-compartment modeling approaches because accuracy is dependent on duration of sampling. For example, Agarwal et al. demonstrated that short sampling intervals can overestimate GFR, particularly in patients with severely reduced GFR. In individuals with GFR more than 30 mL/min/1.73 m2 (greater than 0.29 mL/s/m2), a 2-hour sampling strategy yielded GFR values that were 54% higher compared with 10-hour sampling, whereas the 5-hour sampling was 17% higher. In individuals with GFR less than 30 mL/min/1.73 m2, the 5-hour GFR was 36% higher and 2-hour GFR was 126% higher than the 10-hour measurement. The authors proposed a 5- to 7- hour sampling time period with eight plasma samples to be the most appropriate and feasible approach for most GFR evaluations.

Iohexol

Lohexol, a nonionic, low osmolar, iodinated contrast agent, has also been used for the determination of GFR. It is eliminated almost entirely by glomerular filtration, and plasma and renal clearance values are similar to observations with other marker agents: Strong correlations of 0.90 or greater and significant relationships with iothalamate have been reported. These data support iohexol as a suitable alternative marker for the measurement of GFR. A reported advantage of this agent is that a limited number of plasma samples can be used to quantify iohexol plasma clearance. For patients with a reduced GFR more time must allotted – more than 24 hours if the eGFR is less  than 20 mL/min.

Radiolabeled Markers

The GFR has also been quantified using radiolabeled markers, such as 125I-iothalamate, 99mTc-DPTA, and 51Cr-ethylenediaminetetraacetic acid. These relatively small molecules are minimally bound to plasma proteins and do not undergo tubular secretion or reabsorption to any significant degree. 125I-iothalamate and 99mTc-DPTA are used in the United States, whereas 51Cr-EDTA is used extensively in Europe. The use of radiolabeled markers allows one to determine the individual contribution of each kidney to total renal function. Various protocols exist for the administration of these markers and subsequent measurement of GFR using either plasma or renal clearance calculation methods. The non renal clearance of these agents appears to be low, suggesting that plasma clearance is an acceptable technique except in patients with severe renal insufficiency (GFR less than 30 mL/min). Indeed, highly significant correlations between renal clearance among radiolabeled markers has been demonstrated. Although total radioactive exposure to patients is usually minimal, use of these agents does require compliance with radiation safety committees and appropriate biohazard waste disposal.

Optical Real-Time Glomerular Filtration Rate Markers

A clinically applicable technique to rapidly measure GFR, particularly in critically ill patients with unstable kidney function, is highly desirable. The currently available GFR measurement approaches, as outlined above, are technically demanding, time-consuming, and often cost-prohibitive. Research is underway to develop rapid, accurate, safe, and inexpensive techniques to address this need.

Creatinine

Although the measured (24-hour) CLcr has been used as an approximation of GFR for decades, it has limited clinical utility for a multiplicity of reasons. Short-duration witnessed mCLcr correlates well with mGFR based on iothalamate clearance performed using the single-injection technique. In a multicenter study of 136 patients with type 1 diabetic nephropathy, the correlations of simultaneous mCLcr, and 24-hour CLcr (compared to CLiothalamate) were 0.81 and 0.49, respectively, indicating increased variability with the 24-hour clearance determination. In a selected group of 110 patients, measurement of a 4-hour CLcr during water diuresis provided the best estimate of the GFR as determined by the CLiothalamate. Furthermore, the ratio of CLcr to CLiothalamate did not appear to increase as the GFR decreased. These data suggest that a short collection period with a water diuresis may be the best CLcr method for estimation of GFR.

A limitation of using creatinine as a filtration marker is that it undergoes tubular secretion. Tubular secretion arguments the filtered creatinine by approximately 10% in subjects with normal kidney function. If the nonspecific Jaffe reaction is used, which overestimates the Scr by approximately 10% because of the noncreatinine chromogens, then the measurement of CLcr is a very good measure of GFR in patients with normal kidney function. Tubular secretion, however, increases to as much as 100% in patients with kidney disease, resulting in mCLcr values that markedly overestimate GFR. For example, Bauer et al. reported that the CLcr-to-CLinulin ratio in subjects with mild impairment was 1.20; for those with moderate impairment, it was 1.87; and in those with severe impairment, it was 2.32. Thus, a mCLcr is a poor indicator of GFR in patients with moderate to severe renal insufficiency, that is, stages 3 to 5 CKD.

Because cimetidine blocks the tubular secretion of creatinine the potential role of several oral cimetidine regimens to improve the accuracy and precision of mCLcr as an indicator of GFR has been evaluated. The CLcr-to-CLDPTA ratio declined from 1.33 with placebo to 1.07 when 400 mg of cimetidine was administered four times a day for 2 days prior to and during the clearance determination. Similar results were observed when a single 800-mg dose of cimetidine was given 1 hour prior to the simultaneous determination of CLcr and CLiothalamate; the ratio of CLcr to CLiothalamate was reduced from a mean of 1.53 to 1.12. Thus a single oral dose of 800 mg of cimetidine should provide adequate blockade of creatinine secretion to improve the accuracy of a CLcr measurement as an estimate GFR in patients with stage 3 to 5 CKD.

To minimize the impact of diurnal variations in Scr on CLcr, the test is usually performed over a 24-hour period with the plasma creatinine obtained in the morning, as long as the patient has stable kidney function. Collection of urine remains a limiting factor in the 24-hour CLcr because of incomplete collections, and interconversion between creatinine and creatine that can occur if the urine is not maintained at a pH less than 6.

