Canine renal disease

Introduction

The term “kidney disease” encompass a large group of congenital and acquired diseases that affect the integrity or the functioning of the kidney (1). With either a partial or total failure of some of the kidney’s multiple functions, a dog’s overall health can be severely affected, and a broad spectrum of acute or chronic systemic signs can be expected. This emphasizes the need for a thorough and systematic diagnostic approach, as well as the use of more specific analyses to clearly define the underlying condition and the manifestations of the kidney problem. 

The use of global terms such as “acute kidney injury” (AKI) or “chronic kidney disease” (CKD) should not hide the need for a specific diagnosis, as this will dictate the therapeutic strategy and the expected outcome for an individual animal. The value of these terms lies mostly in the recognition and the emphasis of similarities in signs and treatment needs between closely related conditions. In early CKD however, the approach not only aims at symptomatically addressing the clinical signs, but it should also attempt to identify the primary etiology, with the goal of influencing or reversing the course of the disease. 

Chronic kidney disease 

Chronic kidney disease (CKD) is a progressive and irreversible condition in which the kidneys lose their ability to function over time. Even though the histological pattern of a chronic interstitial nephritis is quite uniform and rarely identifies the primary disease in advanced stages, the underlying causes, which include genetic, infectious, toxic, immune or degenerative conditions, can vary. Chronic kidney disease can thus be viewed as the irreversible result of a variety of chronic diseases (1). Current opinion is that CKD in dogs often results from a glomerular disease, in which the resulting metabolic disturbances and the proteinuria progressively damage the tubulo-interstitial compartment. Unfortunately, CKD is often diagnosed late in its course, when treatment options are limited and primarily oriented towards symptomatic or palliative support. The diagnostic approach to a dog with suspected CKD typically involves 4 steps: 

1. Confirmation of kidney disease and chronicity. 
2. Identification of the underlying etiology. 
3. Staging and characterization of the clinical and metabolic consequences of CKD. 
4. Evaluation for disease activity and risk of progression. 

A diagnosis of CKD is based on the collective information from history, physical examination, clinicopathological data, and imaging findings. It should ensure that pre- and post-renal causes of azotemia are excluded (or minimal in combined cases) and that the disease persists for more than three months. Typically, a CKD diagnosis will result from the indirect observation of a decreased glomerular filtration rate via increased serum concentration of the surrogate markers creatinine or symmetric dimethylarginine (SDMA) (e.g., persisting azotemia), of an abnormal glomerular function (e.g., persisting renal proteinuria), of an abnormal tubular function (e.g., loss of urine concentrating ability, inappropriate loss of urinary potassium, glucose, or bicarbonate), or of an altered renal structure (e.g., cysts, infarcts, uroliths or neoplasia). As none of these diagnostic variables is pathognomonic for CKD, a final diagnosis should always include a broad approach, combining blood tests and urinalysis (1,2). 

Based on the recommendations of the International Renal Interest Society (IRIS), the preferred criteria for a diagnosis of CKD should include increased creatinine or SDMA concentration combined with decreased urine concentrating ability (USG <1.030) and evidence of chronicity (from persistence of laboratory changes, ultrasound, and palpation). In early stages of CKD, urine concentration may not be affected, and a suspicion could be formulated: 

• with slowly increasing serum creatinine or SDMA within the normal range, 
• in the absence of apparent prerenal causes; with a persistently elevated SDMA; 
• with abnormal kidney imaging; or with persistent renal proteinuria (i.e., urine protein:creatinine ratio (UPC) > 0.5) (2).

It should be emphasized that even evaluation for possible early-stage kidney disease can never be considered complete without urinalysis, whether this is for identification of its cause or of its consequences. Azotemia alone is not equivalent to kidney disease; it solely reflects altered kidney or urinary tract function, even when “confirmed” with sensitive biomarkers of early CKD such as SDMA. Increased serum creatinine or SDMA concentrations can also be seen with pre-renal conditions (e.g., dehydration or hypovolemia) and post-renal conditions (e.g., urinary tract obstruction or rupture), as well as with primary kidney disorders. 

