Consensus Recommendations for Treatment for Dogs with Serology Positive Glomerular Disease
This article is corrected by:
- Errata: Erratum Volume 30, Issue 4, 1554, Article first published online: 30 May 2016
- All subgroup members of the IRIS Canine GN Study Group contributed equally in the preparation of this manuscript
enzyme-linked immunosorbent assay
Federal Drug Administration
indirect fluorescent antibody technique
neutrophil gelatinase-associated lipocalin
polymerase chain reaction
Implications of Seropositivity in Dogs with Glomerular Disease
The finding of glomerular proteinuria concurrent with a positive titer for an infectious agent with recognized potential to incite glomerular disease is often interpreted to support a cause–effect relationship between these two findings. Such a conclusion is risky and may erroneously influence clinical decisions including the diagnostic approach, diagnosis, therapeutic strategies and risks, and outcomes of the disease. Although any infection can be causally associated with glomerular diseases, infections with Borrelia burgdorferi and Leishmania in dogs are especially problematic because of the seemingly common association of these infections with proteinuric conditions (Tables 1, 2). However, in some areas of the United States, common exposures to heartworm, Borrelia burgdorferi, Ehrlichia, Anaplasma, or Babesia spp. lead to seroconversion without development of proteinuria; and in Mediterranean countries exposure to Leishmania promotes a positive IFAT result that indicates exposure to the infection but not necessarily active infection. Thus, serology alone is not conclusive evidence that an infectious agent is the cause of a coexisting glomerular disease (Tables 1, 2).
Table 1. Tick-borne and nontick-borne infectious agents associated with glomerulonephritis.
| Anaplasma phagocytophilum ||Rickettsial||Granuloctye||Ixodes|| |
| Anaplasma platys ||Rickettsial||Platelet||Rhipi|| |
|Bartonella spp.||Bacterial|| |
|Ixodes, fleas, other ticks|| |
|Borrelia burgdorferi (Lyme disease)||Spirochete||Extracellular near fibroblasts||Ixodes|| |
|Babesia canis, rossi, vogeli, large B.||Protozoan||Rbc||Rhipi|| |
|Babesia gibsoni, conradae, small B.||Protozoan||Rbc||Rhipi|| |
| Babesia microti ||Protozoan||Rbc||Ixodes|| |
| Brucella canis ||Bacterial|| |
| Cytauxzoon felis ||Protozoan||Rbc, schizonts in macr|| |
| Ehrlichia canis ||Rickettsial||Monocytic wbc||Rhipi|| |
| Ehrlichia chaffeensis ||Rickettsial||Monocytic wbc|| |
| Ehrlichia ewingii ||Rickettsial||Granulocyte||Ambly||PCR||X||X||D||X|
| Hepatazoon americanum ||Protozoan||Myocyte, Lymphoid, Liver, Wbc|| |
(dog eats tick)
|PCR Muscle biopsy||No|| ||spc||X|
|Leishmaniasis||Protozoan||Extracellular Macrophages|| |
|Mycoplasma spp.||Bacterial||Epi-rbc||Fleas, Ticks|| |
|Rickettsia rickettsii (Rocky Mountain Spotted Fever, RMSF)||Rickettsial||Endothelial cells|| |
Table 2. Infectious diseases associated with proteinuria, polyarthropathy, or cytopenias.
