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27.03.2015
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Glomerulonephritis in cats: Contemporary diagnostic, treatment and prevention techniques (clinicopathologic analysis)

Roman A. Leonard – DVM, PhD, practicing veterinarian, the Head of veterinary clinic “Doberman”, Chelyabinsk, Russia. President of Russian Scientific and Practical Association of Veterinary Nephrologists and Urologists (www.vetnefro.ru)

This monograph deals with one of the most actual problems of contemporary veterinary medicine – diagnosis and treatment of glomerulopathy and  glomerulonephritis, the most common kidney disease in cats. The book generalizes the author’s experience accumulated for many years and concerning a specific course of analysis, diagnosis and treatment of nephropathy in cats. The results of clinical and live morphological research are presented using light optic and electron microscopic analysis performed in more than 2000 cats. The role of the puncture biopsies for diagnosis of renal diseases is described in details, as well as its methods, indications and contraindications.

The quantitative assessment of severity of glomerulopathy in a large number population of cats is presented, with a special reference to the data on etiology, pathogenesis and clinical signs.

The author gives detailed recommendations for the treatment and prevention of glomerulonephritis and other nephropathies in cats.

The book will be of interest for general practitioners, as well as for specialists occupied with advanced study of kidney pathologies.  

The book contains 6 pictures, 63 photos and 15 tables made by the author.

All rights reserved. This publication/monograph may not be used or reproduced, stored, in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the author.

e-mail: romana74@mail.ru

List of abbreviations:

  • VI - viral infection
  • GN – glomerulonephritis
  • GP – glomerulopathy
  • GC – glucocorticoids
  • GCS–     glucocorticosteroid  
  • CKD – chronic kidney disease
  • CRI – chronic renal insufficiency
  • IN – interstitial nephritis
  • Urolithiasis
  • VLC – viral leukemia in cats
  • VIC –viral immunodeficiency in cats
  • ESR – erythrocyte sedimentation rate
  • – C-reactive protein

Basic principles

  1. CKD is the most common cause of death or euthanasia of cats which didn’t attain physiological senility.
  2. Clinical signs of CKD appear only when more than 67-70% of structural elements of renal tissue suffer radical changes (fibrosis, atrophy).
  3. Treatment of CKD nowadays is possible only by means of symptomatic (supportive treatment) and substitution therapy (maintenance hemodialysis, peritoneal dialysis, renal transplantation).
  4. Various nephropathies can lead to CKD, so etiotropic and pathogenetic treatment of any nephropathy must be carried out long before the signs of uremia arise.
  5. Various glomerulopathies arise in cats in overwhelming majority of cases at a young age, have chronic course and are the most often cause of CKD’s in this species.
  6. Further development of modern veterinary nephrology is impossible without active introduction into veterinary clinical practice of invasive methods of nephropathy diagnostics (intravital puncture and aspiration biopsy) and large-scale  study of renal parenchyma by means of histomorphological methods after post-mortem

Introduction

Kidney diseases are very common in cats all over the world.

«Kidney diseases are very common in cats and for this reason, they sometimes tend to be considered as almost normal in older felines. However, cats can suffer from a wide spectrum of renal injuries, some of them acute and potentially reversible if treated appropriately; others are chronic and may need specific management for optimal outcome. It is therefore essential for the veterinarian to know the major renal diseases encountered in the cat, including some of the newer high-profile ones (Francey T., Schweighauser A., 2008). 

The earlier clinician succeed in diagnosing of nephropathy, then the higher probability to retard the disease and eo ipso considerably to prolong active life period of the patient.

It’s necessary to remember that kidneys have huge compensatory ability and can support homeostasis of organism over the years, even against a background of severe lesion of parenchyma and renal pelvises. (for years).

Abnormal [pathological] changes initially reveal itself in urine analysis, than in blood tests and only later on clinical signs of ill-being appear. 

That’s why doctor attending physician rather often has a possibility to start treatment of the patient long before clinical signs of nephropathy arise.

Nevertheless, nowadays the most popular “diagnosis” among veterinary general practitioners is CRI and CKD. And, if CKD in some cases is a correct diagnosis, CRI is always only a symptom complex or complication, during leading or underlying disease which has renal, pre-renal or post-renal genesis. CRI is only a statement of the fact (though very often it’s a belated statement) of accumulation of noxious metabolic products in blood. This diagnosis doesn’t reflect the key factors in genesis, development and clinical behavior of pathologic process in renal tissues (if any exist) and allows attending physician to institute reasonably only symptomatic (supportive treatment) or to recommend substitutional therapy.

At the same time, correct nephrological diagnosis in animals can be and ought to be made long before establishing the fact of CKD. 

General subjects

Chronic kidneys’disease.

Whether it is always possible to consider this diagnosis correct?

CKD is a diagnosis stating the fact that kidneys of animal already are not in a condition to support homeostasis of an organism and from 50% up to 70% of particular elements (glomeruli, for example) or most of the renal structures has already suffered very serious  structural changes. CKD is an above nosological and, to a greater extent a syndromic concept.

And indeed, when pathologic process in renal parenchima leads to such serious and profound structural changes that it’s not possible to determine nosological form (i.e. primary disease) of primary renal lesion, and in nephrologicall practice the illness is diagnosed as CKD.

CKD characterized according to azotemia level (or according to the level of decrease of glomerular filtration rate, when it’s possible), and according to possible complications such as uremic gastritis or/and pericarditis, anemia and so on.

There are three scenarios for nephropathy leading to chronic kidney disease in cats are possible.

