Pyelonephritis

Adapted from the IRIS education article by Joanna White (Sydney, Australia) and Reidun Heiene (Oslo, Norway).

Definition: a bacterial infection, typically ascending from the lower urinary tract, of the renal pelvis (pyelitis) or of the renal pelvis and kidney tissue (pyelonephritis).

Introduction

One of the main challenges for veterinarians in diagnosing and treating pyelonephritis is balancing the risk of overtreating a patient with subclinical bacteriuria against the benefit of detecting and treating pyelonephritis, which can cause kidney disease, speed its progression, and lead to other illness and sepsis.

Most of the veterinary literature on pyelonephritis consists of case reports or small case series. The diagnosis of pyelonephritis is based on a combination of clinical, laboratory, and ultrasound findings. A major limitation in reviewing the literature is that the criteria for diagnosing pyelonephritis are inconsistent and sometimes unstated. When clinical and laboratory signs are used to define pyelonephritis, those same data cannot then be used to describe the clinical and laboratory signs caused by it.

Prevalence

Dogs and cats with normal urogenital tracts are resistant to experimental 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 were identified at necropsy in only one of 160 cats (125 with CKD and 25 healthy) (Lucke, 1968). In contrast, pyelonephritis was diagnosed or suspected in about 1.5% of cats with ureteral obstruction (1 of 69 cats), in 2% to 5% of cats after surgical correction of ureteral obstruction (Berent et al., 2014; Kopecny et al., 2019), in 5% to 6% of cats with chronic kidney disease (CKD) (DiBartola et al., 1987; White et al., 2013), and in 23% of cats with indwelling urinary catheters (7 of 30 cats) (Barsanti et al., 1992).

Many case reports of cats with pyelonephritis describe other conditions that probably predisposed the cat to an ascending infection, such as ureteral obstruction (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 result from, sepsis (Brady et al., 2000) or other urinary tract infections (Pointer and Murray, 2011). Fungal urinary infections are reported uncommonly (Coldrick et al., 2007; McQuitty and Branter, 2018).

Dogs

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

About 75% of dogs with clinically and histologically diagnosed pyelonephritis have another condition that may have predisposed them to ascending infection. These include abnormalities of the urogenital tract, such as urinary obstruction, incontinence, and inflammatory diseases (for example pyometra and cystitis), and systemic immunosuppression, such as diabetes mellitus, neoplasia, corticosteroid treatment, 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

Pyelonephritis was diagnosed in 2% of dogs with acute kidney injury (AKI) (Vaden et al., 1997). In a meta-analysis of AKI in dogs and cats, only 1.7% of cases 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 15% of dogs (Dunaevich et al., 2020) with acute-on-chronic kidney disease. It has been identified as a possible but uncommon cause of uremic crisis in cats without ureteral obstruction (Quimby et al., 2017).

Chronic Kidney Disease

Whether pyelonephritis causes CKD or contributes to its progression in dogs and cats has not been definitively established. Positive urine cultures are common in dogs (18% to 32%) (Foster et al., 2018; Lamoureux et al., 2019) and cats (17% to 22%) (Mayer-Roenne et al., 2007) with CKD, but most animals with positive urine cultures have no clinical signs of lower urinary tract disease or pyelonephritis and probably have subclinical bacteriuria. There is no association between a positive urine culture and the severity of CKD in either dogs (Foster et al., 2018; Lamoureux et al., 2019) or cats (Hindar et al., 2020). The same groups of patients are at increased risk of subclinical bacteriuria, cystitis, and pyelonephritis, and individual dogs or cats with CKD can have multiple episodes of either over time (Foster et al., 2018; Hindar et al., 2020).

A necropsy survey of dogs with kidney disease found pyelonephritis in 8%. One-third of these dogs had urinary tract obstruction, and the rest had other conditions that could have predisposed them to ascending infection (Wettimuny, 1967).

Pyelonephritis was diagnosed in 5% of 74 cats (DiBartola et al., 1987) and 40% of 40 dogs (Foster et al., 2018) with CKD. The prognosis for dogs with CKD and pyelonephritis was poor, probably because of pre-existing kidney dysfunction: 60% of 33 dogs with CKD and pyelonephritis were euthanized within one month of diagnosis despite antimicrobial treatment (Foster et al., 2018). In contrast, a case report described two dogs with azotemia and pyonephrosis, without obvious predisposing factors, whose azotemia resolved with antibiotic treatment (Szatmári et al., 2001).

Comparative Medicine: Pyelonephritis in People

Acute pyelonephritis is diagnosed more often in women than in men, with an increased incidence in very young, young adult, and older women (over 50 years) (Czaja et al., 2007). The diagnosis of acute pyelonephritis in people is a clinical one, based on clinical and laboratory signs including fever or low body temperature, abdominal or flank pain, lower urinary tract signs, and a positive urine culture of a known uropathogen (Raz et al., 2003).

