Serum concentrations of leptin and adiponectin in dogs with chronic kidney disease

BackgroundAn imbalance in adipokines is associated with the progression of chronic kidney disease (CKD) in humans. However, alterations in adipokines in dogs with CKD remain unclear.ObjectivesTo examine whether adipokine concentrations in serum differ between healthy dogs and dogs with CKD and to determine the correlation between serum adipokine concentrations and CKD severity in dogs.AnimalsTwenty dogs with CKD and 10 healthy dogs.MethodsIn this cross‐sectional study, serum concentrations of leptin, adiponectin, interleukin (IL)‐6, IL‐10, IL‐18, and tumor necrosis factor (TNF)‐α were measured in healthy dogs and dogs with CKD, which were classified according to the International Renal Interest Society guidelines.ResultsSerum leptin concentrations were positively correlated with systolic arterial blood pressure (r = .41), creatinine concentrations (r = .39), and symmetric dimethylarginine concentrations (r = .73). Serum adiponectin concentrations (median [range]) in CKD dogs with borderline or non‐proteinuric (20.25 [14.9‐45.8] ng/mL) were significantly higher than those in proteinuric CKD dogs (13.95 [6.4‐22.1] ng/mL; P = .01). Serum IL‐6 (median [range]; 43.27 [24.30‐537.30] vs 25.63 [6.83‐61.03] pg/mL; P = .02), IL‐18 (median [range]; 25.98 [11.52‐280.55] vs 10.77 [3.53‐38.45] pg/mL; P = .01), and TNF‐α (median [range]) concentrations (11.44 [8.54‐38.45] vs 6.105 [3.97‐30.68] pg/mL; P = .02) were significantly different between proteinuric and borderline or non‐proteinuric CKD dogs.Conclusions and Clinical Importanceleptin and adiponectin concentrations in serum might be associated with severity of CKD and proteinuria in dogs with CKD, respectively.     

Glomerular filtration rate in dogs with leishmaniasis and chronic kidney disease

BACKGROUND: Glomerular filtration rate (GFR) measurement is an indicator of kidney function. However, its usefulness in dogs at early stages of spontaneous chronic kidney disease (CKD) of glomerular origin, where routine laboratory techniques are not sufficiently sensitive, remains unproved. HYPOTHESIS: That GFR is reduced in proteinuric nonazotemic or mildly azotemic dogs with CKD secondary to leishmaniasis. ANIMALS: Twenty-six dogs with CKD secondary to leishmaniasis and 10 healthy dogs (control group). METHODS: CBC, serum biochemistry, and urinalysis (microalbuminuria and urine protein/creatinine ratio [UPC]) were performed in all dogs. GFR was calculated by measuring exogenous creatinine clearance. Based on degree of proteinuria and serum creatinine concentration (SCr), dogs were classified as group A (control; n = 10): UPC < 0.2, SCr < 1.4 mg/dL; group B (n = 8): UPC, 0.2-0.5, SCr < 1.4 mg/dL; group C (n = 10): UPC > 0.5, SCr < 1.4 mg/dL; group D (n = 5): SCr, 1.4-2 mg/dL; group E (n = 3): SCr > 2 mg/dL. Results: GFR (mL/kg/min) was 3.9 +/- 0.29, 4.4 +/- 0.74, 4.5 +/- 1.44, 2.8 +/- 0.97, and 1.5 +/- 0.43 for groups A, B, C, D, and E, respectively. Eleven dogs (1 from group B, 3 from group C, 4 from group D, and all 3 dogs from group E) had an abnormally low GFR. Four dogs from group B and 5 dogs from group C had a GFR above the upper reference range (>4.5 mL/min/kg). CONCLUSION AND CLINICAL RELEVANCE: Some proteinuric nonazotemic or mildly azotemic dogs with leishmaniasis have low GFR, but glomerular hyperfiltration occurs in other dogs.     

Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers

Background: Proteinuria is a feature of pyometra‐associated renal dysfunction, but its prevalence and clinical relevance are not well characterized. Objectives: To define which subset of dogs with pyometra has clinically relevant kidney injury by quantification of proteinuria; light, immunofluorescence, and electron microscopic examination of kidney biopsy specimens; and measurement of urinary biomarkers. Animals: Forty‐seven dogs with pyometra. Ten clinically healthy intact bitches of comparable age. Methods: Prospective study. Routine clinicopathological variables including urinary protein to creatinine ratio (UPC) were analyzed. Validated assays were used to quantify urinary biomarkers for glomerular (urinary albumin, urinary immunoglobulin G, urinary C‐reactive protein, urinary thromboxane B₂) and tubular function (urinary retinol‐binding protein, urinary N‐acetyl‐β‐d ‐glucosaminidase). Kidney biopsy specimens from 10 dogs with pyometra and dipstick urine protein concentrations of 2+ or 3+ were collected during ovariohysterectomy. Urinalysis was repeated within 3 weeks after surgery in 9 of the 10 dogs. Results: UPC (median, range) was significantly higher in dogs with pyometra (0.48, 0.05–8.69) compared with healthy bitches (0.08, 0.02–0.16) (P < .01). Twenty‐two of 47 dogs with pyometra had UPC>0.5, 12 had UPC>1.0, and 7 had UPC>2.0. Glomerulosclerosis and tubulointerstitial nephritis were common kidney biopsy findings in proteinuric dogs with pyometra. Dogs with glomerulosclerosis (5/10), either global or focal and segmental, had UPC>1.0 at ovariohysterectomy and afterward. Dogs with structural glomerular and tubular changes mostly had urinary biomarker to creatinine ratios above the 75th percentile. Conclusion: Dogs with pyometra and UPC>1.0 or high ratios of urinary biomarkers appear likely to have clinically relevant renal histologic lesions and require monitoring after ovariohysterectomy. Future studies should evaluate the role of pyometra‐associated pathogenic mechanisms in causing or exacerbating focal and segmental glomerulosclerosis in dogs.     

Kidney Injury Molecule-1 in the detection of early kidney injury in dogs with leptospirosis

Renal damage, a common feature in canine leptospirosis, ranges from a subclinical affection to kidney dysfunction and death. Chances of recovery can be improved by early intervention. However, traditional biomarkers (serum urea and creatinine) have limited relevance for precocity. Kidney Injury Molecule-1 (KIM-1) is a transmembrane protein upregulated in early stages of tubular injury. This study evaluated the use of urinary KIM-1 to detect early renal injury in naturally occurring canine leptospirosis. This exploratory research included 30 dogs divided into two groups: (1) dogs with leptospirosis (n = 25) and (2) healthy dogs (n = 5). Leptospira sp. infection was diagnosed through urine PCR and/or direct bacteriologic culture and/or serology (single MAT titters ≥800). Additionally, stage of infection was further characterized in acute and subacute phases based on the onset of clinical symptoms from 3 to 7 days. Urinary KIM-1 (uKIM-1) concentrations were measured in both groups with a commercial canine ELISA kit.uKIM-1 levels were statistically different (P < 0.01) between the studied groups, especially in non-azotemic dogs (P = 0.0042). The biomarker showed 88 % sensibility to diagnosis of kidney injury at> 1.49 ng/mL cut-off. Urine KIM-1 was negatively correlated with urine specific gravity (USG) but accompanied histopathological evidence of renal degeneration, necrosis and regeneration processes, extending information on kidney health. Measurement of KIM-1 in the urine of canine patients was able to detect naturally occurring acute and subacute leptospirosis accompanied by tubular injury in early non-azotemic infections.     

Perioperative urinary heat shock protein 72 as an early marker of acute kidney injury in dogs

