Deejay is a ten-year old mastiff who spends most of his days racked out on the couch, watching the grass grow, and generally seems to feel good about that. He was brought to your clinic for his annual checkup; a routine urinalysis showed that his urine specific gravity was 1.008.
Something caused his SG to drop to this low level, and at his age you have to consider renal failure. A follow up serum chemistry reveals urea nitrogen and creatinine concentrations to be at the high limit of normal.
Deejay is getting up there in years and you are concerned about early renal disease. You have a talk with his owners about dietary changes and fluid therapy.
Deejay has developed renal insufficiency secondary to chronic interstitial nephritis (CIN). CIN is common in older dogs. It's one consequence of living a long time. In this disease the interstitium of the kidney parenchyma, particularly that of the cortex, becomes inflamed from chronic antigen stimulation. The interstitial spaces become fibrotic (even sclerotic), and eventually glomerular filtration is adversely affected.
Deejay has isosthenuria, a condition in which his kidneys can't make urine with a higher or lower specific gravity than protein-free plasma. Coupled with the absence of elevated urea nitrogen and creatinine, this indicates that his kidneys are about 67 percent damaged. Another way of putting this is to say that when two-thirds of the nephrons are no longer functional, the kidneys lose their ability to concentrate urine but they still will be capable of filtering out toxic waste products. If 75 percent of the nephrons were to become nonfuctional, the blood urea nitrogen and creatinine would rise, a condition called azotemia. If unchecked, azotemia will eventually cause uremia, the clinical signs associated with toxic levels of those waste products.
Deejay has renal insufficiency but is not yet in renal failure. Dietary management of proteins, sodium, and phosphorus plus fluid therapy will help, but not cure. Patients with chronic kidney disease like this can't be cured or have their conditions reversed, but their lives can be comfortably extended with thoughtful care.
Chronic interstitial nephritis is one example of chronic inflammation. There are of course many others. Remember that inflammation is a continuum. Acute inflammation progresses into chronic inflammation if the condition cannot readily be resolved. Chronic inflammation is simply the progression of an inflammatory response into an ongoing and long-term event.
Chronic inflammation differs from the acute form most notably in 1) the nature of the cell-types involved; 2) the length of time involved; and 3) evidence that healing has begun. Because it's an inflammatory response, the same hallmarks are present: heat, pain, swelling, redness, and loss of function. Chronic inflammation usually doesn't show these signs as strongly as acute inflammation.
Clinical pathology shows a change in leukocyte populations when acute inflammation becomes chronic. Rather than a severe leukocytosis consisting of a neutrophilia, a less pronounced leukocytosis may exist and neutrophil count is usually not outside the nomal reference value. This change can occur as little as 24 hours into an inflammatory event, but more often occurs over 5 days to one week's time.
The major leukocyte associated with acute inflammation is the neutrophil, but in chronic cases it's the mononuclear cells, particularly the macrophage. The neutrophil is capable of rapid deployment and one-shot phagocytosis: but macrophages have a much longer life span and engage in several phagocytic events.
Nevertheless, the two cell types work together. Macrophages arrive at the scene of inflammation because neutrophils summon them with cytokines gradients. Once activated by cytokines, macrophages elaborate their own cytokines to maintain their numbers and to summon yet more macrophages. At the same time, they begin to phagocytize whatever is causing the inflammatory stimulus and destroy it with a respiratory burst. If the macrophages can't engulf their targets, they form giant cells and try again.
At the same time that macrophages are active fibroblasts are called in to begin the process of repair by elaboration of connective tissue, or fibrosis. In regions of chronic inflammation, large numbers of fibroblasts will appear: they produce collagen and fibronectin, and their work is seen in the light microscope as an organized webbing of new connective tissue.
This very low magnification image (left) is a wedge of a kidney from a similar case. There is interstitial thickening within the renal cortex as well as foci of inflammatory cells, which aren't especially conspicuous at this magnification, but which are shown in more detail at medium magnification (right). Even at low magnification the cortex shows multifocal and coalescing regions of pale staining tissue: these coincide with the thickened regions, and they're suggestive of fibrous connective tissue deposited within the interstitium.
This closer view of the renal cortex shows some tubules and a glomerulus. The delicate architecture of the cortex has been severely disrupted by collagen from chronically stimulated fibrocytes. The inflammatory infiltrate in the middle of this field consists primarily of lymphocytes and macrophages.
Notice that the inflammation and fibrotic change is located not in the glomeruli or the tubules, but within the interstitium. Although the major focus of the inflammation is within the interstitium, the functional components of the kidney are also affected. The glomerulus has a poorly defined and somewhat reduced vascular bud; Bowman's capsule is noticeably thickened. Many of the tubular epithelial cells are vacuolated and appear damaged. The pink matrix within several tubules is likely a proteinaceous fluid suggestive of glomerular damage. The nephron in the left image is not fully functional: the one served by the renal corpuscle on the right isn't functional at all, its glomerulus having been completely obliterated and its capsule enormously thickened. Fibrosis (scarring) has occurred in the space around the corpuscle.
What's going to happen to this patient is that as he ages his kidneys will lose more and more nephrons to this ever-encroaching chronic inflammation/repair cycle; they will be replaced by scarring (a process already well begun). A healthy and fully-functional set of kidneys has a huge reserve capacity, but it isn't infinite. Given his advanced age and the certain loss of more and more concentration and detoxification capacity, in a year or two he'll experience end-stage renal failure that will kill him no matter what is done.
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