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

Adapted from the IRIS education article by Gregory F. Grauer, DVM, MS, DACVIM, Kansas State University, Manhattan, Kansas (2018).

Introduction

Kidney damage and disease can be caused by acute or chronic insults to the kidney. The terms "renal disease" and "renal damage" indicate that kidney lesions are present, but they say nothing about the cause, distribution, or severity of those lesions and, importantly, nothing about how well the kidneys are working. Chronic kidney disease (CKD) can be caused by diseases or disorders that affect any part of the nephron, including the glomerulus, the tubule, the blood supply, and the surrounding interstitium. Most definitions of CKD require a lesion to be present for at least 3 to 4 months, to allow time for compensatory hypertrophy to influence kidney function. Early detection of CKD allows appropriate intervention that could preserve kidney function, or at least slow its progressive decline.

Early Diagnosis of CKD: Serum Creatinine

Early, non-azotemic CKD can be diagnosed in dogs and cats with abnormal kidney palpation or imaging findings, persistent renal proteinuria, or a urine concentrating deficit caused by kidney disease. In most cases, however, CKD is diagnosed on the basis of persistent azotemia together with an inability to produce concentrated (hypersthenuric) urine. Cats with CKD often keep the ability to concentrate their urine in the early stages of the disease.

Serum creatinine (sCr) is commonly used as a surrogate marker of glomerular filtration rate (GFR) in dogs and cats, but it has several limitations. The relationship between sCr and GFR is not linear, which limits the sensitivity of sCr for detecting early kidney disease. Because creatinine is produced by the non-enzymatic breakdown of creatine and creatine phosphate in skeletal muscle, sCr is affected by the patient's muscle mass, which results in a wide reference range. The interpretation of sCr can also be influenced by the method of analysis (the Jaffé reaction versus enzymatic methods, and bench-top analyzers versus reference laboratories). One of the most troubling aspects of interpreting sCr is the relatively large variation in reference intervals between laboratories, which can lead to false-positive and false-negative diagnoses of azotemia (references 1 and 2). Reference ranges need to be specific to each laboratory, but IRIS Board members have suggested that dogs and cats whose sCr is persistently in the upper end of most reference ranges, that is, above 1.4 mg/dL (125 µmol/L) in adequately hydrated dogs and above 1.6 mg/dL (140 µmol/L) in adequately hydrated cats, probably have a decreased GFR and deserve closer monitoring.

Serum Creatinine and the IRIS CKD Stages

  • Stage 1: below 1.4 mg/dL (125 µmol/L) in dogs; below 1.6 mg/dL (140 µmol/L) in cats
  • Stage 2: 1.4 to 2.8 mg/dL (125 to 250 µmol/L) in dogs; 1.6 to 2.8 mg/dL (140 to 250 µmol/L) in cats
  • Stage 3: 2.9 to 5.0 mg/dL (251 to 440 µmol/L) in dogs and cats
  • Stage 4: above 5.0 mg/dL (440 µmol/L) in dogs and cats

The creatinine values for dogs in Stages 2 and 3 were changed when SDMA was added to the staging system (see below, and our article on the IRIS staging system for CKD).

Serum creatinine must always be interpreted in light of the patient's muscle mass, urine specific gravity, and physical examination findings, to rule out volume-responsive (pre-renal) and post-renal causes of azotemia. Dogs vary greatly in muscle mass, from a miniature poodle to a greyhound, which tends to widen reference ranges. Despite these confounding factors, following sCr over time, measured by a consistent method, is an excellent way to assess kidney function and diagnose early CKD. For example, an sCr that rises from 0.6 to 1.2 mg/dL over several years, without evidence of dehydration, increased muscle mass, or post-renal causes, could indicate at least a 50% reduction in GFR. In fact, it could indicate that more than 50% of nephrons have been lost, because compensatory hypertrophy increases the functional capacity of the remaining nephrons and so partly offsets the decrease in GFR.

Serum Symmetric Dimethylarginine (SDMA)

SDMA is formed by the methylation of L-arginine within cell nuclei by protein-arginine methyltransferases, and it is released into the blood when proteins are broken down. SDMA is eliminated mainly by glomerular filtration and is not affected by tubular reabsorption or secretion, so it can be used as a surrogate marker of GFR. Multiple studies in people have documented the usefulness of serum SDMA as a biomarker of kidney function, and a meta-analysis of 18 studies involving more than 2,100 people found a high correlation of SDMA with both GFR and sCr (reference 3).

SDMA has also received attention in veterinary medicine as a biomarker of kidney excretory function. In one of the first studies, in older client-owned cats, there was a linear relationship between the reciprocal of serum SDMA and GFR measured by iohexol plasma clearance (R² = 0.82, P < 0.001), similar to the relationship between the reciprocal of sCr and GFR in the same cats (reference 4). As well as correlating well with GFR, serum SDMA may be a more sensitive marker of early CKD than sCr, especially in dogs with low muscle mass and therefore a low baseline sCr. In longitudinal studies of dogs and cats that developed CKD, SDMA rose above normal a mean of 9 months (dogs) and 17 months (cats) before sCr became persistently increased, above 1.8 mg/dL in dogs and above 2.1 mg/dL in cats (references 5 and 6). How these early retrospective studies, carried out in colonies of dogs and cats, translate to general practice populations screened for CKD, in terms of the sensitivity and specificity of SDMA for identifying new cases of CKD, awaits large prospective population studies.