ObjectiveAcute kidney injury (AKI) may be a complication in dogs undergoing surgery. Urinary heat shock protein 72 (uHSP72) is a sensitive biomarker of canine AKI. To assess the occurrence of perioperative AKI, based on uHSP72 compared with serum creatinine (sCr), and whether its occurrence is associated with the American Society of Anesthesiology physical status (ASA status).Study designClinical prospective study.AnimalsA total of 80 client-owned and shelter dogs.MethodsDogs scheduled for elective or emergency surgery were assigned ASA status (ASA I–IV). Preoperative and 24 hour postoperative serum and urine samples were collected. sCr, uHSP72 and urinary creatinine (uCr) were measured.ResultsPostoperative uHSP72/uCr concentration [median (range)] of all dogs undergoing surgery [2.40 (0.14–252) ng mg⁻¹] was significantly increased compared with preoperative uHSP72/uCr [1.30 (0.11–142) ng mg⁻¹] concentration (p < 0.001). Conversely, postoperative sCr concentration of all dogs [0.88 (0.3–1.6) mg dL⁻¹] significantly decreased compared with preoperative sCr concentration [0.8 (0.2–5.0) mg dL⁻¹; p = 0.001]. Median uHSP72/uCr concentration differed both preoperatively (p = 0.007) and postoperatively (p = 0.019) among the ASA status groups. Increased uHSP/uCr was measured in 20 dogs preoperatively and 33 dogs postoperatively, whereas only five dogs fulfilled the criteria of AKI based on sCr.ConclusionsThe occurrence of increased uHSP72/uCr perioperatively suggests that the proportion of dogs with AKI is considerably higher than perceived.Clinical relevanceDogs undergoing surgery should be closely monitored for AKI before and after anesthesia, using currently available markers (e.g., sCr) and more sensitive markers.     

Renal biomarkers in cats: A review of the current status in chronic kidney disease

Serum creatinine concentration, the classical biomarker of chronic kidney disease (CKD) in cats, has important limitations that decrease its value as a biomarker of early CKD. Recently, serum symmetric dimethylarginine concentration was introduced as a novel glomerular filtration rate biomarker for the early detection of CKD in cats. However, data on its specificity are still limited. The limitations of conventional biomarkers and the desire for early therapeutic intervention in cats with CKD to improve outcomes have prompted the discovery and validation of novel renal biomarkers to detect glomerular or tubular dysfunction. Changes in the serum or urinary concentrations of these biomarkers may indicate early kidney damage or predict the progression of kidney before changes in conventional biomarkers are detectable. This review summarizes current knowledge on renal biomarkers in CKD in cats, a field that has progressed substantially over the last 5 years.     

Evaluation of albuminuria and its relationship with blood pressure in dogs with chronic kidney disease

Background: Microalbuminuria and hypertension have long been associated with a guarded prognosis in human patients with a variety of diseases. In veterinary medicine, tests for microalbuminuria have been used for detecting early kidney damage, but there is little information regarding its association with high blood pressure in dogs with chronic kidney disease (CKD). Objective: The objective of this study was to evaluate albuminuria and its association with arterial hypertension in dogs with CKD. Methods: Urinary albumin:creatinine (UAC) ratio, urinary protein:creatinine (UPC) ratio, and systolic blood pressure were determined in 39 clinically healthy dogs and 40 dogs with CKD. Results: UAC in dogs with CKD (range, 0.002–7.99; median, 0.38) was statistically different from that of control dogs (range, 0.0005–0.01; median, 0.002). Microalbuminuria (UAC 0.03–0.3) and macroalbuminuria (UAC>0.3) were detected in 32.5% and 50% of dogs with CKD, respectively. Sixty percent (24/40) of dogs with CKD had systolic pressure ≥180 mmHg; in these dogs, UAC ratio (range, 0.006–7.99; median, 1.72) was significantly higher than in dogs with CKD and systolic pressure<180 mmHg (range, 0.002–4.83; median, 0.10). Of hypertensive dogs with CKD, those with UPC>1.0 usually had macroalbuminuria, those with UPC 0.5–1.0 usually had microalbuminuria, and those with UPC<0.5 usually lacked albuminuria. Conclusions: UAC ratio was higher in hypertensive than in normotensive dogs with CKD. Tests designed to detect microalbuminuria may be useful for hypertensive dogs with CKD and a UPC≤1.0 to detect the onset and magnitude of albuminuria. Once macroalbuminuria is overt, the UPC ratio itself can be used for the same purpose.     