| Anaplasma phagocytophilum ||X||X||X||X||X||X||X||X|| |
| Anaplasma platys || ||?||?||?||X||X||X||?|| |
|X||X||?||Rare|| || ||X if PLN||X|| |
|Babesia canis, rossi, vogeli, large B|| ||X|| ||X||X||Varied||X||X||?|
|Babesia gibsoni, conradae,small B|| ||X|| || ||X||Varied||X||?||?|
| Babesia microti || ||X?|| || ||X?|| ||X?||X?||?|
| Babesia canis ||X||X|| ||X|| || || ||X||X|
| Cytauxzoon felis || || || || ||X||Varied||X||X|| |
| Ehrlichia canis ||X||X||X||X||X||X||X||X||X|
| Ehrlichia chaffeensis ||X||X||X||X||X||X||X||X||X|
| Ehrlichia ewingii ||X||X||X||X||X||X||X||X||X|
| Hepatazoon americanum ||Muscle||X|| || ||X||Up|| ||X||X|
|Mycoplasma spp.||?||?|| ||X||X|| ||X||?||?|
|Rickettsia rickettsii (Rocky Mountain Spotted Fever)||X||X||X||X||X||X||X||X||Down|
If a patient has clinical evidence of an active infectious disease associated with proteinuria, it is compelling to presume the linkage between the serology and glomerular disease may be real. This is clearly evident for Leishmaniasis in which serology has a 98% predictive sensitivity, but is less compelling for dogs with Borrelia-associated glomerular disease in which less than 30% of dogs with concurrent seropositivity and glomerular disease have nonrenal signs consistent with active Lyme disease. Proteinuria is an uncommon finding in dogs with Lyme-seropositivy, and may be recognized in less than 2% of seropositive dogs. Furthermore, clinical signs ascribed to an infectious agent like Borrelia may be the result of a coinfection with another organism (ie, Rickettsia rickettsii, Ehrlichia spp., etc) that also can cause proteinuria and similar clinical signs (Table 2). Lyme seropositivity, at a minimum, is a marker for tick and wildlife exposure, and co-infections which cause proteinuria should be considered. Similarly depending on the phase of disease and magnitude of the titer, up to 55% of seropositive dogs with titers for Leishmaniasis do not manifest evident clinical signs of the disease. The response to anti-infective treatment also is not reliable proof of causation because other infectious agents may be sensitive to the treatment, and therapies like doxycycline may have anti-inflammatory and antiarthritic properties sufficient to resolve clinical signs unassociated with an infectious cause.[4, 5]
Renal histopathology can be helpful to support an association between the seropositivity and the glomerulopathy if lesions characteristic for the disease are identified in the biopsy, but this too cannot prove a cause–effect relationship unless agent-specific antigens associated with active immune deposits in glomerular lesions are proven to be from the infectious agent. However, currently this testing is not available clinically. In a study of Lyme-positive dogs with glomerular disease, 84% had Lyme-specific immune deposits in their glomeruli. Agent-specific immune deposits, however, may have been deposited nonspecifically in abnormal glomeruli. Nonetheless, a properly processed and evaluated renal biopsy provides a basis for guiding decisions to intervene with immunotherapy. (See “Consensus Recommendations for Immunosuppressive Treatment of Dogs with Glomerular Disease Based on Established Pathology” and “Pathologic Evaluation of Canine Renal Biopsies: Methods for Identifying Features That Differentiate Immune Mediated Glomerulonephritides from Other Categories of Glomerular Diseases” in this Supplement.)
If results of a renal biopsy are not available to guide this decision, the cautious approach is to assume that there is a role for the infectious agent in the origin of glomerular injury until proven otherwise. As mentioned above, of particular concern in the United States is the glomerular disease associated with Borreliosis, which may be rapidly progressive and fatal.[7, 8] On this basis, treatment for both proteinuria and the organism may be justified in these patients. Dogs with chronic suppurative infections may have positive serology for specific fungal or bacterial agents associated with a concurrent glomerular disease that either could be immune-mediated or secondary to amyloidosis. Under these circumstances, renal histopathology is essential to diagnose the associative disease and direct appropriate treatment.
Recommendations for the Management of Glomerular Disease in Dogs with Serologic Positive Test Resultsa for an Infectious Agent Absent the Results of a Renal Biopsy or before Obtaining Results of a Renal Biopsy
Recommendation 1: Serology alone cannot confirm a cause–effect relationship between an infectious agent and causation of glomerular disease. Nonetheless, a properly processed and evaluated renal biopsy may provide a basis for guiding decisions to intervene (or not) with immunotherapy. If results of a renal biopsy are not available to guide this decision, the cautious approach is to assume that there is a role for the infectious agent in the origin of glomerular injury until proven otherwise.
90% of voting consensus members agreed with Recommendation 1, and 55% of these voters expressed “strong agreement.”
Recommendation 2: In serologically positive dogs with glomerular disease, Standard Treatment is recommended when the urine protein:creatinine ratio (UPC) is persistent and ≥0.5.
86% of voting consensus members agreed with Recommendation 2, and 55% of these voters expressed “strong agreement.”
