Pyelonephritis

One of the main challenges for veterinarians in the diagnosis and treatment of pyelonephritis is balancing the risks of overtreating a patient with subclinical bacteriuria against the benefits of detecting and treating pyelonephritis, a potential cause of kidney disease, progression of kidney disease, other morbidities and sepsis.

Most of the veterinary literature on pyelonephritis consists of case studies or small case series. The diagnosis of pyelonephritis is based on a combination of clinical, laboratory and sonographic findings. One major limitation in reviewing the literature is the inconsistent and sometimes unspecified, criteria for the diagnosis of pyelonephritis. When clinical and laboratory signs are used to define pyelonephritis, these data cannot be used to describe the clinical and laboratory signs due to pyelonephritis.

Dogs and cats with normal urogenital tracts are resistant to induction of bacterial cystitis and pyelonephritis (Scott, 1964; Harrison et al., 1973; Kelly et al., 1979).

Cats: Pyelonephritis appears to be uncommon in cats with normal urogenital tracts; bacteria was identified at necropsy from only one of 160 (125 with CKD and 25 healthy) cats (Lucke, 1968). In contrast, pyelonephritis was diagnosed or suspected in 1.5% (1/69 cats) with ureteral obstruction, in 2-5 % of cats after surgical correction of ureteral obstruction (Berent et al., 2014; Kopecny et al., 2019), in 5 to 6 % of cats with CKD (DiBartola et al., 1987; White et al., 2013) and in 23 % (7/30) cats with indwelling urinary catheters (Barsanti et al., 1992).

Many case reports of cats with pyelonephritis identified co-morbidities that likely predisposed the cat to an ascending infection such as ureteral obstructions (Berent et al., 2018; Cray et al., 2018; McQuitty and Branter, 2018), implants (Vedrine, 2017) and urinary tract malformations (Robin et al., 2019). Pyelonephritis can cause or be secondary to sepsis (Brady et al., 2000) or other urinary tract infections (Pointer and Murray, 2011). Fungal urinary infections are uncommonly reported (Coldrick et al., 2007; McQuitty and Branter, 2018).

Dogs: Pyelonephritis appears uncommon in dogs, diagnosed in 0.4-1.3% of dogs at necropsy (Bouillon et al., 2018), 5% of dogs with a positive urine culture (Wong et al., 2015) and 8% of dogs with kidney disease (Wettimuny, 1967).

Many dogs (~ 75%) with clinically and histologically diagnosed pyelonephritis have concomitant disease that potentially predisposed them to ascending infection. These include abnormalities of the urogenital tract such as urinary obstruction, incontinence, inflammatory diseases (e.g. pyometra, cystitis) and systemic immunosuppression such as diabetes mellitus, neoplasia, corticosteroids or chemotherapy (Wettimuny, 1967; Jergens et al., 1988; Lewis et al., 1988; Hylands, 2006; Choi et al., 2010; Bouillon et al., 2018).

Acute kidney injury (AKI): Pyelonephritis was diagnosed in 2% of dogs with AKI (Vaden et al., 1997). In a meta-analysis of AKI in dogs and cats only 1.7% were associated with pyelonephritis (Legatti et al., 2018)

Acute on chronic kidney disease: Pyelonephritis was suspected in 8% of cats (Chen et al., 2020) and in 15% of dogs (Dunaevich et al., 2020) with acute on chronic kidney disease. Pyelonephritis has been identified as a potential but uncommon cause of an uremic crisis in cats without ureteral obstruction (Quimby et al., 2017).

Chronic kidney disease (CKD): The potential for pyelonephritis to cause or contribute to the progression of CKD in dogs and cats remains to be definitively determined. Positive urine cultures are common in dogs (18%- 32%) (Foster et al., 2018; Lamoureux et al., 2019) and cats (17-22%) (Mayer-Roenne et al., 2007) with CKD but most animals with positive urine cultures do not have clinical signs of lower urinary tract or pyelonephritis and likely have subclinical bacteriuria. There is no association between a positive urine culture and disease severity in either dogs (Foster et al., 2018; Lamoureux et al., 2019) or cats (Hindar et al., 2020) with chronic kidney disease. Similar cohorts of patients are at increased risk for subclinical bacteriuria, cystitis and pyelonephritis. Individual dogs or cats with CKD can have multiple episodes of either disease over time (Foster et al., 2018; Hindar et al., 2020).

