If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Internal Medicine, Wright State University, Dayton, OH, USABoonshoft School of Medicine, Wright State University, Dayton, OH, USADayton VA Medical Center, Dayton, OH, USADepartment of Infectious Diseases, Wright State University, Dayton, OH, USA
Xanthogranulomatous pyelonephritis (XGP) is a rare variant of chronic pyelonephritis, occurring in the setting of obstructive uropathy and recurrent urinary tract infections (UTIs). It is difficult to diagnose as it can be asymptomatic until late-stage disease. Localized symptoms such as flank pain and dysuria may be attributed to nephrolithiasis or UTIs without prompting need for further workup. Extrarenal manifestations, most notably fistula formation, may present distal to the kidney and not be readily attributed to a renal pathology. The only known definitive therapy is nephrectomy. A delay in diagnosis can lead to fulminant complications or a more technically difficult nephrectomy. We present three cases of XGP, which serve to highlight the possibility of earlier diagnosis and resultant management options, including the potential for nephron-saving strategies. Early clinical and radiologic suspicion through awareness of risk factors may play an important role in preventing disease progression, avoiding late-stage complications, and improving treatment outcomes.
Introduction
Xanthogranulomatous pyelonephritis (XGP) is an unusual variant of chronic pyelonephritis in the presence of obstructive uropathy, resulting in severe renal parenchymal destruction. The disease is difficult to diagnose due to its nonspecific findings, sometimes proceeding insidiously until the evolution of late-stage extrarenal sequelae. Unchecked progression of the disease invariably leads to complications requiring nephrectomy. Here we present three illustrative cases of XGP and a relevant literature review pertaining to current diagnostic and therapeutic dilemmas.
Patient 1
A 51-year-old male with a history of recurrent urinary tract infections (UTI) and nephrolithiasis was admitted for complicated UTI. Computed tomography (CT) scan of the abdomen and pelvis demonstrated large right-sided staghorn calculi with hydronephrosis, suggestive of underlying XGP. Notably, a prior CT scan performed two years ago had demonstrated mild hydronephrosis, a single 1mm intrarenal stone, and a single 2mm distal right ureteral stone (Figure 1A). Urine cultures grew Pseudomonas aeruginosa. The patient improved on antibiotics and was discharged with active surveillance. Follow-up CT scan 10 months later showed further progression of hydronephrosis and nephrolithiasis (Figure 1B-C). Nuclear medicine (NM) renal scan demonstrated right kidney function at 27%. The patient subsequently underwent curative open right flank nephrectomy. Specimen analysis confirmed XGP.
Fig. 1(A) Baseline CT scan demonstrating a single small right-sided renal stone and mild hydronephrosis. Malek and Elder (M&E) Stage I. Focal disease. (B) CT scan two years later at time of diagnosis of XGP, demonstrating significantly increased nephrolithiasis. M&E Stage I. Diffuse disease. (C) Follow-up CT scan 10 months later, immediately prior to nephrectomy, demonstrating continued progression of nephrolithiasis, and inflammation in the surrounding tissues. M&E Stage II. Diffuse disease.
A 70-year-old female with a history of hypertension, type 2 diabetes, and recurrent UTIs was admitted for generalized fatigue, abdominal pain, nausea, and cough. CT scan of the abdomen demonstrated right-sided hydronephrosis, staghorn calculi, and surrounding inflammatory changes, with the radiologic impression listed as “pyelonephritis with associated staghorn calculus” (Figure 2A). The patient was discharged after a 3-day hospitalization to complete a 10-day course of antibiotics. One month later, the patient was admitted for sepsis. CT scan this time demonstrated findings consistent with XGP, in addition to a new perihepatic abscess (Figure 2B). She required a prolonged ICU stay, IV antibiotic therapy, CT-guided drainage of the abscess, and percutaneous nephrostomy tube placement. There was no growth on urine or blood cultures. After spending 3 weeks in the hospital, she was discharged and later underwent a scheduled laparoscopic right nephrectomy. The surgery was successful despite extensive adhesions and the patient did well postoperatively.
Fig. 2(A) Initial CT scan in the coronal view demonstrating the classic “bear paw sign” with surrounding inflammation. M&E Stage II. Diffuse disease. (B) CT scan one month later demonstrating perihepatic abscesses. M&E Stage III. Extrarenal disease.
A 76-year-old female with a history of nephrolithiasis was seen in the office for left hip pain. Physical examination demonstrated an open wound draining scant serosanguinous fluid in left lateral hip area (Figure 3A). X-ray of the left hip was unremarkable. She was diagnosed with a superficial abscess and underwent surgical debridement and antibiotic therapy. Wound cultures grew no organisms. However, the wound continued to drain. CT scan of the abdomen and pelvis was ordered and revealed left-sided XGP and a fistulous tract from the left kidney to her left hip area (Figure 3B-C). The patient subsequently underwent laparoscopic left nephrectomy. No postoperative antibiotics were given. Two weeks later, the patient developed fever and purulent drainage at her surgical site. CT of the abdomen revealed a new abdominal wall abscess. She underwent CT-guided left renal fossa drain placement and completed a total of 4 weeks of antibiotics. The patient did well at her follow-up appointment and no further complications were noted.
