Exposure to tick-borne diseases increases risk of developing chronic kidney disease

Introduction


Tick encounters are increasingly hard to avoid. These adaptable parasites are responsible for spreading a variety of diseases throughout the United States, and their range is increasing. To protect our pets and ourselves, we need to stay alert to the risks. That means regularly screening pets—including asymptomatic or seemingly healthy ones—to identify exposure to infected ticks.

Remember that a single tick can transmit multiple infectious agents that can cause serious illness, including kidney disease. The harmful impact that any given infection has on a pet’s health can sometimes be challenging to ascertain, particularly in asymptomatic pets.

Clinical presentation of Lyme disease and ehrlichiosis are inconsistent


For Lyme disease, controlled-infection studies have demonstrated that only a fraction of the dogs with joint capsule pathology show clinical signs of polyarthritis.1,2 Even fewer exposed dogs demonstrate severe kidney involvement manifested as acute progressive and often fatal protein-losing nephropathy that is classically recognized as Lyme nephritis.3 Therefore, simply relying on clinical signs of lethargy or shifting-limb lameness may not be sufficient to alert veterinarians to an underlying disease process affecting the joints, kidneys, or other body systems.

Similarly, for Ehrlichia, practitioners may rely on hematologic and biochemical abnormalities, such as thrombocytopenia and hyperglobulinemia, to indicate active infection in a seropositive dog. However, during the subclinical phase of ehrlichiosis, these abnormalities may be inconsistent or mild4 due to compensatory mechanisms.

Study design


A retrospective study was performed at IDEXX to determine if exposure to tick-borne disease could be associated with an increased risk of kidney disease.5 Complete chemistry panel (including IDEXX SDMA Test) and complete urinalysis results by patient were obtained from the IDEXX Reference Laboratories database between July 13, 2015, and January 17, 2017. Vector-borne disease data was then obtained for these same patients from a combination of the IDEXX Reference Laboratories database and the IDEXX in-house (IDEXX SmartService Solutions) database between January 1, 2003, and January 1, 2017. To be included in the analysis, a patient must have been identified as a canine residing in the United States that was 1 year of age or older as well as having had a minimum of one SNAP 3Dx, SNAP 4Dx, or SNAP 4Dx Plus test result and at least one IDEXX SDMA Test result and one creatinine result. A total of 846,626 unique canine patients met the criteria.

Patients exposed to infected ticks were defined as having a minimum of one positive vector-borne disease test result in their available history. Patients that were not exposed to infected ticks were defined as having no positive vector-borne disease results in their available history. Well-established chronic kidney disease (CKD) was defined as concurrent increased SDMA (>14 μg/dL) and creatinine (>1.5 mg/dL) for a minimum of 25 days with inappropriate urine specific gravity (USG <1.030) during that time. Additionally, to establish persistence, neither SDMA nor creatinine levels could return to normal ranges in the available patient history.

Canine age, breed, and geographic region (variables not under investigation) were controlled for in patient exposure groups using propensity score matching. For each vector-borne disease, Lyme disease and Ehrlichia, a logistic model was created to predict the probability of each patient’s membership in the exposure group using the following factors: age (discrete by year), breed (161 levels), and region (up to 22 levels depending on vector-borne disease).

The probability of exposure was then used to match each exposed patient to 4 unexposed patients using a nearest neighbor matching algorithm. Contingency tables were then used to compare the dichotomous variables of exposure to infected ticks and CKD outcome. Additionally, patient results were analyzed according to the geographies known for local transmission of Borrelia burgdorferi (causative agent of Lyme disease) and E. canis (figure 1). The estimate of relative risk of CKD was then calculated. 

Figure 1. Patient population evaluated by U.S. location. Each blue and red dot represents the originating ZIP Code of the practice submitting a patient’s specimen. Regions in red represent those used for the Lyme disease and E. canis analyses.

Results


The population of canine patients used in this study had an age range of 1 to 25 years, included all genders and breeds (160 named breeds plus “other” comprising 34.4% of the population). The relative risk of CKD for patients exposed to ticks carrying B. burgdorferi within the defined Lyme disease region was found to be 1.43 with 95% confidence interval (CI) [1.27, 1.61], P < 0.0001. The relative risk of CKD for patients exposed to ticks carrying Ehrlichia for the entire U.S. was found to be 1.12 with 95% CI [0.90, 1.39], P = 0.2858. The relative risk of CKD for patients exposed to ticks carrying Ehrlichia within the E. canis region was found to be 4.00 with 95% CI [1.67, 9.59], P = 0.0026. For each comparison that was performed statistical significance was defined by a P value of < 0.05. A summary of each comparison is shown in figure 2.

Figure 2. Number of patient results by category following propensity score matching for Lyme disease, Ehrlichia, and E. canis.