The value of widely available imaging modalities such as ultrasound for the early diagnosis of CKD depends vastly on the experience of the imager, with a risk of overinterpretation of normal variants. Imaging should nevertheless always be an integral part of kidney evaluation, as it can indicate specific changes in renal architecture, with important therapeutic considerations (Figure 1). For example, identification of multiple renal cysts can point to a genetic etiology of CKD; moderate pyelectasia and ureteral dilatation can indicate an ectopic ureter with secondary CKD; or the presence of uroliths can indicate repeated episodes of obstructive uropathy with secondary CKD. 

The mere diagnosis of CKD is never sufficient in the evaluation of an affected dog. Depending on its severity, it may just be an incidental finding without current relevance for the immediate clinical question, or it may be a death sentence in end-stage disease (Figures 2 and 3). A diagnosis of CKD should therefore be refined by assessing its severity (i.e., staging) and establishing an actual list of its clinical and metabolic complications for the affected individual (1). This detailed approach aims at providing a basis for prognosis and establishing an individualized treatment plan. A first evaluation of disease severity is usually based on the staging, using serum creatinine and SDMA concentrations at steady state, following the IRIS criteria (Table 1). It is important to emphasize that the staging system is not aiming at diagnosing CKD, but rather as the basis for a standardized nomenclature, and it provides first rough guidelines concerning treatment and monitoring. It therefore should be performed after confirming a diagnosis of CKD, and when the dog has stable kidney function. Substages of CKD are based on the presence of proteinuria (via UPC) and systemic hypertension (measured as systolic blood pressure, SBP), the two main complications associated with faster progression of CKD (2). 

 

Table 1. Staging of canine CKD (from (2)).

As more metabolic derangements are expected with advanced disease, the diagnostic needs will increase in later stages compared to earlier stages of CKD. The value of an individualized and systematic approach is particularly obvious with the example of systemic hypertension. Dogs with CKD are at risk of hypertension at any stage of the disease, but this risk increases with disease progression. Although a dog with stage 1 CKD is not likely to develop hypertensive complications, it is nevertheless possible that sight loss will occur due to retinal detachment, emphasizing the importance of a systematic assessment of blood pressure in the evaluation of all dogs with suspect CKD. A recent study has shown that urinary cystatin B was able to differentiate dogs with stable versus progressive CKD (3). This kidney injury biomarker should therefore be considered for both initial and follow up characterization of dogs with CKD. A full “CKD checklist” (Table 2) can be used to establish a prioritized and individualized problem list for a dog with CKD, and to design an appropriate treatment plan (1). 

 

Table 2. CKD checklist of expected manifestations.

 

Acute kidney injury (AKI)

Acute kidney injury is defined as a new-onset injury to the renal parenchyma (4). Depending on its specificity and extent, it can affect one, multiple, or all kidney functions, or it may only be recognized by measurement of specific injury biomarkers (e.g., urine casts; renal glucosuria; urinary gamma-glutamyl transferase (GGT), urinary cystatin B, or urinary neutrophil gelatinase-associated lipocalin (NGAL)) when renal function is not noticeably altered. Various mechanisms can lead to AKI (Table 3) and, depending on the presentation, it is possible to differentiate between community-acquired AKI and hospital-acquired AKI (5). 

 

Table 3. Main causes of AKI in the dog.

 

Dogs with the former (e.g., toxicities, leptospirosis) tend to present in advanced stages of kidney failure, and the diagnosis of AKI is usually obvious (Figure 4). In the latter category, the clinical signs are typically dominated by the primary disease (e.g., sepsis, acute pancreatitis) and the renal involvement tends to be more subtle. However, even when secondary, AKI can cause catastrophic and life-threatening failure of all kidney functions, and even mild forms of hospital-acquired AKI have been shown to markedly affect the outcome of the primary disease. For example, in a recent study 40% of dogs having surgery for septic peritonitis were diagnosed with AKI at presentation or during hospitalization (6). Affected dogs had 80% decreased odds of survival to discharge compared to non-affected dogs (mortality rates 39% vs. 9%). Therefore, clinicians must maintain a high suspicion and pro-active monitoring for dogs with critical illness at risk of AKI, before renal failure dominates the clinical picture. 

