Chronic kidney disease: The new paradigm of early diagnosis and evolving treatments
CHRONIC KIDNEY DISEASE: THE NEW PARADIGM OF EARLY DIAGNOSIS AND EVOLVING TREATMENTS
Serge Chalhoub DVM, DACVIM (SAIM); Soren Boysen DVM, DACVECC
Faculty of Veterinary Medicine, University of Calgary
Calgary, AB Canada
It is generally accepted that 30% of cats may develop chronic renal azotemia after 9 years of age. Above age 15, it is thought that over 50% of cats will have some form of CKD. In dogs, the prevalence of CKD is accepted to be less than 1% based on a recent U.K. study. Therefore, most of the discussion below will be based on cats and CKD. There are numerous possible causes of CKD in cats, but its exact pathophysiology has not yet been established. There is increasing suspicion that CKD evolves from possible multiple mini active kidney injuries secondary to ischemia or chronic inflammation (IRIS Napa meeting 2016). Unfortunately, as of now we do not have biomarkers sensitive enough to catch these mini-AKIs. However, this may change our future approach to chronic kidney disease in cats as it may highlight certain preventative stratgies.
Traditionally, the diagnosis of CKD has been based on the presence of renal azotemia and inappropriate USG for at least 3 months’ duration. However, this assumes that we have eliminated post renal causes of azotemia (such as ureteroliths) AND that the azotemia has been chronic. AIt takes a 75% decrease in nephron mass for azotemia to appear, which is defined as an increase in creatinine (MUCH more stable and predictable) and/or BUN (MUCH less reliable and variable) above established reference ranges. These references ranges can vary greatly from one reference laboratory to another. TThe development of isosthenuria is not much better in diagnosing CKD, as its appearance signifies a 68-70% decrease in renal function. Also, multiple conditions will affect USG (endocrine disease, afternoon urine sample, diet etc.).
Symmetric dimethylarginine (SDMA) is a molecule that has become quite important in the early diagnosis and also staging of CKD in cats and dogs. SDMA has no physiologic role in the body. Studies in veterinary medicine have shown that SDMA increases at roughly at 40% of renal dysfunction, and in some cases will detect a 25% in renal function. Using this biomarker will take some getting used to because we are so used to seeing a normal creatinine and USG and concluding there is no CKD! We are now able to diagnose CKD much earlier than before, and this will hopefully lead to new treatments. SDMA is more sensitive than creatinine at detecting CKD especially at earlier stages of CKD. It is a specific biomarker as well based on studies. In cats with CKD, SDMA shown to increase 17 months earlier; and in dogs an average of 9 months earlier (Hall et al, JVIM 2014). SDMA is not impacted by muscle mass, thereby much more accurate in low BCS geriatric animals. This is very important because most of our geriatric cats have decreased muscle mass. In addition, with CKD there is progressive muscle mass loss and therefore CKD stage may be understated because of the reliance on creatinine. SDMA is stable, and intraday and interday variability negligible. There is no impact from hemolysis, icterus, lipemia.
Once CKD has been diagnosed, it is important to then refer to staging principles. The IRIS staging guidelines have become a mainstay of staging cats and dogs with CKD. They have permitted us to create clear and objective guidelines on how to treat our patients based on creatinine (because it is more stable and predictable than BUN), proteinuria, and hypertension. The IRIS guidelines underline the importance of regular physical exam and lab work for our patients. For instance, proteinuria and hypertension are often silent. If left undiagnosed and untreated, not only will organ damage occur, but CKD also progresses much faster.
