Progression of Chronic Renal Disease in the Dog (1)

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Review

J Vet Intern Med 1999;13:516–528

Progression of Chronic Renal Disease in the Dog

Delmar R. Finco, Scott A. Brown, Cathy A. Brown, Wayne A. Crowell, Tanya A. Cooper,

and Jeanne A. Barsanti

Progressive loss of nephron function may be caused by persistence of factors that initiated renal disease. However, newer studies

suggest that nephron damage is self-perpetuating once renal mass is reduced to some critical level. Original theories on mechanisms

of self-perpetuated nephron injury focused on intraglomerular hypertension and glomerular hypertrophy, but several other factors

have now been incriminated, including tubulointerstitial responses, proteinuria, and oxidative stress. Studies of dogs with surgically

reduced renal mass (remnant kidney model of chronic renal disease) have allowed investigation of the self-progression theory in

this species. Use of this model eliminates pre-existing renal disease as a confounding factor. Data from these studies indicate that

self-perpetuated renal injury is initiated when mild azotemia is induced (plasma creatinine concentration 2 to 4 mg/dL). Thus,

with naturally occurring renal disease(s), it is likely that self-perpetuated nephron damage is occurring before or at the time when

most cases of chronic renal disease are diagnosed. In dogs with remnant kidneys, loss of renal function often occurs at a linear

rate over time, but non-linear patterns are common as well. The reciprocal of plasma creatinine concentration, which has been

used to monitor rate of progression, is only a fair marker of renal function when compared to GFR. Thus, clinical results from

creatinine measurements on cases of naturally occurring disease should not be interpreted too stringently. In remnant kidney dogs,

the magnitude of proteinuria (UPC ratio) was not predictive of the rate in decline of GFR, casting doubt on importance of proteinuria

in causing progression of renal disease. However, progressive increases in UPC may be a marker of an accelerated rate of renal

injury. Self-perpetuation of renal injury in dogs could be the sole mechanism by which naturally occurring renal diseases progress.

When more information is available on the rate of progression of naturally occurring diseases, it may become apparent whether

factors initially inciting renal damage have an additive effect on rate of progression.

Key words: Dog; Remnant kidney; Self-perpetuation.

Clinical impression suggests that naturally occurring

chronic renal failure in the dog is a progressive mal-

ady, ending in uremia and death. This impression is so com-

monly accepted that documentation of this progression is

strikingly meager. We are aware of only a single report,

based on measurements of plasma creatinine concentration,

that addresses the rate of progression of chronic renal fail-

ure in dogs.1 Knowledge about the progression of renal fail-

1 Homer Smith, an eminent renal physiologist of the past, made the

following statements in his classic 1951 book 16: ‘‘This writer does not

have much more confidence in the white rat as an experimental animal

for comparison with man than he does in the rabbit. It should be noted

that the Wistar strain, for example, comes from the King A albino

strain established by Helen Dean King at the Wistar Institute in 1904,

and has been bred successively for 139 generations. Although in recent

years it has been crossbred rather than inbred, the net biologic effect

of selection within the strain for rapidity of maturation, size of litters,

docility, etc. has not been evaluated. Had a sibling pair of H. sapiens

or Canis familiaris been selected on a similar basis and inbred or

narrowly crossbred for 139 generations (at 25 years to a generation,

from 1525 BC) few students of physiology would expect them to react

to stresses in a manner comparable to H. sapiens or Canis familiaris,

both of which are generally represented in physiological investigations

by mongrel individuals.’’From the Department of Physiology and Pharmacology (Finco, S.A.

Brown, Cooper), Veterinary Pathology (C.A. Brown, Crowell), and

Small Animal Medicine and Surgery (Barsanti), College of Veterinary

Medicine, The University of Georgia, Athens, GA.

Address correspondence to: Dr. Delmar R. Finco, University of

Georgia–CVM, Department of Physiology and Pharmacology, Athens,

GA 30602-7389.

Submitted January 27, 1999; Revised June 18, 1999; Accepted July

23, 1999.

Copyright 1999 by the American College of Veterinary Internal

Medicine

0891-6640/99/1306-0002/$3.00/0

ure is valuable for both prognostic and therapeutic purpos-

es. Owners of dogs with chronic renal failure want infor-

mation on expected lifespan and therapeutic measures that

might increase lifespan while ensuring comfort for their pet.

Efforts to slow progression of renal failure are a significant

part of its management, in view of the limited therapeutic

options.

Traditionally, the progression of chronic renal disease has

been attributed to the persistence of the original cause or

causes of renal damage. In dogs and other species, the caus-es often escape detection. Whether the cause is known or

unknown, renal diseases often are categorized based on an-

atomic lesions to help us understand their pathogenesis.

Dogs with severe glomerular lesions (glomerulonephritis or

amyloidosis) usually have a marked proteinuria and some

of these cases have been attributed to immunologic mech-

anisms.2 However, the etiology is entirely speculative for

the more commonly encountered forms of chronic renal

disease in dogs, in which tubulointerstitial lesions predom-

inate and only mild to moderate proteinuria exists.3 Because

of our ignorance, we may be lumping many diseases with

different causes into one or a few categories, even though

the progressions may be different when the causes are dif-ferent. When the cause of disease is unknown and the dis-

ease is progressive, we might assume that the inciting factor

has persisted. However, the natural history of many diseases

includes periods of remission and exacerbation. These var-

iations could explain changes in the apparent rate of disease

progression, apart from the effects of any therapeutic or

management measures taken.

In the 1980s, a revolutionary theory was proposed that

has fundamentally changed our perception of the mecha-

nisms of renal disease progression. This theory postulated

that when renal mass is reduced to some critical value, sub-



517Progression of Chronic Renal Disease in the Dog

sequent damage is a self-perpetuating phenomenon that

continues even if the initiating cause(s) of renal dysfunction

are eliminated.4 Since its proposal, the self-perpetuation

theory has been examined exhaustively for its validity and

potential mechanisms and for associated therapies that

might modify the rate of disease progression. These ex-

aminations have been conducted primarily in certain strains

of highly inbred rats, with the hope or assumption that in-formation acquired from them applies to other species.1 Al-

though most available data are from rats, some studies also

have been performed in other species.

