Diabetes mellitus (DM) can result in vascular complications such as nephropathy, systemic hypertension, and retinopathy. These comorbidities are well documented in dogs with experimentally induced DM and were found to develop after several months to 2.5 years of disease, depending on the model.[1-3] While systemic arterial hypertension, nephropathy,[4, 5] and retinopathy[6-8] are recognized in dogs with spontaneous DM, little is known about the prevalence of these conditions in dogs, their onset after diagnosis of DM, nor etiopathogenic factors leading to their development and progression.
Vascular complications of DM are very important causes of morbidity and mortality in humans. Nephropathy associated with DM is the most common cause of end-stage renal disease in humans. Renal injury manifest by microalbuminuria occurs in 20–40% and overt proteinuria because of diabetic nephropathy is present in approximately 10–20% of humans with type 1 DM within 7–15 years of diagnosis with conventional treatment.[10-12] The presence of microalbuminuria is a predictor of the development of end-stage renal disease in diabetic humans, and hypertension is associated with its progression. Although diabetic retinopathy is an important cause of vision loss in humans, being more prevalent than nephropathy,[10-12] it appears to be of little clinical significance in the dog. However, its association with duration of DM and presence of hypertension has not been examined.
The purpose of this study was to document longitudinal changes in prevalence of systemic hypertension, proteinuria, and retinopathy in a group of dogs with spontaneously occurring DM and to evaluate the impact of glycemic control and duration of DM, as estimated by time since DM diagnosis, on the development and progression of these conditions. We hypothesized that vascular complications in dogs with DM, including systemic hypertension, retinopathy, and proteinuria, are progressive and that they are associated with duration and control of disease.
- Top of page
- Materials and Methods
- Supporting Information
Diabetic vascular complications, including hypertension, proteinuria, and retinopathy were documented in this longitudinal study, but there were no significant associations between these conditions and time since DM diagnosis or degree of glycemic control. In addition, no significant associations were found between these various complications in this group of dogs.
The prevalence of systolic and diastolic hypertension in the present study was similar to that previously reported in dogs with spontaneous DM.[4, 17] The severity of systolic hypertension, when considered as risk of target organ damage, was mild in all but 2 dogs, which had a risk considered “moderate” at most measurements, and “severe” at 1 measurement for 1 dog. Similar to a previous report, diastolic hypertension occurred more frequently than systolic hypertension. Additionally, the diastolic pressure elevation was higher in magnitude than the systolic pressure, relative to proposed risk to target organs. However, the 2 dogs with complete follow-up that reached a diastolic BP >120 mmHg did not have overt proteinuria or retinopathy.
Blood pressure did not significantly increase during the course of the 2-year study, leading to the conclusion that any effect of DM on BP may occur early in the course of the disease. This is not consistent with a previous study that found the risk of hypertension to increase with more prolonged DM. However, dogs were evaluated once in that study, where the median time from diagnosis of DM to evaluation was 6 months, rather than longitudinally as in the present study. In addition, dogs with unilateral nephrectomy and induced DM had a peak increase in mean arterial pressure after 4 months that then decreased through the remainder of the 1-year study. In humans, hypertension occurs in approximately 30% of those with type 1 DM and 50–80% of those with type 2 DM. Hypertension is commonly present at the time of diagnosis of diabetes in humans with type 2 disease, while in type 1 diabetes, it occurs later in the course of disease and is most commonly believed to be a consequence of nephropathy.
Microalbuminuria develops in 30–60% of humans with type I diabetes,[21, 22] and commonly precedes the development of overt glomerular disease and proteinuria. However, there is a paucity of information regarding urine albumin concentration in dogs with spontaneous DM. Mazzi et al reported mean ± SD urine albumin concentrations of 20 ± 43.3 mg/dL in a group of 20 diabetic dogs. Elevated urine albumin was found in 55% of the dogs, with over half of them having concurrent elevation in UPC. The prevalence of microalbuminuria of 59% in the present study, with 7/17 dogs also having elevated UPC, is similar. Although 2 of the 3 dogs with microalbuminuria and normal UPC at initial evaluation developed an elevated UPC during the longitudinal study, the degree of proteinuria remained modest (ie, UPC <1.0).
In dogs, a UPC >0.5 is considered abnormal. Based upon this definition, the prevalence of abnormal UPC in our study population ranged from 48.3 to 60% over the course of this investigation. Urine samples with positive bacterial culture were included in the analysis, as statistical findings were unchanged after removing instances of positive urine culture. Although inflammation associated with lower urinary tract infection is a commonly cited source of proteinuria, the majority of pyuric samples in a recent study were not albuminuric nor did they have elevated UPC. Microalbuminuria commonly precedes the development of overt proteinuria in humans, but we were unable to document a similar course of disease in our study population. This may be a reflection of the fact that the vast majority of dogs demonstrating increased urine albumin concentration already had elevated UPC at the time of albuminuria diagnosis. This does not preclude the possibility that screening for microalbuminuria may prove a useful tool to predict the onset of diabetic nephropathy in dogs, but earlier testing may be necessary. Alternatively, the overall lack of significant progression of proteinuria for the 2-year duration of the study may be an indication that the proteinuria is not a result of diabetic nephropathy. Based on the tests utilized, diabetic dogs in this study did not have progression of renal dysfunction during the 2-year study period. Lack of progression of renal dysfunction is consistent with the described lack of clinically important nephropathy in dogs with spontaneous DM, despite development of lesions typical of diabetic nephropathy in dogs with spontaneous and experimentally induced DM.[2, 5] In addition, no significant effect of time since DM diagnosis, glycemic control or BP on urine albumin or UPC could be demonstrated.