Once glomerular disease has been identified in a dog with known exposure to an infectious agent suspected to be associated with glomerular pathology, Standard Treatment should be instituted as early in the course of the disease as possible in addition to treatment for the infectious disease. (See “Consensus Recommendations for Standard Therapy of Glomerular Disease in Dogs” in this Supplement.) The threshold advised to trigger standard treatment is a persistent UPC of 0.5 or above. The efficacy of Standard Treatment should be assessed by the changes in UPC, serum creatinine and potassium concentrations, and systemic blood pressure, every 1–2 weeks after initiation or modification of Standard Treatment depending on the stage of disease and stability of the patient. The response to both anti-infective treatment and Standard Treatment should be monitored every 4 weeks thereafter for the first 3 months or until the disease has stabilized, and then accordingly as recommended for Standard Treatment (see above). The recommendation to initiate the treatment at this level of proteinuria, even in nonazotemic dogs, is justified by the potentially dire consequences should the dog develop progressive kidney disease associated with the infection. The prognostic value of the UPC for the extent of glomerular injury and response to Standard Treatment may be difficult to interpret during the active phase of the infection (especially for leishmaniasis) and should be reassessed after the course of treatment for the infection.
Use of Anti-Infective Treatment against Serology Predicated Pathogens
The recommendation for starting Standard Treatment does not imply a priority of management relative to that of the attending infection suggested by the positive serology.
Recommendation 3: The possibility that an infectious agent induced the glomerular injury highlights the rationale to initiate specific anti-infective treatment immediately when the coexistence of glomerular disease and seropositivity is recognized, despite the lack of evidence for causality of the infection and the proteinuria.
95% of voting consensus members agreed with Recommendation 3, and 50% of these voters expressed “strong agreement.”
The use of anti-infective medications that are potentially nephrotoxic (eg, amphotericin B) should be avoided if possible. When potentially nephrotoxic anti-infective drugs are the most appropriate or the only therapeutic option, they should be used cautiously with heightened efforts to monitor renal function and minimize additional renal injury. Monitoring of renal biomarkers [like neutrophil gelatinase-associated lipocalin (NGAL)] that have potential to signal the early onset of kidney injury may facilitate dosing of nephrotoxic drugs. Quantitative serology (eg, quantitative C6 antibody for Borrelia burgdorferi infection or quantitative serology for fungal infections such as coccidioidiomycosis or cryptococcosis) should be utilized for disease surveillance where serology is thought to correlate with elimination of the infectious agent or resolution of clinical disease.
Use of Anti-Inflammatory or Immunotherapy in Seropositive Patients Absent Biopsy Findings
Recommendation 4: Clinically stable dogs without azotemia, progressive increases in serum creatinine or UPC, or clinical consequences associated with their proteinuriab should be managed initially only with specific anti-infective treatment against the suspected infectious agent plus Standard Treatment for glomerular disease.
91% of voting consensus members agreed with Recommendation 4; however, only 30% of these voters expressed “strong agreement.”
Recommendation 5: For seropositive dogs that are azotemic (IRIS CKD Stage II or greater), or have progressive nonazotemic (IRIS AKI Grade I) to azotemic (IRIS AKI Grade II or greater) increases in serum creatinine, or have evidence of rapidly progressive glomerular disease based on clinical and/or laboratory assessments, the following are recommended:
- (1) A thorough search for possible geographic-specific coinfections (eg, for Babesia microti-like infection in Spain).
- (2) A renal biopsy evaluated by a nephropathologist using appropriate light, immunofluorescent, and electron microscopic imagingc to support potential intervention with immunosuppressive treatment.
- (3) In the absence of a renal biopsy, immunosuppressive treatment should be considered to manage potential immune causes of the glomerular injury.d
86% of voting consensus members agreed with Recommendation 5; however, only 30% of these voters expressed “strong agreement.”
Timing of Immunosuppressive Treatment
The decision to initiate anti-infective treatment and Standard Treatment may precede the decision to recommend renal biopsy. Renal biopsy may or may not be recommended in nonazotemic dogs with mildly increased UPCs and a normal albumin concentration that do not show evidence of progressive kidney disease. The glomerular injury in dogs with stable renal function and UPCs may no longer be active and progressive and may represent an earlier insult. The recommendation for renal biopsy should be advocated more strongly in patients with more severe clinical and laboratory abnormalities or those whose disease is progressive. Standard and anti-infective therapies should not be delayed while deciding whether or not to perform a biopsy.
