Reassessment of "normal" values in dogs and cats with chronic kidney disease

Gregory F. Grauer, KS, USA

Chronic kidney disease (CKD) is a major cause of morbidity and mortality in dogs and cats. The prevalence of CKD has been estimated to be 0.5-1.0% in dogs and 1.0-3.0% in cats,^1,2 but it increases with age, especially in cats. It has been estimated that as many as 30-50% of cats 15 years of age or older have CKD.^3-5 Nephron damage associated with CKD is usually irreversible and often progressive. In dogs, where proteinuric kidney disease occurs more frequently, the progressive loss of renal function tends to be common, linear, and relatively rapid compared with cats. Cats may have stable renal for months to years and be relatively unaffected by the CKD or they may have slowly progressive disease over several years. Animals may be stable for a long period of time but then experience an abrupt, unpredictable decline in renal function. Soft tissue mineralization, systemic hypertension, intraglomerular hypertension, and proteinuria have been associated with progression of CKD (Figure 1). Although it's not possible to improve renal function in CKD, it's logical to assume that early diagnosis of CKD might improve clinical outcomes for dogs and cats. There is firm evidence for dietary treatment and increasing evidence that anti-proteinuric treatments can slow the progressive nature of azotemic CKD.

ADD FIGURE 1 HERE

AA = afferent arteriole, EA = efferent arteriole, RAAS = renin angiotensin aldosterone system Image copyrighted by the University of Georgia Educational Resources Center

Early diagnosis of CKD: Blood creatinine concentration

Early, non-azotemic CKD (IRIS Stage 1) 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 on the basis of persistent azotemia superimposed on an inability to adequately concentrate urine (some cats with CKD retain the ability to concentrate urine). Blood creatinine concentration is the most commonly used 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. Blood 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 blood creatinine is the relatively large variation in reference intervals between laboratories which can lead to false-positive and false-negative azotemia.^6,7 Reference ranges need to be individualized to each laboratory but many veterinary nephrologists have suggested that renal azotemia may begin with blood creatinine concentrations lower than most reference ranges (i.e., 1.4 and 1.6 mg/dl in dogs and cats, respectively).⁸

Blood Creatinine Concentrations (mg/dl) and IRIS CKD Stages for Dogs and Cats

Species	State 1 (Non-azotemic CKD)	Stage 1 (Mild renal azotemia)	Stage 3 (Moderate renal azotemia)	Stage 4 (Severe renal azotemia)
Cat	< 1.6	1.6 - 2.8	2.9 - 5.0	> 5.0
Dog	< 1.4	1.4 - 2.0	2.1 - 5.0	> 5.0

Blood 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. There can be a large variation in muscle mass in dogs (e.g., miniature poodle vs. greyhound) that will tend to increase the breadth of reference ranges⁹ rendering blood creatinine concentration an insensitive marker of decreased kidney function in some breeds, when the interpretation of blood creatinine concentrations is dichromic (i.e., within or outside the reference interval). Despite these potential confounding issues, longitudinal assessment of blood creatinine concentrations (analyzed by consistent methodology), is an excellent tool to assess renal function and diagnose early CKD. For example, a blood 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 despite the fact that blood creatinine remains within the reference range. It is likely that, in this example, the nephron loss will exceed 50%. This is because compensatory hypertrophy of remaining nephrons increases the functional capacity of the remaining nephrons. In addition, the exponential relationship between blood creatinine and GFR means a doubling of creatinine is associated with more than a 50% reduction in GFR in the early stages of kidney disease.

Serum symmetrical dimethylarginine (SDMA) is derived from intranuclear methylation of L-arginine by protein-arginine methyltransferases and released into the circulation after proteolysis. SDMA is eliminated primarily by renal clearance and represents a potential biomarker for diagnosing and monitoring CKD.^10,11 In two recent longitudinal studies, one in dogs and one in cats that developed CKD, SDMA concentrations increased above normal approximately 17 months prior to blood creatinine concentration increasing above reference range (> 1.8 mg/dl in dogs and > 2.1 mg/dl in cats).^10,12 Interestingly, if a creatinine concentration of > 1.6 mg/dl had been considered abnormal in the feline study,¹⁰ both creatinine and SDMA would have identified renal azotemia in these cats at nearly the same time. SDMA increases above 14 µg/dL and especially above 20 µg/dL, could be used as early diagnosis when there are other alterations in renal palpation or renal imaging findings or persistent renal proteinuria or urine concentrating deficits. If the only alteration is the increase of SDMA, this could be suggestive of CKD but the increase should be persistent over at least 2-3 months.

Early diagnosis of CKD: Urine protein/creatinine ratio

Proteinuria in dogs and cats with 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 increase 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 that 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 than 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 further loss of nephrons. Proteinuric renal disease and systemic hypertension often co-exist 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 sulfosalicylic acid turbidimetric test, urine protein/creatinine ratio (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 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. Once persistent renal proteinuria has been documented, it needs to be quantified (if not accomplished earlier) by measuring the UPC, which is used to guide and monitor treatment. Sequential UPC measurements should indicate 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-proteinuric
0.2-0.4 (cats); 0.2-0.5 (dogs)	Borderline proteinuric
> 0.4 (cats); > 0.5 (dogs)	Proteinuric

Current recommendations suggest that persistent proteinuria of renal origin of a magnitude > UPC 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 (UPC of 0.2 to 0.5 in dogs, or 0.2 to 0.4 in cats) warrants increased monitoring. Note, however, that borderline and even "normal" levels of proteinuria in cats have been associated with progressive disease.