This article summarizes information about the progres-

sion of renal failure that has been collected from species

studied more extensively than the dog, then provides data

gathered specifically from dogs. We hope this information

will help veterinarians understand progressive renal failure

and improve the management of dogs afflicted with it.

Progression—Renal Disease versus RenalFailure

Progression of renal failure can be defined as the devel-

opment or exacerbation of clinical signs or as directional

changes in laboratory measurements consistent with a pro-

gressive loss of renal function. This broad definition is help-

ful for some aspects of clinical management but lacks the

specificity required for analytical clinical judgements or in-

vestigation. Renal functions may be influenced by extrare-

nal factors affecting renal hemodynamics or urinary out-

flow, such as dehydration, cardiac insufficiency, urinary

outflow obstruction, or adrenocortical insufficiency. There-

fore, changes in clinical signs and laboratory measures as-

sociated with declining renal function do not necessarily

mean that the kidney has deteriorated structurally or in

functional potential. A more restrictive evaluation separates

factors into ‘‘extrarenal’’ and ‘‘renal’’ so that each is con-sidered separately for diagnostic, therapeutic, and prognos-

tic purposes. This review emphasizes ‘‘renal’’ factors in-

volved in the progression of chronic renal failure, and that

category will be referred to as ‘‘progression of renal dis-

ease.’’ When renal factors cannot be separated from extra-

renal factors, the more general phrase ‘‘progression of renal

failure’’ will be used.

Documenting Progression of Renal Disease

Destruction of renal parenchyma is accompanied by loss

of function. Serial tests of renal function may be employed

for detecting progression. This approach is valid if reliable

tests are used and extrarenal factors are not contributing.

Morphologic examination of kidney tissue at timed inter-

vals is theoretically valid for monitoring progression but

certain limitations exist.

Renal Function Tests

No test of renal function can distinguish progression of

renal disease from progression of renal failure. Glomerular

filtration rate (GFR) is considered the single most useful

and most sensitive test of renal function overall; tests esti-

mating or measuring GFR have been used extensively for

monitoring. Measuring GFR by the urinary clearance of an

appropriate test substance is the gold standard for monitor-

ing progression of renal disease, but that method is too

cumbersome for clinical usage. Plasma clearance tech-

niques of measuring GFR have been used in clinical trials

in humans; their potential use in dogs is mentioned subse-

quently.

Among commonly used tests of renal function, blood

urea nitrogen is well known for fluctuating in response toextrarenal factors,5 so it should never be used for monitor-

ing progression of renal disease. Plasma creatinine concen-

tration, or its reciprocal, has been used extensively in stud-

ies of the progression of renal failure in humans. Although

used sometimes, plasma creatinine concentration is gener-

ally not considered adequate for discriminating judgements

for several reasons6: errors from tubular secretion of cre-

atinine by humans, influence of muscle mass on creatinine

generation, the possibility of increased enteric degradation

of creatinine as renal failure progresses, and the lack of

specificity of the assay for creatinine.

Microscopic Evaluation Of Renal Tissue

In animal models of renal disease, development of renal

lesions is a more sensitive indicator of renal disease than

GFR measurement. However, in clinical patients, morpho-

logic study is often not employed or is limited to a single

needle biopsy obtained for diagnosis. Even in research stud-

ies, serial biopsies are seldom used because heterogeneous

distribution of lesions makes it difficult to procure a rep-

resentative tissue sample. In addition, serial biopsies induce

parenchymal damage that may be difficult to differentiate

from disease progression.7

Incidental Observations

A major study on progression of renal disease in humans,

the Modification of Diet in Renal Diseases (MDRD) study,identified biologic events that were significantly correlated

with more rapid progression of renal disease in humans:

hypertension and proteinuria.8

Factors and Mechanisms Involved inProgression of Renal Disease—Other Species

Primary Disease

Even in humans, the species in which naturally occurring

renal disease has been most widely studied, its primary

cause often cannot be determined. However, a thorough an-

atomic characterization of renal disease exists in humans,

and some correlations have been made between the anatom-

ic classification of disease and the rate of its progression.

When diseases are examined by both cause and anatomic

classification, adult humans with diabetic nephropathy,

polycystic disease, and glomerulonephritis are reported to

have more rapid progression of renal disease than those

with interstitial nephritis or glomerulosclerosis.9

Self-Perpetuation

As previously indicated, this theory postulates progres-

sion of renal disease even when primary inciting disease is

no longer a factor. The theory is based on studies in labo-



518 Finco et al

ratory rats that underwent surgical reduction of renal mass,

leaving them with a ‘‘remnant kidney.’’ This model is ideal

for studying self-perpetuation, because preexisting renal

disease does not complicate the process of progression. In

addition, normal kidney tissue obtained during surgery is

available to compare to the remnant kidney at the end of

the study. The use of this model in rats has notably ad-

vanced our understanding of the progression of renal dis-ease.

The most important new recognition is that self-perpet-

uation of renal disease is a reality, at least in rats. In ad-

dition, several theories have been advanced and studied to

explain the basis of that self-perpetuation. These studies

have initiated a search for knowledge about the mechanisms

of self-perpetuation, with the ultimate aim of slowing or

eliminating injury by modifying the factors responsible.

Glomerular hypertension. The glomerular hypertension

theory of self-perpetuated renal damage attributes glomer-

ular injury to increased intraglomerular capillary pressure.

This theory has remained popular since its formulation in

the early 1980s, when micropuncture studies in rats with

reduced renal mass demonstrated increased glomerular cap-illary pressure associated with glomerular injury.10 In-

creased hydraulic pressure itself has been incriminated as

the instigator of such injury, but a variety of factors may

contribute to the overall process. Abnormalities in glomer-

ular endothelial, epithelial, and mesangial cell morphology

and function have been described. Mesangial matrix accu-

mulation also occurs.11–15

Glomerular hypertrophy. The capacity to generate new

nephrons is lost before or soon after birth, so the kidney

responds to injury and reduced function by hypertrophy and

hyperplasia of cellular elements of the remaining viable

nephrons. Hypertrophy is the predominant response, though

hyperplasia also occurs in immature rats. Cells of all por-

tions of the nephron undergo hypertrophy, resulting in in-creased glomerular volume, tubular diameter, and tubular

length. These changes have been documented in a wide

variety of species.16 Increase in functions of all segments

of the nephron occur after hypertrophy; GFR is most fre-

quently used to measure those functional consequences.