Uncomplicated pyelonephritis is particularly common in young, sexually active women with a personal or maternal history of urinary tract infection (UTI) (Scholes 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, urinary stones, neurogenic bladder dysfunction, or diabetes mellitus (Anumudu and Eknoyan, 2019).

Complicated pyelonephritis refers to pyelonephritis with systemic predisposing factors (such as HIV infection, diabetes, neoplasia, or collagen disease) or anatomical ones (such as urinary stones, obstruction, or reflux nephropathy) (Piccoli et al., 2011).

Childhood urinary tract infections can result in CKD (Pleniceanu et al., 2020), but the risk of CKD in children without other abnormalities is low (Sreenarasimhaiah and Hellerstein, 1998; Salo et al., 2011). In children, risk factors for pyelonephritis include vesicoureteral reflux (VUR), and the combination of reflux and infection was traditionally considered a common cause of kidney scarring and CKD (Murugapoopathy et al., 2020). However, the effects of vesicoureteral and intrarenal reflux and the role of ascending infection remain unresolved, because kidney scarring may be due to developmental renal dysplasia (Hewitt and Montini, 2020).

People with CKD are at increased risk of infections, including UTI, because urine loses its normal antibacterial properties and because uremia suppresses the immune system (Sarnak and Jaber, 2000; Syed-Ahmed and Narayanan, 2019). In contrast, in cats, a reduced ability to concentrate urine has not been a consistent risk factor for positive urine cultures (Bailiff et al., 2008). Although the risk of infection is greatest in people with end-stage kidney failure, even mild to moderate reductions in kidney function are associated with increased risk of infection (Naqvi and Collins, 2006; Ishigami et al., 2017). Specific kidney diseases, including polycystic kidney disease, severe vesicoureteral reflux, and obstructive uropathy, are often associated with ascending infections. Bacteremia and sepsis caused by severe urinary tract infections could worsen the progression of kidney failure, but aggressive treatment of milder infections is considered unlikely to improve kidney function in people with CKD (Grabe et al., 2013).

Diagnosis of Pyelonephritis in Dogs and Cats

Diagnosing pyelonephritis is challenging. It traditionally requires systemic signs (fever, increased thirst and urination, abdominal pain), compatible changes on the complete blood count (such as an increased white cell count, neutrophilia, a left shift, and toxic change) and urinalysis, and supportive changes on abdominal ultrasound (Weese et al., 2019). However, these "classic" signs were present in fewer than one-quarter of dogs, and in even fewer cats, with histologically confirmed pyelonephritis (Bouillon et al., 2018; Cheney et al., 2018), although these necropsy-based studies may represent animals with more complex and severe disease. Azotemia has been an inconsistent inclusion criterion (Quimby et al., 2017; Cheney et al., 2018; Foster et al., 2018).

Ultrasound

Ultrasound changes seen in dogs with experimentally induced pyelonephritis include dilation of the renal pelvis and proximal ureter, a hyperechoic lining within the renal pelvis or proximal ureter, and changes in the echogenicity of the cortex or medulla (Neuwirth et al., 1993). In dogs with histologically confirmed pyelonephritis, dilation of the renal pelvis (pyelectasia, in 66% of dogs) and of the ureter (in 44%) were reasonably common, while reduced corticomedullary distinction, changes in kidney size, and increased kidney echogenicity were uncommon (Bouillon et al., 2018).

Ultrasound was a specific test (no false positives) with acceptable sensitivity (82%) for distinguishing normal dogs from dogs with experimentally induced pyelonephritis (Neuwirth et al., 1993). However, imaging is likely to be less accurate for distinguishing pyelonephritis from CKD and ureteral obstruction. The ultrasound changes associated with pyelonephritis also occur with other conditions; for example, pyelectasia can occur with diuresis, obstruction, and CKD (D'Anjou et al., 2011). The presence and degree of ureteral dilation can help distinguish normal cats and cats with CKD from cats with pyelonephritis or ureteral obstruction, but it cannot distinguish between the latter two. Dilation of the renal pelvis was less useful, with overlap between CKD, pyelonephritis, and ureteral obstruction in both dogs and cats (D'Anjou et al., 2011; Quimby et al., 2017).

Pyelocentesis and Biopsy

Pyelocentesis, collecting material from the renal pelvis for cytology and culture, is the gold standard test for distinguishing upper from lower urinary tract infection. However, complication rates range from 16% to 40%, and 2% (confidence interval 1% to 10%) of complications were serious. Bacterial culture of urine obtained by pyelocentesis did not give a better diagnostic yield than culture of urine obtained by cystocentesis (Etedali et al., 2019), although pyelocentesis is likely to be the better test when the ureter is completely obstructed. Pyelocentesis is therefore unlikely to become a routine test for dogs and cats with possible pyelonephritis in general practice.

