Upper urolithiasis in cats with chronic kidney disease: prevalence and investigation of serum and urinary calcium concentrations

Abstract

Objectives

This study aimed to define the prevalence of upper urolithiasis in cats with chronic kidney disease (CKD) in a referral population, and to compare urinary calcium:creatinine ratio (UCa:Cr), and total and ionised calcium between cats with CKD with and without upper urolithiasis.

Methods

The medical records of cats diagnosed with CKD were reviewed for signalment, body weight, diet and prevalence of upper urolithiasis. Cats with preserved urine samples were further classified into two groups: urolithiasis group (upper urolithiasis identified by abdominal ultrasonography) and control group (CKD of unknown origin). Serum biochemical analysis, CKD stage, blood gas analysis, urine specific gravity and UCa:Cr were compared between groups using a two-sample t-test or Mann–Whitney U-test for continuous variable and a χ² test or Fisher’s exact test for categorical variables. Multivariable binary logistic regression analysis was used to identify risk factors.

Results

Among the 140 cats with CKD, the prevalence of upper urolithiasis was 73%. Fifty cats (5, 29 and 16 cats with CKD stages 1, 2 and 3, respectively) with urine samples met the inclusion criteria and were included in the analysis. Among cats with CKD, being purebred (odds ratio [OR] = 81.56; P = 0.03) and being fed dry food only (OR = 25.06; P = 0.001) were identified as independent upper urolithiasis risk factors; those with upper urolithiasis were more likely to be exclusively fed with urine-acidifying food (P <0.001) and have increased serum ionised calcium (iCa) (P = 0.044), fractional excretion of calcium (P = 0.45) and UCa:Cr (P = 0.005) than cats with CKD without upper urolithiasis.

Conclusions and relevance

Cats with CKD that were purebred, fed dry food and fed urine-acidifying food only often had upper urolithiasis. A higher UCa:Cr may be a result of increased serum iCa and may cause upper urolithiasis.

Keywords

Calcium oxalate hypercalciuria obstructive nephropathy ureteroliths

Introduction

Ureterolithiasis is the most common cause of ureteral obstruction.¹ Similarly, nephroliths can also cause ureteropelvic junction obstructions or ureter obstruction after migrating into the ureter, resulting in damage to the kidney.² The prevalence of feline ureteral obstructions has been increasing in recent years.¹ As clinical signs are not always apparent in the case of unilateral obstructive nephropathy, upper urolithiasis may contribute, at least in part, to cases of chronic kidney disease (CKD) with an unknown origin. Although there are reports of feline upper urolithiasis, the features of cats with CKD and concurrent upper urolithiasis and the relationship between the two diseases remain underexplored.^3–5

The formation of feline uroliths is multifactorial and includes dietary, metabolic, genetic and infectious causes.⁶ To prevent ureteral obstructions, it is important to monitor the factors associated with urolith formation. Feline ureteroliths are mainly composed of calcium oxalate (CaOx).¹ Being a castrated male,^7,8 having hypercalcaemia,^7,9 hypercalciuria^10,11 and hyperoxaluria,^12,13 and eating a diet formulated to maximise urine acidity^13,14 are risk factors associated with calcium oxalate urolithiasis in cats. Hypercalciuria occurs in human cases of CaOx urolithiasis, and the urinary calcium:creatinine ratios (UCa:Cr) of both spot urine samples and 24 h urine samples are used as a marker of urinary calcium excretion.^15,16 Moreover, the recurrence of upper urolithiasis is reported to be associated with elevated UCa:Cr in humans.¹⁷ A significantly higher UCa:Cr has also been reported in dogs with CaOx uroliths, compared with those without CaOx uroliths.¹⁸ Given that 98% of ureteroliths in cats are composed of CaOx,¹ UCa:Cr may be a useful measure to evaluate whether feline upper urolithiasis may also express hypercalciuria. However, there are few reports assessing UCa:Cr in cats.¹¹

The aims of this study were to define the prevalence of upper urolithiasis in cats with CKD in a referral population, and to compare UCa:Cr, and total and ionised calcium between cats with CKD with and without upper urolithiasis.