The hypertrophy and accompanying increase in GFR that

occur after renal mass reduction have traditionally been

considered advantageous to the animal, but more recent ev-

idence suggests that they may be harmful. A retrospective

study of children with minimal-change nephrotic syn-

drome17 indicates that progression was associated with glo-

merular enlargement. In adult humans with focal glomer-

ulosclerosis, glomerular hypertrophy was associated with

mesangial expansion, interstitital fibrosis, and prevalence of glomerulosclerosis.18 In rat models as well, hypertrophy

seems related to renal injury.19,20 However, some of these

studies did not clearly establish that hypertrophy was re-

sponsible for the associated renal damage. Other studies did

not demonstrate an adverse effect of hypertrophy when glo-

merular hypertension was prevented; in one study, hyper-

trophy actually prevented or ameliorated the early stages of

glomerular injury.21 One school of thought is that glomer-

ular hypertrophy accelerates injury from glomerular hyper-

tension but is not injurious in the absence of glomerular

hypertension.22

Tubulointerstitial injury. A growing body of evidence

suggests a significant role of the interstitium in the pro-

gression of renal disease. Tubulointerstitial changes may be

the major determinant of progression of renal damage.23–30

In humans with glomerulonephritis and other nephropa-

thies, the severity of tubulointerstitial lesions is better cor-

related with decline in GFR and rate of renal disease pro-

gression than severity of glomerular lesions is. Previousthinking has emphasized the primary role of glomerular

lesions in the progression of renal disease. However, more

recent observations suggest not only that tubulointerstitial

changes are a better predictor of progression but also that

tubulointerstitial injury may be a primary factor in the

events leading to progression.

Proteinuria. Magnitude of proteinuria has been associ-

ated with rate of progression of renal disease in both hu-

mans and rats. In humans with nephrotic syndrome due to

various glomerular lesions, progression of renal disease is

more rapid than in patients without the nephrotic syn-

drome.31 The MDRD study of humans also found a positive

relationship between severity of proteinuria and rate of loss

of renal function in patients without nephrotic syndrome.8

In rats with remnant kidneys, measures that decrease pro-

teinuria (low protein diets32 and administration of angioten-

sin-converting enzyme (ACE) inhibitors33) are associated

with slower progression of renal disease.

As with hypertrophy, proteinuria’s association with the

progression of renal disease does not prove it is the cause

rather than the effect. To determine whether proteinuria

causes renal damage, several researchers have performed

primary studies, which have also prompted review arti-

cles.34–39 Examination of the evidence indicates that proteins

may cause injury to both glomerular mesangial cells and

proximal tubule cells. Mesangial cell injury has been attrib-

uted to components of LDL lipoproteins or their oxidation

products, which may cause increased matrix production, actas chemoattractants for monocytes, and increase generation

of growth factors that stimulate sclerosis. Several possibil-

ities have been proposed for tubular injury. One theory is

that tubular reabsorption of massive quantities of any type

of protein passing the glomerular filtration barrier causes

tubule cell damage by overload, swelling and rupturing the

lysosomes. This damage mechanism may apply particularly

to nephrotic syndrome, but it may not apply to diseases

with only moderate proteinuria. Other theories attribute tu-

bule cell injury and interstitial fibrosis to toxic effects of

transferrin or iron, to lipoproteins, to fatty acids attached to

albumin, and to cytokines and chemoattractants that accu-

mulate in the area. Protein-loading studies have often used

proteins foreign to the species injected, which may detractfrom applying these findings to naturally occurring cases.

Oxidative stress and ‘‘hypermetabolism.’’ Evidence has

accumulated that reactive oxygen metabolites (ie, hydrogen

peroxide, superoxide radicals, and hydroxyl radicals) me-

diate injury to several tissues, including the kidneys. Both

glomerular and tubulointerstitial injury have been reported,

and several mechanisms of injury have been postulated.

Oxygen consumption per nephron is increased in rats with

remnant kidneys, suggesting the potential for generating re-

active metabolites. In addition, tissues from remnant kidney

rats have increased lipid peroxidation and alterations in glu-




Fig 1. The relationship between GFR and 1/creatinine in 129 dogs

with reduced renal mass. Although a linear relationship exists ( R2

.84), 95% confidence intervals predict considerable variation in GFR

for any value of plasma creatinine concentration. Adapted from ref-

erence 64.

tathione redox ratios. The findings that supplementation

with free-radical scavengers protects tissue from injury and

that depleting antioxidants induces injury have both been

considered supportive of the oxidative-stress theory.40–43 Di-

ets deficient in antioxidants may have adverse renal effects

(proteinuria, mild tubulointerstitial disease, and decreased

GFR) by upregulating genes in cells of distal renal tubular

epithelium that direct collagen synthesis and transforminggrowth factor–1 production. Deficient diets also cause in-

creased renal mitochondrial production of hydrogen per-

oxide.41 In addition, reactive oxygen species may increase

glomerular basement membranes’ susceptibility to proteo-

lytic damage by inactivating proteinase inhibitors that nor-

mally prevent degradation of the glomerular basement

membrane.44

Acidosis. Both extrarenal and renal effects have been

attributed to metabolic acidosis that may accompany chron-

ic renal failure. Acidosis was reported to accentuate pro-

gression of renal injury in remnant kidney rats by immu-

nologic mechanisms via ammonium activation of the alter-

native complement pathway.45 However, another study did

not confirm progressive renal injury due to metabolic aci-dosis in rats.46 Chronic mild acidosis in cats with remnant

kidneys did not accelerate the progression of renal disease

(Polzin D. Purina Nutrition Symposium, St Louis, MO,

June 1998).