  1. Acute pathologic processes in kidneys which lead to galloping (hours – days) significant structural changes in renal parenchyma. Acute processes of glomerular lesion in cats are not a frequent phenomenon (in relation to the total number of this animal species, which suffer from nephropathy) and mainly connected with:

- renal imaging agent poisoning (ethylene glycol, agent contained in lilies, gold salts,  sublimate, insecticides, some agents used against rodents) and with iatrogenia (the use of aminoglycoside, amphotericin B, polymyxin B, cisplatin and some of non-steroidal anti-inflammatory agents (NSAIAs));

- glomerular ischemia  (the outcome of which is collapse followed by “coalescence” of capillary loops) caused by pre-renal RI and/or by a shock, as well by use of some drugs for general anesthesia, which can significantly reduce arterial blood pressure;

It’s also possible to refer here fulminant and acute forms of certain viral infections (e.g. viral peritonitis (coronavirus) and viral leukemia), usually affecting mainly kittens and young animals, and lead to pyogranulomatousis (hematogenous channel of contamination) in renal parenchyma (shouldn’t be confuse with pyelonephritis, in which pelvis is affected).

If after illness the animal survives and its state of health becomes stable (and its secretory system is not a subject to medical checkup, which very often detect nosological form of disease), then years later CKD can be diagnosed.

  1. Age-related necrosis of glomeruli in cats, which are over the age of 15-20years.
  2. In the majority of cats CKD results in various chronic nephropathies (glomerulonephritis, tubulo-interstitial disease, amyloidosis and so on) which develop in the organism for years without any clinical signs.

It’s possible to speak about any etiotropic or pathogenetic treatment of CKD only conditionally. And symptomatic and/or replacement therapy (hemodialysis, enterodialisis, renal transplantation) of the disease, even carried out at the so-called “early stage” of CKD,  will help only to mend the homeostasis (up to certain degree) but is unlikely to change significantly the pathologic state of renal parenchyma.

The doctor has right to diagnose illness as CKD only after all possible efforts to find out more precise diagnosis have been made (for example, glomerulonephritis,  pyelonephritis, amyloidosis etc.) and variants of etiotropic and/or pathogenetic treatment were suggested to the animals’ owners. 

If the cat has been observed in the same clinic during, let’s say, 10 years and suddenly, the doctor diagnoses the illness as CKD or CRI, in this case a question arises: where has the doctor been all this years, during which the kidneys were dying slow but sure.  Was it really not possible to take some measures at earlier stages of primary illness?

The secret of popularity of diagnosis CKD is that it’s very opportune, and its possible to provide a basis for any nephropathy (or even any type of azotemia) according to doctor’s choice, neither taking the trouble of searching the cause of its genesis (in particular patient or in population of cats in particular region), nor  applying efforts for etiopathogenetic therapy.

Correct nephrological diagnosis – what is it?

An overwhelming majority of various nephropathies in animals take clinically silent course for a long period of time.  But the absence of clinical signs is not the reason for a doctor to make no effort to detect a specific nephrological diagnosis in time and begin therapy before the symptoms of uremia arise.

 Clinical diagnosis in nephrology, in the majority of cases, is made on the grounds of laboratory examinations of biological fluids (blood serum, urine).  However, diverse pathologic changes in renal parenchyma (especially glomerular and tubulo-interstitial diseases) can lead to very similar changes in the results of laboratory diagnostics at all stages of its development.

Rather often some processes in which the condition of renal parenchyma (especially at initial phase of pathological process) remains normal (pre and post-renal RI) result in CRI.

That’s why diagnosis made only on the level of non-invasive diagnostic techniques, such as:

  • anamnesis
  • clinical checkup of the animal
  • laboratory examinations of biological fluids (blood serum, urine);
  • US and/or X-rays of kidneys with contrast medium, very often can be considered as a probable (clinical) diagnosis.  

But in majority of cases the doctor in charge comes to nothing more than CKD or CRI as a “diagnosis” and institutes only symptomatic (supportive) treatment which doesn’t neither suppress aetiological factors of NP (if it’s possible), nor represses  (or significantly retards) the pathogenetic processes in structural elements of kidney.

Nowadays, final diagnosis and institution of complex therapy are possible only on the basis of invasive diagnostic techniques (aspiration and puncture biopsies of kidney). A whole number of researches also hold the same opinion.

“Differentiation of kidneys diseases is not possible on the base of clinical symptoms and results of blood serum examinations only; renal biopsy in this case is an irreplaceable method” (Qsborn et al, 1974; Minkus et al, 1994).

When defining diagnosis, making optimal therapeutic decisions and medical prognosis the doctor should appeal both functional and morphological data (intravital biopsy). Repeated biopsy may be needed for monitoring of clinical behavior of KD or therapy response. (Wright et al, 1981).

These methods of diagnostics, due to the high level of modern medical technologies development are easy to use, low-traumatic and highly informative.

Besides, “severe complications after percutaneous puncture or aspiration nephrobiopsy are very seldom are rare” (Edwards, 1983; Smith, 1991). Also, Leveille et al. (1993) severe complications detected only in 3 out of 223 (1,2%) of dogs and cats after biopsy.

According to the results of own practical work (more than 200 intravital puncture and aspiration biopsy) it’s possible to draw a conclusion that correctly performed minor operation is easily tolerated by cats and in overwhelming majority of cases this operation has no significant aftereffects for animal health (serious complications were reported only in less than 4% of cases).

