Cutaneous and renal glomerular vasculopathy in dogs

Introduction

Cutaneous and renal glomerular vasculopathy (CRGV) is a rare and potentially life-threatening condition seen in dogs. An awareness of the disease, and its apparent prevalence in the UK, has risen considerably over the last decade or so (1). CRGV causes ulcerative lesions of the skin and mucous membranes, but in some animals acute kidney injury (AKI) can also develop (Figure 1), and when this occurs the mortality rate is very high (90-95%) (2). Whilst the exact cause of CRGV currently remains under investigation, this article offers an overview of the condition, its diagnosis and treatment.

What’s in a name?

CRGV is often referred to by the colloquial term “Alabama Rot”. This stems from cases that appeared in Alabama, USA in the 1980’s (3,4); these were reported exclusively in greyhounds, and were variably associated with skin lesions and (in some cases) development of AKI (3-5). Histopathology performed on these cases identified a process called thrombotic microangiopathy (TMA) (3-5). At the time, it was postulated that the cause may have been enterotoxigenic Escherichia coli causing hemolytic uremic syndrome (a condition associated with TMA), given that affected dogs had been fed a raw beef diet, but this was not confirmed (4,5). Following this, a similar presentation was reported in a single pet greyhound in the UK in 2000 (6) and in a Great Dane in Germany in 2002 (7). Whilst cases have been reported in the Republic of Ireland (8) and in Scotland, clear evidence of the disease being reported in mainland Europe is not currently present. It is not known if the CRGV in the original greyhounds was the same disease as UK CRGV or a different form of TMA.

What is thrombotic microangiopathy?

TMA is a pathological lesion – observed in a wide spectrum of diseases – that describes a pattern of endothelial damage with associated platelet activation and consumption, leading to vascular occlusion, often with intraluminal microvascular thrombus formation (Figure 2). Thrombosis leads to ischemia, and subsequent end-organ (e.g., kidney) injury (9). CRGV is a type of disease manifesting TMA, rather than TMA being unique to CRGV. 

TMA may often be accompanied by clinical features of microangiopathic hemolytic anemia (and resulting abnormalities such as schistocytosis), thrombocytopenia and ischemic end-organ injury (9). The kidney is the most frequently injured organ, but in humans other systems including the central nervous system, cardiovascular, respiratory and gastrointestinal tract may also be affected (9). Interestingly, in humans, renal-limited forms of TMA are not infrequently encountered (9). A variety of causes – including protein abnormalities, complement dysfunction, drug reactions and infections – are documented in humans, with several conditions involving genetic abnormalities (9) (Table 1). Treatment strategies are specific to the causal disease – for example, plasma infusion in congenital thrombotic thrombocytopenic purpura (TTP), or complement inhibition in complement-mediated TMA (CM-TMA) using eculizumab (9). Some of these medical therapies are cost-prohibitive in veterinary medicine and have not been used (10).

 

Table 1. Major causes of thrombotic microangiopathy (TMA) in humans (not exhaustive).

 

Thus far, CRGV has not proved exactly analogous to any human TMA. Skin lesions are infrequently seen in human cases, though are possible with CM-TMA (11). However, in CM-TMA or TTP, ongoing disease or relapse is also a concern (12), but this does not seem apparent in dogs surviving CRGV (whether affected by skin lesions only or AKI). An acquired process that does not appear to recur would seem more likely associated with infection/toxin-induced disease (e.g., hemolytic uremic syndrome (HUS)). On the other hand, HUS due to bacterial toxins such as Shiga toxin-producing E. coli (STEC) is usually associated with prodromal diarrhea (13) and is not typically accompanied with skin lesions. HUS has rarely been reported in dogs without skin lesions (14). 

In dogs with CRGV, TMA appears to mainly affect the renal glomerulus (1,2,4). It is important to note that the skin lesions are not causal to the AKI but reflect a shared pathology – the microangiopathy affecting the cutaneous vasculature, leading to ischemia and ulceration. In some dogs fibrinoid necrosis may be seen in skin biopsies, but these are less useful than renal analysis for diagnosis. 