Materials and methods

The medical records of 140 cats diagnosed with CKD at the Animal Medical Centre, Nippon Veterinary and Life Science University from January 2013 to February 2021 were reviewed. All cases were referred to our institution for a second opinion regarding urology and renal diseases. The prevalence and distribution (as being unilateral or bilateral) of both ureterolithiasis and nephrolithiasis were investigated. CKD was determined by the presence of a persistent (⩾3 months) renal azotaemia and/or structural abnormalities of the kidney based on abdominal ultrasonography. Renal azotaemia was defined based on serum creatinine concentration ⩾1.8 mg/dl (the upper limit of the reference interval at our institution) and urine specific gravity (USG) <1.035. Structural abnormalities of the kidney were characterised by a decrease in size, decrease in corticomedullary differentiation and/or irregular renal contours upon abdominal ultrasonography. Diagnosis of urolithiasis was determined by abdominal ultrasonography performed by an experienced nephrologist. Uroliths were defined as hyperechoic structures within the renal pelvis or lumen of the ureter causing acoustic shadowing. If nephroliths or ureteroliths were present, they were further characterised as unilateral or bilateral. Information, including signalment, body weight and diet, was extracted from the medical records.

Of the 140 cats, those with preserved urine samples (n = 50) were further classified into two groups: urolithiasis group (cats with an upper urinary urolith identified by abdominal ultrasonography) and control group (cats with CKD of an unknown origin without an upper urinary tract urolith). To ensure that disease stage was uniform, as severe renal failure could alter urinary calcium excretion,^19,20 cats with serum creatinine concentrations ⩾5.0 mg/dl or serum inorganic phosphorus >6.0 mg/dl were excluded from the groups. In addition, cats diagnosed with polycystic kidney disease (n = 3), acute kidney injury (n = 17) or cystitis (n = 23) were excluded. CKD stage, serum biochemical analysis, blood gas analysis, USG and the results of quantitative analysis of uroliths were extracted from the medical records. CKD stage (1–4) was classified according to the 2019 International Renal Interest Society (IRIS) staging of CKD guidelines, based on serum creatinine concentration.²¹ All blood and urine samples were collected from conscious cats without sedation. Urine samples were obtained via catheterisation or cystocentesis and preserved at −30°C prior to analysis. The fractional excretion of calcium (FECa) and UCa:Cr was measured by an external laboratory (FUJIFILM VET System) using preserved urinary samples. Serum biochemical analysis was performed with an automated analyser (7180 Biochemistry Automatic Analyzer; Hitachi High-Technologies) to determine the levels of blood urea nitrogen (BUN), creatinine, inorganic phosphorus, total calcium (tCa), sodium, potassium, chloride, total protein and albumin. The serum concentration of ionised calcium (iCa) and bicarbonate were assessed with a blood gas analyser (GEM PREMIER 3500; Instruments Laboratory). FECa was calculated as 100 × ([urinary calcium] × [serum creatinine]/[serum calcium] × [urinary creatinine]). UCa:Cr was calculated as [urinary calcium]/[urinary creatinine].

Statistical analysis was performed using a commercial software package (SPSS 24 for Windows; IBM Japan). Data normality was assessed using the Shapiro–Wilk test. Either a two-sample t-test or Mann–Whitney U-test was used to compare the levels of BUN, creatinine, inorganic phosphorus, tCa, sodium, potassium, chloride, total protein, albumin, iCa, bicarbonate, FECa and UCa:Cr between the control group and the urolithiasis group. Categorical variables were compared with either a χ² test or Fisher’s exact test, as appropriate. Variables associated with upper urolithiasis at P <0.05 were entered into a multivariable binary logistic regression analysis with forward method to identify independent risk factors. A Hosmer–Lemeshow test was used to evaluate goodness-of-fit of the final model. Statistical significance was set at P <0.05.

Results

This study included 140 cats with CKD, of which 102 (73%) had concurrent upper urolithiasis. Among the cats with upper urolithiasis, nephroliths and ureteroliths were identified in 71 (69%) and 82 (80%) cats, respectively. Of the 102 cats with concurrent upper urolithiasis, 20 (20%) had only nephroliths, 31 (30%) had only ureteroliths and 51 (50%) had both nephroliths and ureteroliths (Table 1).