Conclusions


Dogs with antibodies to the C6 peptide of B. burgdorferi had a 43% increased risk of developing CKD, and dogs with Ehrlichia antibodies in E. canis endemic areas had a 300% increased risk of developing CKD. Both results were statistically significant and clinically relevant, indicating that regular monitoring of these seropositive patients is medically necessary. Dogs exposed to Ehrlichia, inclusive of all U.S. regions, not just E. canis endemic areas, did not demonstrate a significant increased risk of having CKD. Although the design of this retrospective study does not allow for determination of a causal relationship, the findings reveal a statistically significant association between positive Lyme disease or Ehrlichia test results and an increased risk for CKD in endemic areas. It should be noted that although E. canis is found in higher frequency in certain geographic regions of the U.S., dogs infected with E. canis can be found throughout the U.S. E. canis has been identified via polymerase chain reaction (PCR) testing in specimens submitted to IDEXX Reference Laboratories from 42 of 50 states since 2011. Screening patients exposed to infected ticks with a chemistry panel that includes the IDEXX SDMA Test, which detects a highly sensitive and specific biomarker of kidney function, can help identify early kidney disease that may be a complication of vector-borne diseases such as Lyme disease and ehrlichiosis.

Symptomatic dogs that have been exposed to ticks infected with B. burgdorferi or Ehrlichia have an increased risk of multisystemic disease.3,6 This study supports that dogs who test positive for Lyme disease or Ehrlichia are associated with a statistically significant increased risk of developing CKD in endemic areas. Dogs that met the criteria for the definition of CKD in this study had a median age of 11 years, with a range from 1 to 19 years. This study design does not allow for conclusions to be drawn about the timing of development of CKD in relation to the first vector-borne disease exposure; it indicates that these patients are associated with increased risk for CKD. The data identified that an animal had a positive vector-borne disease result but did not indicate when the actual exposure took place. Consequently, patients of any age that test positive for Lyme disease or Ehrlichia should be considered for comprehensive evaluation. At every annual visit, the patient should receive a physical examination, a complete blood count (CBC), a complete chemistry panel with the IDEXX SDMA Test, and a complete urinalysis to monitor for multisystemic disease.

As noted by the International Renal Interest Society (IRIS), creatinine can be within the reference interval in early stages of kidney disease and serial testing may be needed to identify increases in creatinine.7 Therefore, the IDEXX SDMA Test is an essential component of the chemistry panel to identify when a patient’s kidney function is starting to decline. SDMA, symmetric dimethylarginine, is excreted by the kidneys, according to the patient’s glomerular filtration rate (GFR). SDMA concentrations increase in the bloodstream earlier than traditional kidney biomarkers, when there is as little as 25% loss of renal function and on average 40% decrease in GFR.8–10 In contrast, creatinine doesn’t increase until up to 75% of kidney function is lost, typically when CKD patients have substantial nephron loss and the disease is more advanced, and likely to progress, thereby limiting management options. Also, SDMA is not only more sensitive but also more specific than creatinine, as it is independent of lean body mass.11,12

Since patients with vector-borne disease may have other systemic issues or chronic lameness resulting in decreased muscle mass, creatinine concentrations will no longer be a good estimate of renal function. Incorporating SDMA testing into the diagnostic profile will help to identify kidney changes that might otherwise be missed since SDMA is a more reliable biomarker than creatinine. In the patients that are seropositive for B. burgdorferi, Lyme quantitative C6 antibody testing (Lyme Quant C6 Test) is also recommended.

Finding an increased SDMA in a dog with verified tick exposure indicates an immediate course of action to investigate, manage, and monitor possible kidney disease with guidance from the IDEXX SDMA Test diagnostic algorithm.* If SDMA increases are stable, then CKD treatment based on International Renal Interest Society (IRIS) staging can be initiated. Recent evidence from a prospective study of client-owned dogs with IRIS CKD Stage 113 supports established findings that proper nutrition with a renal therapeutic diet is key to early management of CKD.14 Research into the benefits of early intervention for CKD is ongoing.

In summary, this study identified an association between dogs with positive Lyme disease or Ehrlichia test results and an increased risk for CKD in endemic areas. A limitation of this study is that the design does not allow inference of a causal relationship, rather it indicates a statistically significant association between the two conditions. Additional study limitations include that the data does not identify the following: (1) time of tick exposure, (2) time of onset of vector-borne disease, (3) clinical presentation, (4) treatment, or (5) patient outcome. Future studies should be conducted to explore these areas.

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References

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  5. Data on file at IDEXX Laboratories, Inc. Westbrook, Maine USA.
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  11. Hall JA, Yerramilli M, Obare E, Yerramilli M, Yu S, Jewell DE. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine, and medium-chain triglycerides. Vet J. 2014;202(3):588–596.
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  13. Hall JA, Fritsch DA, Yerramilli M, Obare E, Yerramilli M, Jewell DE. A longitudinal study on the acceptance and effects of a therapeutic renal food in pet dogs with IRIS-Stage 1 chronic kidney disease. J Anim Physiol Anim Nutr. In press.
  14. Polzin DJ. Evidence-based step-wise approach to managing chronic kidney disease in dogs and cats. J Vet Emerg Crit Care. 2013;23(2):205–215.

*The IDEXX SDMA diagnostic algorithm is available at idexx.com/algorithm
†For more information on IRIS CKD staging and treatment guidelines, visit idexx.com/IRISstaging.