The role of acidosis in causing kidney damage must be

distinguished from its extrarenal effects. Substantial data

from both humans and rats indicate that acidosis occurring

during chronic renal failure is associated with biochemical

events that result in tissue catabolism.47–49 Progression of

renal failure may occur by such extrarenal mechanisms.

Other factors. Many other factors have been proposed

to explain the self-perpetuation of renal damage. One hy-

pothesis is that ‘‘toxins of uremia’’ result in renal damage

in addition to adverse effects on many other organs.50 The

list of factors considered to be uremic toxins is impres-

sive,51–53 but evidence of specific renal toxicity for most of

these materials is sparse. Most evidence suggests that ure-

mic toxins affect extrarenal tissues rather than causing renal

injury.

Several hormonal, paracrine, and autocrine factors have

been identified that may help perpetuate renal injury once

damage has been imposed. Endothelin, a potent vasoactive

peptide, has been incriminated in rats because administra-

tion of an endothelin-receptor antagonist reportedly amelio-

rates disease progression in the remnant kidney.54 Andro-

gens have been suggested as another factor, because males

(both humans and some strains of rats) have a more rapidprogression of renal disease.55 Castration of unilaterally ne-

phrectomized male rats inhibits glomerular hypertrophy and

proteinuria, lending support to this hypothesis.56 A role for

angiotensin II and transforming growth factor– in the pro-

gression of renal disease has been explored extensively. 57–61

Other cytokines have also been associated with renal injury

at both glomerular and tubulointerstitial sites. However, it

is not clear whether some of these factors are significant in

sustaining the injury, are merely observers, or actually help

to resolve the injury. Other factors have been shown to

influence the progression of renal disease, including dietary

factors (eg, caloric intake, protein intake, and lipid intake),

but considerable interspecies variability seems to occur.

Progression of Chronic Renal Disease in Dogs

Reliability of Methods Used to Monitor Rate of Progression

In research, urinary clearance of inulin is the gold stan-

dard for monitoring changes in GFR. We have compared

simultaneous urinary clearance of inulin with exogenous

creatinine clearance and found the latter to be a valid mea-

sure of GFR in dogs with reduced renal functions.62

En-dogenous creatinine clearance also can be an accurate tech-

nique for measuring GFR in dogs if a creatinine-specific

assay is employed.63 Unfortunately, the commonly used

method of creatinine assay (kinetic Jaffe method) under-

estimates GFR by variable degrees due to variable propor-

tions of creatinine to noncreatinine reactants in plasma (but

not in urine).5

Clinically, plasma creatinine concentration is commonly

measured to assess renal function as a crude estimate of

GFR. We reported a comparison of GFR values (by exog-

enous creatinine clearance) with plasma creatinine concen-

tration when both tests were conducted simultaneously on

129 dogs with reduced renal mass (Fig 1).64 Confidence

intervals derived from these data indicate that, in a popu-lation of dogs with reduced renal function, plasma creati-

nine concentration was a mediocre predictor of GFR. For

example, a dog with a plasma creatinine concentration of

2.5 mg/dL could have a GFR between 0.64 and 1.44 mL/

kg per minute. Conversely, a dog with a GFR of 1.0 mL/

kg per minute could have a plasma creatinine value be-

tween 1.9 and 5.0 mg/dL. These wide ranges emphasize

that plasma creatinine concentration (and its reciprocal)

must be considered a crude estimator of GFR. When used

clinically, plasma creatinine values or their reciprocals do

not allow a specific value for GFR to be assigned. However,



520 Finco et al

serial measurements from the same patient would be valu-

able for judging the progression of renal disease if intradog

sources of error were consistent (See below).

Plasma clearance tests have been used experimentally to

measure GFR and are beginning to be used clinically as

well. Iohexol has been tested extensively in humans and

pigs, and it has been evaluated somewhat in dogs.65–68 The

relative ease of performing plasma clearance procedures,compared to urinary clearance procedures, makes them at-

tractive.

Renal scintigraphy also has been examined as a method

for determining GFR in dogs, but that method does not lend

itself to widespread use because of the equipment and ra-

dioactive materials it requires.69–70

For both plasma clearance methods and renal scintigra-

phy, we have encountered major discrepancies between val-

ues provided for GFR and the actual GFR determined by

urinary clearance methods. We do not consider either plas-

ma clearance or renal scintigraphy methods acceptable un-

less each operator making the measurement has taken steps

to validate its reliability. The method should be validated

by comparing its results with GFR values obtained by clas-sic urinary clearance measurements. Such measurements

should be made in several dogs having a wide range of

GFR values, and the two tests should be performed simul-

taneously or immediately after each other.

Renal biopsy is used in dogs to provide anatomic data

that may be helpful in establishing a prognosis. To our

knowledge, no serial biopsy studies of dogs with either ex-

perimental or naturally occurring renal disease have been

conducted to determine the value of tissue examination for

monitoring the rate of progression of renal disease.

Progression—The Role of Primary Disease

As previously stated, the etiologies of naturally occurringchronic renal disease in dogs are almost always unknown,

making routine categorization on the basis of etiology im-

possible. Anatomic classification of chronic renal disease of

dogs is primitive compared to human nephrology and offers

limited help in predicting progression based on the ob-

served lesions. Currently, the rate of progression for various

causes of naturally occurring chronic renal failure is an

enigma, leaving us with no help in the prognosis of indi-

vidual cases as they are managed. Only when more infor-

mation is available on specific causes, or more meaningful

histologic classification of renal disease can be correlated

with rates of progression, will the primary disease’s effect

on the rate of progression be better understood. This sce-

nario is predicated on the assumption that primary diseaseis a significant factor in the rate of progression compared

to self-perpetuated injury.

