Diagnosing and Staging CKD in Anorexia Nervosa: Limitations
Overview
Diagnosing and staging CKD involves assessing GFR and kidney damage. In assessing CKD, there are 2 major limitations in individuals with AN. First, these patients often have very low muscle mass (and, less notably, dietary intake of meat), potentially leading to overestimation of GFR. Second, kidney damage in AN more often is tubular than glomerular. In clinical practice, albuminuria and/or total proteinuria are the most convenient ways to evaluate kidney damage. However, albuminuria is a marker of glomerular damage: in AN, other markers of damage should be ascertained. Urine sediment examination for hematuria and leukocyturia should be performed in patients with AN with CKD. Similarly, electrolyte disorders due to tubular defects also can satisfy the criteria for kidney damage. In most settings, estimating GFR is the most practical method to assess global kidney function.
Assessing Proteinuria in Anorexia Nervosa
In healthy individuals, urinalysis shows minimal quantities of protein, with persistently elevated proteinuria marking kidney damage. Excretion of specific types of protein, such as albumin or low-molecular-weight globulins, depends on the type of kidney disease. Albuminuria may be a better marker than total urine protein for kidney damage due to diabetes, hypertension, and glomerular disease, whereas increased excretion of low-molecular-weight globulins is a sensitive marker for some types of tubulointerstitial diseases. Such tubular proteinuria is less frequent than albuminuria in the general population because "pure" tubulointerstitial diseases are relatively rare. In AN, detecting CKD with albuminuria might be misleading because the dipstick may not detect the globulins of tubular proteinuria. This concept is analogous to the insensitivity of the urine dipstick for urinary Bence-Jones proteins in multiple myeloma. To avoid false-negative results in patients with AN, we recommend measuring proteinuria by a quantitative method, potentially including assessment of tubular injury markers such as urine β2-microglobulin, and, if measured on a spot specimen, normalizing these results to urine creatinine level to account for urine concentration. However, normalization to urine creatinine should be undertaken with caution, and if there are concerns regarding validity, timed collections may be more appropriate. If creatinine excretion is relatively constant throughout the day and similar among individual samples, protein-creatinine ratio in an untimed sample will reflect the excretion of that protein. However, in patients with AN, urinary creatinine excretion might be very low compared with patients without AN. In theory, this low value could result in abnormally high levels of normalized proteinuria, and notably, the overall validity of spot protein-creatinine ratios have not been assessed in the context of AN.
Measuring and Estimating GFR
Measuring GFR and Body Surface Area Adjustment Using creatinine-based equations to estimate GFR may be misleading in many patients with AN. Accordingly, measurement of GFR should be considered in patients with AN. Reference methods for measuring GFR include determining clearances of inulin, Cr-EDTA, Tc diethylenetriaminepentaacetic acid, iohexol, or iothalamate. In case of edema, methods using renal clearance are preferred to those using plasma clearances. GFR results classically are adjusted for body surface area. Such an adjustment is not a major concern in patients with normal body size; however, body surface area adjustment may have much greater effects in patients with AN, reflecting a lower denominator in the body surface area equation due to low body weight. Although there is no definite proof affirming that nonadjusted GFR is the "true" GFR, several researchers have promoted using nonadjusted GFR to describe kidney function.
Serum Creatinine and Creatinine Clearance For most people and in most settings, serum creatinine is the optimal marker to estimate GFR. However, there are limitations to the use of this biomarker. The most important limitation is that serum creatinine concentration is largely dependent on muscle mass. In individuals with reduced muscle mass, there is lower production of creatinine. Dietary intake of creatine contained in meat also may affect serum creatinine concentration, and a diet poor in meat, which obviously is frequent in AN, also could contribute to the low serum creatinine level seen in patients with AN. Based on this understanding of serum creatinine, for any given GFR, serum creatinine level will be lower in individuals with reduced muscle mass compared with those with normal muscle mass and normal diet. This is the explanation for the sex and age adjustments seen in all equations that use creatinine to estimate kidney function. In patients with AN, serum creatinine concentration may be in the reference range despite decreased GFR, resulting in failure to identify "true" decreased GFR in a patient with AN. For this reason, the most recent NKF-KDOQI (National Kidney Foundation's Kidney Disease Outcomes Quality Initiative) guidelines recommend creatinine clearance measurement by 24-hour urine collection in patients with very abnormal muscular mass, such as those with paraplegia. This method could be used in patients with AN, again keeping in mind the important limitations of creatinine clearance calculated from 24-hour urine collection. First, in addition to being filtered by glomeruli, creatinine is secreted by renal tubular cells, which can lead to overestimation of GFR. This overestimation is somewhat variable. The second limitation is the high intraindividual coefficient of variation. Urinary creatinine clearance may vary in the same patient from 20%-40% if successive measurements are repeated in a limited period. This high variation is due to both variation in creatinine excretion and errors in urine collection. Such errors in urine collection may be even greater in patients with psychiatric disorders.
Creatinine-Based Equations Several creatinine-based equations are used to estimate GFR. These equations incorporate serum creatinine level and other factors that affect serum creatinine level independent of kidney function, such as sex and age. Among these equations, the Cockcroft-Gault equation and MDRD (Modification of Diet in Renal Disease) Study or CKD-EPI (CKD Epidemiology Collaboration) equations are the most widely used. There are limitations to the use of these equations, with few studies specifically evaluating their accuracy in individuals with AN. Our group previously measured GFR by the Cr-EDTA reference method in 27 patients with AN, showing that the MDRD Study equation and the Cockcroft-Gault equation both substantially overestimated measured GFR. This finding also was evident in the subgroup with body mass index <18 kg/m in another study that did not focus on patients with AN, likely reflecting muscle mass reduction. In conclusion, using creatinine level or creatinine-based equations could be misleading and falsely reassuring in patients with AN.
Cystatin C Cystatin C is a low-molecular-weight protein that belongs to the family of cysteine proteinase inhibitor proteins. Several studies have shown that cystatin C is a good marker to estimate GFR. Cystatin C is present in all nucleated cells and its production is constant. Cystatin C is freely filtrated through the glomeruli and then completely reabsorbed by tubular cells, where it is fully catabolized. Accordingly, serum cystatin C concentration is correlated highly with GFR, whereas urinary cystatin C concentration is near zero in healthy individuals. Higher urinary cystatin C concentrations can occur after kidney tubular damage. Theoretically, this marker could be a useful tool to detect tubulointerstitial nephritis in patients with AN, but to our knowledge, this urinary marker has not been studied to date in this specific population. Different authors have suggested that serum cystatin C concentration could vary according to hormonal or medical conditions independently of a change in GFR. Moreover, it recently has been shown that serum cystatin C level also is dependent partly on muscle mass. The influence of muscle mass on cystatin C production is explained because muscle cells constitute the largest number of nucleated cells in the body. Nevertheless, the variability in serum cystatin C levels due to muscle mass is far lower than that of serum creatinine. In the previous work discussed, we showed that cystatin C was better than serum creatinine for detection of stage 3 CKD (GFR <60 mL/min) in patients with AN. This result should be confirmed on a larger sample.