It goes without saying that use of invasive diagnostic techniques is justified only in the case when instituted therapy based on non-invasive diagnostic techniques didn’t give expected positive results or it’s suspected that a particular patient has amyloidosis or hereditary nephropathy (what is especially important for thoroughbred animals).

At the same time, value of invasive diagnostics technique (in ill and experimental animals) and total renal tissue examination after autopsy followed by light and electron microscopy consists in:

  1. Possibility to make final nephrological diagnosis (without correct diagnosis its not possible to institute etiotropic and appropriate pathogenetic therapy in clinically difficult cases).
  2. Detection of tendencies and mechanisms of development of nephropathies in cats, as well as in data acquisition for statistical analysis of the most frequent kidneys diseases in cats in particular countries and regions.   It will simplify diagnosing and institution of complex treatment without use of invasive diagnostic techniques for the general practitioner (according to the principle: “frequent-frequently, rare – rarely”).
  3. Detecting of development mechanisms and possible etiotropic factors, involved in process of development of nephropathies in cats.
  4. Compilation of data base for the in order to initiate of drugs development, introduction of new medical and dietary products for prophylaxis and treatment of nephropathies in cats (especially at an early stages of disease).

Correct nephrological diagnosis should be made at the earliest possible stages of pathologic process, when medicamentous therapy is the most effective.

In other words, if diagnosis is correct, scientifically grounded and made at an early stage of pathologic process, the doctor has strong reasons to recommend the patient drug therapy (including hormonotherapy and dietotherapy) for a long period of time (from a course of treatment and up to continuous lifelong therapy).

            A doubt may arise whether total early diagnostics (and treatment, of course) of nephropathies in cats is possible, because the owners of the animals mainly start to think about the pets’ health only when they begin to feel not very well. But all over the world the pets’ owners willingly vaccinate their animals against infections and treat pets with preparations from endoparasites and ectoparasites before the animal becomes ill.

The absence of such practice in veterinary nephrology is solely explained by lack of elementary knowledge in this field among the owners of the cats. Popularization of such knowledge is the task for the veterinary doctors. 

Own scientific studies and results of scientific and practical work

Clinical (initial stage) of research.

In 2004 – 2010 during clinical examinations of 907 cats (anamnesis, examinations of biologic fluids, US of abdominal cavity organs) in the age from 5 month to 19 years with various health problems, in 871 animals various nephropathies were detected (with RI or without it).

Though, animals with characteristic symptoms of urolithiasis and/or urocystitis, according to anamnesis and US, as well as those with confirmed pre - or post - renal RI were not taken into consideration.

In 721 animals (82,8%) out of 907 without RI or with CKD of the 2nd or 3rd stage (according to the classification given by the site www.iris-kidney.com), based on anamnesis and data of non-invasive laboratory diagnostic a provisional clinical diagnosis was made – chronic glomerulonephritis (at the stage of remission or exacerbation). In 150 animals (17, 8%) other diagnosis were made or the cause of RI remained uncertain (table 1). 

Table 1.

Clinical diagnosis

N

Note

Polycystic renal disease

34

According to data of US diagnostics

Hypoplasia of both kidneys

2

According to data of US diagnostics

Neoplasia of both kidneys

26

With following autopsy validation

Pyelonephritis

 

16

Diagnosis was made according to data of bacterial inoculation of urine, received with by direct urine inoculation method. US showed no signs of cystitis/

Tubulo-interstitial disease

(clinical diagnosis)

 

20

in anamnes morbi of the animal –high doses of aminoglycosides.

CKD, accompanied by CRI of the 3rd-4th grade (according to the data given by www.iris-kidney.com)

 

 

34

 

Animals in which or the cause of RI remained obscure

 

18

 

Research tasks

Taking into consideration the circumstance that the most frequently recorded disorders in cats are various nephropathies, the following tasks were set: 

  1. To work out and introduce invasive diagnostics techniques of nephropathies in cats into therapeutical and diagnostic process, without it it’s not possible to make a correct (final) nephrological diagnosis.
  2. To carry out total study of cat’s renal parenchyma obtained after autopsy (euthanasia, death of animal during treatment and etc.) by means of light and electron microscopy, with use of biotechnology. 

Object of the research is:

  1. Establishing of correct nephrological diagnosis by means of invasive diagnostic techniques in clinically difficult cases (without it it’s not possible to institute etiotropic and grounded pathogenetic threatment).
  2. Detecting of regularities and mechanisms development of glomerulopathies in cats.
  3. Collection of statistical data of the most common nephrological disease in cats.
  4. Detect new or specify insufficiently studied mechanisms of development of glomerulopathy in cats.
  5. To establish the cause why exactly cats are particularly susceptible to various glomeruropathies.
  6. Enrich the scientific database with knowledge in glomerulopathy in cats for initiating the development of medical and dietary products, as well as the correct use of already available products for prevention and treatment of these pathologies (including pathologies at the most early stages of its genesis). 

Active promotion of knowledge in the field diagnosis and treatment of nephropathy in animals among general practitioners, as well as exchanges of information with other scientists is an integral part of this work. 

Material and methods

In the period from the year 2007 to 2009 histomorphological research of kidneys was carried out in 102 cats, died from various diseases or euthanized because of injures or some other pathologies incompatible with life.

Age of animals ranged from 5 months to 22 years. Moreover, only kidneys of those cats without clinical signs of any renal pathology and urinary system pathology in a post-mortem epicrisis has been sent for analysis.  Isolated nephritic syndrome was diagnosed in majority of animals. Creatinine level in blood serum was within the normal limit.

