An older study from 2007 investigated factors that may predict reduced survival in CKD cats. The study involved a total of 190 cats with chronic kidney disease (= CKD) and was able to identify several prognostic factors. Although there are now other prognostic factors such as the blood concentration of Indoxyl sulfate or FGF-23, some of the prognostic factors from 2007 are still important in the diagnosis and staging= Classification of the cat into a stage of chronic kidney disease according to IRIS... of CKD by the IRIS (International Renal Interest Society). These are presented below.
Unfavourable prognosis
In addition to the age of the cat, an elevated creatinineCreatinine is a breakdown product of muscle metabolism. Its blood level is dependent, among many factors, on age, weight, nutritional status and muscle mass. Hence, creatinine levels in the blood vary from individual to individual. Creatinine is continuously excreted in the urine. Increased blood creatinine... blood level and an elevated UPC (urine protein to creatinine ratio) play an important role as independent and adverse prognostic factors in CKD. Elevated blood phosphate is also associated with blood creatinine and is considered an adverse prognostic factor.
Creatinine
Creatinine is a substance produced by muscle metabolism. Depending on how muscular the cat is, creatinine is excreted in the urine at a constant rate by the healthy kidneys. This results in an individual high blood creatinine level, which is the result of the amount of creatinine produced by muscle metabolism and its excretion by the kidneys. The creatinine level in blood plasma is a measure of the kidney’s ability to excrete creatinine. It increases when creatinine excretion decreases. Creatinine excretion decreases as kidney function decreases. Blood creatinine concentration is therefore directly related to renal function (there are exceptions to this). Therefore, a high creatinine blood level is prognostically unfavourable, as it indicates low renal function (although there are exceptions). Therefore, the creatinine blood level is used by the IRIS for diagnosis and classification into different stages of CKD.
Protein loss via the kidneys
Protein loss is caused by the loss of protein selectivity in the glomerular filtration system. Protein loss in CKD is diagnosed using the UPC. This means that protein loss is detected by the UPC as increased protein excretion in the urine (= proteinuriaIncreased protein in urine, leading to loss of protein. Normally, only a very small amount of protein is excreted in the urine. In chronic kidney disease, the amount lost may increase. High blood pressure damages blood vessels in the nephrons making them more permeable and...). The UPC can therefore only be determined from a urine sample. The test measures the amount of protein and creatinine in the same urine sample and expresses the difference between the two in terms of ratios. For example, the protein-creatinine ratio in urine measures whether protein excretion is higher than expected compared to creatinine excretion. If this is the case, proteinuria is present.
When kidney function is reduced and the urine cannot be concentrated sufficiently and becomes dilute (= specific gravity decreases), traces of protein in the urine are sufficient to indicate chronic kidney disease.
CKD cats with a UPC > 0.4 have a 4 times higher risk of death than CKD cats with a UPC < 0.2.
The IRIS categorises the UPC values as follows:
Inflammation and bleeding lead to protein in the urine
Protein in the urine may have various causes, including bleeding and inflammation in the urinary system, which are often associated with conditions such as urinary tract infections, bladder stones or tumours. If a significant amount of protein is detected in the urine without any signs of inflammation or bleeding, it may indicate CKD. Therefore, additional blood tests, known as a kidney profile, are carried out to diagnose CKD.
Due to the reasons mentioned above, it is recommended that the protein-creatinine ratio is only measured from urine samples that are free from blood and inflammatory cells. To ensure the suitability of the sample for the protein-creatinine test, a complete urinalysis and sediment analysis is performed beforehand. The presence of blood and inflammatory cells can cause a falsely high urine protein to creatinine ratio, which may indicate kidney disease even if another cause is present.
Before diagnosing primary kidney disease, it is necessary to demonstrate persistent protein loss via the kidneys, in addition to assessing the kidney profile in the blood (concentration of creatinine, SDMASDMA = Symmetrical Dimethylarginine, which is a degradation product of the amino acid arginine and is excreted solely through the kidneys. SDMA is a highly specific biomarker for kidney function in cats. Read more: SDMA test (blood test)..., ureaUrea is the nitrogen-containing breakdown product of protein metabolism. The nitrogen from the proteins is converted to ammonia in the liver, which is combined with carbon dioxide to form urea. This is continuously excreted via the kidneys but also via sweat. Urea is one of..., phosphate and other electrolytesElectrolytes are substances that produce an electrically conducting solution when dissolved in water, releasing mineral ions such as sodium, potassium, chloride and calcium. These ions can either be the positively or negatively charged or, combined as a salt, neutral...., FGF-23, indoxyl sulfate). It is recommended to repeat the protein-creatinine ratio (with complete urinalysis) in several consecutive urine samples. The longer the protein loss persists, the greater the likelihood of serious kidney disease.
