Patients with chronic kidney disease (CKD) have stable or slowly progressing azotemia as increasing numbers of nephrons become non-functional. Causes of progression of CKD may be due to the continuation of the initial cause. However there appears to be a point in the development of renal disease when the process becomes self-perpetuating. This appears to occur when serum creatinine is in the 2-4 mg/dl range.

Chronic kidney disease can be congenital, familial or acquired (Table 1). A high incidence of CKD has been observed in litters and lines of many breeds of dogs and cats and the list of breeds involved continues to get longer. This suggests that various forms of familial CKD may be possible in almost any breed given the right circumstances even though the series of events necessary to produce most forms of congenital and familial CKD is not understood at this time.

Table 1. Etiology of chronic renal failure

 Irreversible acute renal failure

 Congenital renal dysplasia and aplasia

 IgA nephropathy (dogs)

 Fanconi Syndrome

 Polycystic kidney disease

 Glomerular disease

 Glomerulonephropathy

 Amyloidosis

 Tubulo-interstitial disease

 Pyelonephritis

 Idiopathic

 Chronic outflow obstruction

 Trigonal tumor with ureteral obstruction

 Renoliths (particularly if infected)

 Neoplasia

 Lymphosarcoma

 Feline infectious peritonitis

 Hypercalcemia

 Borreliosis

Many animals develop CKD after incomplete recovery from an episode of acute renal failure where the cause of the initial insult is known. In addition, there are several well defined primary initiating causes of CKD (Table 1). However, in most patients that are recognized to have the syndrome of CKD, owners have no knowledge of a primary insult.

Several factors make identification of the primary initiating insult difficult. Current hypotheses propose that an initiating insult begins the process of CKD and nephron dropout continues long after the initial insult has gone. Because patients do not show clinical signs associated with CKD until GFR is reduced to 25-30% of normal, the syndrome becomes apparent only after a prolonged period and after continued loss of a vast amount of functional tissue. Histologic features that may elucidate the nature of the primary insult are overwhelmed by non-specific tissue changes associated with chronic progression.

During the early clinically silent phase of CKD leading up to the point where GFR is reduced to 25-30 % of normal, the kidneys undergo a series of functional and anatomical adaptations. The histologic appearance of renal tissue from patients with CKD sometimes indicates primarily glomerular, tubular, or interstitial changes but this usually does not allow identification of a primary cause. However, the histologic appearance of the kidneys from most patients with advanced CKD tends to be similar regardless of the primary initiating cause because the kidney can only respond to injury and reduced functional renal mass with stereotypical structural and functional changes,

Animals with early CKD may have a variable outcome. Some patients seem to stabilize for a long period with no further reduction in renal function, some are stable for a while but tend to suffer intermittent periods of sudden further loss of function, and others continue to progress unrelentingly.

Causes of Progression

Dietary phosphorus

Phosphate is cleared by renally by glomerular filtration followed by active reabsorption of a proportion of the filtered load in the proximal tubule. Early in the course of CKD, as GFR declines, the filtered load of phosphorus (GFR x serum phosphorus) tends to decrease. However, daily phosphorus excretion is maintained at the same level by reduced tubular reabsorption. Reabsorption of phosphorus is under the control of parathyroid hormone (PTH), which inhibits active phosphorus reabsorption in the proximal tubule. As GFR continues to decline the concentration of PTH necessary to maintain normal phosphorus excretion increases. This PTH mediated tubular adaptation allows plasma phosphorus level to remain normal until GFR is reduced to 20% of normal. At that point, further decreases in GFR will cause plasma phosphorus levels to rise.

Hyperphosphatemia induces metastatic calcification when the total serum calcium concentration multiplied by the serum phosphorus concentration exceeds 70 according to the formula: [serum calcium (mmol/L) /0.25] x [serum inorganic phosphate (mmol/L)/0.32]. Metastatic calcification is most prominent in the stomach and kidney where it can induce rapid deterioration in renal function. However, many other organs are also affected.

It has been well understood for many years that normal phosphorus diets fed to patients with CKD will cause progression of renal disease and dietary phosphorus restriction tends to slow the decline in GFR. Low phosphorus diets prevent soft-tissue mineralization including mineralization of the kidney. Parathyroidectomy in dogs failed to show a beneficial effect in dogs in induced CKD beyond that anticipated by the effects of dietary phosphorus restriction.

Glomerular damage

Studies in many species including dogs and cats indicate that patients with CKD tend to develop increased intraglomerular capillary pressure in the remnant nephrons and there is considerable evidence that this adaptive change may be detrimental. Increased intraglomerular capillary pressure may be induced by systemic hypertension or local glomerular hemodynamic events.