What is the incidence of CRGV?

There have been 326 confirmed cases of dogs with skin lesions and AKI with histopathological evidence of TMA within the kidney in the UK since 2012 (15), but there are additionally suggestive cases that have not had histopathology. There is also a convincing population of dogs with unexplained “typical” skin lesions that do not develop AKI, and moreover, there have been situations where dogs in the same household as a dog with histopathologically confirmed TMA have developed skin lesions but have shown no progression to biochemical evidence of AKI (1,2). 

CRGV appears to follow a seasonality, with cases mostly occurring between November and May (91%), particularly January and February (2). However, cases have been identified throughout the year. It appears that cases are also associated with woodlands, increasing mean maximum temperatures in winter, spring and autumn, increasing mean rainfall in winter and spring, and decreasing cattle and sheep density (16). Therefore, wet winter weather in woodland areas would pose the highest risk, as opposed to summer in pasture areas. Areas such as East Anglia appear thus far to be relatively unaffected (15). These findings imply that environment in some way is likely to play a role in the occurrence of disease – whether providing favorable conditions for an infectious cause, or providing exposure to a toxin. Investigations into flora in typical locations has not identified a likely culprit. Whilst evidence is lacking for prevention, advice is often given to wash the lower limbs of dogs after muddy walks during the “at-risk” season, and this appears a reasonable precaution. 

Certain breeds appear more likely to develop CRGV. Hounds and gun dogs had the highest risk of being diagnosed with CRGV compared with terriers, whilst toy dogs were not identified in the initial cases examined (17). In particular, Flat-coat Retrievers, Manchester Terriers, Hungarian Vizslas, Saluki and Whippets were more affected (17); this therefore may imply a susceptibility or predisposition to the development of the disease in certain breeds. 

How does CRGV present?

In a study of 178 histopathologically confirmed cases, a lesion of the skin or oral cavity was reported and occurred prior to AKI in 98.9% of cases (2). Lesions were most commonly found on the limbs (80.9% at presentation; 85.4% overall) and if so, commonly on the pads, foots or digits (73.6% of leg lesions) (Figure 3). Multiple limbs were affected at presentation in 17.6% of dogs, and further lesions may develop, including on multiple limbs (Figure 4). Lesions may also be found in the oral cavity (8.4%) (2) (Figure 5). The time taken from a skin lesion to be noted to the identification of AKI is reported at a median of 3 days (from 4 days prior to 45 days after AKI develops) and less than 13 days in 97.6% of cases (2). 

Skin lesions have been described variably; these include the appearance of pyoderma, pododermatitis, swellings, edema, bruising, excoriations, puncture wounds or ulcers (2). A classic lesion would be a well demarcated full-thickness skin lesion on the lower limb without an obvious explanation such as trauma. 

Systemic signs of illness may be seen prior to the skin lesion being noted, and dogs often develop vomiting during their illness/AKI (65.5%) and diarrhea (26.6%). Lameness (4.5%) may be seen prior to skin lesions developing. Over the course of illness, neurological signs were seen in 18.6% of cases, including seizures, ataxia, anisocoria, horizontal nystagmus and proprioceptive abnormalities. In one report, two dogs presented with seizures as the primary presenting complaint (1.1%) (2). Whilst AKI itself may induce neurological signs (i.e., via uremic encephalopathy), histopathology of the brain has identified TMA within the brain (18). 

What laboratory abnormalities may be detected?

The major finding of concern is the development of AKI. Whilst there are multiple definitions of AKI, this has typically been considered to be a creatinine level >140 µmol/L, or a rise in creatinine of 26.5 µmol/L within 48 hours on the same analyzer (19). Thrombocytopenia is common (83.9%; median 49 x 10⁹/L) and hyperbilirubinemia presents in half of cases (51.9%). Non-/pre-regenerative anemia may also be seen, and a hemogram may show signs of fragmentation injury (34.5%) (2). The urine protein:creatinine (UPC) ratio is often abnormally elevated (median 2.93) and rarely may be increased prior to AKI (2); glucosuria may be seen (29.6%), implying tubular damage (2). 