Recommendation 6: If the results of renal biopsy document an active immune component to the glomerular disease, appropriate immunosuppressive treatment is indicated.c At this stage, the glomerular disease should be considered as having an immune-mediated component, and not infectious alone, and it is not likely to respond merely to anti-infective treatment and irradiation of the infection if severe or progressive.
95% of voting consensus members agreed with Recommendation 6, and 55% of these voters expressed “strong agreement.”
For some seropositive infections, dogs may show no active clinical evidence of the infection despite overt manifestations of active and progressive glomerular disease. Control of the immune events directed at the glomerulus are warranted and required to control this component of the disease. Similarly, it may not be possible to delay treatment with immunosuppressive treatment for the glomerular disease while the infection is being controlled. Initiation of immunosuppressive treatment directed at the glomerular disease poses the likelihood to compromise control of the predisposing infection. This is clearly a therapeutic dilemma, but the glomerular disease and the infection must be considered and managed as separate comorbid diseases. Proceeding with immunosuppressive or anti-inflammatory treatment without biopsy confirmation for their specific indications imposes the potential for greater therapeutic risk in dogs with active or sequestered infection based on positive serology compared to dogs treated without an infectious comorbidity. Conversely, dogs with peracute and rapidly progressive disease associated with seropositivity (ie, Lyme-associated nephritis) often die from consequences of their glomerular disease within days of diagnosis and require immediate and aggressive immunomodulatory treatment in addition to supportive treatment for renal failure.
Assessment and Management of Specific Infection-Associated Glomerular Diseases
Lyme-Associated Glomerular Disease
In North America, glomerular disease associated with seropositivity for Borrelia burgdorferi (Lyme nephritis) may be seen and may be severe and progressive. There is no experimental model for Lyme nephritis, and the exact pathogenesis and natural progression of this entity is unknown. Most (95%) Lyme-seropositive dogs show no signs of illness (neither Lyme arthritis nor Lyme nephritis). Nonclinical seropositive dogs may have very high quantitative C6 antibody levels with circulating immune complexes and it is unknown why or how a subset of dogs with Lyme-specific circulating immune complexes develop Lyme nephritis. Because certain breeds are predisposed to Lyme nephritis (eg, Labradors and Golden Retrievers), it may be that an underlying genetic podocytopathy or immunodysregulatory defect causes illness with deposition of Lyme-specific antigen-antibody complexes in glomeruli, which in severe forms is accompanied by tubular degeneration and necrosis. There may be earlier stages or milder forms of the disease that are treatable with antimicrobials and standard treatment alone. However, as indicated above, progressive or severe disease does not respond to these general therapies, and additional aggressive immunotherapy appears warranted. Prospective clinical trials need to be performed to find the best therapeutic approaches for these cases.
Definitive evidence for the length of doxycycline treatment needed to eliminate Borrelia burgdorferi is lacking. One month of doxycycline at 20 mg/kg/d only cleared 85% of experimentally infected dogs, based on culture and PCR of skin biopsies taken from the area where ticks were placed on the dogs.[11-14] The criterion for effective treatment usually includes response to treatment based on improving clinical signs and laboratory findings. For Borreliosis, baseline and 6-month posttreatment assessment of the quantitative C6 titer may help assess the effectiveness of treatment. Successful treatment may be defined as a ≥50% decrease from pretreatment values. However, anecdotally when the initial Lyme C6 titer is relatively low, the decline in titer observed with treatment may be small. Additional anecdotal observations indicate the qualitative SNAP-4Dx results often remain positive for years, despite treatment, but the Lyme quantitative C6 titers usually wane, sometimes to less than 30, with treatment even when the SNAP-4Dx C6 peptide antibody test still documents a positive result. Anti-infective treatment for Borrelia burgdorferi with doxycycline is typically initiated at 10–20 mg/kg/d; however, the optimal dose and length of treatment for Borrelia burgdorferi infection is unknown, but may be greater than 1 month of doxycycline at 20 mg/kg/d per os. Consequently, in cases of suspected Lyme-associated nephropathy, doxycycline treatment perhaps should be continued until clinical resolution or until the C6 quantitative titer is determined to have declined to less than 50% from pretreatment values, which may take up to 6 months.