As a result only in 5 cats (4, 9 %) during histology of renal tissue by means of light and/or electron microscopy no nephropathology was found.  

All other animals aged from 11 month to 22 years old of both sexes had glomerulopathy of minor degree (12 animals or 11,8 %), of mean degree (52 cats or 50,9 %) and severe degree (33 cats or 32,4%). 

Conditional differentiation of severity of glomerulopaty was conducted on the basis of quantitative and qualitative changes in the glomeruli and renal cortical layer (see Table 2)

In the years 2008 - 2010, in 207 cats of both sexes aged from 11 months to 18 years, out of the 237 cats taken for the research (i.e., 87.3%), clinical (provisional) diagnosis of chronic glomerulonephritis was confirmed in vivo (by means of invasive methods of diagnosis) or postmortem by means histomorphological studies of renal parenchyma using light and / or electron microscopy. 

On the gropunds of carried out research, its possible to make a conclusion that different glomerulopaties are the major cause of chronic kidney disease and chronic renal failure in cats.  

Glomerular kidney disease in cats

Definition.

Glomerulonephritis in cats is a group of morphologically heterogenous immune-inflammatory diseases of kidneys which are primary characterized by glomerule dominating lesion and the subsequent involvement of the other kidneys structures into the pathological process. Glomerulonephritis in cats are taking chronic course in overwhelming majority of cases (lifelong period).

Classification of GP and GN in cats.

There is no integrated (unified) common classification of GN and GP that answer the demands of clinician of different fields, transplantologists and morphologists, up to now.

In this review an attempt to synthesize various classifications of GN was made, in order to help vet general practitioner in:

  • In understanding the mechanisms of genesis and development of GN;
  • In establishing of correct nephrological diagnosis with the help of invasive and non-invasive techniques;
  • In administration of combined therapy at an early stage of disease;

Traditionally classification of GN is subdivided into aetiological  (by genesis), pathogenetic (immunological)and morphological (based on the types of abnormal changes in glomeruli and renal parenhima,  presentations during analysis with the help of light and electron microscopy).

Aetiological classification

The key point of aetiological classification of GN is the detection of endogenous or exogenous AG (activating agents), which initiate a cascade of immunological responses, which finally by-turn lead to glomeruli lesion.

Taking into consideration the fact that GN starts to develop weeks or even month after AG impact (and often diagnosed even later), it is very difficult or impossible to determine primary cause (sensitization factor) in every specific patient. Therefore, more often clinicians have to attribute GN to idiopathic disease.

  1. Plotnick (2008) points out the role of some exogenous and endogenous AG as probable etiotropic factor in GN development in cats’ populations. (Table. 3)

 

Table 3.  Possible aetiological factors (sensitization agents) GN in cats.

Infectious

Not infectious

Particular

- Viral infections: FeLV, FIV, coronavirus;

- Bacterial infections (dermatitis, pyometra, gingivitis, endocarditis and etc.);

- Mycotic infections;

- borreliosis;    

- Brucellosis;

- Parasitic infections;

- Iatrogenic (medicinal);

- serums and vaccines;

- Various poisons ;

- heavy metal salts ;

- Radioactive emission;

- inherited causes (hereditary GN and GP);

Probably, one of the leading factors of GN in cats is various low pathogenic viruses, which are constantly, over a lifelong period, persist in organism of the majority of animals (latent and chronic infections).

Also, there are suppositions that various viral AG (antigens), injected during vaccination may be a significant starting factor of GN development in cats.

Of no small importance is the fact that in human, for example, postinfectious GN develops weeks later after recovery from bacterial or viral infection, (streptococcic or staphylococcic infection) against the background of practically complete elimination of AG agent out of the organism.

Virus induced GN in cats, most probably develops under permanent pressing impact of various viral AG. Especially it’s applied to cats which are kept in groups where constant interchange of microflora takes place.

Evident consequence of this process is a constant formation of immune complex of AT + (antibody) + AG (antigen) + C3 with filtration and its attachment and deposition in glomeruli (it’s the most probable but not the only variant of GN development). Perhaps, in connection due to it exactly in cats CKD is diagnosed more often (developed as a direct outcome of chronic course of GN).

Detection of aetiological factors of GN onset in cats is very important for:

  • Prevention of disease onset in healthy cats;
  • Decreasing of the morbidity and mortality level in population of cats in general.

Pathogenetic (immunological) classification.

Non-immune (infrequent) and immune mediated inflammation of glomerule (prevailing type of lesion) are differentiated.

GN of non-immune genesis (secondary) in most cases is a concomitant [coexistent] disease (e.g. in diabetes mellitus or thyroid gland disease) and not taken into consideration in this research. 

Immunologic disorder

 Immune response, which in the final analysis results in glomerulopathy, carried out by a composite multicomponent system that consisting of components of immune system, humoral immunity and coagulation system.

AG (viral antigen, for example) or its part initiates a cascade of responses which finally cause firstly necrosis of glomerular capillary net and then aseptic immune mediated inflammation.

As of today 2 types of process are well known - immune complex and antibody-mediated. Also, as direct pathogenic viral impact on kidney’s cells is not ruled out (non-immune inflammation).

The development mechanism of immune-complex GN is as follows. CIC (circulating immune complex) attach to endothelium of vessels in glomerule and phagocytize by Kupffer's cell or begin to eliminate through filter of glomerule (damaging it). Congregating in glomerule, CIC accumulate on the capillary vascular wall eventually causing microcirculation abnormality.