How should a dog with a skin lesion be monitored?

It should be remembered that there are many differentials for skin lesions in general, though the combination of skin lesions and AKI is not common, and significant differentials for the classical signs are limited. Whilst all differential diagnoses for AKI should be considered, other causes of AKI are unlikely to cause erosive or ulcerative skin lesions. Several suggested possible causes of particular note are listed in Box 1. 

 

Box 1. Suggested differentials for skin lesions with acute kidney injury (AKI).

 

After initial identification of an evocative skin lesion, it is salient to consider CRGV risk factors to help support the likelihood of a diagnosis, which in turn can guide the frequency of monitoring (Figure 6). Overall, a monitoring period of up to 13 days will generally be reasonable (2), with the degree and nature guided by the level of concern. For any possible case it is prudent to check the baseline complete blood count (CBC) and biochemistry, particularly to assess platelets, total bilirubin and creatinine concentration. When possible, a urine dipstick and/or UPC ratio can be useful to help identify evidence of tubular damage/unexpected proteinuria. During this time, nephrotoxic medication should be avoided, and symptomatic treatment provided, such as analgesia with paracetamol or antibiosis if there is evidence of wound infection (e.g., purulent discharge/cytological presence of bacteria). 

Thereafter, consider repeat assessment of (at least) creatinine on the same analyzer and – ideally – a platelet count on a manual smear every 24-48 hours to permit timely detection of AKI. Subjective assessment of urination should also be made, with guidance that oliguria can indicate AKI. Figure 7 highlights two example scenarios. 

 

Figure 7. Two examples of how suspected cases may be monitored, depending on the level of concern for CRGV.

 

If azotemia does not develop within 13 days but skin lesions do not improve, particularly with multifocal lesions, consider investigation for other causes (Box 1), for example with punch biopsies/culture. In a “low” risk case this may be worth considering sooner in the monitoring process, particularly with severe lesions and an absence of hematological changes. Note that the absence of a “typical” feature at presentation does not eliminate the possibility of skin-only CRGV, or exclude the risk that AKI will develop at a later stage.

How is CRGV treated?

Treatment is aimed at standard therapy for AKI when identified – i.e., with restoration of a euhydrated state, maintenance of adequate urine production, management of uremia and any other complications of AKI, such as hypertension (avoiding ACE inhibitors). Patients will often require nutritional support with a feeding tube (e.g., naso-esophageal tube) and an indwelling urinary catheter can be very useful to manage fluid balance and prevent overhydration (“ins-and-outs” monitoring) (19). 

Prior to the development of AKI, no specific therapy is known to prevent the onset of kidney dysfunction, but symptomatic treatment is sensible; e.g., avoidance of dehydration, and use of anti-emetics as required. Wound management may also be required, alongside analgesia (Figure 8). Potentially nephrotoxic medications such as NSAIDs should be avoided. Lesions with secondary infection may require topical or systemic antibiosis.

At present there is no clear indication for a specific drug therapy for CRGV. Pentoxifylline is a drug that has been used in canine vasculitis and ischemic dermatopathies (20), although evidence to support its use in TMA is not present. It has a myriad of effects, including anti-inflammatory and hemorheological properties, such as the ability to reduce blood viscosity through small vascular spaces (20). Corticosteroid therapy has also been considered, at a range of doses from 1-2 mg/kg/day. Immunosuppression is of benefit in humans with some acquired forms of TMA (12), namely TTP, transplant-associated or autoimmune-associated TMA. Therefore, there is a small possibility that if there is an immune-mediated component in the pathogenesis of CRGV (e.g., autoantibody development against complement proteins), immune modulation may play a role; however, evidence remains lacking. 

