Utility of Creatinine, UPC, and SDMA in the Early Diagnosis of CKD

Gregory F. Grauer, DVM, MS, DACVIM
Kansas State University, Manhattan, Kansas

Renal damage and disease can be caused by acute or chronic insults to the kidney. The terms renal disease and renal damage are used to denote the presence of renal lesions; these terms however imply nothing about the cause, distribution, or severity of the lesions and importantly nothing about the level of renal function that exists. Chronic kidney disease (CKD) can be caused by diseases/disorders that affect any portion of the nephron, including the glomerulus, the tubule, the vascular supply, and surrounding interstitium. Most definitions of CKD require the lesions to have been present for at least 3-4 months to allow time for compensatory hypertrophy to influence renal function. Early detection of CKD, prior to the onset of renal azotemia/failure, should facilitate appropriate intervention that could stabilize renal function or at least slow its progressive decline.

Early diagnosis of CKD: Serum creatinine concentration

Early, non-azotemic CKD (IRIS Stage 1 and early Stage 2) can be diagnosed in dogs and cats with abnormal renal palpation or renal imaging findings, persistent renal proteinuria, or urine concentrating deficits due to renal disease. In most cases however, CKD is diagnosed based on persistent azotemia superimposed on an inability to form hypersthenuric urine (some cats with CKD retain the ability to concentrate urine). Serum creatinine concentrations are commonly used as a surrogate marker of glomerular filtration rate (GFR) in dogs and cats. Creatinine is produced from the non-enzymatic degradation of creatine and creatine phosphate in skeletal muscle and therefore serum creatinine concentrations reflect the patient's muscle mass as well as GFR. Interpretation of serum creatinine concentrations can also be influenced by the method of analysis (Jaffe's reaction vs. enzymatic and bench-top vs. reference laboratory). One of the most disconcerting aspects of interpretation of serum creatinine is the relatively large variation in reference intervals between laboratories which can lead to false-positive and false-negative azotemia. Reference ranges need to be individualized to each laboratory, but many veterinary nephrologists have suggested that dogs and cats with serum creatinine concentrations persistently in the upper end of most reference ranges (i.e., 1.4 and 1.6 mg/dl in dogs and cats, respectively) likely have decreased GFR and deserve closer monitoring.

Serum Creatinine Concentrations and IRIS CKD Stages for Dogs and Cats

Serum Creatinine
Concentrations
(mg/dl)
Stage 1
(Non-azotemic CKD)
Stage 2
(Non-azotemia to mild azotemia)
Stage 3
(Moderate renal azotemia)
Stage 4
(Severe renal azotemia)
Cats <1.6 1.6-2.8 2.9-5.0 >5.0
Dogs <1.4 1.4-2.0 2.1-5.0 >5.0

Serum creatinine concentrations must always be interpreted in light of the patient's muscle mass, urine specific gravity, and physical examination findings in order to rule out pre- and post-renal causes of azotemia. In dogs there can be a large variation in muscle mass (e.g., miniature poodle vs. greyhound) that will tend to increase the breadth of reference ranges. Despite these potential confounding issues, longitudinal assessment of serum creatinine concentrations (analyzed by consistent methodology), is an excellent tool to assess renal function and diagnose early CKD. For example, a serum creatinine concentration that increases from 0.6 to 1.2 mg/dl over several years, without evidence of dehydration or an increase in muscle mass, could indicate at least a 50% reduction in GFR (at least 50% nephron loss because compensatory hypertrophy of remaining nephrons increases the functional capacity of those nephrons).

Serum symmetric dimethylarginine concentration:

SDMA is derived from intranuclear methylation of L-arginine by protein-arginine methyltransferases and released into the blood after proteolysis. SDMA is eliminated primarily by glomerular filtration and is not affected by tubular reabsorption or secretion and therefore can be used as an intrinsic GFR marker. Multiple studies in people have documented the utility of serum SDMA concentrations as a biomarker of renal function; a meta-analysis of 18 studies involving over 2100 people documented a high correlation of SDMA to both GFR and sCr. Recently SDMA has received attention in veterinary medicine as kidney excretory function biomarker. In one of the first studies involving aged, client-owned cats, an inverse linear relationship between serum SDMA concentration and GFR (Iohexol plasma clearance) was observed (R2 = - 0.82, P < .001). In addition to correlating well with GFR, serum SDMA may be a more sensitive biomarker for detection of early CKD compared with sCr. In longitudinal studies in dogs and cats that developed CKD, SDMA concentrations increased above normal a mean of 9 and 17 months prior to persistent elevations in sCr concentration ( > 1.8 mg/dl in dogs and > 2.1 mg/dl in cats, respectively). In male dogs with X-linked hereditary nephropathy, using a single cutoff value for serum SDMA identified, on average, a < 20% decrease in GFR as measured by Iohexol plasma clearance. In addition, using a single cutoff value for SDMA, reductions in GFR were detected earlier compared with either a single sCr cutoff value or sCr trending over time. Another potential advantage to monitoring serum SDMA concentrations for early diagnosis of CKD compared with monitoring sCr, SDMA does not appear to be influenced by changes in lean body mass in dogs and cats. Preliminary results also suggest that serum SDMA/creatinine ratios may have prognostic value in dogs and cats with CKD (as long as the SDMA value is > 14 µg/dl); ratios > 10 were associated with mortality within one year.

Based on the above studies it appears that compared with sCr, SDMA is a more sensitive renal function biomarker. A persistent elevation in SDMA (>14 mg/dl) in a dog or cat with sCr <1.4 or <1.6 mg/dl, respectively indicates reduced renal function and is compatible with Stage 1 CKD. Similar to sCr, SDMA must always be interpreted in light of the patient's physical examination findings in order to rule out volume-responsive and post-renal causes of azotemia. In addition, longitudinal assessment of serum SDMA concentrations is preferred over one-time assessments.

Follow-up:

Dogs and cats with borderline sCr and/or SDMA concentrations should be retested; initially in approximately 2 weeks to confirm the initial value and then subsequently approximately every 3 months to assess renal function stability. Additional tests that may help further characterize the potential renal disease and/or complications associated with renal disease include a complete urinalysis with urine sediment examination, urine culture, blood pressure, urine protein/creatinine ratio, and urinary tract imaging with radiographs and ultrasound.

Early diagnosis of CKD: Urine protein/creatinine ratio

Proteinuria in dogs and cats with chronic kidney disease (CKD) can occur due to glomerular and/or tubular lesions. Glomerular proteinuria can be caused by loss of integrity of or damage to the capillary wall (e.g., immune complex disease and x-linked hereditary nephropathy). It is also likely that increases in glomerular capillary pressure increases the amount of filtered plasma protein. Intraglomerular hypertension may result from loss of nephrons (loss of autoregulation) and from systemic hypertension being transmitted into glomerular capillaries. Structural glomerular disease and CKD are often accompanied by systemic hypertension which can exacerbate intraglomerular hypertension and glomerular proteinuria. Tubular proteinuria occurs when tubular reabsorption of protein from the glomerular filtrate is compromised. Tubular proteinuria is typically of lesser magnitude compared with glomerular proteinuria. Reduced tubular reabsorption of protein in dogs and cats with CKD can occur with tubulointerstial injury and decreased numbers of functioning tubules. Whether caused by capillary wall lesions, tubular lesions, or intraglomerular hypertension, excessive quantities of protein in the glomerular filtrate may contribute to additional glomerular and tubulointerstitial lesions leading to loss of more nephrons. Proteinuric renal disease and systemic hypertension are often co-existent and therefore, it is difficult at times to separate the effects of high systemic and intraglomerular pressures and proteinuria. Diagnosis of renal proteinuria in cats and dogs with CKD should be accomplished in a step-wise fashion. In health and in disease, albumin is the major urine protein in dogs and cats. The specificity of the dipstick screening test for albuminuria is poor (especially in cats) and therefore confirmation of traditional dipstick positive proteinuria should be confirmed with a more specific follow-up test such as the UPC or species specific albuminuria assays. The second step in assessment of proteinuria is to determine its origin (physiologic or benign proteinuria and pre- and post-renal proteinuria need to be ruled out). Renal proteinuria is persistent and associated with a benign or inactive urine sediment (hyaline casts may be observed in the urine sediment in cases of renal proteinuria). Persistent proteinuria is defined as at least two positive tests at two week intervals. Subsequently, via serial monitoring of the UPC, it should be determined if the proteinuria is stable, increasing, or decreasing over time.