On the other hand, current anatomic classification might

be valid for predicting the rate of progression (even though

it may lump many causes into one category such as ‘‘chron-

ic tubulointerstitial nephritis’’), if the kidney’s limited ways

of responding to injury lead to the same rate of progression

regardless of cause. This concept has already been applied

to the anatomic classification of chronic renal disease (ie,

‘‘end-stage kidney’’). If this unifying hypothesis on the rate

of progression were proved correct, then primary cause as

a factor in progression could become either immaterial or

relevant only for its additive effect on self-perpetuated in-

jury. Extending that speculation, if primary cause were only

a transient event and self-perpetuation were the sole deter-

minant of the rate of progression, then knowing the natural

history of self-progression is even more relevant. Until we

have enough information to characterize the progression of

naturally occurring renal diseases in dogs, we will not beable to weigh the relative contributions of primary cause

and self-perpetuation. It does seem reasonable to ask

whether risk factors for self-perpetuation in other species,

either proven or hypothesized, exist in dogs.

Glomerular Hypertension. We are not aware of any pub-

lished data from micropuncture studies on dogs with nat-

urally occurring renal disease of any type. Dogs with renal

mass reduced surgically by ¾ or more have glomerular hy-

pertension.71,72 However, studies have not been conducted

to demonstrate a cause-and-effect relationship between glo-

merular hypertension and renal damage in dogs.

Systemic Hypertension and Its Relationship to Glomer-

ular Hypertension. Some studies have demonstrated that

dogs with chronic renal disease have elevated systemicblood pressure.73,74,75 One report indicates that blood pres-

sure may be so severely elevated in some cases of naturally

occurring canine renal disease that retinal detachment or

damage to other organs occurs.75 However, one comprehen-

sive study failed to document blood-pressure differences

between dogs with renal failure and those without.76

We are aware of no reports on naturally occurring chron-

ic renal disease in dogs that characterize systemic blood

pressure on the basis of the disease’s cause, anatomic clas-

sification, or stage within a classification system. Dogs with

surgical reduction in renal mass have mild to moderate sys-

temic hypertension.77

Renal autoregulation usually maintains normal glomer-

ular capillary pressure, even with considerable fluctuationsin systemic arterial pressure. For this reason, systemic hy-

pertension is not synonymous with glomerular hyperten-

sion. We are aware of no studies of naturally occurring

renal disease in dogs in which renal autoregulatory mech-

anisms have been examined to determine whether normal

responses are occurring. In the remnant kidney model of

renal disease in dogs, renal autoregulatory mechanisms are

blunted,78 which helps explain the presence of glomerular

hypertension in this model of renal failure.

Renal Hypertrophy. Hypertrophy of both glomerular and

tubular portions of the nephron have been demonstrated in

dogs with chronic renal failure diagnosed as ‘‘chronic in-

terstitial nephritis.’’79 Nephron hypertrophy in remnant kid-

ney dogs is discussed below.Other Factors. In both naturally occurring and induced

renal disease in dogs, little if any information has been

published on the role of tubulointerstitial lesions, protein-

uria, oxidative injury, acidosis, or circulation of metabolites

unique to azotemia in the progression of disease. In natu-

rally occurring glomerulonephritis and glomerular disease

with a genetic basis, angiotensin-converting enzyme (ACE)

inhibitors have been shown to have a beneficial effect on

both the rate of progression of renal disease and on the

magnitude of proteinuria.80,81 However, angiotensin II may

have many effects, including modifying growth-factor pro-




Fig 2. Changes in GFR following an 11 ⁄ 12 reduction in renal mass

(mean SE).83 The increase in GFR was greater when a 32% protein

diet was fed (hollow circles) than when a 16% protein diet was fed

(solid squares). When diets were switched at 7 months, protein effects

were apparent; however, GFR was maintained in each group at 180%

and 220% of original values, respectively.

duction within the kidney58 and modifying oxidative

stress,82 which preclude assigning any beneficial effect to

either systemic vascular effects or to effects on proteinuria.

Among the uremic toxins incriminated in progression of

renal failure, parathyroid hormone has been examined for

its effects in dogs with remnant kidneys; however, no ben-

eficial effect could be attributed to removing parathyroid

hormone by parathyroidectomy.83

Self-Perpetuation of Renal Disease in Dogs—The Remnant Kidney Model

Considering the almost complete lack of data related to

progression of naturally occurring renal diseases in dogs, it

seems presumptuous to endorse or eliminate from consid-

eration any of these factors that have been studied in other

species. Likewise, it seems prudent to acknowledge that

future theories of self-perpetuation may identify mecha-

nisms more important than those now popular.

Although mechanisms responsible for progression cannot

be confidently identified for the dog, knowledge about self-

perpetuation may provide data applicable to any naturally

occurring case of renal disease. With any naturally occur-

ring chronic renal disease, self-perpetuation may be the

only factor operative if the primary renal insult is transitory.

The remnant kidney model has been used in a variety of

species to examine many aspects of renal disease and renal

failure. We have used this model as an experimental tool

to study effects of several dietary or therapeutic agents on

progression of renal disease. A byproduct of these studies

was the accumulation of data on dogs with remnant kidneys

that allow us to characterize self-perpetuation of renal dis-

ease.

The Remnant Kidney Model of Renal Disease

To create this model, 11

⁄ 12 to 15

⁄ 16 of the left kidney isinfarcted by selective ligation of branches of the left renal

artery. The right kidney is later removed. This degree of

reduction of renal mass results in mild azotemia (plasma

creatinine concentration about 2 to 4 mg/dL) after compen-

satory hypertrophy occurs. The level of residual function is

comparable to naturally occurring clinical cases diagnosed

rather early in the course of renal disease. The massive

destruction and removal of kidney tissue required to

achieve mild azotemia is a testament to the amount of re-

serve that exists in kidneys.

Data included in subsequent analysis were derived from

dogs used in several published studies.83–85 In all studies, in

addition to blood hematologic and biochemical measure-

ments, renal function was evaluated at intervals by mea-suring GFR through urinary clearance of exogenous cre-

atinine or inulin. Kidney tissue obtained during the infarc-

tion procedure (preazotemia) was available for histologic

comparison with tissue from the remnant kidney at the end

of the study. Many dogs, although azotemic, completed the

study and were subsequently euthanized while clinically

normal. Other dogs were euthanized during the study be-

cause of progressive uremia. All dogs were carefully eval-

uated for urinary tract infection by serial urine cultures.