High blood pressure = filtration pressure
The filtration apparatus of the kidney is the glomerulus, which is a vascular tangle surrounded by sheaths such as Bowman’s capsule. Together, they form filter pores that act like a sieve, allowing waste products to pass through into the urine passively while retaining important proteins and blood cells. The glomerulus acts as a selective filter, forming a barrier for large and charged molecules, such as plasma proteins, to prevent their loss via the urine. Transport proteins, which are smaller protein molecules, can pass through the filter and end up in the urine. However, they are already recovered at the beginning of the tube system. Protein loss can occur if the recovery mechanisms or the proximal tubule (see glossary) are damaged.
In CKD, protein loss via the kidneys is usually directly related to high blood pressure (hypertensionHigh blood pressure.). This can be hypertension in the glomerulus only, systemic hypertension or both together. Most proteins cannot normally be filtered out due to their size and charge. However, if the blood pressure in the filter apparatus of the nephronsNephrone sind die Filtereinheiten der Nieren...., the glomerula, rises, proteins appear in the urine. The increased blood pressure causes the “filter pores” to widen and the charges to change so that larger molecules can pass through the filters. This is also the case if the “filter pores” or the filter as a whole are damaged, which occurs when there are changes in the filter apparatus (= glomerulopathies).
The blood contains smaller proteins (less than 65 kDa), such as the vitamin A transport protein. These low molecular weight proteins are freely filtered at the glomerulus but are reabsorbed by the proximal tubular cells of the nephron, preventing their loss. However, if increased amounts of low molecular weight proteins are present in the blood, the proximal tubular cells can become overloaded, which also leads to proteinuria.
Effects of proteinuria on the kidneys
Proteinuria can worsen CKD through various mechanisms. Increased protein exposure to proximal tubule cells can trigger the release of inflammatory and other mediators, leading to nephron self-destruction and eventual scarring. This process contributes to the progression of CKD.
Consequences of protein loss for the cat
Protein loss through urine typically involves the plasma proteins albumin and globulin, which maintain the oncotic pressure in the blood. This pressure is essential for retaining water in the blood and preventing it from passing into the tissues. Persistent loss of albumin and globulin can cause fluid to pass into the tissues, leading to oedemaExcess fluid collecting in the tissues of the body, which can cause them to become swollen.... and effusion. Additionally, fluid loss can contribute to high blood pressure. Furthermore, the loss of protein leads to muscle wasting and weight loss, resulting in emaciation of the cat with chronic kidney disease (CKD).
UPC as a marker for improved renal function
If proteinuria is reduced through treatment, the progression of CKD will slow down. In animals with CKD, the urinary protein to creatinine ratio can also be used to monitor kidney function, for example, to determine if kidney function improves in response to treatment. This has been achieved through the use of various antihypertensive drugs.
A recent study conducted at LMU Munich achieved a reduction in UPC by using Porus® One, a high-performance adsorber for the precursors of uraemic toxinsToxic, nitrogen-containing urinary substances responsible for uraemia and kidney damage.... in the intestine. This adsorber was able to reduce the blood level of Indoxyl sulfate, which is involved in many processes of kidney destruction that promote the progression of CKD disease and cause clinical symptoms. The authors suggest that the additional administration of Porus® One could improve the progression of CKD.
Bibliography:
- Abbate, M., Zoja, C., & Remuzzi, G. (2006). How Does Proteinuria Cause Progressive Renal Damage? Journal of the American Society of Nephrology, 17(11), 2974–2984. https://doi.org/10.1681/ASN.2006040377
- Elzenbeck, I., Teichmann-Knorrn, S., Hartmann, K., Zablotski, Y., Suchodolski, J., & Dorsch, R. (2024). Evaluierung des Effekts von Renaltec bei Katzen mit chronischer Nierenerkrankung im IRIS-Stage 2 und 3. [Poster Präsentation]. 31. Jahrestagung der DVG-Fachgruppe “Innere Medizin und klinische Labordiagnostik.”
- IRIS International Renal Interest Society. (2023). IRIS Staging of CKD (modified 2023). Iris-kidney.com. http://www.iris-kidney.com/education/pdf/2_IRIS_Staging_of_CKD_2023.pdf
- King, J. N., Tasker, S., Gunn-Moore, D. A., Strehlau, G., & BENRIC (benazepril in renal insufficiency in cats) Study Group. (2007). Prognostic Factors in Cats with Chronic Kidney Disease. Journal of Veterinary Internal Medicine, 21(5), 906–916. https://doi.org/10.1111/J.1939-1676.2007.TB03042.X
- Schmid, S. M. (2022). When Urine Trouble: A Clinical Approach to Proteinuria. Today’s Veterinary Practice, 12(1), Jan/Feb 2022, 47–57.
- Weir, M., Ruotsalo, K., & Tant, M. S. (o. J.). Urine protein:Creatinine ratios. VCA ANIMAL HOSPITALS. Abgerufen 6. März 2024, von https://vcahospitals.com/know-your-pet/urine-proteincreatinine-ratios