IRIS Classification of Renal Proteinuria in Dogs and Cats

Urine Protein/Creatinine Ratio (UPC) Classification
< 0.2 Non-Proteinuria
0.2-0.4,(Cats); 0.2-0.5 (Dogs) Borderline Proteinuria
> 0.4,(Cats); > 0.5 (Dogs) Proteinuria

Current recommendations suggest that persistent proteinuria of renal origin of a magnitude > UP/C of 0.4 in cats and > 0.5 in dogs with azotemic CKD should be treated with a renal diet and an angiotensin converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Borderline proteinuria is defined as a UP/C between 0.2 and 0.5 in dogs and 0.2 and 0.4 in cats and warrants increased monitoring. It's interesting to note however that borderline and even "normal" levels of proteinuria in cats have been associated with poor outcomes.

For example, in cats with naturally occurring CKD, relatively mild proteinuria (UPC 0.2-0.4) increased the risk for death or euthanasia 2.9-fold compared with cats with UPCs < 0.2. In a prospective, longitudinal cohort study of non-azotemic cats > 9 years, 95 cats (median age = 13) were followed for 12 months or until death or azotemia developed. Azotemia was defined as a serum creatinine concentration > 2.0 mg/dl and 29/95 (30.5%) cats developed azotemia. Proteinuria at presentation (median UPC of 0.19 vs. 0.14) was significantly associated with development of azotemia in these geriatric cats. Finally, when client-owned cats with stable CKD (n=112) were compared with client-owned cats with progressive CKD (n=101), median UPCs in the progressive group were higher when compared with the stable group (0.27 vs. 0.14). A 0.1 increase in UPC was associated with a 24% increase in risk of progression of CKD.

Management of CKD: Systolic blood pressure

Current recommendations are that blood pressure be measured in a quiet area prior to examining the patient, typically in the presence of the owner and after a period of acclimation. The ACVIM Panel on Hypertension suggests discarding the first measurement, then obtaining a minimum of 3, preferably 5-7, consecutive measurements with less than 10-20% variability in systolic blood pressure. The animal's disposition, body position, and heart rate, the cuff size and measurement site as well as all measured values should be recorded in the medical record. Many clinicians suggest that hypertension be documented on more than one occasion before accepting the diagnosis (unless ocular lesions compatible with systemic hypertension already exist).

IRIS Classification of Systolic Blood Pressure in Dogs and Cats

Systolic Blood Pressure,(mm Hg) Risk of Target Organ Damage Arterial Pressure (AP) Category
<140 Minimal Nomotension
140-159 Low Prehypertension
160-179 Moderate Hypertension
>180 High Severe Hypertension

IRIS blood pressure sub-staging for dogs and cats with CKD is based on risk of target organ (ocular, neurologic, cardiac, and renal) damage. Not long ago indirect systolic blood pressure measurements > 170-180 mmHg were considered the threshold for hypertension. Despite the inherent difficulties with indirect blood pressure measurement in dogs and cats, it is appropriate to consider systolic hypertension to be present at lower pressures (e.g., > 160 mm Hg).

In a recent study, 45 dogs with naturally occurring CKD were divided into three groups based on initial systolic blood pressure were followed for up to 2 years. The blood pressure groups were defined as: High (161-201 mmHg), n = 14; Intermediate (144-160 mmHg), n = 15, and Low (107-143 mmHg), n = 16. The initial high systolic blood pressure group had increased risk of uremic crisis and death when compared with the low pressure group (median survival of < 200 days vs. > 400 days). In cats with a remnant kidney-wrap model of CKD, systolic hypertension (mean pressure of 168 vs. 113 mmHg) was associated with reduced GFR (1.34 vs. 3.55 ml/min/kg), increased UPC (1.2 vs. 0.1), and increased glomerulosclerosis. Similarly, in dogs with the remnant kidney-wrap model of CKD, systolic hypertension (> 160 mm Hg) was associated with reduced GFR, increased UP/C ratios, and increased mesangial matrix accumulation, tubular lesions, fibrosis, and cellular infiltrates. Cats with progressive CKD had higher systolic blood pressures than did cats with stable CKD (155 vs. 147 mm Hg). Finally, in 69 cats with naturally occurring CKD, high time-averaged systolic blood pressure (159 vs. 136 mm Hg), was correlated with glomerulosclerosis and hyperplastic arteriolosclerosis.

Summary:

Closer monitoring of serum creatinine, SDMA, and UPC may facilitate early diagnosis of CKD in dogs and cats. Longitudinal assessment of these parameters will almost always provide better data than will one-time evaluations. No laboratory test is perfect; trending laboratory data, with the same test methodology, will tend to improve diagnostic sensitivity. Once CKD has been diagnosed, tighter control of renal proteinuria and systolic hypertension may improve treatment outcome.