Such infections were uncommon and were treated appro-

priately when detected. The low incidence of urinary in-

fection and its prompt eradication led us to conclude that

urinary infection was not a factor in any decrements inrenal function. Diets fed to dogs varied with the study, but

they were either commercial dog food or its equivalent or

experimental diets altered for renal protection (low phos-

phorus, low protein). Thus, diets fed to these dogs were

comparable to or more protective than diets typically con-

sumed by dogs with naturally occurring renal failure when

their disease is first diagnosed.

Hypertrophy Response in the Remnant Kidney

Renal hypertrophy in dogs has been studied previously,

but our studies were conducted over a longer time and with

more mass reduction than other reports. In our studies, in-

crements in GFR following reduction of renal mass wereinterpreted to indicate that hypertrophy had occurred. In 1

study of 11 ⁄ 12 nephrectomized dogs, most hypertrophy oc-

curred during the first 3 months, but a further increase oc-

curred between then and the end of this experiment at 7

months. Hypertrophy as measured both by measurement of

GFR and morphometric studies was positively affected by

protein intake (Fig 2).84

In dogs with 15 ⁄ 16 reduction in renal mass that were stud-

ied for 24–27 months, maximum GFR occurred in ⅓ of the

dogs between 6 and 9 months; some dogs had maximum

GFR values even later (Fig 3).

These findings may have clinical ramifications. The pro-

longed period over which hypertrophy occurred may pro-

vide hope for modest functional improvement over extend-ed periods in cases of acute renal failure, if the primary

disease is resolved. Secondly, when judging progression of

chronic renal failure, we should understand that the level

of function at any time may represent a balance between

nephron destruction and nephron hypertrophy. Stable func-

tion could be due to the absence of destructive elements

without hypertrophy, or alternatively, it could be due to

continued destruction combined with sustained hypertrophy

of residual tissue. We are unsure of the importance of this

prolonged period of hypertrophy in cases of naturally oc-

curring renal failure in dogs. However, data from our dogs



522 Finco et al

Fig 3. Maximum hypertrophy as deduced from GFR measure-

ments performed in 60 dogs at intervals after 15 ⁄ 16 reduction in renal

mass. Although maximum values were attained at about 4 months in

most dogs, substantial numbers of dogs attained their highest GFR

values later.

Fig 4. Declines in GFR consistent with self-perpetuation of renal

disease in dogs with reduced renal mass. Of 60 dogs, only 8 main-

tained a GFR of 90–100% of the maximum GFR observed; 47 of 60

had a decline in GFR of 20%. GFR measurements were performed

at 4-month intervals over periods up to 27 months.

indicate that both renal damage and renal hypertrophy oc-

cur simultaneously, meaning that our demonstration of the

magnitude and duration of the hypertrophy response as

measured by GFR is a conservative estimate. Specific data

have not been collected from dogs with remnant kidneys to

determine whether hypertrophy is a risk factor for progres-

sion of renal disease.

Documentation of Self-Perpetuated Renal Damage

To determine whether self-progression occurs in dogs,

GFR data were analyzed from 60 dogs studied for 24–27

months after reduction of renal mass. Of the 60, 32 sur-vived the study period and 28 were euthanized when they

developed signs of uremia. As already indicated, develop-

ment of uremia is evidence of progressive renal failure but

not necessarily of progressive renal disease. Of the 28 dogs

euthanized, the final GFR from 10 dogs was excluded from

data analysis because of severe signs of uremia and ter-

minal oliguria that was unresponsive to fluid therapy. We

judged that prerenal factors could not be excluded as a

cause of extremely low terminal GFR values in these 10

dogs and excluded the terminal values with the risk of un-

derestimating the magnitude of self-perpetuation.

Progression of renal disease was expressed as the final

valid GFR (last measurement in 50 dogs, penultimate mea-

surement in 10 dogs) as a decimal fraction of the highestGFR measurement made during the study. The highest val-

ue occurred several months after reduction of renal mass,

representing an increase in GFR associated with hypertro-

phy. Tabulations indicated that 47 of 60 dogs had decre-

ments in GFR 20% during the study (Fig 4). These results

support the hypothesis that renal disease is a self-perpetu-

ating phenomenon in dogs, as in rats.

When renal mass is reduced by the technique described,

temporary occlusion of a branch of the renal artery causes

color changes in the renal tissue that has been made ische-

mic. This color change helps us judge which branches

should be ligated to achieve the desired reduction in renal

mass. However, ideal choices are not always available. In

any population of dogs whose renal mass has been reduced

by infarction, a range of initial GFR values will be obtained

even when the same mass reduction is attempted in all dogs.

We used this heterogeneity to examine the question of

whether there was a relationship between the degree of

mass reduction and the progression of renal disease. We

found that the initial GFR in survivors (0.84 0.31 mL/

kg per minute) was not significantly different (by 1-way

ANOVA analysis) from the initial GFR in dogs that were

eventually euthanized after developing uremia (0.79 0.26mL/kg per minute). We also did not find a significant re-

lationship between initial GFR and the percent decline in

GFR, either in the entire population or when survivors and

fatalities were considered separately.

Other investigators have reported serial GFR measure-

ments in dogs with substantially smaller reduction in renal

mass. In one study, a ¾ reduction in renal mass was induced

either by vascular ligation and nephrectomy (remnant kid-

ney) or by renal trauma combined with bacterial infection.

This reduction in renal mass was inadequate to cause sus-

tained azotemia. The GFR measured at intervals of 4

years failed to detect a decline in renal function with this

degree of renal mass reduction, but the dogs did develop

renal lesions.86,87 In another study, dogs with 11 ⁄ 12 reductionin renal mass had mild azotemia and developed renal le-

sions, but they did not have consistent decrements in renal

function.88 In a study of aged dogs, unilateral nephrectomy

at age 7.5 years did not result in a progressive decline of

GFR over the subsequent 4 years, but renal lesions devel-

oped in these dogs as well.89 In the latter study, the exper-

iment’s design did not allow separation of the effects of

aging from those of renal mass reduction.

