Kidney Physiology

Kidney disease is extremely prevalent in the aging cat population and is one of the most common medical reasons older cats are seen in veterinary practice. Although good epidemiological data from Europe are lacking, data from the USA suggest that 1 in 3 cats over the age of 12 years have some form of renal insufficiency (Lulich et al., 1992). A study of apparently healthy and biochemically normal cats aged 9 years or older recruited prospectively from primary care practices in central London has demonstrated that, within 12 months, around 1 in 3 cats had biochemical evidence of azotemia (i.e plasma creatinine and/or urea concentrations above upper limits of the reference intervals) (Jepson et al., 2007).

Jonathan ELLIOTT
MA, Vet MB, PhD, Cert SAC, Dipl. ECVPT, MRCVS

Jonathan Elliott graduated from Cambridge University Veterinary School in 1985. After completing a year as an Intern in Small Animal Medicine and Surgery at the Veterinary Hospital, University of Pennsylvania, he returned to Cambridge to undertake his PhD studies in the Department of Pharmacology. He completed his PhD in vascular pharmacology in 1989. In 1990 he was appointed to a lectureship in Veterinary Pharmacology at the Royal Veterinary College in London where he is currently Professor of Veterinary Clinical Pharmacology and has developed research interests in feline chronic renal failure and hypertension and equine laminitis. He was appointed Vice Principal for Research in 2004. He is a Diplomate of the European College of Pharmacology and Toxicology and a member of the Veterinary Products Committee, which advises the UK Government on licensing veterinary medicines. Jonathan Elliott was awarded the Pfizer Academic Award in 1998, the BSAVA Amoroso Award in 2001 and the 2006 Pet Plan Scientific Award for his contributions to companion animal medicine, particularly in the areas of equine laminitis and feline chronic kidney disease.

Denise A. ELLIOTT
BVSc (Hons) PhD Dipl. ACVIM, Dipl. ACVN

Denise Elliott graduated from the University of Melbourne with a Bachelor in Veterinary Science with Honors in 1991. After completing an internship in Small Animal Medicine and Surgery at the University of Pennsylvania, Denise moved to the University of California-Davis where she completed a residency in Small Animal Internal Medicine, a fellowship in Renal Medicine and Hemodialysis, and a residency in Small Animal Clinical Nutrition. Denise received board certification with the American College of Veterinary Internal Medicine in 1996 and with the American College of Veterinary Nutrition in 2001. The University of California-Davis awarded a PhD in Nutrition in 2001 for her work on Multifrequency Bioelectrical Impedance Analysis in Healthy Cats and Dogs. Denise is currently the Director of Scientific Affairs for Royal Canin USA.

Introduction

There are a number of well recognized disease processes which damage the kidney in cats and lead to a well defined pathology. In the majority of cats, once the diagnosis of chronic kidney disease (CKD) is made through demonstration of azotemia in association with an inability to produce adequately concentrated urine (see section 2 for further discussion), the underlying disease is often not recognizable, even on renal biopsy. Quite clearly this disease syndrome is not a single entity and a more complete understanding of the pathological processes involved is needed if progress is to be made in the prevention of some forms of CKD in the cat.

Even when azotemia has been detected in cats with clinical evidence suggestive of CKD, progression to the stage where life is not compatible without renal replacement therapy (dialysis or transplantation) is not inevitable in all cases. Progression occurs at different rates in individual cats, emphasizing the heterogeneous nature of chronic kidney disease in the cat. Progress has been made recently on identifying risk factors for progression and evaluating treatments (including diets) in clinical patients against the gold standard of survival.

When CKD has been identified in an individual patient the diagnostic and therapeutic goals are:

1. Identify factors that are affecting the quality of life of the cat
2. Select treatments (pharmacologic or dietary) that should improve the quality of life of the cat
3. Identify factors that increase the risk of progressive renal injury in the individual cat
4. Select treatments (pharmacologic and/or dietary) that may reduce the risk of progressive renal injury
5. Monitor the response to these treatments and ensure that each treatment is tailored to the individual cat

It is helpful to categorize an individual cat as to the stage of its kidney disease since this will inform the clinician as to the most appropriate treatments and the most likely complications that arise associated with the CKD syndrome.

The aims of this chapter are to:

1. Outline the physiological roles of the kidney that are key to understanding what homeostatic mechanisms fail in CKD
2. Define a staging process for feline CKD
3. Define the management of CKD, making reference to the goals outlined above and to identify the stage at which specific problems will need to be addressed.

1. Kidney Physiology

The nephron (Figure 1) is the functional unit of the kidney. Each feline kidney has around 200,000 nephrons. The kidney has the following major roles:

• Excretion of water soluble waste products in urine
• Homeostasis of the volume and composition of body fluids
• Endocrine functions (production of erythropoietin, angiotensin II and calcitriol)

Figure 1. A schematic diagram of the nephron.