Comparative study of chronic kidney disease in dogs and cats: Induction of myofibroblasts

We investigated the kidneys of dogs and cats to clarify whether renal myofibroblasts induction is associated with the severity of chronic kidney disease (CKD). Immunohistochemical expression of myofibroblast markers, α-smooth muscle actin (SMA) and vimentin, were evaluated quantitatively. The degrees of glomerulosclerosis, glomerular hypertrophy, interstitial cell infiltration, and interstitial fibrosis were also evaluated quantitatively. The plasma creatinine (pCre) concentrations correlated with glomerulosclerosis, cell infiltration, and fibrosis in dogs, and only with fibrosis in cats. The α-SMA expression correlated with pCre, glomerulosclerosis, cell infiltration, and fibrosis in dogs, and with pCre and fibrosis in cats. Tubular vimentin expression correlated with fibrosis in cats, but not in dogs. Interstitial vimentin expression correlated with pCre, glomerulosclerosis, cell infiltration, and fibrosis in dogs, but only with pCre in cats. In conclusion, it was suggested that the severity of CKD in dogs and cats was mediated by different pathways associated with myofibroblasts expression.     

A longitudinal study on the acceptance and effects of a therapeutic renal food in pet dogs with IRIS‐Stage 1 chronic kidney disease

Currently, nutritional management is recommended when serum creatinine (Cr) exceeds 1.4 mg/dl in dogs with IRIS‐Stage 2 chronic kidney disease (CKD) to slow progressive loss of kidney function, reduce clinical and biochemical consequences of CKD, and maintain adequate nutrition. It is unknown if dietary interventions benefit non‐azotemic dogs at earlier stages. A prospective 12‐month feeding trial was performed in client‐owned dogs with IRIS‐Stage 1 CKD (n = 36; 20 had persistently dilute urine with urine specific gravity (USG) <1.020 without identifiable non‐renal cause; six had persistent proteinuria of renal origin with urine protein creatinine (UPC) ratio >0.5; 10 had both). Ease of transition to therapeutic renal food and effects on renal biomarkers and quality of life attributes were assessed. Dogs were transitioned over 1 week from grocery‐branded foods to renal food. At 0, 3, 6, 9, and 12‐months a questionnaire to assess owner's perception of their pet's acceptance of renal food and quality of life was completed. Renal biomarkers, including serum Cr, blood urea nitrogen (BUN), and symmetric dimethylarginine (SDMA), and USG and UPC ratio were measured. Of 36 dogs initially enrolled, 35 (97%) dogs were transitioned to therapeutic renal food. Dogs moderately or extremely liked the food 88% of the time, ate most or all of the food 84% of the time, and were moderately or extremely enthusiastic while eating 76% of the time. All renal biomarkers (Cr, BUN, and SDMA) were decreased (p ≤ .05) from baseline at 3‐months, and remained decreased from baseline at 12‐months in dogs completing the study (n = 20). Proteinuria was reduced in 12 of 16 dogs (p = .045) with proteinuria. Owners reported improvement in overall health and quality of life attributes, and hair and coat quality (all p < .01). In summary, dogs with IRIS‐Stage 1 CKD readily transition to renal food. Decreasing serum biomarker concentrations and reduction in proteinuria suggest stabilized kidney function.     

Iron status and erythropoiesis response to darbepoetin alfa in dogs with chronic kidney disease

Iron metabolism, hepcidin and some blood profiles were investigated in 13 healthy and 31 chronic kidney disease (CKD) dogs. The study consisted of 2 experiments, experiment I included healthy dogs (CONT) and CKD dogs (stage 2, 3 and 4), while experiment II consisted of anemic CKD dogs subjected to 28-day darbepoetin alfa treatment. The response to darbepoetin alfa could divide anemic CKD dogs into responder (RP) and non-responder (NRP) subgroups. The results from experiment I showed that packed cell volume (PCV) and plasma albumin concentration were significantly lower in CKD dogs of all stages while the total iron binding capacity (TIBC) was lower in only CKD stage 3 and 4 compared with dogs in CONT group. The PCV was related to both TIBC and albumin when considering among all dogs or only in CKD dogs. The hepcidin concentration in CKD dogs with anemia was lower than those without anemia (P<0.05). In experiment II before darbepoetin alfa treatment, RP subgroup had significantly higher iron and TIBC compared with NRP subgroup (P<0.05), the iron concentration was decreased only in RP subgroup after darbepoetin alfa treatment (P<0.05). The percent increase in PCV was correlated with initial TIBC (P<0.01). Plasma hepcidin concentration was not different between CONT and CKD groups and between RP and NRP subgroups both before and after darbepoetin alfa treatment. It is concluded that TIBC and plasma iron concentration play role on anemia and erythropoietic response to darbepoetin alfa treatment in CKD dogs.