Leishmaniasis-Associated Glomerular Disease
Diagnosis of leishmaniasis in dogs should be based on consideration of signalment, history, clinical findings, and results of testing to detect the parasite or the immune response of the host. Generally, leishmaniasis can be confirmed by cytologic, serologic, or PCR analyses in dogs with overt clinical signs or severe alterations of relevant clinicopathologic variables. Any breed can be affected by leishmaniasis, which occurs with a bimodal onset at <3 years of age and from 8–10 years of age. The distribution of leishmaniasis varies widely throughout the world, and it is essential to determine if suspect cases have a known travel history to an endemic area of phlebotomine vectors. Consistent clinical features include lymph node enlargement, mucocutaneous lesions, poor nutritional state, hepatosplenomegaly, lameness, joint swellings, and fever.
Specific diagnosis is confirmed by direct cytologic, histologic, or PCR identification of the agent in aspirates or biopsies of affected sites or indirectly by serologic testing and evaluation of cellular immune responses. When injured tissues (including bone marrow) have direct evidence of Leishmania infection, dogs should be considered as affected by leishmaniasis, regardless of serologic results. When there is no direct evidence of Leishmania spp. infection, serologic testing such as IFAT and ELISA is crucial for diagnosis. An antibody titer above the cutoff of reference value for the laboratory with concurrent proteinuria confirms the present of disease.
Anti-Leishmania drugs include antimonial compounds, aminosidine (paromomycin), miltefosine, and allopurinol. For dogs merely exposed to infection, no specific treatment is necessary. Dogs should be monitored serologically for 2–4 months after the finding antibodies against Leishmania spp. at low titers. If characteristic clinical findings develop, additional evaluation is indicated, including parasitological testing performed with a direct method. Dogs with documented infection on the basis of direct detection of the organism or a positive antibody titer require specific antileishmania treatment. Significant comorbidities associated with infection require appropriate ancillary treatment in addition to anti-leishmania drugs. Combination treatment with meglumine antimoniate and allopurinol is the most widely used anti-leishmania treatment protocol and can be administered to dogs with confirmed infection regardless of the severity or clinical stage of the disease. Meglumine antimoniate is given at 100 mg/kg SC once daily for 4 weeks; and allopurinol is provided at 10 mg/kg PO every 12 hours for at least 6 months. The dosage of meglumine antimoniate can be divided into 2 equal doses of 50 mg/kg administered SC every 12 hours for 4–8 weeks.
Rarely, Leishmania infections are recognized in the United States where meglumine antimoniate is not FDA approved for use in dogs, and alternative treatment protocols may be required. Allopurinol is well tolerated and seems to slow the deterioration of renal function in nonazotemic dogs with proteinuria but can predispose to xanthine urolithiasis. For most dogs, the combination of meglumine antimoniate and allopurinol promotes a clinical cure that is sustained for longer than 1 year. This combined treatment decreases the parasite load for several months, which is necessary to reduce transmission of the parasite by phlebotomine vectors. Clinical improvement is highly contingent on the degree and severity of comorbid complications.[17, 19]
For dogs that remain unresponsive to treatment after a confirmed diagnosis and appropriate administration of meglumine antimoniate and allopurinol alternative anti-leishmania treatment should be considered. The combination of miltefonsine administered PO at 2 mg/kg every 24 hours for 28 days and allopurinol, at the same dosage as recommended with meglumine antimoniate, appears promising and as effective as the combination of meglumine antimoniate and allopurinol. However, miltefosine also is not FDA approved for use in dogs in the United States.
Conflict of Interest Declaration: The authors disclose no conflict of interest.
Absent clinical or other evidence supporting active disease in the patient (serologic positivity failing to differentiate between infection and exposure).
Tier I, see “Consensus Recommendations for the Diagnostic Investigation of Dogs with Suspected Glomerular Disease” in this Supplement.
See “Consensus Recommendations for Immunosuppressive Treatment of Dogs with Glomerular Disease Based on Established Pathology” and “Pathologic Evaluation of Canine Renal Biopsies: Methods for Identifying Features That Differentiate Immune Mediated Glomerulonephritides from Other Categories of Glomerular Diseases” in this Supplement.
See “Recommendations for Immunosuppressive Treatment in Dogs with Glomerular Disease Absent a Renal Pathologic Diagnosis” in this Supplement.