It’s supposed that in addition to it, CIC activates a whole number of blood coagulation factor and aggregation of thrombocyte. The result of hypercoagulation is microthrombosis which lead to micronecrosis which finally causes reactive inflammation as a final stage of disease.

The source of antigenemia in GN with the antibody mechanism is a basic membrane of glomerule itself, previously damaged in some way (including CIC or viral agents attack). Antibodies are generated exactly to/against a basement membrane (very often it’s an inherited pathology) or antigens, fixed on it.

But not important which exactly mechanism of pathologic development is responding, practically always there is only one outcome – chronic glomerulonephritis in cats develops.

It’s interesting that in every particular case various immune response factors and coagulation system) are involved into pathologic reactions (including also inflammation mediator. From all these multitude factors combinations  and type of sensitization factor, histologic (morphological) type of damage in glomerulonephritis depends. 

Morphological classification of GN and GP

Morphological classification is based on the type of glomerule reaction to injury.

Histologic pattern helps in diagnosing of in determining the etiology of the disease and in choosing of therapeutic decision for each particular patient.

Classification of glomerule lesion

 

I. Proliferation (excrescence) of cells in glomerule.

Many cells in glomerule composition can proliferate in various pathologic states.

1). Intracapillary proliferation of mesangial cells;

2). Intracapillary proliferation and swelling of endothelial cells;

Morphologically detected through an increased number of nucleus in the nodal part of glomerule and through swelling of fenestrated endothelium cells and mesangial matrix (hipercelling and glomerule hypertrophy).  These processes lead to the obliteration of the vascular lumen and significantly disorder microfiltration processes in glomerule.

Fig 1. Cat, female, 11 months. Glomerule. Norm. H&E. Original magnification  400

Fig 2. Cat, female, 9 years. hypercellularglomerule.

urinaryspace  dilatation.   

H&E. Original magnification  400

  

Fig 3. Cat, female, 11 months.

Electron microscopy. Capillary lumen area. Norm. EM x4000

Author’s graphic design.


Fig 4. Cat, ale, 7 years

 Electron microscopy. Capillary lumen and mesangium areas. Luminal narrowing of capillary (incomplete or absolute).

 Accumulation of membranous material in paramesangium zones.

EM x4000

Author’s graphic design.

 

3). Extracapillary proliferation of epithelial cells of the outer layer of Bowman’s capsule.

When significantly evident, it leads to accumulation of cellular (later proteopexy) deposits in parietal layer of Bowman's capsule (“demilune” of segmental or circular shape) and hyalinosis (with thickening) of capsula glomeruli.

4). Lamination of glomerule loops (“palmation” or “lobulation” of glomerule).

 It happens as a result of anomalous collection of membranous material and/or of increased number of mesangial cells (occurs considerably seldom).  

 

Fig 5. Cat, ale, 15 years. «Demilunes»  in Bowman's capsule (1). Focal fibrinoid necrosis (2). 

H&E. Original magnification  400


Fig 6. Cat, female, 9 years. sclerosis of outer layer of Bowman's capsule. “lobulation” of glomerule. 

H&E. Original magnification  400

 

II Infiltration of cortical layer by inflammatory cells.

In the majority of cases when changes in glomerule are evident, infiltration of cortical layer of kidney with agranular leukocytes (lymphocytes, monocytes) is observed.

Agranular leukocytes (lymphocytes, monocytes) infiltrate into renal parenchyma for immune complexes’ neutralization (most probably), constantly generated as response to chronic (latent) viral infections in cats. 

During the research it was discovered that agranulocytic infiltration of various severity appear in cortical layer of renal parenchyma in the majority of cats (aged from 11 month to 22 years) regardless of GN severity.   

This fact indirectly corroborate the conjecture that the cause of GN development in cats are various chronic or latent viral infections which cause constant sensitization factor and, therefore, continuous filtration of circulating immune complex through glomerule for a lifelong period of an animals. 

Fig 7. Cat, female, 7 years old. «palmated» glomerule  and  thickening (hyalinosis) of outer layer of Bowman's capsule.

H&E. Original magnification  400

Fig 8. Cat, female, 11 years old. ««palmated» glomerule and  thickening (hyalinosis) of outer layer of Bowman's capsule.   Focal periglomerular

 agranulocytic infiltration. Dilatation of urinary space.  H&E. Original magnification  400


Fig. 9 and 10. Cat, male, 14 years old. Focal perivascular agranulocitar  infiltration of  cortical layer. H&E. Original magnification H&E. Original magnification 1000

 

 

Fig.11. Cat, male, 14 years old. Diffuse and focal agranulocitar  infiltration of cortical layer. H&E. Original magnification 40

 

   

Fig. 12 & 13. Cat, male, 15 years old. Polycystic renal disease.  Pus collection in pathologic cavities (1).

 

III. Fibrosis of glomerule.

Can be either segmental (when one capillary segment of glomerule is damaged) or global. Global sclerosis results in total loss of glomerular function and is accompanied by fibrosis and atrophy of nephrons. It (GS) can arise on the basis of structural changes, described above or can be a primary.

 

Fig. 14. Cat, male, 18 years old. Global glomerule sclerosis. Van Gieson's stain400

Long-term consequences of GN.

In the absence of early diagnosis and proper complex therapy, the process of autoimmune inflammation of glomeruli rather quickly leads to sclerosis and subsequent involvement of all parts of nephron (distension of tubules and atrophy of tubular epithelium are observed), and then whole cortical layer and medulla layer of kidney into pathologic process (fig. 15-18) (one of possible clinical diagnosis is CKD).   

