Xanthogranulomatous pyelonephritis

INTRODUCTION — 

Xanthogranulomatous pyelonephritis is an unusual variant of pyelonephritis. Most cases occur in the setting of obstruction due to infected renal stones [1-6]. Affected patients usually have massive inflammatory destruction of the kidney due to granulomatous tissue containing lipid-laden macrophages; the appearance may be confused with kidney malignancy. Additionally, kidney malignancy can coexist with xanthogranulomatous pyelonephritis [7-9].

This topic discusses the clinical features, diagnosis, and management of xanthogranulomatous pyelonephritis. Acute pyelonephritis is discussed in detail elsewhere. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults".)

EPIDEMIOLOGY AND PATHOGENESIS

●Incidence – Xanthogranulomatous pyelonephritis is a rare condition overall, although it is identified in a sizable minority (approximately 4 to 12 percent) of kidneys that are removed for chronic inflammation [1,10-12].

●Risk factors – Reported risk factors include female sex, nephrolithiasis, recurrent urinary tract infection (UTI), and diabetes mellitus [2,8,9,11,13]. As an example, in a review of 40 studies that included 1139 patients with xanthogranulomatous pyelonephritis, 70 percent were female, 69 percent had a history of or concomitant upper tract stones, and 28 percent had diabetes mellitus [13]. In a retrospective review of 27 patients with xanthogranulomatous pyelonephritis between 2001 and 2020, a history of recurrent UTI had been reported in 33 percent [9].

●Pathogenesis – Xanthogranulomatous pyelonephritis is characterized by inflammation in the kidney. It is hypothesized that cycles of obstruction and infection result in destructive inflammation of tissue, potentially related to aberrant macrophage processing of bacteria. When xanthogranulomatous pyelonephritis occurs in kidney transplant recipients, kidney ischemia, lymphatic blockade, and immunosuppression may also be important factors in the pathogenesis [14]. The factors responsible for the accumulation of lipids and cholesterol seen in the associated lesions are not well understood. (See 'Diagnostic pathologic features' below.)

CLINICAL FEATURES

Typical presentation — Xanthogranulomatous pyelonephritis is almost always unilateral, and the presenting features include lateralized local findings as well as systemic symptoms. Bilateral disease rarely occurs; in a review of 1139 cases, only 4 were bilateral [13]. Females account for the majority of patients; the median age is approximately 50 years [11,13].

●Adults – The typical presenting features in adults include flank or abdominal pain, fever, malaise, anorexia, and weight loss. Some patients have a palpable mass. Lower tract urinary symptoms (dysuria and frequency) can also occur but are not universal.

As an example, in a retrospective study from Spain of 27 patients with xanthogranulomatous pyelonephritis, the most common symptoms were flank pain (70 percent) and fever (60 percent) [9]. A renal mass was palpable in 26 percent, and weight loss reported in 11 percent. Similar findings were reported in a retrospective study from India, in which flank pain and fever were similarly the most frequently reported features; dysuria was also reported in 48 percent [8].

●Children – The presenting features in children are largely similar to those in adults, with flank pain and fever as common findings [15-17]. Children can also have slowed growth and poor weight gain. A palpable mass may be more common in children than in adults. As an example, in one series of 10 children (ages 1 to 3 years), all had a tender flank mass [17].

Xanthogranulomatous pyelonephritis has also been reported in kidney transplant recipients, and it can present early in the first weeks post-transplant up to years following transplant [18,19]. In such patients, the clinical features of xanthogranulomatous pyelonephritis can resemble those of rejection.

Laboratory and microbiologic features

●Nonspecific laboratory features – Blood tests are often abnormal, demonstrating anemia and leukocytosis [9,17,20]. Elevated serum creatinine can also occur but is not universal. Liver enzymes and alkaline phosphatase may also be slightly high. The erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) levels are commonly elevated.

●Urine studies and microbiology – Urinalysis usually demonstrates pyuria and bacteriuria. However, sterile urine cultures are reported in 25 to 40 percent of cases [4,8,9,13]; this may be a result of antibiotic therapy prior to obtaining cultures.

Enterobacterales, specifically Escherichia coli and Proteus mirabilis, are the most common urinary isolates. In a systematic review that included 677 patients with xanthogranulomatous pyelonephritis and reported culture results, E. coli was identified in 20 percent, Proteus in 14 percent, Klebsiella in 3 percent, and mixed growth in 7 percent [11]. Other less commonly isolated pathogens included Pseudomonas, Staphylococcus, Streptococcus, Candida, and Enterococcus. This microbiologic spectrum is similar to that of complicated urinary tract infection (UTI). (See "Acute complicated urinary tract infection (including pyelonephritis) in adults", section on 'Microbiology'.)