Antioxidants such as N-acetylcysteine may reduce the incidence of transplant-associated TMA in humans and could be provided in some way to dogs with CRGV as a relatively safe intervention (e.g., S-adenosylmethionine (SAMe)), although evidence is also not present (21). Vitamin E (an antioxidant) has been reported to be helpful for ischemic dermatopathy (20). Anti-thrombotic therapy has been considered to reduce platelet consumption, but is controversial due to the high frequency of thrombocytopenia in CRGV, which may be progressive. Thromboprophylaxis is not commonly provided in human TMA, except with TTP where low molecular weight heparin is considered (once the platelet count is >50 x 10⁹/L) due to an increased risk of thromboembolism; this therefore suggests possible use in a recovery setting rather than disease prevention. Antiplatelet therapy has little evidence base in this condition (12), and indeed clopidogrel has been associated with drug-induced TMA (22). 

The use of therapeutic plasma exchange (TPE) has been reported in dogs with CRGV; 2/6 cases survived, which may imply a survival benefit (23). This is being currently evaluated in a larger group to see if the benefit remains. TPE remains controversial, as there are only certain conditions in humans that benefit from this treatment (9), and it raises the question of why a benefit would be seen. Possible theories include providing functional ADAMTS13, removing autoantibodies against complement proteins, or removing a bacterial toxin. TPE may also be helping to temporarily manage some of the effects of uremia. Given that there is some evidence for a survival benefit from this treatment, the author would currently recommend its consideration when cost and access to the technology allows.

Unfortunately, the prognosis for dogs that develop AKI and CRGV appears very guarded, with a high mortality rate (2), although indeed AKI (whatever the cause) carries a high mortality rate (19). Dogs developing severe AKI in hospital for any reason had a reported 41-66% mortality (24), and mortality rates for CRGV overall have been estimated at between 90-95% (considering rough estimates of likely survivors of CRGV) (2). The mortality rate may be lower in dogs receiving TPE (21). Despite the poor prognosis, with appropriate treatment of AKI, survival is possible. When only skin lesions are present, the prognosis is generally good.

Is CRGV contagious? 

As a bacterial toxin may play a role in the disease pathogenesis, contagion is a reasonable concern. A major differential for AKI would be leptospirosis, a contagious and zoonotic infection. Viral infection has not been identified. However, clear evidence for contagion is lacking. In one study, 42 dogs diagnosed with CRGV were reported to have had contact with at least one other dog, with a total of 60 in-contact dogs (2). 13of these in-contact dogs were reported to have skin lesions alone, whilst four were suspected to have AKI. Two of the in-contact dogs were reported to be siblings of a confirmed CRGV case, one developing a skin lesion and the other having diarrhea but no lesion. Therefore, it appears that dogs may be in close contact with other dogs without developing signs of disease, and the history often rather seems to reflect a shared exposure to a similar environment (e.g., multiple dogs being walked on the same walk). However, standard biosecurity precautions remain prudent. The author will often utilize typical leptospirosis protocols (barrier nursing/personal protective equipment [PPE]) until this option has been deemed an unlikely diagnosis, and then consider a lower level of ongoing PPE depending on the case (e.g., use of gloves). 

Conclusion

Research is ongoing into CRGV, particularly in an attempt to identify a causative organism. Definitive identification of an organism may indicate a hemolytic uremic syndrome, whereby a bacterial toxin initiates a TMA. Sadly, this may not provide many additional therapeutic options, as deceased cases of CRGV often received antibiotics, so the issue may then be the combined toxins and TMA process, rather than the bacteria alone. A lack of response to antibiosis could also indicate the presence of an organism with extensive antimicrobial resistance. However, with recognition of the disease and early intervention with appropriate AKI management, it is hopeful that additional surviving cases will be identified. The benefits of TPE continue to be assessed, and this remains a major therapeutic consideration, particularly early in the course of disease. 

References

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