 

Fig 15. Cat, female, 14 years old. “Lobulation” of glomerule. Sclerosis of Bowman's capsule. Collapse of capillary loop in glomerule. 

H&E. Original magnification 1000

 

   

Fig. 16. Cat. Female, 13 years old. Cystic dilatation of tubule, necrosis of tubular epithelium. Karyorrhexis in stroma (nucleus debris of various size and shape in renal stroma). Hyaline cylinders in tubular lumen.

H&E. Original magnification 400 (photo on the left) and 1000 (photo on the right). 

 

Fig 17. Cat. Female, 13 years old. dilatation of tubule. Karyorrhexis (nucleus debris of various size and shape in renal stroma.

 H&E. Original magnification  400

Fog 18. Cat. Female, 13 years old.

Dilatation of tubule. Karyorrhexis (nucleus debris of various size and shape in renal stroma). Collapse of capillary loop in glomerule.  H&E. Original magnification  100

 

Pyelonephritis

Pyelonephritis (pyelos – pelvis, basin, trough) in cats is a bacterial disease of renal pelvis (not a suppurative inflammation of kidney as this term often translated incorrectly) and, extremely rarely, it’s an inflammation of distal zone of renal tubule (in ascending type of infection). That’s why histology shows granulocytic infiltration of non-cortical layer of parenchyma and, in the worst case, only an infiltration of distal zone of renal tubule is observed.

In cats, by hematogenic tract, bacteria can appear in renal parenchyma in great numbers only during pronounced immunodeficiency state, arising, for example, against extremely pathogenic and virulent viral infections (viral leukemia, viral immunodeficiency, viral peritonitis in cats etc.). However, impetuous colonization of renal parenchyma by bacteria in this case should be correctly identified as a pyo-granulomatosis, not pyelonephritis.

With polycystic kidney disease pus can fill pathologic cavities. But even in this case it is observed only in heavily broken animals.

Types of glomerular lesion

When GN onsets, glomeruli can be damaged to various degree, both all glomeruli and only the part of glomeruli. Focal type of lesion can be defined, when only part of glomeruli are damaged while others remain not affected and diffuse type of lesion, when all glomeruli are damaged.

The glomerule lesion is subdivided/devided into global (all parts of glomerule are injured) and segmental lesion, when only some structures of glomerule are involved into pathologic process.

In cats, in glomerulonephritis, an inflammation has a diffuse character as a rule (circulating immune complex are filtered within all glomerule in some number, and if the changes are not detected in glomeruli with the help of light microscopy at an early stage of pathologic process, they can be detected with electron microscopy) with gradual transformation of segmental lesion into the global lesion.

Table 4. Mechanisms GN presentations, depending on severity.

Mild and average

Severe

  • elevation of permeability of the glomerular capillary wall;
  • compression of glomerular micro capillary net;

 

  • capillary and arteriolar thrombosis and necrosis;
  • glomerular sclerosis and hyalinosis;
  • renal tubular atrophy (rare)

 

At the final stages of development of pathologic process, apparent focal nephrosclerosis and karyorrhexis (which is often precessed by pyknosis) can be observed. 

Clinical classification of GN and GP in cats

There is no generally accepted clinical classification of GN and GP in cats up to now.

Classification system of stages of CKD is based according to stages of renal azotemia and was suggested by IRIS in 2006 (www.iris-kidney.com).
 

Why exactly cats more often develop GN?

Theories and hypotheses. 

  • A large number of species-specific viral infections with chronic or latent types of disease course.
  • Animals are kept in groups where constant interchange of viral agents takes place; this initiate a cascade of immunological responses, and one of the possible outcomes of this process is a formation of immune complex.
  • Insufficiently effective elimination of immune complexes through glomerular microcapillary net, quite possibly because of physiological “characteristic” of this animal species.
  • Limited choice of effective
  • Absence of widespread in veterinary medical practice institution of nephroprotective preparations to the patients (cats) that suffer from or recovered from an acute viral infection.
  • Peculiarities of protein metabolism in obligate predators, which possibly may have negative impact on renal function (especially on microfiltration in glomerule).

Diagnosing of GN and GP

Clinical presentation of chronic glomerulonephritis in man has its typical pattern, and declares itself in the form of urinary syndrome, nephritic and nephrotic (hypertension and congestive subcutaneous edema) syndromes. However, chronic glomerulonephritis in cats, in most cases, and over a long period of time may manifests only with isolated urinary syndrome (microhematuria and proteinuria), and possibly later can be attended by concomitant latent CRI (abnormal [pathological] changes in blood examinations, however, clinical signs may be minor or may absent).

Just this fact is the basic issue with this pathology. The cat’s owners usually do not notice any kind of changes in animal’s general well-being and chronic glomerulonephritis frequently is diagnosed as a chance founding during examinations connected with some others pathologies.

Clinical signs (usually they are nonspecific, asthenia, anorexia, vomiting, oliguria, health aggravation, skin and hair coat quality aggravation) onset when pathosis has gone too far and considerable part of glomeruli were destroyed.

In other words, the overwhelming majority of cats’ owners consult a doctor only when CRI had already developed mean or severe form.  Hydrosarca edema and hypertension, with the exception of severe cases of AKI, occur rarely.

Chronic glomerulonephritis is delayed-action bomb. First of all it’s a pathologic process which will slowly or quickly destroy the kidney during lifetime period, and eventually will result in serious dysfunctions in organism.