Despite the lack of significant effect of duration of DM on proteinuria, the 4 dogs with a UPC >0.5 at initial evaluation had increases in UPC throughout the study period despite treatment with enalapril (Fig 1). At the end of the 24-month study, all 4 dogs had a UPC >2, and would be considered candidates for intervention as was done in the present study. Further investigation is warranted to determine if a subset of dogs with DM have progressive glomerulopathy as in humans.
Elevated BP is associated with increasing risk of diabetic nephropathy in humans and dogs with experimentally induced DM. While angiotensin-converting enzyme inhibitors attenuate progression of diabetic nephropathy in alloxan-induced diabetic dogs, results of the present study did not discern an association between BP or hypertension status and indicators of nephropathy (ie, microalbuminuria or overt proteinuria). Enalapril was administered to 4 dogs to address persistent and substantially elevated UPC; in no dog was it administered for the treatment of hypertension. The number of dogs being treated with enalapril at 6, 12, 18, and 24 months were 1/11, 1/11, 2/11, and 4/11, respectively. A consistent reduction in proteinuria was not noted in any dog receiving enalapril. While it is possible that this treatment may have influenced both BP and proteinuria, removing instances of enalapril treatment from analysis did not change the statistical outcomes for either condition.
In dogs whose fundus could be examined, the prevalence of ophthalmoscopically detectable retinopathy ranged from 9.1 to 20.0% over the 2-year course of the study. The lesions detected in this study were similar to those previously described and consisted of single to multiple retinal hemorrhages/microaneurysms visible in the tapetal fundus. Prevalence of retinopathy in humans with diabetes in the United States was recently reported as 28.5%, with a strong correlation with duration of diabetes. Previous studies describing retinopathy in dogs with naturally occurring diabetes have reported similar prevalence values as this study, ranging from 3 to 21%.[5, 7, 29, 30] Although hypertension is also a well-known risk factor for development and progression of diabetic retinopathy in humans,[28, 31] a similar correlation was not found in the present study. Time since DM diagnosis and glycemic control scores were also not correlated with presence of ophthalmoscopically visible retinopathy in this study. Studies comparing methodologies for diagnosis of diabetic retinopathy are lacking in dogs, but it is reasonable to assume that ophthalmoscopy alone may miss subtle lesions. Although ophthalmoscopy is accepted as the most commonly used screening tool for diabetic retinopathy in humans, fluorescein angiography and multiple field stereoscopic fundus photography are more sensitive than ophthalmoscopy alone in detecting the condition.[32, 33] However, neither multiple field stereo fundus photography nor fluorescein angiography is practical to employ on a routine basis with clinical veterinary patients. Additionally, fluorescein angiography carries a risk of severe adverse reaction, which is not justifiable in context of what is regarded as an essentially benign condition in the dog.
Because a primary objective of this study was to assess the relationship of glycemic control with the development of vascular complications, multiple means of evaluating this factor were employed, including serial blood glucose measurement, serum fructosamine concentration, and owner observations. Although a previous study reported that owner perceptions of polyphagia, polyuria, and polydipsia correlated well with other measures of glycemic control, this was not evident in the present study. Agreement between MBG8h and serum fructosamine concentration was better, but only fair. In general, owners tended to assess their pets control as better than was suggested by MBG8h or serum fructosamine concentration. While the effect of variable glycemic control on progression of vascular complications would best have been evaluated by prospectively assigning dogs to more or less intensive treatment, use of client-owned dogs with spontaneous DM made this ethically impossible.
The spectrum of vascular complications associated with DM in the dog is similar to that recognized in humans and includes systemic hypertension, proteinuria, and retinopathy. Failure to document progression of these complications in the present study despite less than optimal glycemic control may have resulted from the small sample size or insufficient time for progression to manifest. Some investigators report that morphologic nephropathy develops consistently only after experimentally induced DM of >2 years duration, whereas others report glomerular changes within 6–23 months. In addition, dogs with unilateral nephrectomy developed increased mean arterial pressure and proteinuria within 2–8 months induction of DM and had increased GFR, renal blood flow, glomerular capillary pressure and histopathologic changes of diabetic nephropathy after 1 year.[1, 2, 18] Yet another factor that necessitates caution in interpretation of the results of the present study is the considerable variability in proteinuria that is noted between samples from the same dog, particularly at the modest levels present in most dogs of this study. The variability could mask statistical elucidation of progression of the proteinuria. Subsequent studies of spontaneous DM should be continued for a longer duration, particularly in dogs with overt proteinuria at diagnosis, to determine if clinically important complications occur.