Complications and comorbid malignancy

●Extension to other organs – Fistula formation and extension to extrarenal organs have been reported, including to the skin, duodenum, colon, spleen, diaphragm, and lung [14,18,21]. In a systematic review that included 291 patients with xanthogranulomatous pyelonephritis, fistula was reported in 23 (8 percent) [13].

●Secondary amyloidosis – Some patients have a relatively prolonged course of chronic inflammation before they are diagnosed with xanthogranulomatous pyelonephritis. In this setting, secondary amyloidosis (amyloid AA) can occur, leading in some cases to the nephrotic syndrome [19,22]. (See "AA amyloidosis: Causes and diagnosis".)

●Comorbid kidney malignancy – Kidney cancer is a differential diagnosis of xanthogranulomatous pyelonephritis. Additionally, the two processes can coexist [7-9]. In one case series of 40 patients with xanthogranulomatous pyelonephritis, two patients also had malignancy in the same kidney [8]; in another series of 27 patients, one had concurrent kidney cancer [9].

DIAGNOSIS

Presumptive clinical diagnosis — The presumptive clinical diagnosis can be made in patients who have characteristic imaging findings, particularly in the context of urinary tract infection (UTI) and/or nephrolithiasis. Because other conditions can have similar appearances on imaging, the diagnosis should be confirmed on pathologic examination, typically following nephrectomy. (See 'Diagnostic pathologic features' below.)

When to suspect — Xanthogranulomatous pyelonephritis can be detected when patients undergo abdominal imaging for any reason (eg, for flank pain or as part of the workup for nephrolithiasis). The possibility of xanthogranulomatous pyelonephritis should also be considered in patients who have complicated UTI that is recurrent, persistent despite appropriate antibiotic therapy, or associated with obstruction, all of which should prompt imaging of the urinary tract. While xanthogranulomatous pyelonephritis is not a common cause of such presentations, clinicians should be aware of the possibility and assess whether the imaging findings, as discussed below, could be consistent with the diagnosis.

The importance of having a low threshold for considering the diagnosis is highlighted by the frequency of missed or delayed diagnoses [20]. In a systematic review that included 470 patients with pathologically confirmed xanthogranulomatous pyelonephritis who had a preoperative diagnosis recorded, only 43 percent were correctly diagnosed clinically [11].

Characteristic imaging findings — Contrast-enhanced computed tomography (CT) of the abdomen is the preferred diagnostic imaging method for xanthogranulomatous pyelonephritis and should be performed when the condition is suspected.

The characteristic finding on CT is an enlarged kidney with the parenchyma replaced by several rounded, low-density (15 to 18 Hounsfield units) rim-enhancing lesions that result in a multiloculated appearance (image 1) [10]. These findings are similar in appearance to the paw print of a bear and are known as the "bear's paw sign" (image 2) [23,24]. The imaging abnormalities correspond to dilated calyces lined with necrotic xanthomatous tissue extending into the kidney parenchyma. Involvement can also appear more focal, as a hypodense, cyst-like mass. Hydronephrosis and kidney stones, often staghorn calculi, are frequently detected [8]. Other potential findings include a contracted renal pelvis and thickened renal fascia. Since xanthogranulomatous pyelonephritis is almost always unilateral, the contralateral kidney is typically unaffected, although compensatory hypertrophy has also been described [25].

CT can also determine the extent of the lesion, which can be classified into three stages, which may have treatment implications (see 'Surgical resection as definitive treatment' below):

●Stage 1 – Localized disease confined to kidney parenchyma.

●Stage 2 – Inflammation involves the perinephric fat.

●Stage 3 – Inflammation involves the perinephric spaces and/or abdominal wall. In the most advanced forms, the mass of xanthogranulomatous tissue can involve the adjacent gastrointestinal tract and fistulize into the colon or duodenum [1,20,21].

Other imaging modalities have a more limited role. Ultrasound features include renal enlargement, parenchymal thinning, and hydronephrosis, but in general ultrasound is less sensitive and specific than CT [26]. Intravenous pyelography (IVP) is abnormal but generally not diagnostic. It usually reveals the shadow of a nonfunctioning, enlarged kidney containing several renal stones or a staghorn calculus. In cases in which part of the kidney is still functioning, the IVP shows a space-occupying lesion resembling kidney cancer. Magnetic resonance imaging (MRI) and positron emission tomography (PET)-CT do not appear to provide additional diagnostic value over standard CT.

Diagnostic pathologic features — The definitive diagnosis of xanthogranulomatous pyelonephritis is made by pathologic analysis of resected tissue. (See 'Surgical resection as definitive treatment' below.)

●Gross features – The kidney is enlarged and usually destroyed by the inflammatory process. Necrotic yellow material surrounded by layers of orange-colored tissue is typically seen (picture 1 and picture 2). Renal stones, including staghorn calculi, are usually present within the mass. If there is perirenal extension, the inflammatory mass is adherent to the surrounding structures.

