Chronic kidney disease is one of the leading causes of morbidity and mortality in geriatric cats, affecting conservatively 30% of the population of older cats. Despite the common nature of the disease, its etiology is yet unknown. In cats, this condition is characterized by histologic features of tubulointerstitial inflammation, tubular atrophy and fibrosis, with secondary glomerulosclerosis, and is commonly described as the final common pathway after any one of multiple possible renal insults. Regardless of the initial insult, once a threshold of renal damage has been reached, progression is irreversible and appears consistent in character. Various etiologies have been proposed for feline CKD including age, viral infections (FIV, feline morbillivirus), extrarenal disease (hyperthyroidism, dental disease, hypertension, heart disease), environmental factors (stress, vaccines), ischemia, hypoxia and other renal insults.¹ However the majority of cats lack evidence of a definitive cause and likely disease results from a combination of factors that may vary between individuals.¹

Impairment of renal function is correlated with the degree of tubulointerstitial injury, including inflammation, tubular atrophy, and tubulointerstitial fibrosis.^2,3 In a recent retrospective study that assessed the correlation between CKD and histopathology in cats, fibrosis was found to be significantly correlated with the stage of CKD. Hyperfiltration, proteinuria, tubulointerstitial inflammation, oxidative damage, hypoxia and induction of the renin- angiotensin-aldosterone system (RAAS) are major factors that are thought to contribute to the process of tubulointerstitial injury.^4-6

Loss of functional nephrons results in hyperfiltration due to an increase in remaining single nephron GFR. Combined with a loss of the ability to autoregulate blood flow to the kidney, hyperfiltration results in intraglomerular hypertension, which can be further exacerbated by systemic hypertension.⁵

Mechanical and sheer stress on the glomerular apparatus causes damage resulting in stretching of the membrane and leakage of proteins into the interstitium. Although the kidney filters a large amount of protein on a daily basis, urinary protein levels probably underestimate the filtered protein load due to the enormous capacity of the proximal tubule for protein reabsorption. However, proximal tubule cells are therefore prone to damage as a result. Proteins are reabsorbed through megalin/cubulin-mediated endocytosis and then processed lysosomally.⁵ Protein excess results in overload of the lysosomal system and resultant rupture is damaging to tubular cells and instigates recruitment of inflammatory cells to the area. In addition, substances carried by the proteins, such as LPS, FFA, PG, heavy metals, and hormones, result in oxidative stress as well as direct damage to the cells.⁵

Tubulointerstitial inflammation is characterized by an inflammatory infiltrate in the interstitium that usually consists of mononuclear leucocytes including nephritogenic T-cells, monocytes and macrophages. These cells are thought to play a pivotal role in progression and fibrosis.⁷ In cats, tubulointerstitial inflammation is more strongly correlated with decreasing renal function than glomerular damage is, even though most renal diseases in humans and dogs are glomerular in origin. The presence of interstitial inflammation affects the ability of the kidney to autoregulate by directly affecting the afferent arteriole's ability to respond to contractile stimuli.⁸ Impaired autoregulation exacerbates the already present hyperfiltration and intraglomerular hypertension leading to additional damage. Nephritogenic T-cells are thought to exacerbate the conditions present in the kidney through direct cytotoxic effects as well as non-cytotoxic mechanisms such as cytokine release, altered tubular function and proliferation of interstitial fibroblasts and fibrosis.⁵ Once fibrosis occurs, conditions become increasingly suboptimal as loss of peritubular capillaries and increased interstitial volume create resistance to oxygen diffusion and resultant hypoxia, which in turn stimulates more fibrosis. Loss of peritubular capillaries, increased interstitial volume and fibrosis are also strongly correlated with decreasing renal function as well as worse prognosis.⁷

The RAAS system is also a critical component in the pathophysiology of renal progression.⁶ Although normally protective in emergency situations such as shock or hypotension, the RAAS system becomes maladaptive in CKD. Combined with a loss of autoregulation in the diseased state, angiotensin II plays a major role in this pathologic process as it vasoconstricts the efferent arteriole to maintain GFR. Although GFR is maintained, the downsides of this mechanism are hypoperfusion of post-glomerular capillaries, including the interstitium, and glomerular capillary hypertension. Angiotensin II also has detrimental non-vascular effects including activating tubular cells, oxidative stress, stimulation of inflammatory cell accumulation and promotion of fibrosis. The importance of the RAAS system is further supported by clinical evidence in humans demonstrating a distinct clinical benefit from RAAS blockade.⁶

