21 Mar 2016
Laura Holm looks at how to spot the early signs of cutaneous and renal glomerular vasculopathy, such as the onset of lesions, and discusses ways of managing it.
Laura Holm
Job Title
Cutaneous and renal glomerular vasculopathy lesion affecting forelimb digits.
Cutaneous and renal glomerular vasculopathy (CRGV) is a canine disease that became apparent in the UK in 2012, but was recognised in the US in the 1980s.
It manifests as ulcerative skin lesions affecting distal extremities, ventrum, muzzle and/or oral cavity, and is variably associated with clinically significant acute kidney injury (AKI).
A variety of breeds, ages, weights and sexes of dog have been affected and, in spite of much research over the past three-and-a-half years, the cause remains unknown. Since November 2012, 65 cases of CRGV have been confirmed in the UK. The highest case numbers are between December and March, suggesting possible winter seasonality, and there have been small geographical clusters.
The diagnosis of CRGV can only be confirmed on postmortem examination, with histopathology of renal and, if possible, dermal tissue, which reveals thrombotic microangiopathy (TMA). This is characterised by damage to glomerular, and sometimes dermal, vascular endothelium with resultant widespread formation of microthrombi.
When microthrombi occlude blood supply in dermal vessels, dermal cell death occurs and cutaneous ulceration develops, whereas microthrombi in the glomeruli reduce glomerular blood supply and glomerular filtration rate, potentially causing azotaemia and oliguria or anuria. In some cases, microthrombi cause shear damage to erythrocytes, leading to microangiopathic haemolytic anaemia, hyperbilirubinaemia and haemoglobinuria. Consumptive thrombocytopaenia and resultant blood loss anaemia may also develop.
Evidence suggests the median time from the onset of a skin lesion, to development of azotaemia, is 3 days (range 0 to 10 days) and in these cases, 63% are thrombocytopenic, 34% are hyperbilirubinaemic and 20% are anaemic at presentation.
There does, however, appear to be a subset of dogs that develop skin lesions without azotaemia (non-azotaemic CRGV). This situation was also reported in the cases identified in the US, with about 75% of cases remaining systemically well following development of skin lesions and only about 25% developing clinical signs attributable to AKI.
CRGV has not been reported in species other than dogs. In humans a group of diseases exist that are characterised by TMA and bear some similarities to CRGV, namely: haemolytic uraemic syndrome (HUS), atypical haemolytic uraemic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP).
These are relatively rare diseases in humans, with HUS being the most common. This tends to be identified in infants following haemorrhagic diarrhoea caused by Shiga toxin-producing bacteria, such as certain strains of Escherichia coli. This illness often occurs in geographical and temporal clusters, due to contamination of food or water. Outbreaks are most commonly identified in the summer months.
When CRGV was first reported in the US in the late 1980s, only racing greyhounds appeared to be affected. Shiga toxin producing E coli were suspected to be the trigger, due to the similarity between CRGV and HUS and due to the practice of feeding racing greyhounds raw beef. However, as with the UK cases, neither Shiga toxin nor E coli were ever identified in any of the affected dogs. Feeding practices for the greyhounds were changed and the consensus is the incidence of disease is now lower, but as surveillance has not continued, the true prevalence of CRGV in the US is unknown.
In people, atypical HUS (aHUS) is caused by genetic abnormalities in the complement system; however, a trigger for the acute appearance of clinical signs is still suspected as many people with genetic abnormalities of their complement system only develop signs of aHUS later in life.
Mutations have been identified in many of the complement proteins and regulatory proteins. Complement factor H, membrane cofactor protein, complement factor I, C3, complement factor B, thrombomodulin and complement factor H-related proteins 1, 3 and 4 are most commonly affected by mutations in humans with aHUS. It is unknown whether dogs affected by CRGV have abnormalities of their complement system, but this would represent an area for future CRGV research.
Another human TMA – TTP – is caused by abnormalities of part of the coagulation cascade. These abnormalities can be genetic mutations or immune-mediated destruction of the protein ADAMTS13, which normally cleaves ultralarge von Willebrand factor (ULVWF) multimers. These multimers are anchored to endothelial cells and function as hyperadhesive sites – initiating platelet adhesion and aggregation – and activating surfaces for the alternative complement pathway (AP).