A diagnosis of AKI is based on a combination of historical data, clinical and laboratory examination findings that document acute (within 48 hours) decline in kidney function and/or increase in kidney injury biomarkers. An increase of serum creatinine by 0.3 mg/dL (26 µmol/L) even when within the reference range should be considered diagnostic for AKI. Although this could be the functional consequence of a primary pre-renal condition (e.g., dehydration, hypovolemia) rather than a true injury to the renal parenchyma, this change represents at best a non-optimal condition for the kidney, and therefore a risk for injury. This global definition, based on serum creatinine alone, should not be viewed as a license to bypass urinalysis in a suspect patient. Progressive azotemia with high USG may indicate a need to optimize fluid therapy and to improve vascular volume status (Figures 5-6). Even when associated with an apparently stable renal function, the presence of multiple granular casts in the urinalysis of a critically ill dog should always provoke a detailed review of the cardiovascular status, control of the primary disease (e.g., sepsis), the possibility of secondary infectious or inflammatory complications (e.g., sepsis, pancreatitis), and of the appropriateness of the drugs used. The role of imaging in the diagnosis of AKI primarily aims at identifying the primary etiology of the disease and to rule out unrecognized underlying CKD, which has strong prognostic implications. As with CKD, a AKI diagnosis should not stop at recognizing the disease, but should include categorization (Table 4) and a thorough evaluation of the associated metabolic alterations (see the “AKI checklist” in Table 5). This will allow establishment of an individualized treatment and monitoring plan. 

 

Table 4. IRIS Grading of AKI (9).

 

Table 5. AKI checklist of expected manifestations.

Placing the focus on injury rather than on functional failure, the new nomenclature of AKI emphasizes the importance of early diagnosis by recognizing the presence of injury before failure dominates the picture (4). A next step could be to further highlight the activity of the disease and injury. A more active kidney injury should be addressed diagnostically with a more intensive approach than an inactive form of AKI, in order to reverse the course of disease and avoid additional kidney damage. The availability of new injury biomarkers (e.g., urinary cystatin B, NGAL) may therefore improve our ability to evaluate this aspect of the disease. This concept of disease activity may however blur the distinction between CKD and AKI, as rapidly progressive CKD may not be vastly different from a low activity AKI, as suggested in a recent review (11). 

Acute on chronic disease

The acute exacerbation of a known CKD (“acute on chronic kidney disease”) is a particular form of AKI in which the kidney has already been damaged prior to the onset of the current injury (12). The exact condition of the kidney at that time is however rarely known, and the clinician is usually limited to the possibility of either an AKI on an apparently intact kidney, or an AKI on an obviously pre-damaged kidney. These mixed acute-chronic forms of kidney disease are quite prevalent due to the predisposition of animals with CKD to suffer acute decompensation episodes (acute-on-chronic) and to the frequent chronic sequelae of dogs with AKI with only partial recovery (chronic-on-acute). The mixed features of acute and chronic kidney disease are typically approached as mentioned above: i.e., as a dog with AKI during active phases and as a dog with CKD during stable and quiet phases. This further emphasizes the importance of considering disease activity rather than to focus solely on timing characteristics of the disease. 

Glomerular diseases (GD)

This is a heterogenous set of kidney diseases, primarily characterized by a qualitatively abnormal glomerular filtration pattern with persistent renal proteinuria (Table 6) (13). Most GD in the dog are chronic, with a marked tendency to progress from a disease dominated by the consequences of proteinuria (e.g., edema, systemic hypertension, protein malnutrition, thromboembolism) to a disease dominated by a slowly emerging azotemia and uremia. Occasionally, a more acute form of the disease is recognized in the dog, as may be seen with infections with Borrelia burgdorferi. 