●Histologic features – The lesion consists of three layers centered by a calyx [27]. The inner zone contains necrosis, leukocytes, lymphocytes, plasma cells and macrophages. The middle zone contains vascularized granulation tissue interspersed with hemorrhage. The inflammatory cells are largely lipid-laden macrophages, which account for the yellow color (picture 3). The outermost part of the lesion is characterized by giant cells and cholesterol clefts [10].

DIFFERENTIAL DIAGNOSIS — 

The primary differential diagnosis of xanthogranulomatous pyelonephritis is renal cell carcinoma, given the similar clinical presentation and imaging features. Evidence of chronic urinary tract infection (UTI; eg, pyuria and bacteriuria) and CT findings can often distinguish xanthogranulomatous pyelonephritis, although rarely the two can occur together.

Patients with renal or perinephric abscess may present with similar clinical features, although the imaging findings are distinct. However, histologic evaluation is often necessary to distinguish xanthogranulomatous pyelonephritis from two other inflammatory conditions, renal parenchymal malakoplakia and megalocytic interstitial nephritis [28]. (See "Renal and perinephric abscess", section on 'Differential diagnosis'.)

TREATMENT

Antibiotic therapy

Patients with fever or systemic signs of infection — Some patients present with fever and other systemic symptoms consistent with acute pyelonephritis when the clinical diagnosis of xanthogranulomatous pyelonephritis is made on imaging. In such cases, the approach to empiric and directed antibiotic selection is the same as that for acute complicated urinary tract infection (UTI), which is discussed in detail elsewhere (table 1). (See "Acute complicated urinary tract infection (including pyelonephritis) in adults".)

Such patients often warrant percutaneous intervention to address urinary obstruction (see 'Relief of obstruction' below), in which case urine specimens from nephrostomy in addition to voided urine culture can be used to tailor the empiric antibiotic regimen.

We generally proceed to definitive surgical treatment at the time of presentation, particularly if signs and symptoms of infection do not improve within a few (eg, six) days of adequate antibiotic treatment. This may be most likely when patients have disease that extends beyond the kidney parenchyma (stage 2 or 3 on CT) or have infection complicating an obstructive stone. We continue antibiotic therapy through the procedure and postoperatively, but the optimal duration is uncertain and should be individualized for the clinical course and extent of resection. In patients with an uncomplicated postoperative course in whom all grossly infected tissue has been removed, we favor a postoperative course of approximately 5 to 10 days with close clinical follow-up for recurrence, whereas longer courses (eg, two weeks or longer) may be warranted for patients with residual infected tissue, postoperative collections requiring drainage, or other infectious complications. Such complications are reportedly common following nephrectomy for xanthogranulomatous pyelonephritis [29]. (See 'Surgical resection as definitive treatment' below.)

If patients with limited disease improve rapidly with antibiotic therapy, it may be reasonable to defer surgery until a later date. In such cases, we continue antibiotic therapy for limited disease for about 10 days.

Data informing the use of antibiotic therapy are limited to retrospective studies and case series. In a systematic review of 40 studies that included 1139 patients with xanthogranulomatous pyelonephritis, all received antibiotics at some point, although in some cases antibiotics were limited to a single dose of preoperative prophylaxis [13]. In a retrospective study of 61 patients who had undergone complete or partial nephrectomy, 50 had been treated with a preoperative antibiotic course beyond standard preoperative prophylaxis (18 with intravenous, 13 with oral, and 19 with a combination of intravenous and oral antibiotics) [30]. Among patients undergoing laparoscopic nephrectomy, a preoperative duration of antibiotic therapy longer than 28 days (median 87) was independently associated with a shorter length of stay and fewer postoperative complications compared with a duration shorter than 28 days (median 5 days). However, confidence in this finding is low because of the small number of cases and potential for confounders to impact the results.

Afebrile patients — Some patients present with indolent symptoms and no fever or systemic signs of acute infection. In such cases, a course of antibiotic therapy beyond standard preoperative antibiotics to prevent surgical site infection following definitive resection is likely not necessary. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults".)

The need for postoperative antibiotics depends on intraoperative findings and extent of resection.

Relief of obstruction — Patients with xanthogranulomatous pyelonephritis often require intervention for upper urinary tract obstruction. In a review of 40 studies that included 1139 patients with xanthogranulomatous pyelonephritis, almost all of whom underwent ultimate nephrectomy, 161 of 286 (56 percent) underwent initial decompression, mainly with percutaneous nephrostomy [13]. Management of urinary tract obstruction is discussed in detail elsewhere. (See "Management of urinary tract obstruction".)