Table 1

Prevalence and distribution (unilateral or bilateral) of upper urinary tract uroliths in cats diagnosed with chronic kidney disease at the Animal Medical Centre, Nippon Veterinary and Life Science University from January 2013 to February 2021 (140 cats)

	Bilateral	Unilateral	Total (%)
Nephrolithiasis only	9	11	20 (20)
Ureterolithiasis only	13	18	31 (30)
Both	42	9	51 (50)

CKD cats with upper urolithiasis consisted of 102 cats (52 castrated males, four intact males, 42 spayed females and four intact females). Signalment, body weight and diet type from these 140 cats are shown in Table 2. Seventy-seven cats with CKD with upper urolithiasis were purebred and 25 were crossbred, with a median age of 5.6 years (range 0.5–15.3) and a median body weight of 3.8 kg (range 1.9–7.3). CKD cats without upper urolithiasis consisted of 38 cats (20 castrated males, one intact male, 16 spayed female and one intact female). Sixteen cats with CKD without upper urolithiasis were purebred and 22 were crossbred, with a median age of 7.6 years (range 0.5–16.2) and median body weight of 4.1 kg (range 3.7–5.4). Of cats with CKD, cats with upper urolithiasis were more likely to be purebred (P <0.001), fed dry food only (P = 0.002) and fed urine-acidifying food only (P <0.001) than cats without upper urolithiasis. Multivariable binary logistic regression analysis identified that being purebred (odds ratio [OR] 81.56; P = 0.003) and being fed dry food only (OR 25.06; P = 0.001) were significantly associated with the presence of upper urolithiasis.

Table 2

Median (range) age, body weight and count according to sex, diet type and breed from cats with chronic kidney disease (CKD) with (102 cats) and without (38 cats) upper urolithiasis (January 2013 to February 2021)

	Urolithiasis (n = 102)	CKD (n = 38)	P value
Age (years)	5.6 [0.5–15.3]	7.6 [0.5–16.2] (n = 37)	0.484
Body weight (kg)	3.8 [1.9–7.3] (n = 70)	4.1 [2.4–5.4] (n = 12)	0.633
Sex (n)			0.964
Intact male	4	1
Castrated male	52	20
Intact female	4	1
Spayed female	42	16
Diet (n)
Dry food only	67	6	0.002
Both dry and wet food	11	5
Wet food only	0	1
Urine-acidifying food	42	0	<0.001
Other	35	13
Breed (n)			<0.001
Purebred	77	16
Crossbred	25	22

Among the cats with CKD, urine samples from 50 were preserved. These were further classified into a urolithiasis group and a control group. The urolithiasis group consisted of 41 cats (five were IRIS stage 1, 25 were IRIS stage 2 and 11 were IRIS stage 3), and the control group consisted of nine cats (four were IRIS stage 2 and five were IRIS stage 3). Quantitative analysis of uroliths was performed in 7/41 cats with upper urolithiasis, all of which were CaOx.

Table 3 lists the results of the serum biochemical analysis, blood gas analysis, USG, FECa and UCa:Cr, according to group. Serum iCa concentration (P = 0.044), FECa (P = 0.045) and UCa:Cr (P = 0.005) were significantly higher in cats in the urolithiasis group; however, there was no significant difference between the two groups for the remaining parameters, including serum tCa (P = 0.889; Figure 1).

Table 3

Laboratory results from cats with chronic kidney disease with (41 cats) and without (nine cats) upper urolithiasis (January 2013 to February 2021)

	Urolithiasis (n = 41)	Control (n = 9)	P value
BUN (mg/dl)	35.8 [29.5–47.9] (n = 40)	35.6 [27.0–43.9]	0.757
Creatinine (mg/dl)	2.22 [1.84–2.78]	2.51 [2.07–3.23]	0.277
Total protein (g/dl)	7.00 [6.70–7.30] (n = 40)	7.60 [6.95–7.85]	0.070
Albumin (g/dl)	2.40 [2.20–2.87] (n = 40)	2.70 [2.30–3.15]	0.217
Total Ca (mg/dl)	10.8 [10.0–12.0]	11.1 [10.1–11.9]	0.889
Inorganic phosphorus (mg/dl)	3.80 [3.32–4.10] (n = 40)	3.70 [3.00–3.95]	0.560
Sodium (mEq/l)	153.5 [151.0–156.0] (n = 40)	153.0 [150.0–155.5]	0.622
Potassium (mEq/l)	4.00 [3.27–4.30] (n = 40)	4.10 [4.00–4.90]	0.191
Chloride (mEq/l)	118.0 [116.0–120.7] (40)	116.0 [114.5–119.5]	0.237
Ionised Ca (mmol/l)	1.33 [1.28–1.38] (n = 38)	1.30 [1.24–1.32]	0.044
Bicarbonate (mmol/l)	18.1 [15.8–20.6] (n = 38)	19.1 [16.4–20.2]	0.787
USG	1.021 [1.014–1.027] (n = 40)	1.021 [1.012–1.040]	0.660
FECa (%)	0.324 [0.148–1.160]	0.133 [0.065–0.692]	0.045
UCa:Cr (mg/mg)	0.025 [0.006–0.043]	0.006 [0.002–0.020]	0.005

