Biomarkers of renal failure in human and their application in veterinary medicine.

Abstract

Chronic kidney disease (CKD) is a common disease in domestic cats and dogs, with an overall prevalence of 1.6 to 20% and 0.5 to 7% in dogs respectively. This prevalence increases to over than 31% in cats above 15 years old and to 15% in dogs over 10 years of age. CKD prevalence appears to be increasing and is considered one of the most common causes of illness and death in geriatric cats and dogs. Indeed, together with degenerative joint disease and neoplasia, CKD is the most prevalent disease in elderly cats and dogs. The irreversible loss of kidney function in cats and dogs with CKD makes the disease a serious problem in small animal medicine, especially in geriatric cats. For that reason the identification of reliable biomarkers of early kidney injury, of progression is therefore an emergent area of clinical research. In humans, during the last few decades besides the increasing prevalence of CKD in patients with over 65 years old, there have been several advances in the management of CKD patients and in dialysis techniques, however the mortality continues unacceptably high in these patients increasing the need for biomarkers of early kidney injury, of progression of disease as well the identification of predictive biomarkers of morbidity and mortality. CKD is a progressive disease characterized by a severe reduction in glomerular filtration rate (GFR) through tubulointerstitial damage. The etiology of feline and canine CKD is heterogeneous and includes specific disease processes that initiate renal damage or dysfunction, such as polycystic kidney disease, renal amyloidosis, renal dysplasia and renal lymphoma. However, in the majority of the cases no specific cause was identified. Although it is often referred that kidneys are capable of adequate filtration until a certain threshold of loss (e.g., loss of 75-80 percent of renal nephrons), there is evidence that this cutoff may not be so sharply defined, as demonstrated in CKD cats induced through surgical reduction of renal mass. Notwithstanding, the clinical relevance of CKD, the early diagnosis can be challenging, in both human and veterinary medicine. Glomerular filtration rate (GFR) is considered the gold standard for assessing renal function. However, in veterinary medicine direct measurement of GFR is impractical in clinical setting. Moreover, the currently used biomarkers, serum levels of creatinine and urea, show a poor performance as surrogates of GFR and their rise above normal range are related with later stages of CKD (IRIS stages). Therefore, there is a need for better methods to diagnose and monitor patients with renal disease, including its early diagnosis. Novel serum and urine biomarkers are under evaluation in human and veterinary patients in an attempt to improve the ability to diagnose both acute and chronic kidney diseases, by allowing a more specific and sensitive diagnostic capability, and with potential for early disease detection. Furthermore, these biomarkers could help in the identification of the processes occurring during the development of the kidney disease, such as glomerular damage, decreased GFR, and tubular stress or dysfunction. The development and validation of new renal biomarkers is presently an active field of research. Indeed, many human studies have demonstrated that novel biomarkers are superior to the serum levels of urea and creatinine in the assessment of GFR, namely cystatin C. Moreover, several markers have been studied as markers of tubular dysfunction, namely kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, N-acetyl-β-O-glucosaminidase, γ-glutamyl-transpepsidase, retinol binding protein and interleukin-18. However, markers of renal tubular injury are not routinely used and little is known about their role in kidney diseases (acute or chronic) in cats and dogs. Moreover, higher levels of several biomarkers of systemic inflammation and profibrotic have been associated with low kidney function, namely, transforming growth factor beta, components of the renin–angiotensin–aldosterone system such as angiotensin II, endothelin-1, transglutaminase 2, alpha-1 acid glycoprotein, interleukin- 6, tumor necrosis factor-α and interleukin-18. Considering that, many of these new biomarkers have not yet been evaluated in cats and dogs, and those that have been already evaluated require a further evaluation in the context of large clinical trials before widespread clinical implementation, it is our believe that cat and dog forth coming studies should focus in the following aspects: 1)compare the performance of a large number of renal-associated biomarkers in the diagnosis, including the potential for early disease detection, and monitoring CKD patients; 2) find a panel of biomarkers with clinical utility for assessing CKD; and 3) evaluate the role of inflammation in the pathophysiology of CKD in cats and dogs.