Nature of progression – a unifying hypothesis
CRF is clinically characterized in dogs and cats by the development of variably progressive irreversible intrarenal lesions and loss of renal functions. Progressive loss of various renal functions seems inevitable in most patients with advanced stages of chronic renal disease. Progression will occur if the underlying renal insult cannot be treated (e.g. glomerulonephritis due to an unidentified antigen, amyloidosis) but can also progress at times when the cause of the initial injury has been removed. The "inexorable progression of chronic renal failure" only occurs however after substantial loss of renal mass has already occurred regardless of the original inciting injury. A variety of interventions (diet and drugs) can slow the progression of the renal disease, improve the quality of life for the patient, and/or extend the quantity of life.
"Super-nephrons" that result from hypertrophy of renal function and increased glomerular volume in remaining viable nephrons may result in their eventual demise. Hemodynamic adaptations in remnant nephrons cause increased single nephron GFR, glomerular plasma flow, and increased transglomerular capillary hydraulic pressure that are initially adaptive to maintain excretory function and total kidney GFR at higher levels that would be otherwise. Ongoing intraglomerular hypertension and increased glomerular volume eventually harm glomeruli. Tubular hypermetabolism, hyperammoniagenesis, renal mineralization, secondary hyperparathyroidism, systemic arterial hypertension, intrarenal coagulation, and immune mechanisms may also contribute to chronic progressive renal injury. It is not possible to predict the rate of this progression in experimental or clinical animals.
Compensatory increases (so called adaptations) in glomerular hemodynamics and glomerular volume may actually be maladaptive in some instances as shown in this figure.
Early diagnosis of progressive renal disease
BUN and serum creatinine concentrations are used as surrogates to estimate GFR but do not become increased until at least 75% of the nephron mass is non-functioning. Dogs and cats with advancing chronic renal disease often show no clinical signs until at least 50 to 67% of renal mass is lost with polyuria and polydipsia developing before the onset of azotemia. The ability to produce maximally concentrated urine is progressively lost as renal mass declines from 50 % until the region of isosthenuria (1.007-1.017 urinary specific gravity) is reached when 67% or more or renal mass has been lost. The development of clinical signs, sub-maximally concentrated urine, and azotemia occur following loss of substantial functional renal mass.
The range for normal serum creatinine concentrations is large for when groups of dogs or cats are considered but is much narrower for an individual animal. The International Renal Interest Society (IRIS) has recommended that the upper limit for normal serum creatinine in the dog to be less than 1.4 mg/dl and less than 1.6 mg/dl for cats. These upper limits are substantially less than those noted for most commercial laboratories. When these values are used, more animals with renal disease will be detected earlier but also some normal animals will be included in this group based on magnitude of serum creatinine alone. With the increasing attention to wellness and geriatric examinations that include laboratory testing, individual trends for change in serum creatinine can be detected IF the same laboratory is used that determines the creatinine measurement. Analysis of serum creatinine concentration by the same lab on the same sample is usually quite closely repeatable whereas there can be greater variance when samples are measured by different laboratories. Sequential increase in serum creatinine still within the normal range can suggest progressive loss of renal mass.
Table 1: Serum creatinine concentrations for assignment of IRIS stage of CKD in dogs and cats
Observations of changes in the degree of maximal urinary concentration can provide early clues that nephron mass is decreasing. First morning urine samples (before eating and drinking) usually have the highest urinary specific gravity (USG) in dogs, often with USG greater than 1.040. Substantial variation of the USG occurs in dogs throughout the day depending on timing following eating, drinking, and exercise. Less variability in USG occurs throughout the day in cats. Cats with normal kidneys that eat mostly dry food usually make urine with a USG of greater than 1.035. A USG cut-off of 1.040 is recommended as less-likely to have substantial renal disease in those with borderline azotemia; the cut-off in dogs is 1.030. Sequential UA that reveal decreasing USG provide concern that renal mass could be decreasing.
Proteinuria in the absence of an active urinary sediment is an early marker of many generalized progressive renal diseases. The development of renal proteinuria usually precedes the development of dilute urine and azotemia. Proteinuria detected by dipstrip measurement can be falsely positive due to effects in highly concentrated urine and can be falsely negative in those with dilute urine. Dipstrip methods measure mostly urinary albumin and become positive when there is more than 20 or 30 mg/dl present. A positive dipstrip reading for protein assumes more importance to indicate relevant proteinuria when the urine is less concentrated. Urine protein to creatinine ratio (UPC) measurement removes the confounding effect of urinary concentration or dilution on the concentration of measured protein since urinary creatinine serves as a maker to neutralize this ; this is a unitless measurement. Measured protein includes both albumin and globulins. Normal UPC is less than 0.4: this cut-off allows for early detection of renal proteinuria. UPC is useful to monitor therapy also. The magnitude of the urine protein/creatinine ratio is roughly correlated with type of glomerular disease present. Microalbuminuria (MA) uses dog and cat specific ELISA capture methods to measure urinary albumin. MA is designed to detect urinary albumin from 1-30 mg/dl; urine is diluted to a standardized 1.010 USG before measurement. MA in normal dogs and cats is less than 2 mg/dl and is reported as not detectable. MA can be run in-house and reported as negative or positive; mild, moderate, and high positive is further defined based on depth of color reaction. MA sent to referral labs can provide albumin in mg/dl that is more precise. In progressive generalized renal diseases, MA is the first marker of proteinuria to become positive followed by UPC and then dipstrip. MA is very sensitive in the detection of proteinuria at early stages of renal disease but its presence does not necessarily mean that the animal will have progressive renal injury and eventual development of renal failure.
Table 2: Proteinuria (assessed by urine protein/creatinine ratio) for assignment of IRIS sub-stage of CKD in dogs and cats