Oxidative damage to tubular cells is also an important factor in cell attrition and occurs from several sources. As previously discussed, it can occur as a result of direct harm from reabsorbed substances, some of which are attached to reabsorbed proteins. However, increased filtration of substances, such as glucose or protein, also greatly increases the metabolism of tubular cells and this leads to increased production of free radicals. It has been shown that antioxidant defense systems are decreased in CKD, and thus the kidney is little prepared to address this increase and oxidative stress results.⁹ In addition, increased metabolic demand of the remaining tubular epithelial cells results in relative hypoxia as cells receive the same amount of blood flow, but have a higher demand. The environment is further exacerbated if anemia is present. Hypoxia results from decreased oxygen presentation to the tissues and oxidative stress is increased as erythrocytes have a major antioxidant role.⁴

One prevalent theme in the previous discussion that should be reiterated is the importance of hypoxia in the progression of CKD.⁴ In summary, tubulointerstitial inflammation leads to loss of peritubular capillaries which decreases blood flow to the tubules and creates a hypoxic environment. VEGF is integral to vascular health, and it appears that late-stage renal patients have compromised VEGF levels.¹⁰ Distortion and destruction of peritubular capillary blood supply by inflammatory infiltrate, extracellular matrix and fibrosis is a characteristic histologic feature of CKD in all species; this expansion of the interstitial area further impairs oxygen diffusion. Glomerular damage and vasoconstriction of afferent arterioles decrease postglomerular peritubular capillary blood flow.⁴ Angiotensin II also directly constricts efferent arterioles, as well as induces oxidative stress, which hampered efficient utilization of oxygen by tubular cells. Relative hypoxia occurs as a result of increased metabolic demand of tubular cells and anemia further exacerbates all by hindering oxygen delivery.⁴ Unfortunately, hypoxia is a strong stimulus for further formation of fibrosis, which sets in motion a vicious cycle of fibrosis and further hypoxia. Hypoxia also leads to apoptosis or epithelial-mesenchymal transdifferentiation of tubular cells into myofibroblasts. As a result of the multitude of factors involving hypoxia, researchers have recently argued that it is a critical component of CKD progression in other species and therefore a key therapeutic target.⁴ A better understanding of the pathogenesis of feline CKD will provide additional opportunities for therapeutic intervention.

References

4.  Brown CA, Elliott J, Schmiedt CW, et al. Chronic kidney disease in aged cats: clinical features, morphology, and proposed pathogeneses. Vet Pathol. 2016;53:309–326.

5.  Chakrabarti S, Syme HM, Brown CA, et al. Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction. Vet Pathol. 2013;50:147–155.

6.  McLeland SM, Cianciolo RE, Duncan CG, et al. A comparison of biochemical and histopathologic staging in cats with chronic kidney disease. Vet Pathol. 2015;52:524–534.

7.  Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17:17–25.

8.  Harris RC, Neilson EG. Toward a unified theory of renal progression. Annu Rev Med. 2006;57:365–380.

9.  Siragy HM, Carey RM. Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease. Am J Nephrol. 2010;31:541–550.

10. Rodriguez-Iturbe B, Garcia Garcia G. The role of tubulointerstitial inflammation in the progression of chronic renal failure. Nephron Clin Pract. 2010;116:c81–88.

11. Sanchez-Lozada LG, Tapia E, Johnson RJ, et al. Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation. Kidney Int Suppl. 2003;86:S9–14.

12. Keegan RF, Webb CB. Oxidative stress and neutrophil function in cats with chronic renal failure. J Vet Intern Med. 2010;24:514–519.

13. Mayer G. Capillary rarefaction, hypoxia, VEGF and angiogenesis in chronic renal disease. Nephrol Dial Transplant. 2011;26:1132–1137.