In male dogs with X-linked hereditary nephropathy, a single SDMA cut-off value identified, on average, a decrease in GFR of less than 20% as measured by iohexol plasma clearance, and it detected reductions in GFR earlier than either a single sCr cut-off value or sCr trends over time (reference 7). Another potential advantage of monitoring SDMA rather than sCr for the early diagnosis of CKD is that SDMA does not appear to be influenced by changes in lean body mass in dogs and cats (references 8 and 9). Preliminary results suggest that the serum SDMA-to-creatinine ratio may have prognostic value in dogs and cats with CKD, as long as SDMA is above 14 µg/dL, with ratios above 10 associated with death within one year (reference 10). The effects of dietary arginine are not yet known, but serum SDMA concentrations are not correlated with serum arginine concentrations in dogs and cats, and dietary arginine has no effect on serum SDMA in people (reference 11).

Based on these studies, SDMA appears to be a more sensitive marker of kidney function than sCr and provides additional information when the two are used together. A persistent increase in SDMA above 14 µg/dL in a dog with sCr below 1.4 mg/dL, or a cat with sCr below 1.6 mg/dL, indicates reduced kidney function and is compatible with Stage 1 CKD. Basing a diagnosis of CKD solely on a persistently increased SDMA may reduce specificity, so that some dogs and cats are incorrectly classified as having CKD. Until large longitudinal prospective studies have been done, the true specificity of mild SDMA increases used in this way remains to be determined.

As with sCr, SDMA must always be interpreted in light of the patient's physical examination findings, to rule out volume-responsive and post-renal causes of azotemia, and repeated measurements over time are preferred over a single result. With mild increases in SDMA, IRIS recommends examining other factors that support or refute a diagnosis of CKD in the individual patient, recognizing that the desire to diagnose CKD as early as possible will inevitably lead to some dogs and cats being falsely diagnosed. The current recommendations for dogs and cats in IRIS CKD Stage 1 are to monitor, to investigate, and to avoid exposing the patient to drugs that can damage the kidneys, all of which seem appropriate for patients with an SDMA persistently above 14 µg/dL but no other evidence of CKD.

Serum SDMA and the IRIS CKD Stages

SDMA values were added to the IRIS CKD staging system as follows:

  • Stage 1: below 18 µg/dL in dogs and cats
  • Stage 2: 18 to 35 µg/dL in dogs; 18 to 25 µg/dL in cats
  • Stage 3: 36 to 54 µg/dL in dogs; 26 to 38 µg/dL in cats
  • Stage 4: above 54 µg/dL in dogs; above 38 µg/dL in cats

The IRIS Board recommends using serum creatinine or SDMA, and ideally both, to stage stable CKD patients, because evaluating both is likely to improve the assessment of GFR. If the creatinine and SDMA values place the patient in different stages, consider the patient's body condition and muscle mass, and retest in 2 to 4 weeks. If the values remain discordant, consider assigning the patient to the higher stage.

Our understanding of situations in which SDMA may be increased by medical problems unrelated to CKD is likely to develop with time and experience in routine practice. In the unusual cases where serum creatinine is increased but SDMA is normal, consider the patient's muscle mass (well-muscled dogs may have relatively high sCr), whether the patient was fasted (dogs and cats that have not been fasted may have a higher sCr), and whether the blood sample was hemolyzed, because hemolysis can interfere with the SDMA assay and produce falsely low results. The addition of SDMA to the IRIS CKD staging system was accompanied by a change to canine IRIS CKD Stage 2 based on sCr, broadening this stage to align it with cats.

Follow-Up

Dogs and cats with borderline sCr or SDMA values should be retested, first in about 2 weeks to confirm the initial value, and then about every 3 months to assess the stability of kidney function. Additional tests that can help characterize possible kidney disease and its complications include a complete urinalysis with urine sediment examination, urine culture, blood pressure measurement, the urine protein-to-creatinine ratio, and imaging of the urinary tract with radiographs and ultrasound.

Blood pressure deserves particular attention. Systemic hypertension is common in CKD, it can both result from and worsen kidney damage, and guidelines recommend measuring blood pressure in every dog and cat with kidney disease (reference 17). In dogs with CKD, a higher systolic blood pressure at diagnosis has been associated with an increased risk of uremic crisis and death (reference 18), and experimentally induced hypertension has been shown to damage the kidneys of cats (reference 19).