In dogs with induced CKD subdivided according to their systemic blood pressure, those with systemic hypertension had increased protein: creatinine ratio (UPC) and increased mesangial matrix, tubular damage and interstitial cellular infiltrate and fibrosis.

Intraglomerular hypertension has been observed in both dogs and cats in models of induced CKD. In a 6 month study of dogs with CKD, treatment with enalapril did not change GFR compared with untreated controls but did reduce systemic blood pressure and UPC. Although glomerular hypertrophy was unaffected, tubulo-interstitial lesions decreased.

In cats with induced CKD, the ACE inhibitor benazepril given for 6.5 months decreased both systemic arterial blood pressure and intraglomerular capillary pressure and simultaneously increased GFR. No histologic differences were observed between the two groups. In another study in cats with induced CKD, amlodipine given for 36 days reduced systemic blood pressure and albuminuria.

Dietary lipids can have detrimental and sparing effects on the glomerulus in CKD. In dogs with induced CKD, diets high in fish oil (n-3 polyunsaturated fatty acids) reduced GFR compared with dogs supplemented with safflower oil (n-6 PUFA) or beef tallow. However the fish oil supplementation protected against renal mesangial matrix expansion, glomerulosclerosis and interstitial fibrosis. The protective effect may be mediated by the effect of fish oil to decrease intraglomerular capillary pressure and to blunt mediators of inflammation in the mesangium.

Thus, there is evidence that reduced intraglomerular capillary pressure and reduced GFR may be protective.

Dietary protein is known to affect GFR in dogs and cats with CKD where high protein diets increase GFR and low protein diets reduce it. While numerous studies in dogs with mild to moderate CKD failed to demonstrate a protective effect of low protein diets on the progression of CKD, in a model of advanced CKD, histologic lesions were more severe in dogs fed a 42% protein diet compared to an 18% protein diet. A similar effect was noted in cats with induced CKD fed low and high protein diets.

The mechanism of glomerular injury associated with high protein diets may be mediated in part through increased intraglomerular hydrostatic pressure and subsequent increased filtration of plasma albumin. Increased albumin load on podocytes increased the presence of both mRNA and actual protein of transforming growth factor-beta1, a known inducer of sclerosis.

Tubulo-interstitial damage

This is mounting evidence that increased traffic of plasma proteins across the glomerular capillary wall does more than damage just the glomerulus and that tubular reabsorption of excessive filtered protein plays a major role in the progression of CKD.

In human patients with non-diabetic CKD, treatment with angiotensin converting enzyme inhibitors (ACEi) reduced proteinuria and the progression renal disease and in another study the protective effect of the ACEi was more marked in those patients that had heavier proteinuria. Further, in a Heymann nephritis model of CKD in rats, simultaneous treatment of ACEi, an angiotensin receptor antagonist and a statin drug that diminishes interstitial inflammation provided the best protection.

Current theories of the impact of filtered albumin and other proteins on the tubules in CKD focus on the observation that albumin upregulates tubular epithelial cell genes encoding for endothelin and a series of chemokines and cytokines that can lead to detrimental effects. Albumin is reabsorbed from the lumen of the proximal convoluted renal tubule into the apical membrane of epithelial cells by endocytosis into lysosomal vesicles. Central to subsequent processes is protein kinase C-dependent production of reactive oxygen species, nuclear factor-kappaB (NF-kappaB), and other protein kinases. NF-kappaB induces elaboration of fractalkine and other cytokines and chemokines that attract and increase adhesion for mononuclear cells, which play a role in inflammation and disease progression.

No studies have been performed to confirm these mechanisms in dogs and cats but in a proteinuria model in rats, treatment with ACEi and an endothelin-A and-B receptor antagonists, proteinuria, renal lesions and NF-kappaB production was suppressed.

There is speculation that chronic tissue hypoxia may also play a role in progression of CKD due to cellular energy depletion, loss of peritubular capillaries and interstitial fibrosis.

Hypokalemia is observed in cats with CKD but not in dogs. Affected animals have whole body potassium depletion and the classical signs are weakness, a stiff gait and ventroflexion of the neck. Serum creatine phosphokinase levels are usually elevated. The precise cause of hypokalemia in cats in not clear. However, recent evidence points to activation of the rennin-angiotensin-aldosterone system due to low sodium diets with subsequent avid tubular reabsorption of sodium and concurrent obligatory secretion of potassium. There is evidence that hypokalemia may be a cause of progression in cats with CKD. Enhanced tubular production of ammonia in hypokalemia could lead to tubular damage.