IRIS guidelines have been modified in 2015-2016 to reflect the addition of SDMA as both a diagnostic tool and also a staging tool. An SDMA that is persistently above 14ug/dl is consistent with CKD. This values reflects IRIS stage 1 and 2 patients if the SDMA is below 25ug/dl. These patients often have minimal to absent clinical signs. SDMA above 25ug/dl usually indicates IRIS stage 3, and this is important for cats and dogs with creatinine values in stage 2 but that have muscle mass loss. Therefore, these patients have an underestimated renal function and are likely in stage 3 with that SDMA level. This changes their prognosis and treatment recommendations. The same is true for a creatinine above 45ug/dl. If a cat or dog has a creatinine that puts them in IRIS stage 3 but an SDMA of 45ug/dl, this pet is actually in stage 4. The treatment recommendations and prognosis vary greatly between these 2 stages (prognosis 778 days for IRIS stage 3 vs. 30-60 days for IRIS stage 4).
Stage 1 has long been a mystery. It was almost impossible to diagnose as there are usually no clinical signs associated with this stage, and our diagnostics tests were not sensitive enough. However, now with SDMA we can diagnose cat in this stage. This has helped us learn a lot more about early stage CKD and discovered that in fact some cats do have symptoms such as mild weight loss. In addition, we are understanding that stage 1 is not a benign state as previously thought. Because of early diagnosis, this is allowing research to advance in early stage treatments (especially diets).
TREATMENT OF CKD
The treatment for CKD should be tailored to an individual patient’s needs. It is important to avoid standard “recipes” for every case. Not every cat or dog will need the same treatments. Treatments are not benign, can lead to a decrease in quality of life (anxiety, adverse reactions) and also decreased compliance by the owner (if there are many treatments to give or if they have to struggle with the cat to administer the treatments). As CKD progresses, especially to stage 4, quality of life is primordial.
Evidence-based medicine is often limited in veterinary medicine compared to human medicine, but studies do exist and their findings should be interpreted to guide our treatment choices as much as possible. Only diet as a treatment will be discussed below based on current new trends, but other therapies will be discussed in lecture.
The use of renal diets in cats and dogs is considered grade 1 evidence. It has been shown that cats fed a renal diet in upper-stage 2 or stage over 24 months had no uremic crisis compared to control cats eating a formulated “grocery store” diet (26% uremic crisis). Deaths from renal causes were 0% vs. 22% on the other diet. These diets generally contain reduced protein, phosphorous, sodium, and modified lipid and fatty acid content. They usually come in dry and wet food formula. Wet food diets have the advantage of bringing more water to a cat, thus limiting dehydration and pre-renal azotemia. Dogs have similar beneficial evidence. At least 3 separate studies show the benefits of a renal diet (Ross et al, Elliott et al 2000, Plantinga et 2005)
The IRIS recommendation is to feed these diets at IRIS upper Stage 2 and certainly stage 3 (dogs +/- stage 2-3). One common complaint is that cats will not eat the new renal diet. It is important to remember that cats with CKD are likely uremic at upper stage 2 and stage 3, and therefore have nausea. In addition, cats in general don’t like change. Therefore, it may be of some value to slowly introduce the new renal diet by mixing it with the cat’s old food over multiple weeks. In addition, it may be worthwhile working on nausea and appetite (mirtazapine, maropitant). There is recent debate on the use of renal diets and the fact that they may promote muscle loss in cats, which is detrimental to their survival. There are suggestions that cats with CKD should be fed higher protein diets but that phosphorus should be controlled. This is certainly an interesting debate on multiple fronts.
There is a new paradigm shift when it comes to renal diets.Current recommendation is to start renal diets once a cat or dog was in IRIS stage 2 CKD. However, now that we have the ability to diagnose CKD earlier than before, we can better diagnose stage 1 and early stage 2 cats and also recognize that they would benefit from early nutritional intervention. As such, cats in stage 1 may likely benefit from a geriatric-type diet or an early-stage kidney diet. A study by Hall et al demonstrated possible benefits of cats in stage 1 eating an early kidney disease diet, and a similar study done on dogs by the same author also showed a similar benefit. There are multiple reasons why these diets are likely beneficial including decreased phosphorus and increased omega-3 fatty acids.
Sparkes AH, Caney S, Chalhoub S et al. ISFM consensus guidelines on the diagnosis and management of feline chronic kidney disease. J Feline Med Surg. 2016;18(3):219-39.