The reduced concentration of ADAMTS13 leads to increased levels of ULVWF multimers and results in an increase in thrombosis and activation of the AP. This leads to generation of terminal complement complexes, such as the membrane attack complex, which triggers endothelial cell damage, initiating the TMA process.
The small vessels of the CNS are often preferentially affected. Again, a trigger for the onset of clinical illness is often present or suspected as not all patients with reduced ADAMTS13 concentrations develop clinical signs of TTP. This may represent another area for CRGV research.
Human TMA patients tend to present with thrombocytopaenia and haemolysis, plus other signs varying with each disease. Patients with HUS and aHUS develop AKI, whereas patients with TTP more commonly develop neurological signs.
Some patients with aHUS also develop ulcerative skin lesions (appearing clinically similar to dogs with CRGV), and histopathology of skin biopsies from aHUS patients, even in the absence of clinically apparent skin lesions, reveals microvascular changes, such as loose luminal platelet thrombi. In contrast, skin lesions are not reported in humans with HUS or TTP.
Dogs with CRGV are presented for investigation of unexplained skin lesions. These are generally circular, ulcerated lesions with variable surrounding bruising, erythema and oedema. Central necrosis may be present. The lesions may appear similar to severe bites or stings and are most commonly seen on paws, distal limbs or ventrum. Oral cavity, nasal, and/or muzzle lesions may also be present.
Dogs may be clinically well initially, but many present with concurrent anorexia, vomiting, lethargy, lameness, pyrexia, polyuria, polydipsia or diarrhoea. More severely affected dogs may be hypothermic, icteric and/or show signs of bleeding (petechiae, epistaxis, haematochezia or haematemesis).
As there is no single antemortem test for CRGV, the following options could be considered for dogs with unexplained ulcerative skin lesions that are clinically well and not azotaemic:
Even in dogs that are well initially, repeat serum biochemistry may reveal azotaemia or increasing serum creatinine concentration. It is important to note a 25% increase in serum creatinine concentration, or a rise of 26.5μmol/L, above baseline could be significant, even if the serum creatinine concentration is within the reference range. Other signs of disease progression may include elevated serum liver enzyme activity, hyperbilirubinaemia, hyperphosphataemia and/or electrolyte derangements.
Urinalysis may reveal isosthenuria, or poorly concentrated urine (urine specific gravity; USG<1.035), renal casts, proteinuria and/or glycosuria. Any combination of these could support the presence of renal impairment/damage, although it is important to note USG varies throughout the day in healthy patients and a single reading of USG<1.035 should not be interpreted in the absence of other signs.
Haematology findings with progressive disease can include thrombocytopenia, anaemia and neutrophilia. Smear examination may reveal the presence of schistocytes or burr cells. In some cases, platelet numbers fall prior to any other haematological or biochemical changes.
For patients presenting with signs of systemic illness and azotaemia, investigations are primarily aimed at differentiating prerenal, renal and postrenal azotaemia. If renal azotaemia is confirmed, chronic kidney disease must be differentiated from AKI.
Initial investigations should include:
Faecal culture (including PCRs for genes encoding virulence factors if E coli is cultured) may be helpful to further understand whether any of these cases appear to be caused by Shiga toxin.
Patients developing AKI require intensive monitoring and management, and a referral should be considered.
Urine production must be assessed (commonly via placement of an indwelling urinary catheter) to determine whether the patient is polyuric, oliguric or anuric, and volume status must also be accurately assessed to avoid hypovolaemia or volume overloading. Close attention must also be paid to acid-base and electrolyte status.
Therapy is aimed at trying to improve renal function, via management of fluid and electrolyte balance, urine output and treatment for vasculopathy. Additionally, management for hypertension, haematological abnormalities and their consequences, nausea, pain and nutritional status, may be necessary.
Patients can be managed for other causes of AKI by matching fluid input to urine output plus insensible and other fluid loss, such as vomiting and diarrhoea. Regular (qid) monitoring of bodyweight is useful to assist with monitoring volume status.