From all the available data, it is apparent that a substan-

tial reduction in functional renal tissue must occur for renal

disease to be self-perpetuating in dogs. This raises the ques-




Fig 5. Data from 2 dogs depicting intradog correlation between GFR and 1/creatinine. Although this correlation was excellent in some dogs

(a), a very mediocre correlation occurred in others (b). These results suggest that plasma creatinine concentration must be interpreted with caution

even from serial tests in the same dog.

Table 1. Repeatability of GFR measurements (mL/min

per kg body weight) in normal dogs over a 27-day period

when maintained under controlled laboratory conditions.

Urinary clearance of exogenous creatinine was used to

measure GFR.

Day of Study

Dog

1 2 3 4

1

7

14

21

28

2.3

2.4

2.5

2.4

2.7

2.3

2.5

2.2

2.3

2.2

2.4

2.4

2.4

2.8

ND

2.3

2.4

2.4

2.3

2.3

ND, not determined.

tion of whether self-perpetuation is occurring in clinicalpatients when the disease is diagnosed. With 15

⁄ 16 reduction

of renal mass, azotemia is only moderate (plasma creatinine

2–4 mg/dL) after renal hypertrophy has occurred. This level

of azotemia or higher is often encountered in clinical pa-

tients at the time of initial diagnosis. Consequently, dogs

diagnosed with naturally occurring renal disease when azo-

temia is mild to moderate are probably undergoing self-

perpetuating renal disease, either as the only mechanism or

in addition to the primary etiology.

Plasma Creatinine Concentration as a Predictor of GFR—Intradog Correlation

Examination of the data in Figure 1 reveals that plasmacreatinine concentration is a relatively poor predictor of

GFR across a population of dogs (interdog variation), but

some of the sources of variation are minimized in repeated

sampling of the same dog. Our protocols included sampling

for plasma creatinine concentration immediately before

GFR measurements. We examined the statistical correlation

between plasma creatinine concentration and GFR on dogs

with a marked (40%) decrement in GFR over 12–20

months (3–5 GFR measurements). Reliability of plasma

creatinine concentration as a predictor of GFR was highlyvariable from dog to dog, with R2 ranging from .220 to

.996 in 21 dogs. The mean R2 value for the group was .801

.219. In some dogs, plasma creatinine concentration was

an excellent predictor of change in GFR (Fig 5a), whereas

in others it was a poor predictor (Fig 5b). Whether the lack

of correlation between GFR and plasma creatinine concen-

tration was due to lack of specificity in creatinine measure-

ments as a marker for GFR or due to variability in GFR

measurement is arguable. However, under the conditions in

our laboratories, sequential GFR measurements were very

reproducible (Table 1), leading us to postulate that plasma

creatinine concentration was the source of the inconsisten-

cy.

Relationship between Proteinuria and Progressionof Renal Disease

In the 60 dogs that were studied for 24–27 months, urine

protein : creatinine measurements (UPC) were made at 4-

month intervals on samples obtained by urinary catheteri-

zation. Each dog’s average UPC was computed. Values in

survivors (2.08 1.78) were not significantly different (P .076) from those in fatalities (2.98 2.07), with a sta-

tistical power of 70% to detect an effect. Likewise, terminal

UPC values in survivors (2.76 2.07) were not signifi-

cantly different (P .148) from those in fatalities (3.84

3.32), although statistical power for this analysis was low

(45%).We defined progression as the decrement in renal func-

tion computed by expressing the final valid GFR as a dec-

imal fraction of the highest GFR measurement made during

the study. This measure of progression was tested for its

correlation to the average UPC of each dog (Spearman’s

value), and the resulting value was significant (P .014).

We also determined the correlation between this measure

of progression and the last UPC obtained, obtaining a near-

significant value (P .087). The same comparisons were

made separately for survivors and fatalities; in survivors,

no significant correlation existed between magnitude of



524 Finco et al

Fig 6. Relationship between UPC and rate of progression of renal disease in 45 dogs with a progressive decline in GFR. The UPC values

obtained before a decline in GFR (a) were not predictive of later progression (P .266). The UPC values obtained after detecting a decline in

GFR (b) were numerically greater than before and related to the rate of decline in GFR (P .031, Spearman’s test).

progression and average UPC (P .276) or last UPC (P .331). In fatalities, the magnitude of progression was

significantly correlated with both average UPC (P .048)

and final UPC (P .050).

To examine the relationship between proteinuria and pro-

gression in another way, the rate of progression (rather than

its magnitude) was computed. For each dog, the percent

decline in GFR per month was computed [((highest GFR

final valid GFR)/highest GFR)/months of declining

GFR] and the mean UPC was tabulated for the time before

progression was detected. Likewise, mean UPC was com-

puted for each dog during the period after progression was

identified. In 45 dogs (47 of 60 dogs demonstrated pro-

gression; 2 of those dogs were excluded because of UPC

outliers), the correlation between preprogression UPC and

rate of eventual progression was not significant (P .266,

Fig 6a). There was a significant correlation between rate of

progression and UPC values after progression began (P

.031, Fig 6b).

Our data on the relationship between proteinuria and pro-

gression were limited by the 4-month intervals between

UPC determinations. However, the results suggest that pro-

teinuria increases in association with an accelerated rate of

renal disease progression. The nonsignificant correlation

between UPC measured before onset of progression and the

rate of eventual progression suggests that proteinuria may

be an effect of progression rather than its cause.

Pattern of Progression of Renal Damage

We examined the reciprocal of plasma creatinine con-

centration as a marker for rate of renal disease progression.

According to the clearance formula, 1/creatinine is linearly

related to GFR. Despite the limitations of creatinine for

estimating GFR, this test is commonly used to monitor pro-

gression of renal failure in clinical patients.