Secondly, effect of any nephrotoxic agents (such as aminoglycoside antibiotics, nonsteroidal anti-inflammatory drugs, NSAID (non-steroidal anti-inflammatory drugs), cytostatic agent, heavy metal salts) and stress s well, can lead to galloping renal insufficiency with fatal [lethal] termination. 

What does standard nephrological examination include?

  • Anamnesis
  • clinical examination and palpation of urogenital system
  • complete blood count
  • biochemical analysis of blood
  • urinalysis (with microscopy of urinary sediment )
  • ultrasound examination of kidneys and urinary tracts
  • bacterial inoculation by direct urine inoculation method (urine is obtained out of bladder, rarely , out of renal pelvis)
  • virological examination 

Anamnesis.

Complains of the animals’ owners (according to the heal level of animal and clinical signs) during various nephropathy (excluding urolithiasis) are presented in the table 5.

Table 5.

Very often

 

Often

(inherently a result of   azotemia)

Not often

Seldom

(mostly at the 3d-4th   (terminal) stage of  chronic renal insufficiency)

- no any nephrological  complaints

 

- deterioration of skin and hair coat condition

- vomiting;

- asthenia;

- anorexia;

- cachexia;

 

 

- macrohematuria;

- oliguria;

- strangury;

- uremic [azotemic] gastritis;

 

- «ammoniac»  breath;

- labored respiration, «abdominal breathing» (hydrothorax, pulmonary embolism);

- high intraocular pressure (accommodation of eye disorder,

 « edema » and retina hemorrhage);

- paresis or paralysis of limbs ;

- Epileptoid attack, tonic [tetanic] convulsions;

- lethargy;

- polyarthritis;

 

 

Clinical examination and palpation of urogenital system organs.

During clinical examination it’s necessary to pay attention to:

  • Condition of hair coat and cutaneous covering (as a rule intensive fall-off and/or deterioration of hair coat condition, xerosis, also seborrhea sicca (or, seldom, seborrhea oleosa) with dandruff are detected).
  • Urinary bladder capacity (attention should be paid both to the lack of urine (oliguria - or anuria is possible), and pay attention to replete of urinary bladder (obstruction of urinary tracts and development of postrenal uremia are possible).
  • Size (comparatively to the size of the other kidney) and density of kidneys during palpation (pronounced tuberosity of kidney may be indicative of polycystic renal disease, and pathologic induration of kidney, its dissimilar size can be indicative of sclerosis of parenchyma (nephrosclerosis), renal amyloidosis or neoplasia)).
  • The type and respiratory rate (“abdominal” type of breathing is an unfavorable, inauspicious and alarming symptom, which can be indicative of hydrothorax and lesser in [pulmonary] circulatory congestion);
  • Condition of mucous membranes (inconspicuousness of membrane may indicate anemia, and xerostomia may indicate hypovolemia);
  • The body temperature (hypothermia ,very often, is a sign of terminal (4th) stage of pyelonephritis and is a threatening symptom; hyperthermia in renal disease is a very rare phenomenon (even if pyelonephritis and pyogranulomatosis) and is a consequences of concomitant [coexistent] diseases (viral infection, for example));

 

Laboratory diagnostics

Laboratory diagnostics of biologic fluids helps not only to confirm (indirectly) tentative clinical diagnosis but also to detect associated pathology of other organs and systems.

Table 6. Pathological changes in results of laboratory examinations of biologic fluids in various types of GN.

Type of laboratory research

Acute glomerulonephritis or  relapse of chronic glomerulonephritis

Chronic glomerulopathy or

chronic glomerulonephritis

 

Complete blood count         

- erythrocyte sedimentation rate, ESR - increased from average to high;

- moderate leukocytosis;

- leukogram, left shift;

- ESR - norm or slightly increased;

- minor leukocytosis;

-

Leukogram, left shift

 

Complete

urine analysis

- proteinuria *;

- erythrocyturia (possibly  macrohematuria);

- granular cylinders in urinary sediment

- proteinuria *;

- erythrocyturia (less apparent than  in AGN);

- leucocyturia;

- cylindruria;

 

 

 

Biochemical blood analysis

- Creatinine ratio (concentration) and  urea’ ratio are raised(depending upon stage of glomerular damage);

- general protein - norm;

- ά-2 globulins - increased;

- severe hyperkalemia

- C-reactive protein (CRP) is raised from mild to high

Creatinine ratio (concentration) and  urea’ ratio are raised(depending upon stage of glomerular damage);

- - general protein – from average to slightly C-reactive protein (CRP)from normal to slightly raised

* The degree of proteinuria should correlate with the density of urine. For example, a small value of protein in urine (traces - 1 +) of normal density (> 1.035) may be a variant of the norm. At the same time, if density of urine below 1.020, even traces of the protein indicate nephropathy.

Important. Presence of fat drops in urine of cats is the norm. It’s connected with the fact that in cytoplasm of high columnar epithelium of proximal renal tubules in cats lipidic vacuoles are normally found.

Fig 19. Cat, female, 2 months. Lipidic vacuole (peach color) in cytoplasm of tall cylindrical epithelium of proximal tubule. Sudan 40.

 

Fig. 20. Cat, female, 19 years old. Lipidic vacuole (peach color) in cytoplasm of tall cylindrical epithelium of proximal tubule in cat is on the border between cortical and medulla layers.  Sudan 40.


Ultrasonic scanning of urogenital system

At early stages of GN and GP development there are no US characteristic signs.

Structural changes of renal parenchyma (such as thickening, induration, thinning and individual cysts) come to light during US and, as a rule, at later stages of disease development.