Surgical resection as definitive treatment — Definitive treatment of xanthogranulomatous pyelonephritis is surgical resection of the involved tissue. Ultimately, the approach to resection depends on the extent of disease and expertise of the surgeon. Since xanthogranulomatous pyelonephritis is almost always unilateral and is associated with virtually complete destruction of the kidney, total nephrectomy is performed in the majority of patients. Specifically, patients with disease that extends beyond the kidney (stage 2 or 3 (see 'Characteristic imaging findings' above)) require radical nephrectomy, with removal of the surrounding tissue. In contrast, localized disease that is limited to one kidney pole may be amenable to partial nephrectomy (eg, nephron-sparing laparoscopic surgery) [4,31]. Partial nephrectomy has also been reported in rare cases of bilateral disease to allow some residual kidney function and avoid dialysis [32].

In a systematic review of 31 studies that reported nephrectomy rates for xanthogranulomatous pyelonephritis, nephrectomy was performed in all but 2 of 841 patients: one patient refused surgical intervention and another resided in a resource-limited setting [11]. However, since almost all studies included only patients with a histologically confirmed diagnosis, it is possible that some patients with a presumptive clinical diagnosis have been managed conservatively. However, surgical management of patients with xanthogranulomatous pyelonephritis remains the standard definitive treatment.

Although open nephrectomy was historically the most common approach, laparoscopic nephrectomy and robotic nephrectomy have also been reported. Among the 839 patients who underwent nephrectomy, 67 percent underwent an open procedure and 33 percent underwent minimally invasive surgery (laparoscopic or robotic) [11]. In a meta-analysis of a subset of those cases, minimally invasive surgery was associated with lower postoperative complications, blood transfusion requirements, and length of stay. Approximately 13 percent of laparoscopic procedures were converted to open.

PROGNOSIS — 

Data on the prognosis of xanthogranulomatous pyelonephritis are mainly limited to case series and small observational studies. In a systematic review that included 27 studies reporting on mortality rates, 18 of 630 patients died within the first year of diagnosis (weighted proportion of 1.44 deaths per 100 patients) [13]. All four patients with bilateral disease survived. In contrast, over 25 percent of those with fistulae died.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urinary tract infections in adults".)

SUMMARY AND RECOMMENDATIONS

●Definition and risk factors – Xanthogranulomatous pyelonephritis is a rare variant of chronic pyelonephritis in which there is massive destruction of the kidney by granulomatous tissue containing lipid-laden macrophages. Reported risk factors include female sex, nephrolithiasis, recurrent urinary tract infection (UTI), and diabetes mellitus. (See 'Epidemiology and pathogenesis' above.)

●Clinical features – Xanthogranulomatous pyelonephritis is almost always unilateral, and the presenting features include lateralized local findings (flank or abdominal pain) as well as systemic symptoms (fever, malaise, anorexia and weight loss). Some patients, especially children, have a palpable mass. (See 'Clinical features' above.)

Urine culture is usually but not always positive. Enterobacterales, specifically Escherichia coli and Proteus mirabilis, are the most common urinary isolates. (See 'Laboratory and microbiologic features' above.)

●Complications – Inflammation can extend to involve adjacent organs directly or through fistulous tracts. Chronic inflammation can also lead to secondary amyloidosis and the nephrotic syndrome. Kidney cancer can both be confused for and coexist with xanthogranulomatous pyelonephritis. (See 'Complications and comorbid malignancy' above.)

●Imaging to establish the clinical diagnosis – Contrast-enhanced computed tomography (CT) of the abdomen is the preferred diagnostic imaging method. The characteristic finding is an enlarged kidney with its parenchyma replaced by rounded, low-density, rim-enhancing lesions resulting in a multiloculated appearance (image 1 and image 2). (See 'Diagnosis' above.)

●Definitive pathologic diagnosis – On gross examination, the kidney is enlarged with necrotic yellow material surrounded by layers of orange-colored tissue (picture 1 and picture 2). Microscopically, the lesion consists of three layers of inflammatory cells, including lipid-laden macrophages, surrounding the calyx. (See 'Diagnostic pathologic features' above.)

●Antibiotic therapy – For patients who present with fever or other systemic signs of acute infection, our approach to antibiotic selection is the same as that for acute complicated urinary tract infection (UTI) in general (table 1). We continue antibiotics through definitive surgical resection and individualize the duration of postoperative antibiotics based on extent of resection and clinical course. Afebrile patients without signs of acute infection who have complete resection of involved tissue without complications generally do not require antibiotic therapy beyond preoperative prophylaxis. (See 'Antibiotic therapy' above.)

●Surgical management – Patients often require intervention for upper urinary tract obstruction. Resection of the involved tissue, usually with total or radical nephrectomy is required for definitive treatment. (See 'Relief of obstruction' above and 'Surgical resection as definitive treatment' above.)