Estimating of Glomerular Filtration Rate

Because of the invasive nature and technical difficulties of directly measuring GFR in clinical settings, many equations for estimating GFR have been proposed over the past 10 years. A series of related GFR estimating equations have been developed for the primary purpose of identifying and classifying CKD in many patient populations. The initial equation was derived from multiple regression analysis of data obtained from the 1,628 patients enrolled in the Modification of Diet in Renal Disease Study (MDRD) where GFR was measured using the renal clearance of 125I-iothalamate methodology. A four-variable version of the original MDRD equation (MDRD4), based on plasma creatinine, age, sex, and race, was shown to provide a similar estimate of GFR results when compared to a six-variable equation predecessor. However, this equation was shown to be inaccurate at GFR more than 60 mL/min/1.73 m2, for reasons not associated with standardization of Screening assay results. A recent study conducted by the FDA compared the eGFR estimated by the MDRD4 equation to the CLcr estimated by the Cockcroft-Gault equation in 973 subjects enrolled in pharmacokinetic studies conducted for new chemical entities submitted to the FDA from 1998 to 2010. The MDRD4 eGFR results consistently overestimated the CLcr calculated by the CG method. The FDA investigators concluded that “For patients with advanced age, low weight, and modestly elevated serum creatinine concentration values, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in approved product information labeling.”

A single eGFR equation may not be best suited for all populations, and choice of equation has been shown to impact CKD prevalence estimates. This has led to a revitalized interest in the development of new equations to estimate GFR. The newest equations to be proposed for the estimation of GFR have been derived from wider CKD populations than the MDRD study, and include the CKD-EPI and the Berlin Initiative Study (BIS). The CKD-EPI equation was developed from pooled study data involving 5,500 patients, with mean GFR values of 68 +- 40 mL/min/1.73 m2. It has been reported that the CKD-EPI equation is less biased but similarly imprecise compared to MDRD4.

CKD-EPI Equation

The CKD-EPI study equation was compared to the MDRD equation using pooled data from patients enrolled in research or clinical outcomes studies, where GFR was measured by any exogenous tracer. The results of the study indicated that the bias of CKD-EPI equation was 61% to 75% lower than the MDRD equation for patients with eGFR of 60 to 119 mL/min/1.73 m2. Based on these findings, the CKD-EPI equation is most appropriate for estimating GFR in individuals with eGFR values more than 60 mL/min/1.73 m2. Both KDOQI and the Australasian Creatinine Consensus Working Groups now recommend that clinical laboratories switch from the MDRD4 to CKD-EPI for routine automated reporting. If one’s clinical lab does not automatically calculate eGFR using the CKD-EPI, it becomes a bit of a challenge since the equation requires a more complex algorithm than the MDRD equation.

Limitations of the pooled analysis approach used to develop the MDRD and CKD-EPI equations include the use of different GFR markers between studies, different methods of administration of the GFR markers and different clearance calculations. These limitations may partly explain the reduced accuracy observed with the MDRD4 equation at GFR values more than 60 mL/min/1.73 m2. Additionally, a recent inspection of the MDRD GFR study data showed that large intrasubject variability in GFR measures was a likely contributor to the inaccuracy of the gold standard method that was used to create the MDRD equation.

Cystatin C-Based Equations

Addition of serum cysC as a covariate in equations to estimate GFR has been employed as a means to improve creatinine-based estimations of GFR that historically were limited to the following variables: lean body mass, age, sex, race, and Scr.

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  • Alb, serum albumin concentration (g/dL); BUN, blood/serum urea nitrogen concentration (mg/dL);CKD, chronic kidney disease; cysC, cystatin C; eGFR, estimated glomerular filtration rate; Scr, serum or plasma creatinine (mg/dL).
  • k is 0.7 for females and 0.9 for males, alpha is -0.329 for females and -0.411 for males, min indicates the minimum of Screening/k or 1, and max indicates the maximum of Scr/k or 1.

A significant limitation of serum cysC as a renal biomarker is the influence of body mass on serum concentrations. When using a serum cyst-based estimate of GFR, which incorporates the serum cysC, age, race, and sex, a higher prevalence of CKD was reported in obese patients when compared to the MDRD4 equation. In a recent retrospective analysis of over 1,000 elderly individuals (mean age 85 years) enrolled in Cardiovascular Health Study, GFR was estimated using the CKD-EPI and CKD-EPI-cysC equation, specifically equation 9 in Table e42-6. In this population, all-cause mortality rates were significantly different between equations, suggesting that cysC does not accurately predict mortality risk in patients with low Screening, reduced muscle mass, and malnutrition. The combined use of serum cysC and creatinine in modified CKD-EPI equations has recently been reported. The CKD-EPIcreatinine_cystatin C, equation 10 in Table e42-6 is now recommended for use in patients where unreliable serum creatinine values are anticipated, such as extremes in body mass, diet, or creatinine assay interferences.

Liver Disease

Evaluation of renal hemodynamics is particularly complicated in patients with liver disease and cirrhosis, where filtration fraction is associated with the degree of ascites, renal artery vasoconstriction, and vascular resistance. The estimation of CLcr or GFR can be problematic in patients with preexisting liver disease and renal impairment. Lower-than-expected Scr values may result from reduced muscle mass, protein-poor diet, diminished hepatic synthesis of creatine (a precursor of creatinine), and fluid overload can lead to significant overestimation of CLcr.

Evaluations of new eGFR equations for use in patients with liver disease have yield mixed results. In summary, renal function assessment in patients with hepatic disease should be performed by measuring glomerular filtration, and GFR estimation equations that combine creatinine and cysC are preferred.

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