Median [interquartile range] levels of components of serum biochemical analysis, blood gas analysis, urine specific gravity (USG), fractional excretion of calcium (FECa) and urinary calcium:creatinine ratio (UCa:Cr) are shown according to group

BUN = blood urea nitrogen

Figure 1

Serum ionised calcium (iCa), serum total calcium (tCa), fractional excretion of calcium (FECa) and urinary calcium:creatinine ratio (UCa:Cr) in cats with chronic kidney disease with (41 cats) and without (nine cats) upper urolithiasis (January 2013 to February 2021). Boxes represent the 25th and 75th percentiles, and central lines in the boxes represent median values. Whiskers extend from the minimum to the maximum values. *Significant differences, P <0.05

Discussion

In this study, upper urolithiasis was present in >50% of cats with CKD. This result is similar to the findings of a previous report,²² and indicates that upper urolithiasis is a common concurrent disease in cats with CKD within a referral hospital setting. Although the aetiology of feline CKD, including chronic tubulointerstitial nephritis, renal ischaemia, pyelonephritis, amyloidosis and obstructive nephropathy, has been described,²³ the clinical diagnosis of the specific cause of feline CKD remains challenging; most cases are classified as idiopathic chronic tubulointerstitial nephritis. In this study, the high prevalence of upper urolithiasis suggested that upper urolithiasis itself may be a cause of CKD as obstruction of ureteroliths or nephroliths can unknowingly damage the kidney when occurring unilaterally and where there is no pre-existing renal disease. In a case-control study of cats, the concurrence of nephrolithiasis in cats with CKD had no effect on the progress of CKD or the mortality rate, when compared with the control group (with CKD without nephrolithiasis).³ Conversely, in humans, nephrolithiasis is thought to lead to a greater risk of developing CKD.²⁴ As our study was cross-sectional by design, a prospective study is necessary to clarify if nephrolithiasis and ureterolithiasis is associated with the development and progression of CKD in cats. Urolithiasis must be diagnosed via imaging.²⁵ Given the high prevalence of upper urolithiasis in this study, imaging should be performed for all cats with CKD to identify the presence of any stones because they may have been the cause of the CKD.

According to previous reports, CaOx urolithiasis is common in middle-aged and older cats (5–12 years),¹³ and most often identified in 7.3-year-old cats.¹² In contrast, our study showed that cats with CKD and concurrent upper urolithiasis were younger than 7.3 years of age.

Among the CKD cats in our study, cats with upper urolithiasis were more likely to be fed dry food only and fed urine-acidifying food only than cats without upper urolithiasis. An increase of urine concentration is a risk factor for urolithiasis, and it can result from a reduction of total water intake.²⁶ Dry food reduces the total water intake of cats fed dry food only. Unlike struvite uroliths, calcium uroliths, which account for 98% of feline ureteroliths,¹ are indissoluble; thus, it is important to prevent the formation of calcium uroliths.²⁶ In humans, increasing water intake is an effective means of preventing the formation of calcium uroliths via diluting urine concentrations.²⁷ In a retrospective study of 173 cats, cats fed food with a higher moisture content had a one-third reoccurrence rate of CaOx urolithiasis, compared with cats fed food with a lower moisture content.¹⁴ Similarly, our study identified being exclusively fed dry food as a risk factor for upper urolithiasis in CKD cats. However, acidified urine resulting from urine-acidifying food, a common treatment for lower urinary tract disease, is an additional risk factor for calcium urolithiasis in cats.^27,28 Therefore, the high prevalence of upper urolithiasis in the cats in our study could also contribute to a decrease in urinary volume caused by lower total water intake and urine acidification caused by urine-acidifying food. Although there was no significant difference between the USG of CKD cats with and without upper urolithiasis in our study, this could be because CKD lowered the glomerular filtration rate, making it difficult to directly compare the USG. Consequently, in cats with CKD and concurrent upper urolithiasis, feeding wet food may be beneficial for preventing urolithiasis recurrence and deterioration, which could otherwise further contribute to the progression of CKD.