Kidney biopsies are unlikely to help diagnose pyelonephritis, because biopsies are designed to sample the renal cortex rather than the renal pelvis and inner medulla, where pyelonephritis begins.

Diagnosing pyelonephritis in populations of dogs and cats with a high prevalence of subclinical bacteriuria, such as older female animals, is difficult, and a positive urine culture alone is not enough. In future, there may be markers that are increased in animals with pyelonephritis but not in those with subclinical bacteriuria (Jessen et al., 2020).

Importantly, neither clinical signs of lower urinary tract disease nor azotemia is consistently present, and neither should be considered necessary for a diagnosis of pyelonephritis.

Treatment

Antibiotic treatment of pyelonephritis in dogs and cats should always be supported by urine culture and antimicrobial susceptibility testing. Drugs excreted by the kidneys, such as the beta-lactam antibiotic amoxicillin, reach much higher concentrations in urine than in plasma and are first-line antibiotics for empirical treatment of lower urinary tract infections (Weese et al., 2019). However, many E. coli isolates from dogs and cats with UTIs are resistant to amoxicillin and amoxicillin-clavulanic acid at the concentrations reached in tissues. Bacteria isolated from urine samples of dogs and cats suspected of having pyelonephritis should therefore be evaluated against plasma (tissue), rather than urine, susceptibility breakpoints (Boothe, 2012).

Current recommendations for empirical treatment of known or suspected pyelonephritis in dogs and cats include fluoroquinolones and third-generation cephalosporins, such as cefpodoxime and cefotaxime (Weese et al., 2019). There is anecdotal evidence from Scandinavian countries that trimethoprim-sulfonamide (TMP/S) is an effective treatment for pyelonephritis, although the well-known potential adverse effects of TMP/S are a concern.

Antibiotics that can cause acute kidney injury should be avoided, especially in patients with pre-existing CKD. Aminoglycosides are well known to damage the kidneys through acute tubular necrosis. Beta-lactam antibiotics, trimethoprim-sulfonamide, and fluoroquinolones have all been associated with acute interstitial nephritis in people, and fluoroquinolones can cause thrombotic microangiopathy (Morales-Alvarez, 2020), but these complications have not been recognized in dogs and cats. Enrofloxacin can damage the retina in some cats, especially at high doses and when kidney function is reduced (Ford et al., 2007). Pradofloxacin is not associated with retinal toxicity (Messias et al., 2008), but as a third-generation fluoroquinolone it should be used cautiously to limit the development of widespread antimicrobial resistance.

Responsible Antimicrobial Use

Widespread use of antimicrobials, especially fluoroquinolones, in animals with subclinical bacteriuria or with diseases unrelated to the urinary tract is not responsible antimicrobial use. The risks of inappropriate use include increasing antimicrobial resistance in treated animals (Moyaert et al., 2017; Marques et al., 2018) and in people (Czaja et al., 2007; Gupta et al., 2011). Fluoroquinolone resistance and extended-spectrum beta-lactamase (ESBL)-producing bacteria can be transmitted to other animals (Johnson et al., 2009) and to people in the same household. Many of the factors that predispose dogs and cats to urinary tract infections are difficult or impossible to resolve, so these animals can have recurrent episodes of cystitis and pyelonephritis, which could repeatedly expose members of the household to uropathogens with increasing antimicrobial resistance.

A further concern for veterinarians and communities is that fluoroquinolones tend to accumulate in the environment and promote the development and spread of bacterial resistance (Ruiz, 2019; Azargun et al., 2020). Enrofloxacin is the most widely used fluoroquinolone in veterinary medicine, and bacterial resistance increased after it entered the world market (Cooke et al., 2002). Modern synthetic antibiotic classes such as fluoroquinolones persist in the environment, unlike older classes, which break down within a few weeks (Paulshus et al., 2019). Environmental fluoroquinolone residues can directly harm ecosystems, especially aquatic environments (Frade et al., 2014; Janecko et al., 2016; Riaz et al., 2018).

Recommendations

Pyelonephritis is an uncommon cause of AKI in previously healthy dogs and cats, so aggressive and prolonged antimicrobial treatment for possible pyelonephritis is not justified in an animal with AKI unless a urine culture is positive. When pyelonephritis is suspected, efforts should be made to classify the infection as uncomplicated or complicated. Based on the human and veterinary literature, acute uncomplicated pyelonephritis is less common than complicated pyelonephritis in dogs and cats, and animals with pyelonephritis should be assumed to have complicated pyelonephritis until a complete medical assessment suggests otherwise.

