Proteinuria has been recognized as a prime factor determining the severity and type of chronic kidney disease (CKD). The degree of CKD has been classified by International Renal Interest Society (IRIS) group (modified 2013)1 as Stage 1 until 4 depending upon the levels of plasma creatinine concentrations in dogs (< 1.4, 1.4–2.0, 2.1–5.0 and > 5.0 mg/dl) and in cats (< 1.6, 1.6–2.8, 2.9–5.0 and > 5.0 mg/dl), respectively. However, substages have been classified base upon systemic blood pressure and proteinuria. Normal dogs and cats should have tiny loss of protein in the urine. Measurement of urinary protein in single urine sampling by divided by urinary creatinine known as urinary protein creatinine (UPC) ratio showed the value less than 0.2. However, if UPC ratio is higher than 0.5 in dogs and 0.4 in cats indicates the protein loss is significant.
How to Detect Proteinuria
1. Urine dipstick - The simple way is to perform urinalysis with dipstick along with urine-specific gravity. The detectable protein with low urine specific gravity (dilute urine) suggesting the severity of renal protein loss compared with high specific gravity. However, the procedure is for screening test.
2. Urinary protein creatinine ratio - The UPC ratio is a semiquantitative methods with easy detection and the number can be used to compare between animal or occasion. Many methodologies were developed to measured protein in the urine which can be detected using calorimetric or turbidity assays. The UPC ratio can be extrapolated using the known equations in order to quantify the 24-h protein loss in each patient using spot urine sample. However, the 24-h urine collection may be more superior and accurate for quantify the urinary protein loss per day.
3. Urinary protein electrophoresis - The technique is more complicated and time consuming. However, the protein loss can be identified as low, middle and high molecular weight which make the clinician yield more information on location of kidney damage.
4. Microalbuminuria - The urine albumin creatinine ration should be very low in normal subjected. It means that albumin may not be detected using the simple method to quantify protein. In early stage of renal disease involving the glomerular disease, the albumin can be loss in the urine when the azotemia has not yet been developed. Thus, the small amount of albumin that can be detected in the urine call "microalbumin" can be used as the early index for screening of kidney disease. Although the ELISA test for human microalbumin has been used in dogs and cats, the sensitivity is so low. The test kit used in animals should be specific for dogs and cats. Detection of microalbuminuria should be performed for screening in breeders or in animals with history of genetically related-renal disease.
Sources of Proteinuria
The proteinuria could be identified according to the sources of protein as follows.
Prerenal proteinuria - Abnormally high plasma protein concentration filters glomerular filtration membrane
Renal proteinuria
Glomerular proteinuria - The most frequently proteinuria found due to pathology of filtration barrier that allows the plasma protein from low to high molecular weight passing
Tubular proteinuria - Since the glomerular filtration barrier may be normal, high molecular weight protein cannot be detected. However, the small molecular weight proteins which normally filter into the ultrafiltrate is unable to reabsorb by renal tubular cell.
Postrenal proteinuria - Abnormal high plasma protein (middle to high molecular weight) leakage from vasculature into the lower urinary tract such as urinary bladder during infection or in case of urolithiasis
In Thailand, either dogs and cats with chronic kidney disease (CKD) or urinary tract infection (UTI) had higher UPC ratio.2 The proteinuria was not related to either blood pressure or plasma creatinine concentrations in CKD.3 It can be detected as early as in Stage I while the degree was increased dramatically and was not different between Stages II and IV. However, the higher the degree of UTI, the higher the protein found in the urine.2 Thus, determination of urine sediment in CKD case should be performed to rule out the white blood cell or inflammation before the urine was sent for determination of UPC ratio.
What Should We Be Aware of for Proteinuria?
The proteinuria should be confirmed as if the protein loss is persistent in each animal. Repeated measurements by different urine samples should be done before the results was verified. Moreover, the magnitude or degree of protein loss should be considerate. Hypoalbuminemia is concerned especially when the UPC ratio is higher than 10.0. Moreover, the complication regarding to low plasma oncotic pressure such as pulmonary edema will be found. Although the high UPC ratio may suggest the lesion is located at the glomerulus rather than the tubule, it may not absolutely be sure. Renal biopsy is the only procedure that can identify the type and location of kidney disease.
Intervention
Low level of protein loss may be monitored without treatment. Some animals may require specific and supportive therapy for treating kidney disease while healing process is awaited. Higher UPC ratio overtime needs to be investigated. However, if the protein loss is prominent, antiproteinuric drugs may be given.
Medications
Up until now, no specific antiproteinuric drugs have been fully verified in dogs and cats. The angiotensin converting enzyme (ACE) inhibitors such as, enalapril and benazepril have been used in human and animals with unpredictable results. If proteinuria cannot be cut off, the angiotensin II receptor blocker (ARB) is added. Losartan is commonly used in dog while telmisartan is used in cats. Giving ACE inhibitor for 2 weeks with additional ARB for another 2 weeks in dogs showed inconsistent results. The reduction was found for low molecular weight protein but not for middle molecular weight protein. The reduction in urinary protein loss was inconsistent to either the decline in degree of azotemia or systolic blood pressure. Plasma potassium seemed to be higher by using drug combination although the fractional excretion of potassium was preserved.
Other medication was also tested in animals with kidney disease. High dose of vitamin C (1 gm/kg) giving in rats receiving cisplatin could preserve glomerular filtration rate (GFR) and tubular excretions of electrolyte but could not alleviate the proteinuric effect caused by cisplatin. In rats, induced nephrotic syndrome induced by doxorubicin, carnitine could prevent the renal damage causing higher GFR and renal blood flow but the proteinuria was unchanged.4
Other medications have been suggested such as omega-3 fatty acid, antioxidant, prednisolone or cyclosporine. However, no such benefit was demonstrated in animals. It has been noted that plasma creatinine concentration and proteinuria were highly related to survival in cats with CKD.5
In conclusion, urinary protein loss in patient with kidney disease should be recognized by clinician immediately. The urine sediment has to be performed to rule out postrenal proteinuria. Blocking the renin angiotensin aldosterone system (RAAS) may be an option while the effectiveness could not be predicted after short time therapy. The lower the degree of proteinuria, the better outcome for long-term therapy.
References
1. International Renal Interest Society. IRIS staging of CKD (Modified in 2013). Available from: http://www.iris-kidney.com/_downloads/IRIS Website Staging of CKD pdf (VIN editor: link was not accessible as of 3/28/2016).
2. Jaturakan O, Vanishwatanaramlouk M, Kornkaew A, et al. SDS-PAGE electrophoresis for urinary protein analysis in dogs with chronic kidney disease and urinary tract infection. Thai J Vet Med. 2013;43(1):75–83.
3. Buranakarl C, Angkanaporn K, Thammacharoen S, et al. Relationships between degree of azotaemia and blood pressure, urinary protein : creatinine ratio and fractional excretion of electrolytes in dogs with renal azotaemia. Vet Res Commun. 2007;31:245–257.
4. Boonsanit D, Kanjanapanka S, Buranakarl C. L carnitine ameliorates doxorubicin-induced nephritic syndrome in rats. Nephrology. 2006;119(4):313–320.
5. Syme HM, Markwell PJ, Pfeiffer D, Elliott J. Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med. 2006 May–June;20(3):528–535.