A necropsy survey of dogs with kidney disease identified pyelonephritis in 8% of which one third had urinary tract obstruction and the remaining had co-morbidities that potentially predisposed them to ascending infection (Wettimuny, 1967).

Pyelonephritis was diagnosed in 5% of 74 cats (DiBartola et al., 1987) and in 40% of 40 dogs (Foster et al., 2018) with CKD. The prognosis for dogs with CKD and pyelonephritis was poor, likely due to pre-existing renal dysfunction. Sixty percent of 33 dogs with CKD and pyelonephritis were euthanized within one month of diagnosis, despite treatment with antimicrobials (Foster et al., 2018). In contrast, a case report described two dogs with azotaemia and pyonephrosis without obvious predisposing factors where azotaemia resolved with antibiotic treatment (Szatmári et al., 2001).

Acute pyelonephritis is more commonly diagnosed in women than men, with an increased incidence in very young, young-adult and adult-older women (> 50 years) (Czaja et al., 2007). The diagnosis of acute pyelonephritis is a clinical one, involving the presence of clinical and laboratory signs including fever or hypothermia, abdominal or flank pain, lower urinary tract signs and a positive urine culture of known uropathogen (Raz et al., 2003).

Uncomplicated pyelonephritis is particularly common in young, sexually active women with a history of previous or a maternal history of urinary tract infection (UTI) (Scholes D et al., 2005). Uncomplicated pyelonephritis in adults does not cause clinically relevant kidney disease (Kunin, 1985; Raz et al., 2003). Urinary tract infections, including pyelonephritis, are rare causes of CKD in adults without predisposing factors such as obstruction, urolithiasis, neurogenic bladder dysfunction or diabetes mellitus (Anumudu and Eknoyan, 2019).

Complicated pyelonephritis refers to the presence of systemic (such as HIV positivity, diabetes, neoplasia or collagen disease) or anatomical (uroliths, obstruction, reflux nephropathy) predisposing factors (Piccoli et al., 2011).

Childhood urinary tract infections can result in CKD (Pleniceanu et al., 2020) but the risk of CKD in children in the absence of concurrent abnormalities is low (Sreenarasimhaiah and Hellerstein, 1998; Salo et al., 2011). In children, risk factors for pyelonephritis include vesico-ureteric reflux (VUR) and traditionally, the combination of reflux and infection were considered common causes of renal scarring and CKD (Murugapoopathy et al., 2020). However, the effects of vesicoureteral and intra-renal reflux and the role of ascending infection are unresolved, as renal scarring may be due to developmental renal dysplasia (Hewitt and Montini, 2020).

People with CKD are at increased risk of infections including UTI due to loss of antibacterial properties of normal urine and the immunosuppression associated with uraemia (Sarnak and Jaber, 2000; Syed-Ahmed and Narayanan, 2019). In contrast, in cats reduced urine concentrating ability has not been a consistent risk factor for positive urine cultures (Bailiff et al., 2008). While the risk of infection is greatest in people with end stage renal failure, even mild to moderate reductions in renal function are associated with increased risks of infections (Naqvi and Collins, 2006; Ishigami et al., 2017). Specific nephropathies including polycystic kidney disease, gross vesico-ureteral reflux and obstructive uropathy are often associated with ascending infections. Bacteraemia and sepsis secondary to severe urinary tract infections could exacerbate the progression of renal failure, however, aggressive treatment of lesser degrees of infection is considered unlikely to improve renal function in people with CKD (Grabe et al., 2013)

A diagnosis of pyelonephritis is challenging and traditionally requires the presence of systemic signs (fever, polydipsia, polyuria, abdominal pain), compatible changes on complete blood count ( for example leukocytosis, neutrophilia, left shift, toxic change), and urinalysis and supportive changes on abdominal sonography (Weese et al., 2019). These "classic" signs were present in less than one quarter of dogs and even number of cats with histologically confirmed pyelonephritis (Bouillon et al., 2018; Cheney et al., 2018) but as necropsy based studies, these may represent animals with more complex and severe disease. Azotaemia has been an inconsistent inclusion criteria (Quimby et al., 2017; Cheney et al., 2018; Foster et al., 2018).