More intensive management, such as plasma exchange and/or continuous renal replacement therapy, can also be considered early during therapy and, in some patients, will become necessary (especially if the patient becomes anuric).
Oliguria and anuria are medical emergencies. It is vital to recognise it early and manage it aggressively. Oliguria is usually defined as less than 0.5ml/kg/hour of urine production; however, when managing dogs with AKI, the goal is often to maintain urine output at more than 2ml/kg/hr.
Drugs aimed at promoting diuresis, assuming the patient is well-hydrated and not hypovolaemic, include furosemide, mannitol and dopamine. Furosemide is usually initially given as a 2mg/kg bolus, which can be followed either by a CRI (0.251mg/kg/hr to 1mg/kg/hr) or by trying incremental dose increases if initially ineffective. If furosemide is ineffective, mannitol is usually given as 0.25g/kg to 0.5g/kg over 10 minutes, and, if effective, this can be followed with a CRI.
Management of AKI should be continued for a minimum of three to five days to allow renal lesions to repair. Unfortunately, development of oligoanuria often prevents ongoing conservative management from being possible and is a known negative prognostic indicator. If medical management of AKI is ineffective, the only remaining options are peritoneal dialysis, or referral for continuous renal replacement therapy.
Therapeutic plasma exchange (TPE) is used for management of human aHUS and TTP. TPE removes large-molecular-weight substances from the plasma, such as mutated overactive complement proteins or harmful antibodies. It is usually carried out using an automated blood cell separator to ensure fluid balance and maintain a normal plasma volume.
Typically, 1 to 1.5 plasma volumes are removed at each procedure. Between 25% to 50% of replacement volume is administered as isotonic crystalloids and the remaining replacement volume is given as fresh frozen plasma for the replacement of normal functional complement factors or ADAMTS13.
As it is unknown whether dogs with CRGV have complement or ADAMTS13 abnormalities, so too is the potential benefit of plasma exchange therapy in dogs.
As patients with azotaemic CRGV are often extremely, systemically unwell, other supportive care should also be used as appropriate. Symptomatic management for uraemic gastritis includes the use of antacids, such as omeprazole, ranitidine or cimetidine, and anti-nausea medication, such as metoclopramide, maropitant, ondansetron or prochlorperazine. Opioids would be the most appropriate choice of analgesic as NSAIDs are contraindicated in patients at risk from, or having, renal dysfunction.
If severe anaemia develops, a blood transfusion may be required. Haematological abnormalities, such as thrombocytopenia, must also be taken into account if invasive procedures – for example, biopsy of skin lesions or placement of a feeding tube – are considered.
Pentoxifylline is considered to be indicated for treatment of vasculitis and vasculopathies, but any controlled studies investigating its use in CRGV are lacking. It increases erythrocyte flexibility and fibrinolysis and decreases blood viscosity. It may also reduce the endotoxic effects of inflammatory cytokines.
There is rationale for its use in CRGV cases; however, it is worth noting it is metabolised in the liver and excreted via the kidneys and its use may be contraindicated in patients with severe hepatic or renal impairment, or those at risk of haemorrhage.
Steroids have not been shown to be beneficial in dogs with CRGV, either at the anti-inflammatory or the immunosuppressive dose, and may be contraindicated in dogs with renal disease.
For CRGV cases that remain non-azotaemic, the prognosis is excellent. Although skin lesions may take weeks or months to heal, a full recovery should be expected.
Unfortunately, the prognosis is significantly less favourable in dogs with CRGV that develop AKI. Overall, more than 85% of CRGV cases with azotaemia have been euthanised or died. In the majority of cases, this is due to oligoanuria, progressive azotaemia or development of worsening clinical signs, such as seizures or collapse.
The outlook may be slightly better for cases managed in referral centres. Approximately 25% of azotaemic-suspected CRGV cases managed in referral centres have survived. However, no single therapy has been used more commonly in surviving cases and this figure is likely to reflect the more intensive monitoring and management generally possible in the referral setting.
Even in humans, the aetiopathogeneses of TMA illnesses are still relatively poorly understood. Definitive diagnosis can be challenging and treatment is not always successful.
It is hoped ongoing CRGV research will further our understanding of this disease and improve the diagnosis, management and prognosis for these patients.