Multidrug-resistant isolates are more common in dogs with complicated urinary tract infections than in those with simple ones (Wong et al., 2015), and complicated pyelonephritis in people is associated with a wider range of organisms, and with more resistant organisms, than uncomplicated pyelonephritis (Nicolle, 2007). It is therefore difficult to recommend empirical treatment for pyelonephritis in dogs and cats, and urine culture with plasma (tissue) breakpoints for minimum inhibitory concentrations is an essential part of diagnosis and treatment.

Diagnostic Categories

There is no biomarker or readily available gold standard for diagnosing pyelonephritis in living dogs and cats, and clinical diagnosis will always be challenging in patients that cannot describe their symptoms. The following diagnostic categories are proposed:

  • Possible diagnosis: a patient with systemic signs of inflammation, including fever, and white blood cells in the urine (pyuria), and a positive culture of a uropathogen from a cystocentesis sample, and no clinical indication of another cause of inflammation outside the urinary tract.
  • Probable diagnosis: all of the above, plus compatible changes on the complete blood count (such as neutrophilia, a left shift, or toxic change), and ultrasound changes compatible with pyelonephritis, although ultrasound changes alone can support but not confirm the diagnosis (Buettcher et al., 2020).
  • Definitive diagnosis: all of the above, plus a positive culture of urine obtained directly from the renal pelvis.

Dogs and cats with suspected pyelonephritis should be checked for other conditions that increase their susceptibility to ascending infection, such as ureteral stones or systemic immunosuppression. Structural abnormalities that increase the risk of pyelonephritis can also affect how urine culture results are interpreted. For example, Enterococcus species are generally of relatively low virulence and are commonly found in cats with subclinical bacteriuria (Puchot et al., 2017). In contrast, most cats (5 of 6) with pure enterococcal cultures after placement of a subcutaneous ureteral bypass had clinical signs, including suspected pyelonephritis (Kopecny et al., 2019).

Supportive and Preventive Measures

Treatments other than antimicrobials should be considered where appropriate, and they may prove to be effective preventive strategies. Approaches that deserve future research include reducing obesity (Semins et al., 2012; Wynn et al., 2016), removing bladder stones, reducing immunosuppressive treatment, optimizing diabetic control, rehabilitation to improve bladder emptying, and increasing water intake (Hooton et al., 2018; Plüddemann, 2019). Immunotherapy, or deliberately colonizing the bladder with bacteria associated with asymptomatic bacteriuria rather than UTI, could be promising alternative treatments for dogs with recurrent UTI and may in future help 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 pyelonephritis, but uremia, and possibly age and protein-energy wasting, may reduce their systemic immunity, as it does in people. Pyelonephritis is a possible 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 separate the contributions of infection and of structural abnormality to kidney damage.

Urinalysis, urine culture, and susceptibility testing, followed by antimicrobial treatment of animals with positive cultures, should be considered in dogs and cats with kidney disease in the following situations, with the risks and benefits of treatment assessed for each patient:

  1. Clinical signs of systemic disease (vomiting, abdominal pain, lethargy) together with signs of systemic inflammation (fever, neutrophilia)
  2. Clinical signs of lower urinary tract disease
  3. At the initial diagnosis of acute or chronic kidney disease
  4. During acute and unexplained deterioration in kidney function
  5. In patients with additional predisposing factors, such as ureteral obstruction

Dogs and cats with positive cultures should be treated with the recognition that many patients with CKD and positive urine cultures have subclinical bacteriuria. Clinical signs can improve for many reasons, including antiemetics, intravenous fluids, pain relief, and time, regardless of antimicrobial treatment. A positive urine culture should not stop the veterinarian from looking for other causes of the patient's signs, and if the patient does not improve, antimicrobial treatment should be stopped. Similarly, if antibiotics were started while awaiting urine culture results and the culture is negative, the antibiotics should be stopped.

In patients with stable CKD and no clinical signs suggesting pyelonephritis or cystitis, a positive urine culture may reflect subclinical bacteriuria that does not need treatment. However, a diagnosis of subclinical bacteriuria depends on the owner's ability to detect clinical signs, which can be subtle. It is controversial whether animals with stable CKD and no relevant clinical signs should be treated, and no consensus has been reached. The best diagnostic and treatment approach to positive urine cultures in dogs and cats with CKD should be a focus of further research.

Subclinical bacteriuria is uncommon in young dogs and cats, so a positive urine culture should be given greater significance in a young animal with systemic signs.

Pyelonephritis and Familial Kidney Disease

A particular note of caution applies to breeding recommendations in breeds with a high prevalence of kidney disease and pyelonephritis. A high prevalence of pyelonephritis is seen in young Boxers and young Flat-Coated Retrievers, both breeds with increased illness and death from kidney disease (Pelander et al., 2015).

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

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