Early Diagnosis of CKD: Urine Protein-to-Creatinine Ratio

Proteinuria in dogs and cats with CKD can result from glomerular lesions, tubular lesions, or both. Glomerular proteinuria can be caused by loss of integrity of, or damage to, the capillary wall, as in immune-complex disease and X-linked hereditary nephropathy. Increased pressure within the glomerular capillaries probably also increases the amount of plasma protein filtered. This intraglomerular hypertension can result from nephron loss, which impairs autoregulation, and from systemic hypertension being transmitted into the glomerular capillaries. Structural glomerular disease and CKD are often accompanied by systemic hypertension, which can make intraglomerular hypertension and glomerular proteinuria worse.

Tubular proteinuria occurs when the tubules cannot reabsorb protein from the glomerular filtrate normally, and it is typically less severe than glomerular proteinuria. In dogs and cats with CKD, tubular reabsorption of protein can be reduced by tubulointerstitial injury and by a decrease in the number of functioning tubules. Whether it is caused by capillary wall lesions, tubular lesions, or intraglomerular hypertension, excessive protein in the glomerular filtrate may contribute to further glomerular and tubulointerstitial lesions, leading to the loss of more nephrons. Proteinuric kidney disease and systemic hypertension often occur together, so it can be difficult to separate the effects of high systemic and intraglomerular pressures from those of proteinuria.

Renal proteinuria in dogs and cats with CKD should be diagnosed step by step:

  1. Confirm the proteinuria. In health and in disease, albumin is the main protein in the urine of dogs and cats. The specificity of the dipstick screening test for albuminuria is poor, especially in cats (reference 13), so a positive dipstick result should be confirmed with a more specific test, such as the urine protein-to-creatinine ratio (UPC) or a species-specific albuminuria assay.
  2. Determine its origin. Physiological or benign proteinuria, and pre-renal and post-renal proteinuria, must be ruled out. Renal proteinuria is persistent and is associated with an inactive urine sediment, although hyaline casts may be seen. Persistent proteinuria is defined as at least two positive tests two weeks apart.
  3. Monitor it. Serial UPC measurements show whether the proteinuria is stable, increasing, or decreasing over time.

IRIS Classification of Renal Proteinuria

  • Non-proteinuric: UPC below 0.2 in dogs and cats
  • Borderline proteinuric: UPC 0.2 to 0.4 in cats; 0.2 to 0.5 in dogs
  • Proteinuric: UPC above 0.4 in cats; above 0.5 in dogs

The ACVIM consensus statement recommends that persistent proteinuria of renal origin with a UPC above 0.4 in cats or above 0.5 in dogs with azotemic CKD be treated with a kidney diet and an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) (reference 12). The IRIS treatment recommendations, as modified in 2026, go further: they advise investigating and treating persistent renal proteinuria above these values at any stage, including non-azotemic Stage 1, and in dogs they name an ARB with a kidney diet as the first step. Borderline proteinuria warrants closer 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 to 0.4) increased the risk of death or euthanasia 2.9-fold compared with cats with a UPC below 0.2 (reference 14). In a prospective longitudinal study of non-azotemic cats older than 9 years, 95 cats (median age 13 years) were followed for 12 months or until death or the development of azotemia, defined as a serum creatinine above 2.0 mg/dL. Twenty-nine of the 95 cats (30.5%) developed azotemia, and proteinuria at presentation (median UPC 0.19 versus 0.14) was significantly associated with the development of azotemia in these older cats (reference 15). Finally, when client-owned cats with stable CKD (112 cats) were compared with client-owned cats with progressive CKD (101 cats), the median UPC at baseline was higher in the progressive group than in the stable group (0.27 versus 0.14), and each 0.1 increase in UPC was associated with a 24% increase in the risk of CKD progression (reference 16).

These data show that, at the population level, the risk of a future diagnosis of CKD, and of CKD progression, in cats rises across the whole range of UPC values measured. The problem with lowering UPC cut-offs to make them more sensitive indicators of early CKD is that specificity falls when they are applied to individual patients, unless they are combined with other indicators.

Summary

  • Serum creatinine is widely used to estimate GFR, but it is insensitive to early loss of kidney function and is affected by muscle mass, hydration, feeding, and the laboratory method. Trends in an individual patient's creatinine over time are more informative than a single value.
  • SDMA is less affected by muscle mass and tends to rise earlier than creatinine. A persistent SDMA above 14 µg/dL with a creatinine in the IRIS Stage 1 range is compatible with Stage 1 CKD, but mild increases should be confirmed and supported by other evidence.
  • IRIS recommends using creatinine and SDMA together to stage CKD, retesting in 2 to 4 weeks when they disagree, and assigning the higher stage if they remain discordant.
  • The UPC confirms and quantifies renal proteinuria. Persistent renal proteinuria above 0.5 in dogs or 0.4 in cats should be investigated and treated, and even borderline proteinuria is associated with a worse outlook in cats.
  • Borderline results should be rechecked in about 2 weeks and then about every 3 months, together with a urinalysis, blood pressure measurement, and imaging where indicated.

References

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