Sonographic changes observed in experimentally induced pyelonephritis in dogs include renal pelvic and proximal ureteral dilatation, hyperechoic mucosa within the renal pelvis or proximal ureter and changes to the echogenicity of the cortex or medulla (Neuwirth et al., 1993). In dogs with histologically confirmed pyelonephritis, pyelectasia (in 66% dogs) and ureteral dilation (44% of dogs) were reasonably common while reduced corticomedullary distinction, changes in renal size and renal hyperechogenicity were uncommon (Bouillon et al., 2018).

Sonography was a specific diagnostic test (no false positives) with acceptable sensitivity (82%) when distinguishing between normal dogs and dogs with experimentally induced pyelonephritis (Neuwirth et al., 1993). However, imaging is likely to be less accurate when attempting to distinguish pyelonephritis from CKD and ureteral obstruction. Sonographic changes associated with pyelonephritis are also present with other conditions eg pyelectasia with diuresis, obstruction and CKD (D'Anjou et al., 2011). The presence and extent of ureteral dilation can help distinguish normal cats and cats with CKD from cats with either pyelonephritis or ureteral obstruction but could not distinguish between the latter. Pelvic dilation was less useful with overlaps between CKD, pyelonephritis and ureteral obstruction in both dogs and cats (D'Anjou et al., 2011; Quimby et al., 2017).

Pyelocentesis to obtain material for cytology and culture is the gold standard test for distinguishing upper from lower urinary tract infection, however, complication rates range from 16-40% of which 2% (confidence interval 1-10%) were serious complications. The diagnostic yield from bacterial culture of urine obtained by pyelocentesis was not superior than samples obtained by cystocentesis (Etedali et al., 2019). It is likely to be a superior test in cases of complete ureteral obstruction. Pyelocentesis therefore, is not likely to be a routine diagnostic test in the evaluation of dogs and cats with possible pyelonephritis in general practice.

Renal biopsies are unlikely to be useful in the diagnosis of pyelonephritis as biopsies are intended to sample the renal cortex rather than the pelvis and inner medulla where pyelonephritis originates.

Diagnosing pyelonephritis in dog and cat populations with high prevalence of subclinical bacteriuria (older, female animals) is difficult but a positive urine culture alone would not suffice. In the future, there may be markers that are upregulated in animals with pyelonephritis compared to those with subclinical bacteriuria (Jessen et al., 2020).

Importantly, neither clinical signs of lower urinary tract disease nor azotaemia are consistent abnormalities and neither should be considered necessary for the diagnosis of pyelonephritis.

Antibiotic treatment of pyelonephritis in dogs and cats needs to be supported always by urine culture and antimicrobial susceptibility tests. Renally excreted drugs, such as the B lactam antibiotic amoxicillin, achieve much higher concentrations in urine than in plasma and are first line antibiotics for the empiric treatment of lower urinary tract infections (Weese et al., 2019). However, many E. coli samples from dogs and cats with UTIs would be resistant to amoxicillin and amoxicillin clavulanic acid at concentrations achieved in soft tissue. Bacterial isolates identified in urine samples submitted for culture and susceptibility testing in dogs and cats suspected of having pyelonephritis should be evaluated using plasma, rather than urine, breakpoints (Boothe, 2012).

The current recommendations for empiric treatment of known or suspected pyelonephritis in dogs and cats include fluoroquinolones and third generation cephalosporins (for example cefpodoxime, cefotaxime) (Weese et al., 2019). There is anecdotal evidence from Scandinavian countries that trimethaprim-sulphonamide (TMP/S) is an effective treatment in animals with pyelonephritis, although the well-known potential adverse effects of TMP/S are a matter of concern.

