Emerging Themes in Canine Kidney Disease Research

In addition to its education articles, the International Renal Interest Society (IRIS) commissions periodic articles and issues statements on topics under active discussion in veterinary nephrology, whose future significance is still being explored. This article summarizes several of those themes as they apply to dogs: active kidney injury biomarkers, FGF-23, SDMA, renal fibrosis, and stem cell therapy.

Active Kidney Injury Biomarkers in the Diagnosis of Kidney Diseases

In June 2023, the IRIS Board issued a statement on active kidney injury biomarkers and their use in diagnosing and monitoring kidney disease.

Early detection of kidney disease is crucial for timely intervention. However, it is challenging because traditional markers of kidney function have limited sensitivity. Commonly used markers such as serum creatinine, urea nitrogen, SDMA concentrations, and urine specific gravity indicate changes in kidney function, but they cannot detect active or ongoing subclinical injury or disease without concurrent changes in kidney function, regardless of its severity. Functional filtration markers are also poor predictors of early decline in kidney function because of their nonlinear relationship with the glomerular filtration rate. Consequently, the diagnosis of both acute kidney injury (AKI) and stable or progressive chronic kidney disease (CKD) may be delayed. The limitations of functional markers have increased interest in novel active kidney injury biomarkers, which could identify active and persistent damage to the kidney tissue, inflammation, oxidative stress, or fibrosis, and so allow earlier diagnosis and better characterization of kidney diseases.

Recent research has focused on active injury biomarkers that are released from stressed, damaged, or ruptured kidney cells and that can predict acute or sustained injury to renal tubular cells when present in urine. Epithelial damage has been observed in animals with AKI before any increase in functional markers, and also in animals with apparently stable CKD based on functional markers. The degree of epithelial damage is also linked to disease progression and survival. However, rigorous evaluation of these markers in longitudinal studies of clinical patients is needed to determine their true predictive value, and IRIS encourages further research published in peer-reviewed journals to establish the evidence for their clinical use.

IRIS anticipates that real-time biomarkers able to identify active or ongoing kidney injury will change how practitioners diagnose, monitor, and treat kidney disease. These novel biomarkers are not meant to replace traditional markers but to complement them, revealing hidden or subclinical kidney disease that is otherwise undetectable. For dogs, this could be particularly valuable in detecting kidney injury early during treatment with drugs that can damage the kidneys, and in hospitalized dogs at risk of AKI.

FGF-23: A New Player in the Regulation of Phosphate

Fibroblast growth factor 23 (FGF-23) is a 30 kD protein secreted by osteocytes and osteoblasts in bone. It was discovered in 2000 as a circulating factor found in excess in human patients with low blood phosphate caused by tumor-induced osteomalacia.

FGF-23 acts on the kidney, together with its co-receptor Klotho, to increase urinary phosphate excretion and to reduce the production of calcitriol, the active form of vitamin D. In dogs with CKD, blood FGF-23 concentrations increase as the disease advances, and they can be raised before blood phosphate becomes abnormal. Like parathyroid hormone, FGF-23 is part of the chronic kidney disease–mineral and bone disorder, and it is being studied as an early marker of disordered phosphate balance that could help guide when to start dietary phosphate restriction.

Read more in our article reviewing the role of FGF-23.

SDMA: A New Biomarker of Kidney Function

Filtration, particularly the glomerular filtration rate (GFR), is the primary indicator of how well the kidneys are working. The severity of most kidney diseases, including AKI and CKD, is judged by their effect on GFR. Although direct measurement of GFR is widely regarded as the gold standard for assessing kidney function, clinicians usually rely on surrogate markers such as blood urea nitrogen or blood creatinine concentration to estimate it. However, these common tests are poor at detecting mild to moderate decreases in GFR. Repeated creatinine measurements in the same animal improve sensitivity, but a baseline value from when the animal was healthy is often not available.

Symmetric dimethylarginine (SDMA) is released into the blood during normal protein breakdown and is removed from the body mainly by glomerular filtration. Unlike creatinine, it is little affected by muscle mass, which matters in dogs because creatinine varies with breed and body size. Very muscular breeds such as greyhounds can have creatinine values above standard reference ranges while their kidneys are healthy.

IRIS now uses SDMA alongside creatinine to stage CKD. In dogs, a persistently increased SDMA above 14 µg/dL suggests reduced kidney function and may be used to diagnose early CKD even when creatinine is below 1.4 mg/dL. Our article on creatinine, UPC and SDMA in the early diagnosis of CKD explains how these tests are used together.

Renal Fibrosis

Kidney disease in dogs often begins in the glomeruli, the kidney's filters. Glomerular disease, which typically causes proteinuria, is more common in dogs than in cats. Whatever the original injury, progressive CKD tends to end in the same place: interstitial fibrosis, interstitial inflammation, and loss of tubules, as working kidney tissue is replaced by scar tissue.

The extent of fibrosis is linked to the severity of kidney dysfunction and to its progression. Factors believed to drive fibrosis include proteinuria, chronic low oxygen levels in the kidney tissue, systemic hypertension, and high blood phosphate. No treatment currently reverses established fibrosis, so research is focused on slowing it. Management today aims to control the factors known to speed progression, especially proteinuria and high blood pressure, which is why IRIS recommends measuring both in every dog with kidney disease.

Stem Cell Therapy for CKD: What Do We Know? (2018)

Regenerative medicine is a pioneering field with promising clinical implications for many diseases in veterinary medicine. Stem cells have regenerative abilities and appear capable of modifying the environment in damaged and diseased tissues. Although this therapy shows potential for CKD, research into its use is still at an early stage, and further investigation is needed.

Published clinical experience with stem cell therapy in dogs with CKD is limited, and there is not yet evidence that it improves kidney function or survival. For now, stem cell therapy for canine CKD should be regarded as experimental and used only within well-designed clinical trials.

What This Means for Your Dog

Most of these advances are still being studied, but some are already part of everyday care. SDMA testing is widely available and can help find kidney disease earlier, especially when combined with creatinine, a urinalysis including the urine protein-to-creatinine ratio, and blood pressure measurement at regular wellness visits for older dogs. Ask your veterinarian how often your dog should be screened for kidney disease, and which tests are right for your dog.