Development of Clinical Guidelines for Management of Glomerular Disease in Dogs
- Co-Chairs – IRIS Glomerular Disease Study Group (Polzin, Cowgill)
chronic kidney disease
International Renal Interest Society
Scope and Clinical Significance of Glomerular Disease in Dogs
Glomerular disease (GD) in dogs has recently experienced a rising profile among veterinarians in part attributable to enhanced efforts to facilitate early recognition, diagnosis, and treatment of kidney disease and particularly proteinuric kidney diseases in dogs. One of the primary goals in developing the IRIS CKD Staging system1 was to increase early recognition of kidney disease with the belief that early diagnosis would improve overall management of dogs and cats with chronic kidney disease (CKD). Furthermore, inclusion of proteinuria as one of the core descriptors of the IRIS CKD Stage has emphasized the importance of proteinuria and glomerular injury. Over the past 6 years, the WSAVA Renal Standardization Project2 has been operating with the goal of developing a unique classification system for canine GD based on light, electron, and immunofluorescent microscopic imaging of the glomerular pathology. The outcome of this study has the potential to advance our understanding of GD in dogs to a new level, potentially opening many new options for improving our ability to diagnose and manage GD in dogs. The apparent association between GD and infectious diseases, such as borreliosis in selected areas within North America and leishmaniasis in the Mediterranean area of Europe, has also enhanced awareness of the importance of GD and potential value of proteinuria as a sentinel for certain infectious diseases.[1, 2]
Although an accurate measure of the prevalence of GD in dogs has not been established, veterinarians generally recognize it as an important cause of morbidity and mortality in dogs. Although not always recognized as such, GD may present as several renal syndromes in dogs, including CKD, acute kidney injury, nephrotic syndrome (NS), or isolated proteinuria. Of these syndromes, the best-defined population data are available for CKD. The prevalence of CKD in dogs has been estimated to be as high as 1.5% of dogs presented in general veterinary practice. Based on renal pathology findings, it has been estimated that GD may account for over 50% of cases of CKD in dogs. Extrapolating from these data, it may be estimated that the prevalence of GD in dogs may be in excess of 0.75% of dogs seen in general practice.
Of particular concern is the observation that many dogs with GD have seemingly poor outcomes when treated with current therapies.[5, 6] A recent study reported that median survival time for dogs with NS was 12.5 days, although survival among nonsurvivors ranged as high as 2,783 days. In this same study, median survival for dogs with non-nephrotic GD was 104.5 days with survival ranging up to 3,124 days. The presence of NS and azotemia, in particular, portended especially poor outcomes in dogs with GD. Nonazotemic dogs with NS had significantly shorter survival times (median of 51 days; mean of 390 days) than nonazotemic dogs with non-nephrotic GD (median of 605 days; mean of 71 days). In contrast, survival for azotemic dogs with NS (median of 10 days; mean of 316 days) and non-nephrotic GD (median of 45 days; mean of 390 days) was particularly grave and not significantly different. Clearly, we need to seek ways to improve our therapeutic success in these dogs. Many of the therapeutic recommendations found in the guidelines provided in this supplement issue are aimed specifically at improving outcomes among dogs with the gravest prognoses.
Need for Treatment Guidelines
In human medicine, therapeutic guidelines are viewed as an important clinical tool in enhancing the overall quality of patient care. Ideally, recommendations provided through clinical guidelines are based on high-quality evidence. However, despite the increased recognition of the importance of GD in dogs, only a few select studies provide high-grade evidence on which to base treatment recommendations. Even the “standard therapy” recommended for dogs with GD, which typically includes an angiotensin converting enzyme inhibitor, diet, and aspirin therapy, has little convincing evidence supporting their effectiveness in improving clinical signs or extending survival times. Obviously, when high-quality evidence is available, developing treatment guidelines is very straight forward and largely noncontroversial. In contrast, developing guidelines absent strong clinical studies to support that the recommendations is challenging. Although one option would be to choose not to make recommendations in the absence of firm evidence, it is often in the areas of greatest uncertainty, and in which the evidentiary base is incomplete, that guidelines are needed most. Clearly, the current state of affairs for treatment guidelines for GD in dogs is of the latter type, and yet the veterinary profession needs guidance in how to manage these difficult cases.
Clinical practice guidelines for managing dogs with GD are needed to improve clinical outcomes. In response to this need, the International Renal Interest Society (IRIS) appointed a 20-member international work group (the IRIS Glomerular Disease Study Group) and charged them with developing clinical guidelines for managing dogs with GD. This charge was made with the understanding that while the limited literature available in dogs with GD will provide underpinning for some recommendations, most recommendations will reflect consensus of opinion based on the literature, review of case material, and the clinical experience of the members of the Study Group. It is our belief that these clinical guidelines are a starting point in the journey to improve the treatment of dogs with GD. They should not be viewed as the final word in management of dogs with GD, and the guidelines should be regularly revisited, reviewed, tested, and updated as new scientific evidence is acquired.
The clinical guidelines presented herein are intended to provide counsel on how to approach diagnosis and treatment as recommended by established experts in the field of veterinary nephrology. The recommendations have been written primarily for an expected audience of veterinary internal medicine specialists, but it is our hope that other veterinarians involved in the management of dogs with GD will also find it useful. However, these guidelines are not intended to replace the veterinarian's own clinical judgment in the application of these recommendations. Application of the recommendations should meet each individual dog's needs and circumstances.