Antibiotics have the potential to cause acute kidney injury, especially in patients with pre-existing CKD should be avoided. Aminoglycosides are well recognized for their potential nephrotoxicity via acute tubular necrosis. Beta-lactam antibiotics, trimethoprim-sulphonamide and fluroquinolones have all been associated with acute interstitial nephritis in people, while fluroquinolones can cause thrombotic microangiopathy (Morales-Alvarez, 2020) but these complications have not been recognized in dogs and cats. Enrofloxacin could cause retinal damage in some cats, especially at high dosage, and with decreased kidney function (Ford et al., 2007). Pradofloxacin is not associated with retinal toxicity (Messias et al., 2008) but as a third generation fluroquinolone, pradofloxacin should be used cautiously to minimize development of widespread antimicrobial resistance.

Widespread use of antimicrobials, especially fluroquinolones, in animals with subclinical bacteriuria and non-urinary tract related disease is not responsible. Risks of inappropriate antimicrobial usage include increasing antimicrobial resistance in treated animals (Moyaert et al., 2017; Marques et al., 2018) and people (Czaja et al., 2007; Gupta et al., 2011). There is potential for transmission of fluroquinolone resistance and extended beta lactamase producing bacteria to other animals (Johnson et al., 2009) and people within households. Many factors that predispose dogs and cats to urinary tract infections are difficult, if not impossible, to resolve and consequently animals can have recurrent episodes of cystitis and pyelonephritis. This could lead to repeated exposure for members of the household to uropathogens of increasing antimicrobial resistance.

Of further concern to veterinarians and communities, is the tendency of fluoroquinolones to accumulate in the environment and facilitate widespread development and transmission of bacterial resistance (Ruiz, 2019; Azargun et al., 2020). Enrofloxacin is the most used fluoroquinolone in veterinary medicine and bacterial resistance increased after its entry into the world market (Cooke et al., 2002).

Modern synthetic antibiotic classes, such as fluoroquinolones, persist in the environment, unlike older classes of antibiotics which are broken down in the environment within a few weeks (Paulshus et al., 2019). Environmental residues of fluroquinolones have the potential to be directly detrimental to environmental ecosystems, especially the aquatic environment (Frade et al., 2014; Janecko et al., 2016; Riaz et al., 2018).

Pyelonephritis is uncommon cause for AKI in otherwise previously heathy dogs and cats, therefore aggressive and sustained antimicrobial treatment is not justified to treat potential pyelonephritis in any animal with AKI without a positive urinary culture. When suspected, efforts should be made to define dogs and cats with suspected pyelonephritis as having uncomplicated or complicated UTI. Extrapolating from the medical and veterinary literature, acute uncomplicated pyelonephritis is less common than complicated pyelonephritis in dogs and cats and those with pyelonephritis should be assumed to have complicated pyelonephritis until complete medical assessment suggests otherwise.

Multidrug resistant isolates are more common in dogs with complicated than simple urinary tract infections (Wong et al., 2010). Complicated pyelonephritis in people is associated with a wider variety of organisms and organisms of increased antimicrobial resistance than uncomplicated pyelonephritis (Nicolle, 2007).

Consequently, it is difficult to make recommendations for empiric treatment of pyelonephritis in dogs and cats, and urine culture with plasma (i.e. soft tissue) MIC breakpoints is an essential part of diagnosis and treatment.

There is no biomarker or easily available gold standard for the antemortem diagnosis of pyelonephritis in dogs and cats. Clinical diagnosis will always be challenging in a non-verbal population. The following are potential diagnostic categories:

Possible diagnosis:

• Patient with systemic signs of inflammation including pyrexia and

• Pyuria and positive culture of uropathogen from a cystocentesis sample and

• No clinical indication of other non-urinary tract causes of inflammation

Probable diagnosis: as above plus

• Compatible changes on complete blood count e.g. neutrophilia, left shift, toxic change and

• Sonographic changes compatible with pyelonephritis, although sonographic changes alone can support but not definitively diagnose pyelonephritis (Buettcher et al., 2020)

Definitive diagnosis: as above plus

• Urine culture obtained directly from the renal pelvis

Dogs and cats with suspected pyelonephritis should be assessed for concurrent disorders that increase their susceptibility to ascending infection (e.g. ureteroliths, systemic immunocompromise). The presence of structural abnormalities that increase the risk for pyelonephritis can affect interpretation of urine culture results. For example, Enterococcus spp. are generally less virulent that other streptococci and are commonly identified in cats with subclinical bacteriuria (Puchot et al., 2017). In contrast, most (5/6 cats) with pure enterococcal cultures post subcutaneous ureteral bypass placement had clinical signs, including suspected pyelonephritis (Kopecny et al., 2019).

