Education

Utility of Creatinine, UPC, and SDMA in the Early Diagnosis of CKD in dogs and cats (updated 2019)

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 provide no information regarding the degree of renal function. 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 presence of the lesion for at least 3-4 months to allow time for compensatory hypertrophy to influence renal function. Early detection of CKD, facilitates appropriate intervention that could preserve renal function or at least slow its progressive decline (Figure 1).

Early diagnosis of CKD: Serum creatinine concentration

Early, non-azotemic CKD 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 (cats with CKD often retain the ability to concentrate urine in the early stages of the disease). Serum creatinine concentrations (sCr) are commonly used as a surrogate marker of glomerular filtration rate (GFR) in dogs and cats. Unfortunately, sCr has multiple limitations. The relationship between sCr and GFR is not linear (Figure 2) which limits the sensitivity of sCr for detection of early renal disease. As creatinine is produced from the non-enzymatic degradation of creatine and creatine phosphate in skeletal muscle, serum creatinine concentrations is affected by the patient's muscle mass, resulting in a wide reference range. 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.^1,2 Reference ranges need to be individualized to each laboratory, but IRIS Board members have suggested that dogs and cats with serum creatinine concentrations persistently in the upper end of most reference ranges (i.e., > 1.⁴ (125) and > 1.6 (140) mg/dl (μmol/l) in adequately hydrated dogs and cats, respectively) likely have decreased GFR and deserve closer monitoring.

Serum Creatinine Concentrations and IRIS CKD Stages

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

* Note the changes in serum creatinine values for dogs in Stages 2 and 3. See updated education article on IRIS CKD Staging System for more details/explanation.

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 volume-responsive 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 (analysed 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, increase in muscle mass or post renal causes, 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 and negate to some extend the decrease in GFR).

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 a surrogate 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.³ SDMA has also received attention in veterinary medicine as a biomarker of kidney excretory function. In one of the first studies involving aged, client-owned cats, a linear relationship between the reciprocal of serum SDMA concentration and GFR (Iohexol plasma clearance) was observed (R2 = 0.82, P < .001), similar to that found between the reciprocal of sCr and GFR in the same cats.⁴ In addition to correlating well with GFR, serum SDMA may be a more sensitive biomarker for detection of early CKD compared with sCr, especially in dogs with low muscle mass (and consequently low baseline sCR). In longitudinal studies of 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).^5,6 How these early retrospective studies undertaken in colonies of cats and dogs translate to the general practice populations of dogs and cats being screened for CKD in terms of the specificity and sensitivity of SDMA in identifying incident CKD awaits large prospective population studies to be determined In male dogs with X-linked hereditary nephropathy, using a single cut-off value for serum SDMA identified, on average, a < 20% decrease in GFR as measured by Iohexol plasma clearance.⁷ In addition, using a single cut-off value for SDMA, reductions in GFR were detected earlier compared with either a single sCr cut-off value or sCr trending over time. ^8,9 Another potential advantage to monitoring serum SDMA concentrations for early diagnosis of CKD compared with monitoring sCr, is that SDMA does not appear to be influenced by changes in lean body mass in dogs and cats. Preliminary results 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 one year mortality.¹⁰ Although the effects of dietary arginine are as yet unknown, serum concentrations of SDMA are not correlated to serum arginine concentrations in dogs and cats and dietary arginine has no effect on serum SDMA concentrations in people.¹¹

Based on the above studies it appears that compared with sCr, SDMA can be a more sensitive renal function biomarker and provides additional information when used together with sCr. A persistent elevation in SDMA (>14 μg/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. Basing the diagnosis of CKD solely on persistently elevated serum SDMA may be associated with reduced specificity, with dogs and cats incorrectly classified as having CKD. Until large longitudinal prospective studies have been undertaken, the true specificity of mild elevations of SDMA used in this way remains to be determined. 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. With mild elevations of serum SDMA, the IRIS recommends examining other factors to corroborate or refute the diagnosis of CKD in the individual patient and recognise that the desire to diagnose CKD as early as possible will inevitably lead to some dogs and cats being falsely diagnosed as having CKD. Currently our recommendations for IRIS CKD Stage 1 dogs and cats are to monitor and investigate and avoid potentially exposure of the patient to nephrotoxic drugs, all of which seem appropriate for patients with serum SDMA persistently >14 μg/dl but with no other corroborating evidence of CKD.

Recently, SDMA values were added to the IRIS CKD Staging system as follows:

Serum SDMA Concentrations and IRIS CKD Stages

Serum SDMA 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	<18	18-25	26-38	>39
Dogs	<18	18-35	36-54	>54

The IRIS Board recommends using either serum creatinine or SDMA (it is ideal to use both) to stage stable CKD patients. Evaluation of both serum creatinine and SDMA will likely improve assessment of GFR. If the serum creatinine and SDMA values are discordant in terms of the Staging system, consider body condition and muscle mass and retesting the patient in 2-4 weeks. If the values are persistently discordant, consider assigning the patient to the higher stage. Our understanding of situations where SDMA may be elevated by other medical problems unrelated to CKD is likely to develop over time and experience in using this marker in routine clinical practice. In those unusual cases where serum creatinine is elevated and SDMA is normal, consider the patient's muscle mass (well-muscled dogs may have relatively higher serum creatinine concentrations), if the patient has been fasted (non-fasted dogs and cats may have higher serum creatinine concentrations), and check to see if there was any hemolysis in the blood sample (hemolysis can interfere with the SDMA assay and produce falsely low results). This addition of SDMA to the IRIS CKD staging system has been accompanied by a change to the canine IRIS CKD stage 2 based on sCr, broadening this stage to align it with the cat (see updated education article on the IRIS CKD staging system for further details).

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 kidney disease and/or complications associated with kidney 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.

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 elevations in glomerular capillary pressure (i.e. glomerular hypertension) increases the amount of filtered plasma protein. Intraglomerular hypertension may result from loss of nephrons (loss of autoregulation in remaining functioning nephrons) and from systemic hypertension being transmitted into glomerular capillaries as a consequence of adaptive afferent arteriolar vasodilatation. 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 leading to proteinuria from primary glomerular pathology which also leads to proteinuria. Diagnosis of renal proteinuria in cats and dogs with CKD should be accomplished in a step-wise fashion.¹² 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 traditional dipstick positive proteinuria should be confirmed with a more specific follow-up test such as the UPC or species-specific albuminuria assays.¹³ 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

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 with a UP/C > 0.⁴ and > 0.5 in cats and dogs with azotemic CKD, respectively, should be treated with a renal diet and an angiotensin converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). ¹² 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 is 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 < 0.2.14 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.15 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 at baseline 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.16 These data indicate that the relationship between risk of future diagnosis of CKD and progression of CKD in cats extends across the whole range of UPCs measured at the population level. The problem with lowering UPC cut-offs to increase the sensitivity as an indicator of early CKD diagnosis is one of reduced specificity when applied to the individual patient unless it is combined with other indicators.

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.

References

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