The kidney functions by non-specifically filtering the blood such that the water components of plasma appear in the filtrate at the same concentration they are found in plasma. Proteins are excluded from the filtrate progressively as their molecular weight (MW) get higher such that very little protein of MW above 70,000 gets across the normal filter. Approximately 20% of the renal plasma flowing through the kidney appears within the glomerular filtrate. The proximal convoluted tubule then functions to return about 65 to 70% of the filtered load to the blood stream. It ensures that substances the body requires (such as glucose and amino acids) are readily returned whereas water soluble waste products, which are of no use to the body, stay in the filtrate and are excreted in the urine.

The rate of excretion of many water soluble waste products from the body is dependent on the glomerular filtration rate (e.g., creatinine - a waste product of muscle metabolism). Some relatively low molecular weight substances are also actively transported from the plasma into the tubular fluid. Specific transporters are able to secrete organic acids or bases from the peritubular capillaries into the proximal convoluted tubular fluid. There are many examples of these transporters. One of the best known is able to secrete penicillins into the tubular fluid where, due to its high hydrophilicity this drug will stay in the filtrate as water is reabsorbed. Hence the urinary concentration of penicillin G following administration of standard doses rates to a cat can exceed the plasma concentration by more than 300 fold.

Whilst this early part of the nephron (proximal convoluted tubule) is responsible for the bulk return of filtered fluid and electrolytes to the plasma, the later parts are responsible for the fine control of urine composition. The loop of Henle is involved in generating a concentration gradient by trapping sodium chloride and urea in the interstitial area of the kidney. The so called "counter-current multiplier system" is responsible for this function. The descending limb of the loop of Henle is impermeable to sodium chloride but permeable to water whereas the ascending limb is impermeable to water and, the thick ascending limb actively transport sodium chloride into the medullary interstitium.

The cat is supremely adapted to produce concentrated urine having a relatively high proportion of nephrons with long loops of Henle. Cats can produce urine with a specific gravity of in excess of 1.080 and the maximal concentrating capacity of the cat kidney has not been assessed. This means that cats are able to exist with very small amounts of water to drink and, if fed a moist diet, often take in enough water with their food and so do not need to drink very much. The ability to produce concentrated urine and therefore conserve water is highly dependent on the number of functioning nephrons available to generate the gradient of sodium chloride in the medullary interstitium. Dietary sodium (or sodium chloride) and dietary moisture are highly effective in stimulating water consumption and diuresis in cats (Burger et al., 1980). Increased diuresis promotes urine dilution (Figure 2).

Figure 2. Influence of dietary sodium on urine volume in cats (Biourge et al., 2001).

The later parts of the nephron are responsible for the fine control of the urine composition. Primitive urine passing from the loop of Henle to the cortical collecting tubule should be hypotonic (relative to plasma) when entering the cortical collecting tubule. This is because sodium chloride has been removed from the filtrate in excess of water. The early part of the distal tubule continues this process where sodium reabsorption occurs without water (diluting segment). In the later parts of the distal tubule, sodium reabsorption occurs under the regulation of the sodium conserving hormone, aldosterone. Calcium, hydrogen and potassium ion composition of the tubular fluid are all regulated by the action of hormones (parathyroid hormone and aldosterone) in the distal tubule and cortical collecting tubule (also known as the late distal tubule). The later parts of the cortical collecting tubule and the collecting ducts respond to antidiuretic hormone (ADH) which regulates water and urea permeability. ADH secretion from the neurohypophysis is regulated by the osmolality of plasma and water conservation is ensured by the kidney minimizing water losses with the production of maximally concentrated urine when necessary.

An important concept to grasp when interpreting clinical laboratory data from cats is that urine composition is highly variable. Physiologically, the kidney is able to vary the composition of urine to ensure that homeostasis is achieved and the following equation balances: Intake of substance = Non-renal losses + Renal losses

In CKD, as kidney function deteriorates (fewer functioning nephrons present), the homeostatic mechanisms struggle to regulate fluid, electrolyte and mineral balances since either:

• Renal losses are limited by the reduced renal mass (limited excretion)
• Tubular flow rates increase in the remaining functioning nephrons so fine control of the composition of urine becomes more difficult as the later parts of the nephron are presented with fluid flowing too quickly (hyperfiltration)
• Compensatory mechanisms become counter-productive leading to a worsening of the electrolyte or mineral imbalance (Figure 3)

Figure 3. Relationship between renal injury, loss of nephrons, renal compensatory adaptations, and progression of renal failure.

Careful regulation of the composition of the diet can help cats with CKD maintain homeostasis, leading to improvements in their quality of life. Possibly, in some cases, it can slow down the progression of CKD to the stage where renal replacement therapy is necessary. The next section of this chapter deals with the staging of CKD and puts forward intrinsic and extrinsic factors that may influence progression of CKD. In subsequent sections manipulation of the different components of the diet for feline CKD patients will be discussed and the rationale for these dietary changes at each stage of CKD explained.