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 < 0.2.¹³ In a prospective, longitudinal cohort study of non-azotemic cats > 9 years, 95 cats (median age 13 years) were followed for 12 months or until death or azotemia developed. Azotemia was defined as a blood 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.¹⁴ Finally, when client-owned cats with stable CKD (n=112) were compared with client-owned cats with progressive CKD (n=101), median UPC in the progressive group was higher when compared with the stable group (0.27 vs. 0.14).¹⁵ A 0.1 increase in UPC was associated with a 24% increase in risk of progression of CKD.¹⁵ These observational studies suggest that the relationship between proteinuria at diagnosis and all-cause mortality / risk of progression of CKD is a continuous one. We need prospective intervention studies to: 1) re-define the proteinuria classification in terms of the level of proteinuria that should trigger an intervention; 2) determine the post-treatment target UPC that indicates success of that intervention and 3) determine which interventions have a positive benefit on survival and progression in dogs and cats that is related to such a reduction in proteinuria.

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 5-10 minutes 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.¹⁶The 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. Hypertension should be documented more than once before accepting the diagnosis and initiating treatment unless the hypertension is accompanied by target organ damage (e.g., ocular lesions).

IRIS Classification of Systolic Blood Pressure in Dogs and Cats

Systolic Blood Pressure (mm Hg)	Risk of Target Organ Damage	Classification
< 150	Minimal	Normotensive
150 - 159	Low	Borderline hypertensive
160 - 179	Moderate	Hypertensive
> 180	High	Severely hypertensive

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 mm Hg were considered the threshold for hypertension. Despite the inherent difficulties with indirect blood pressure measurement in dogs and cats, it may be appropriate to consider systolic hypertension to be present at lower pressures (e.g., > 160 mm Hg). It is important to keep in mind however that lowering blood pressure treatment thresholds will reduce specificity and could result in dogs and cats being treated without need or benefit.

In a recent study, 45 dogs with naturally occurring CKD were divided into three groups based on initial systolic blood pressure and followed for up to 2 years. The blood pressure groups were defined as: high (161-201 mm Hg), n = 14; intermediate (144-160 mm Hg), n = 15, and low (107-143 mm Hg), n = 16. The high blood pressure group had increased risk of uremic crisis and death when compared with the low blood pressure group (median survival of < 200 days vs. > 400 days).¹⁷

In other studies, cats with a remnant kidney-wrap model of CKD, systolic hypertension (mean pressure of 168 vs. 113 mm Hg) was associated with reduced GFR (1.34 vs. 3.55 ml/min/kg), increased UPC (1.2 vs. 0.1), and increased glomerulosclerosis.¹⁸ Similarly, in dogs with the remnant kidney-wrap model of CKD, systolic hypertension (> 160 mm Hg) was associated with reduced GFR, increased UPC ratio, and increased mesangial matrix accumulation, tubular lesions, fibrosis, and cellular infiltrates.¹⁹ Cats with progressive CKD had higher systolic blood pressures than did cats with stable CKD (155 vs. 147 mm Hg).¹⁵ 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.²⁰ All these findings support the view that blood pressure below the currently classified hypertensive cut off (160 mm Hg; i.e. 140-159 mm Hg) may contribute to kidney injury in some animals. For example, treatment targets in hypertensive people that are also proteinuric tend to be lower.²¹

Management of CKD: Serum phosphorus concentrations

Similar to blood creatinine reference ranges, there is variability in serum phosphorus reference ranges between laboratories. This variability is likely at least in part due to higher serum phosphorus concentrations observed in healthy, young, growing puppies and kittens. Soft tissue mineralization of the kidney causes irreversible nephron damage and is associated with CKD progression in dogs and cats. Cats with stable CKD had lower serum phosphorus concentrations than did cats with progressive CKD (4.4 vs. 5.1 mg/dl).¹⁵ Serum phosphorus concentration is a predictor of CKD progression in cats, with a 41% increase in the risk of progression for every 1.0 mg/dl increase in serum phosphorus concentration.¹⁵ In 80 client-owned cats with CKD, serum phosphorus concentrations were correlated with renal interstitial fibrosis.²⁰ In dogs with CKD, a serum calcium times phosphorus product > 70 mg/dl was a poor prognostic indicator.²² These findings have prompted closer scrutiny of therapeutic targets for serum phosphorus in dogs and cats with CKD. IRIS treatment guidelines suggest the following targets which are typically well within laboratory reference ranges.8

IRIS Treatment Recommendations for Serum Phosphorus in Dogs and Cats with CKD

IRIS CKD Stage	Target serum phosphorus (mg2/dl2)	Management Options
1	2.7 - 4.5	Renal diet or normal diet with enteric binder
2	2.7 - 4.5	Renal diet +/- enteric binder
3	2.7 - 5.0	Renal diet with enteric binder
4	2.7 - 5.0	Renal diet with enteric binder

Summary

Closer monitoring of blood creatinine concentration, UPC and SDMA 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, standard of care renoprotective treatment includes a renal diet +/- an enteric phosphate binder for hyperphosphatemia and RAAS blockade and/or calcium channel blockers for proteinuria and hypertension. Tighter control of hyperphosphatemia, renal proteinuria, and systolic hypertension may improve treatment outcome. IRIS guidelines will be kept under continuous review and amended to take account of the most recent evidence that informs clinical practice to aid practitioners in diagnosis, treatment and monitoring of dogs and cats with CKD.

References

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