The presence of marked structural changes in renal parenchyma indicates that the pathological process in the kidney has already led, for example, to the loss (sclerosis) of the majority of glomeruli (nephrosclerosis).

However, specific nephrological diagnosis (for example Glomerulonephritis, tubular interstitial disease, amyloidosis etc.) is not made with the help of US diagnostics.  Usually, in diagnostic decision (US) the conclusion that “structural changes in renal parenchyma” or “structural changes in kidneys” if renal pelvis is involved in patological process, is made.

However, ultrasound by all means must be included in a complex examination of every patient with suspected GN and GP (or any other nephropathy) since it makes possible to carry out  diagnostics of other diseases of urogenital system., such as nephrocalcinosis, urolithiasis, polycystic renal disease, hydronephrosis and so on.

Bacterial inoculation of urine

Is carried out when infectious (bacterial) processes in kidneys and urinary tracts are suspected. Indirect signs of septic inflammation in urinary sediment (in unstained preparation or stained according to Giemsa stain) are as follows:

- bacteria;

- increased number of granulocytes (neutrophil, eosinophilic cells, basophil with  normal or slightly increased number of agranulocytes (lymphocytes, monocytes);

- pieces (fibres) of mucous of urinary bladder;

- leukocyte and granular renal cylinders;

- increased number of epithelial cells;

Urine for bacterial inoculation is taken only by force of urocystocyntesis. Bladder catheterization for bacterial inoculation is incorrect (both from the standpoint of bacteriology, and also because of injuring and contamination of mucous membrane of urethra).

Differented (has a similar clinical presentation as GN) diagnosis – urocystitis.

In urocystitis, in urinary sediment, there is no leukocytic nephric cylinders (or any other), besides, slime layer and detruser of urinary bladder are thickened and obvious during US.

Repeated/multyple ureteric catheterization is also a predisposing factor to urethritis, urocystitis and to ascending infection of urinary tracts and kidneys as a result.

Virological examination

To significant viral infections, the role of which in kidney’s lesion is proved scientifically the following infections refers:

- FeLV,

-FIV

- Coronavirus (Infectious peritonitis);

If there are any viral infections stated in the anamnesis of the animal it is a strong argument for conducting a complex nephrological examination.

Also it’s necessary to remember that GP and GN are not viral but viral induced diseases. Therefore, the symptoms of GN emerge only some time later after recovery from a viral infection. 

 If GN is diagnosed jointly with some other acute infection then most probably that animal already has glomerulopathy at the moment.

Treatment of viral infections in cats should be complexed and carried out under the control over the kidney’ function and, if it’s necessary, include (at the earliest possible stage of disease) nephroprotective and anti-inflammatory drugs (including glucocorticoid in anti-inflammatory and immunosuppressant doses).

Clinical signs of GN and GP in cats with due account taken of anamnesis and non-invasive diagnostic techniques are given in the table 7. 

Table 7.

Often

Not often

Seldom

- nephritic syndrome;

- isolated proteinuria;

- isolated hematuria;

- changing of urinary sediment;

- Latent renal insufficiency;

- chronic renal insufficiency;

- non-specific pathology;

 

- hypertension;

- Rise of intraocular pressure which result in accommodation of the eye disorder, blindness, «edema» and retinal haemorrhage

 - thromboembolism of great blood vessels:

    - pulmonary arteries: dyspnea, tachycardia, hypothermia;

    - iliac arteries:

- paresis or paralysis  of hind limbs ;

- US signs: structural changes in renal parenchyma (diffuse  inhomogeneous sclerosis of parenchyma, as well as its  thinning at later stages);

- metabolic acidosis;

 

- nephrotic  syndrome(syndromum nephroticum);

- hypertension;

-  galloping renal insufficiency

 (with hydrothorax);

 

Hypertension in cats in GN and GP.

Persistent hypertension in humans with GN is one of the most significant clinical signs. However, by virtue of variety of reasons it’s possible to suppose that this symptom in cats is less frequent.

Besides, tonometry in cats is a matter of difficulties. Blood pressure in this animal species can be measured both by means of in situ (direct) and with indirect methods. However, only tonometry by means of catheterization of peripheric vessels can give accurate results.

But this technique is difficult in execution, requires sedation of the patient and of little acceptance in routine work of general practitioner.

Whereas indirect methods of tonometry very often give inaccurate data due to a variety  artifacts relating both to the patient itself (stress in cats caused by presence in clinic, low weigh, deficient pulse and so on) and to technicality (lack of available universal highly sensitive tonometers for (small) animals.).

In addition to it, most of drugs used for symptomatic therapy of GN and GP (angiotensin-converting enzyme inhibitor, calcium channel blockers, and diuretics) have hypotensive effect and usually administered to the patient for a long-term period.

For this reason, tonometry in cats, although it may help in the diagnosis of GN and GP, is not required for the monitoring of this type of disease.

Besides, according to findings of carried out histomorphological research, the signs of persistent intravital hypertension were detected only in less that 2 % of cats.

Moreover, given pathology can be attributed both to consequences of nephropathy and to any other chronic disease, accompanied by hypertension (cardiomyopathy).

Fig 20. Cat, male, 15 years old. Sclerosis of vascular wall. Van Gieson's stain40.

Clinical symptom – persistent intravital hypertension.

Fig 21. Cat, female, 19 years old. Sclerosis of vascular wall. Van Gieson's stain400.

Clinical symptom – persistent intravital hypertension.

 


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