Methodology for Guideline Development
The clinical guidelines provided here were developed by the IRIS GN Study Group, a group composed of 20 veterinarians with expertise in canine GD and nephrology (Table 1). From this larger group, five subgroups were formed to develop proposed clinical guidelines for (1) diagnostic investigation of dogs with suspected GD; (2) standard therapy for dogs with GD; (3) immunosuppressive treatment of dogs with GD based on established pathology findings; (4) immunosuppressive treatment of dogs with GD absent a pathologic diagnosis; and (5) treatment for dogs with GD that are also serology positive for an infectious agent possibly responsible for the GD. Each subgroup performed a literature search, and reviewed any unpublished clinical material available, appropriate and relevant to their topic. Each subgroup (topic steering committee) met as needed by online conferencing to develop recommendations and rationale for each recommendation.
Table 1. Members of the IRIS Glomerular Disease Study Group.
|Claudio Brovidaa||Scott Browna|
|Larry Cowgill (co-chair) a||Sylvie Daminet|
|Mª Josefa Fernández del Palacioa||Jonathan Elliota|
|Thierry Francey||Bernard Gerber|
|Richard Goldstein||Greg Grauera|
|Reidun Heinea||Mary A. Labato|
|Cathy Langston||George Lees|
|Meryl Littman||David Polzin (co-chair) a|
|Barrak Pressler||Gilad Segev|
|Shelly Vaden||Astrid van Dongena|
|Andrea Zatelli|| |
Because much of the evidence available to support recommendations on management of canine GD is limited, inconsistent, indirect, or of poor quality, a formal consensus method was used to validate the recommendations. This approach is particularly useful when available evidence fails to provide a clear path to a recommendation. Specifically, the formal consensus method is particularly useful for developing recommendations when a clear evidence-based recommendation is not available. The formal consensus method involves iterations of independent anonymous voting on draft recommendations and subsequent revisions.[8, 9] Members of the IRIS Glomerular Disease Study Group and the IRIS Board (Tables 1, 2) voted on all recommendations and provided comments on the recommendations and their rationale. Participants were asked to identify their level of support with the recommendations using a scale of “strongly agree,” “agree,” “neutral,” “disagree,” or “strongly disagree.” Anonymity of the voting and submitted comments was maintained by submission of ballots and comments to a disinterested third party who forwarded the masked ballots and comments to one of the co-chairs (djp) for counting and reporting to the subgroups. To achieve a consensus, a minimum of 75% of the voting participants must choose either “strongly agree” or “agree.” The percentage of those supporting the recommendation and the percentage of supporters that voted “strongly agree” are provided as assessments of the strength of consensus for the recommendation. If the recommendation did not achieve consensus after the first vote, the recommendation was returned to the subcommittee with the voter comments for rewriting or reconsideration. If a modified recommendation was developed by the subcommittee, it was subjected to a second round of voting and comment. If a recommendation failed on the second vote, no recommendation was made.
Table 2. Members of the International Renal Interest Society (IRIS) Board.
|Claudio Brovida (Italy)|
|Scott Brown (President, IRIS Board, USA)|
|Larry Cowgill (co-chair; USA)|
|Jonathan Elliot (UK)|
|Mª Josefa Fernández del Palacio (Spain)|
|Greg Grauer (USA)|
|Mary A. Labato (USA)|
|Herve P. Lefebvre (France)a|
|Xavier Roura López (Spain)a|
|Alexander Hüttig (Germany)|
|Reidun Heine (Norway)|
|David Polzin (co-chair; USA)|
|Jean-Louis Pouchelon (France)a|
|Astrid van Dongen (Netherlands)|
|Toshifume Watanabe (Japan)|
|David Watson (Australia)a|
Where Do We Go From Here?
The Clinical Guidelines provided herein are intended to help veterinarians develop diagnostic and therapeutic plans that reflect the opinion of the majority of experts participating in this exercise. Although it is our hope that veterinarians find these guidelines helpful and that they will improve the care of dogs with GD, these guidelines are not intended to be the final statements on managing canine GD. Further studies are needed to confirm or reject these recommendations based on higher levels of evidence such as randomized clinical trials or large observational studies. Ideally, clinical trials will focus on treatments for specific glomerulopathies based on renal biopsy findings. However, even in humans, GD is sufficiently uncommon that it is considered difficult to perform randomized clinical trials to define optimal treatment for many specific glomerulopathies. As a result, multicenter studies are likely to be necessary for future trials to be successful. In addition, perhaps the profession should consider developing a veterinary nephrology database similar to The United States Renal Data System, a national data system that collects, analyzes, and distributes information about end-stage renal disease in humans. Such a database would facilitate performing large observational studies on the guidelines developed here and provide a tool for recognizing changing trends in spontaneous GD.
The authors and IRIS GN Study Group thank the International Renal Interest Society (IRIS) for their charge and guidance in the development of these recommendations.
Conflict of Interest Declaration: Authors disclose no conflict of interest.
The WSAVA RSP is supported by grants from the Hill's Pet Food Company and Bayer Animal Health