The proportion of purebred cats was higher in the urolithiasis group than the control group. The prevalence of CaOx urolithiasis has been reported to be higher in specific purebred cat breeds, such as Persian, Himalayan, Burmese and Ragdoll cats.¹³ In another report from Japan, 72% of cats with ureterolithiasis were purebred cats; they were mostly American Shorthairs (n = 20) and Scottish Folds.²⁸ Our study therefore produced results similar to those noted in previous reports. In dogs, certain breeds are at a greater risk of CaOx urolith formation; in Miniature Schnauzers, in particular, familial hypercalciuria is observed and associated with CaOx urolithiasis.²⁹ Similarly, being purebred was significantly associated with the presence of upper urolithiasis in CKD cats in our study. Therefore, given the high prevalence of upper urolithiasis in purebred cats, genetics may be associated with the onset of upper urolithiasis. Thus, further research is required to evaluate the existence of metabolic abnormalities, such as hypercalciuria, hyperoxaluria and hypocitraturia, as risk factors for upper urolithiasis in specific purebred cats.

In humans with calcium urolithiasis, which account for the majority of upper urolithiasis, UCa:Cr is an indicator of urinary calcium excretion and the recurrence risk of urolithiasis.^18,30 In Miniature Schnauzers and Bichon Frise with a history of CaOx urolithiasis, the UCa:Cr has been reported to be higher than that in those without CaOx urolithiasis.¹⁸ Similarly to humans and dogs, the iCa level, FECa and UCa:Cr in our study were significantly higher in cats in the urolithiasis group. As a result, calcium urolith formation may be associated with a high iCa level and consequent hypercalciuria. As few studies have investigated UCa:Cr in cats, it is unclear whether hypercalciuria is an effective marker of calcium urolithiasis. In our study, a high UCa:Cr was associated with the presence of upper urolithiasis and may be causative. Further research is required to determine the normal reference interval and cut-off value of UCa:Cr in cats, to enable an assessment of calcium urolithiasis risk. There was no difference in the serum tCa across the groups in our study. As serum tCa may not reflect biologically active iCa under metabolic abnormalities, serum iCa must be measured to detect metabolic abnormalities.

This study had a few limitations. First, as this was a retrospective investigation, it may be subject to selection bias. Additionally, data were missing from a number of cases. Secondly, the data in this study were collected from cats that visited the Animal Medical Centre of Nippon Veterinary and Life Science University for a close kidney examination or second medical opinion; as a result, the study may not accurately reflect the wider population of cats with CKD. Thirdly, as serum parathyroid hormone and parathyroid hormone-related protein levels were not measured, the precise cause of high serum iCa levels could not be identified. Fourthly, although most feline ureteroliths are composed of CaOx, a quantitative analysis of the uroliths was not completed for every case, so some non-CaOx uroliths may have been included in the upper urolithiasis group. Finally, compared with the urolithiasis group, the sample size of the control group was small, which lowered the statistical power.

Conclusions

In the referral population of this study, the prevalence of upper urolithiasis was 73%, and being purebred and fed dry food only were identified as risk factors in the cats with CKD. Among the cats with CKD, those with upper urolithiasis were more likely to be fed urine-acidifying food only, have elevated iCa levels, and have a higher FECa and UCa:Cr than cats without upper urinary tract uroliths.

Footnotes

Acknowledgements

We thank FUJIFILM VET Systems for the analysis of fractional excretion of calcium and urinary calcium:creatinine ratio. In addition, the authors would like to thank Enago () for the English-language review.

Accepted: 14 February 2022

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

This work involved the use of non-experimental animals only (including owned or unowned animals and data from prospective or retrospective studies). Established internationally recognised high standards (‘best practice’) of individual veterinary clinical patient care were followed. Ethical approval from a committee was therefore not specifically required for publication in JFMS.

Informed consent

Informed consent (either verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (either experimental or non-experimental animals) for the procedure(s) undertaken (either prospective or retrospective studies). No animals or humans are identifiable within this publication, and therefore additional informed consent for publication was not required.

ORCID iD

Huai-hsun Hsu

Hirosumi Miyakawa

Mizuki Ogawa

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