Sets of data from each of 27 dogs with remnant kidneys

and clear evidence of self-perpetuating renal disease were

evaluated to characterize the relationship of 1/creatinine to

time. The period of progression was defined as the time

during which plasma creatinine concentration progressively

increased. A statistical software program (SPSS version 8,

SPSS Inc, Chicago, IL) was used to determine the best data

fit when plotting 1/creatinine versus time for each dog. Lin-

ear, log, quadratic, cubic, power, and exponential curves

were examined for fit. The number of creatinine observa-

tions per dog in this group was 11.9 5.1 (range, 5–24

samples taken at monthly intervals). For the 27 dogs, R2

values for a linear change in 1/creatinine ranged from .249

to .984 (mean .82 .17). These data indicate that con-

siderable deviation from linearity and dog to dog variation

exists in the rate of renal disease progression as judged by

plasma creatinine concentration. A curve fit of values using

the cubic equation gave higher R2 values (as expected math-

ematically, because any deviation from perfect linearity

would be accommodated more precisely), but no consistent

pattern occurred. Good linearity sometimes occurred (Fig

7a), but patterns of terminal acceleration (Fig 7b), terminal

abatement (Fig 7c), or deviations from linearity during the

midpoint of the observation period were also noted.

The GFR measurements made in our studies provided an

opportunity to examine the progression pattern of self-per-

petuating renal disease with more accuracy than plasma cre-

atinine measurements. Data were analyzed from 18 dogs in

which 4 to 6 GFR measurements had been made at 4-month

intervals over 16–24 months. Ten of these dogs survivedthe 24-month study period but had decrements in GFR; 8

were euthanized because of uremia. In the latter group, final

GFR determination was not used if it occurred within 1

month of euthanasia, a decision made to avoid extrarenal

influences on GFR that may have occurred during terminal

uremia. For the complete group of 18 dogs, R2 values for

linear regression had a range of .81 to .99 (mean .90),

with excellent linearity in some dogs (Fig 8a). The best fit

of data and higher R2 values were obtained in all 18 dogs

with cubic regression analysis, indicating that perfect line-

arity was the exception rather than the rule. Nevertheless,




Fig 7. The change in 1/creatinine with time (dotted line, each point

a plasma creatinine determination) in dogs undergoing substantial loss

of renal function. In some dogs (a) the relationship was very linear

( R2 .984), but a cubic model fit better for other dogs. An apparent

changing rate of progression with terminal acceleration (linear R2

.734, cubic R2 .891 [b]) and a terminal abatement of progression

(linear R2 .923, cubic R2 .976 [c]) were among the nonlinear

patterns observed.

Fig 8. The change in GFR with time (dotted lines, each point a

GFR determination) in dogs undergoing substantial loss of renal func-

tion. Linear fit of data was better for GFR determinations than for 1/

creatinine, lending support to the hypothesis that self-perpetuation of

renal disease progresses at a constant rate (example shown in [a],

linear R2 .994). However, variation in the rate of progression (linear

R2 .830, cubic R2 1.00 [b]; linear R2 .934, cubic R2 .999

[c]) were also observed.



526 Finco et al

curve fits by the cubic method did not have a consistent

pattern (Fig 8b,c), indicating that GFR was not declining

in any consistent manner.

We interpret these results from GFR measurement to in-

dicate that a fairly linear decline in renal function occurs

with self-perpetuating renal disease, with the caveat that the

last month of life was not included in our data from the 8

dogs that were euthanized. The GFR data indicates thatalthough a general linear trend for progression of renal dis-

ease exists, considerable deviation from linearity is ob-

served in some dogs. Because individual dogs in our studies

were managed in the same way once experiments began

(diet, parathyroid hormone status), the variation from line-

arity could not be attributed to changes in management

practices. Discrepancies between GFR measurements and

plasma creatinine measurements reflect the failure of plas-

ma creatinine concentration to consistently reflect GFR,

even in the same dog.

Microscopic Examination of Tissue—RemnantKidneys from Dogs

Studies of remnant kidneys from dogs document the oc-

currence of histologic lesions. These lesions include mes-

angial cell proliferation, mesangial matrix accumulation,

periglomerular fibrosis, tubulointerstitial infiltration with

mononuclear cells, interstitial fibrosis, and mineral deposi-

tion. These lesions are the same as those encountered in

kidneys of dogs with the naturally occurring renal disease

commonly described as chronic interstitial nephritis.

Although empirical examination suggests that patholo-

gists are unable to separate microscopic sections of remnant

kidneys from kidneys of dogs with naturally occurring tu-

bulointerstitial diseases, controlled comparison studies have

not been reported. In studies of dogs with remnant kidneys,

initial and terminal kidney samples have been analyzed but

serial samples from the same dog have never been reported.

Thus, although histologic examination is considered a more

sensitive indicator of self-progression than function tests,

its usefulness in documenting the rate of progression is un-

proven in this model.

Conclusions

Studies of dogs with remnant kidneys have added much

to our knowledge about self-perpetuation of renal disease

in this species. The information can be summarized as fol-

lows:

1. Self-progression of renal disease often occurs at a stage

of renal function reduction at which mild to moderateazotemia exists. Consequently, self-perpetuating renal

disease is likely to be ongoing when naturally occurring

renal failure is first diagnosed.

2. Despite the presence of only mild to moderate azotemia,

severe reduction in numbers of functional nephrons have

occurred at this early stage of disease.

3. The marked and prolonged period of hypertrophy that

occurs after nephron numbers have been reduced masks

the severity of functional tissue loss. Hypertrophy also

makes it difficult to assess the progression of renal dis-

ease with functional measurements, because functional

improvement associated with hypertrophy may compen-

sate for increasing functional losses as the disease pro-

gresses.

4. Urinary protein excretion as measured by UPC may be

a marker for identifying accelerated progression of self-

perpetuating renal disease. It may not be an accurate

predictor, however, of an impending accelerated rate of

progression.5. The pattern of self-progression of renal disease can be

variable, but it is fairly linear over time unless compli-

cated by other factors. Plasma creatinine concentration

must not be interpreted too stringently as an indication

of progression, considering its lack of precision in re-

flecting GFR.

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Progression of Chronic Renal Disease in the Dog (1)