Non antimicrobial adjunct treatments should be considered where appropriate and may prove effective preventative strategies. Treatment strategies that should be the subject of future research include the reduction of obesity (Semins et al., 2012; Wynn et al., 2016), removal of cystoliths, reduction of immunosuppressive treatments, optimization of diabetic control, rehabilitation strategies to increase bladder voiding and increased water intake (Hooton et al., 2018; Plüddemann, 2019). Immunotherapy or the deliberate colonization of the bladder with bacteria that are associated with asymptomatic bacteriuria rather than UTI, could be promising alternative treatments for dogs with recurrent UTI and may in future be effective for dogs and cats with recurrent pyelonephritis (Thompson et al., 2012; Segev et al., 2018).

Recommendations for dogs and cats with CKD:

Animals with non-obstructive CKD do not have structural risk factors for developing pyelonephritis but uraemia (and possibly also age and protein energy wasting) may be associated with reduced systemic immunity in our patients as it is in people.

Pyelonephritis is a potential cause of chronic or acute on chronic kidney disease in cats (Chen et al., 2020) and dogs (Dunaevich et al., 2020). In animals with complicated pyelonephritis, it is difficult to distinguish the relative contribution of infection versus structural abnormality to renal damage.

Proposed recommendations:

i) clinical signs of systemic disease (vomiting, abdominal pain, lethargy) in combination with signs of systemic inflammation (pyrexia, neutrophilia) or

ii) clinical signs of LUT disease

Urinalysis, culture, and susceptibility testing followed by antimicrobial treatment of animals with positive urine cultures should be considered in dogs and cats with kidney disease and the risks and benefits of treatment assessed on an individual basis

iii) at an initial diagnosis of acute or chronic kidney disease or

iv) during acute and unexplained deteriorations in renal function or

v) in patients with additional predisposing factors such as ureteral obstruction

Treatment of dogs and cats with positive cultures should be undertaken with recognition that many patients with CKD and positive urine cultures have subclinical bacteriuria. Clinical signs can improve for a variety of reasons including use of anti-emetics, intravenous fluids, analgesia and time regardless of antimicrobial administration. Identification of a positive urine culture should not prevent veterinary assessment for other possible causes of the patient's clinical signs and failure to improve should result in discontinuation of antimicrobial treatment. Similarly, if antibiotic therapy has been initiated while awaiting results of urine culture and this is negative treatment with antibiotics should be discontinued.

In patients with stable CKD but without clinical signs suggestive of pyelonephritis or cystitis, positive urine cultures could reflect subclinical bacteriuria and not require treatment. However, the diagnosis of subclinical bacteriuria relies on the owner's ability to detect clinical signs which can be subtle. There is controversy whether animals with stable CKD and without relevant clinical signs, should be treated and a consensus has not been reached. The optimal diagnostic approach and treatment strategy to positive urine cultures in dogs and cats with CKD should be the focus of further research.

Subclinical bacteriuria is uncommon in young dogs and cats and therefore greater significance should be ascribed to positive urine cultures in young animals with systemic signs.

Pyelonephritis and familial nephropathies:

A specific note of caution should be given for breeding recommendations in breeds with a high prevalence of renal disease and pyelonephritis. A high prevalence of pyelonephritis is observed in young Boxer as well as in young Flat Coated Retriever dogs; both breeds that have increased morbidity and mortality due to kidney disease (Pelander et al., 2015).

Some breeders and veterinarians may argue that pyelonephritis is "simply an infection" and will ask for documentation of juvenile disease (i.e. fetal glomeruli, or secondary "renal dysplasia") before parent animals are removed from the breeding pool. However, in Boxer dogs, there is substantial diversity in the clinical signs and histopathology of patients with CKD, pyelonephritis and familial nephropathies. Different clinical pictures as well as different histopathological patterns may be present in the same litter (Cecilie Strømstad, personal communication) and histopathological patterns other than those consistent with vesiculo-ureteral reflux have been observed (Chandler et al., 2007).

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