 

Table 6. Main causes of GD in the dog (14).

 

For clinical and therapeutic purposes, a differentiation between immune and non-immune mediated diseases is essential. Immune-mediated GD represent an important subset of dogs presented with GD, although the prevalence varies geographically (e.g., UK 27%, USA 48%) and affected animals are unlikely to respond satisfactorily to standard antiproteinuric treatment without addressing the underlying immune disease (15,16). However, immunosuppression will have only negative effects in dogs with non-immune-mediated GD. A kidney biopsy with extensive evaluation (including special light microscopic stains, immunofluorescence, and electron microscopy) is currently the only possibility to differentiate these entities (Figure 7), and it is therefore highly recommended, particularly in initial stages of the disease (when a dog is proteinuric but not azotemic or only mildly azotemic). Since immune-mediated GD can be secondary to chronic infectious and parasitic diseases, a thorough screening process should be performed, based on the diseases prevalent in the geographic area of interest. The main infections associated with canine GD in central Europe include leishmaniasis, dirofilariasis, babesiosis, ehrlichiosis, anaplasmosis, and borreliosis, as well as localized infections of various etiologies (e.g., abscess, lobar pneumonia, prostatitis, or discospondylitis) (17). 

A confirmation of the glomerular origin of the urinary proteins can be obtained with a urine protein SDS-AGE or SDS-PAGE electrophoresis, which can differentiate large-sized proteins (glomerular origin) from small-sized proteins (tubular origin). This is however not a substitute for a kidney biopsy, as it cannot determine the underlying etiology, nor the disease mechanism (13). 

Further characterization of the disease manifestations should be performed as for AKI or CKD. A special emphasis should be given to a thorough evaluation for systemic hypertension (repeated blood pressure measurement, fundic exam), thromboembolic risk and complications (viscoelastic tests of hemostasis, i.e., thromboelastometry), presence of edema or effusions (physical examination, point-of-care ultrasound), and nutritional status (body condition score, muscle condition score, serial body weight) (18). 

Other kidney diseases

Although most kidney diseases can be grouped in one of the three entities described above, some functional defects in the initial stages may not fit any of these categories. For example, as a specific tubular transporter defect, renal glucosuria does not usually progress to azotemic CKD. This contrasts with its broader tubular defect counterpart, Fanconi syndrome, which shows a wide range of tubular dysfunction and progressive development of azotemia. Other tubular transport defects (e.g., cystinuria) may manifest primarily as obstructive conditions of the lower urinary tract secondary to urolith formation. Specific acid-base disorders (e.g., renal tubular acidosis) may produce clinical signs mostly related to the metabolic disturbances (e.g., hypokalemia, metabolic acidosis) although they will usually tend to progress to CKD over time. As a main regulator of blood pressure, the kidney is typically evaluated in suspect idiopathic forms of systemic hypertension. However, the initial differentiation between primary (idiopathic) hypertension and secondary renal hypertension associated with early-stage CKD may not be definitively possible in some dogs if they are not azotemic. Focal renal diseases (e.g., renal infarcts, renal neoplasia, or renal abscesses) may be found incidentally in the absence of metabolic or functional consequences, although in some dogs they can result in hematuria, which should prompt diagnostic imaging evaluation. 

Conclusion

Despite the trend to simplify the nomenclature of kidney diseases with global terms like chronic kidney disease, acute kidney injury, or protein-losing glomerular diseases, this should not hide the essential need for appropriate diagnostics to identify the exact etiology of the problem and thus provide the basis for designing a proper therapeutic approach. Furthermore, the diagnostic approach should include a complete staging or grading, and a thorough characterization of the clinical, laboratory and metabolic complications of the disease in order to individualize the treatment based on the actual needs of the affected dog. 

References

 

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