Fig. 3(A) A photograph of the patient's skin findings, demonstrating an open wound draining serosanguinous fluid, initially misdiagnosed as a superficial abscess. (B and C) CT scan demonstrating nephrolithiasis of the left kidney, renal atrophy, and surrounding inflammation. A sinus tract could be followed from the kidney in the inferolateral direction, revealing a small enhancing renal stone which had eroded all the way to the left-sided musculature (around the 3 o'clock position in Image 3B) with the sinus tract continuing all the way to the skin. M&E Stage III. Extrarenal disease.
XGP is a rare variant of chronic pyelonephritis in the presence of obstructive uropathy, resulting in severe renal parenchymal destruction. The condition is generally unilateral and accounts for up to 1% of cases of pyelonephritis.
First reported by Schlagenhaufer in 1916, it has likely been recognized in other forms since antiquity: Hippocrates described the renocolic fistula in the 5th century BC, a potential complication of XGP.
It is nearly always associated with a large obstructive calculus in the renal pelvis. If untreated, it progresses to inflammation of the perinephric tissues complicated by possible abscess, adhesion, or fistula formation.
XGP is typically seen in patients with chronic obstructive nephrolithiasis and recurrent UTIs, particularly with Escherichia coli and Proteus mirabilis.
Previous case series with histologically-proven XGP have indicated high though not universal rates of nephrolithiasis (77.8 - 100%) and obstructive uropathy, as evidenced by hydronephrosis (63-90%).
Other risk factors include abnormalities predisposing the urinary tract to obstruction, such as ureteropelvic junction syndrome, ureteropelvic duplication, vesicoureteral reflux, and bladder cancer have been associated with the disease (Table 1).
XGP may also be associated with renal diseases such as chronic interstitial nephritis and renal malignancies including renal cell carcinoma, transitional cell carcinoma, and squamous cell carcinoma.
Systemic risk factors include diabetes, metabolic syndrome, immunosuppression, rheumatoid arthritis, and other conditions associated with a chronic inflammatory state, such as hepatitis C.
Xanthogranulomatous pyelonephritis in a renal allograft associated with xanthogranulomatous diverticulitis: report of the first case and review of the literature.
in which XGP has only partially affected the kidney and some renal function remains preserved. In Stage II, both the nephric and perinephric fatty tissues are involved. It is now often called diffuse disease.
Xanthogranulomatous pyelonephritis in a renal allograft associated with xanthogranulomatous diverticulitis: report of the first case and review of the literature.
In Stage III, the paranephric tissues and organs are additionally involved. XGP reaching this last stage has been complicated by extrarenal involvement into the surrounding organs.
The widespread existing usage of the terms focal and diffuse XGP merit recognition as formal classifications of XGP. Advances in radiographic imaging have permitted the ability to more easily delineate the extent of the disease within the kidney itself. Additionally, there are potential management differences between focal and diffuse disease. Moreover, we propose a new category of extrarenal disease to emphasize the unique clinical presentation and management challenges when the disease process has extended to affect organs beyond the paranephric space (Table 2).
Table 2Classification of Xanthogranulomatous Pyelonephritis
Malek and Elder, 1978
Proposed Classification
Description
Stage I: Nephric
Focal
Partial kidney disease; possibility for nephron-saving management
Stage II: Perinephric
Diffuse
Whole kidney disease, with possible perinephric inflammation, but sparing extrarenal organs
Stage III: Paranephric
Extrarenal
Involving extrarenal organs, including fistula or abscess formation
The kidney affected by XGP is typically grossly distended with yellow, pus-filled nodules in the renal calices. Microscopically, XGP is characterized by inflammatory destruction and replacement of the renal parenchyma by foamy, lipid-laden macrophages (xanthoma cells). These xanthoma cells demonstrate positive cytoplasmic staining for lysozyme, CD68, and vimentin.
They may initially mimic the clear cells of renal cell carcinoma (RCC) or the foamy macrophages seen in papillary RCC. However, in contrast to XGP, clear cell RCC and papillary RCC stain positively for CD10 and epithelial membrane antigen.
XGP should also be distinguished from malakoplakia, a benign chronic inflammatory process. Malakoplakia is characterized by the presence of periodic acid-Schiff (PAS) positive Michaelis-Guttman bodies, whereas XGP is PAS negative. However, there have been reports of their occasional coexistence.
Few studies to date have described the pathogenesis of the disease beyond generalized mechanisms, such as alterations in immunologic response, changes in lipid metabolism, increased lymphatic blockage, and local vascular occlusion.
Recent research on the molecular pathogenesis of the disease has the potential to shed further light on this issue. Ostalska-Nowicka et al demonstrated that regions of the kidney actively affected by XGP strongly expressed vimentin, a tissue factor which attracts macrophages, stimulates phagocytosis, and is involved in lipid regulation. In fact, a vimentin gradient existed in which areas not yet affected by XGP and as well as already-fibrotic regions both expressed less vimentin than areas at the leading edge of the disease, suggesting that the progression of XGP may be vimentin-dependent.
Zarif et al recently demonstrated that XGP specimens were positive for both classically activated macrophages (M1) and alternatively activated macrophages (M2).
M1 macrophages secrete pro-inflammatory cytokines such as IFN-γ, IL-2, and TNF-α, whereas M2 macrophages secrete anti-inflammatory cytokines such as IL-10, IL-23, and VEGF. These findings suggests that the pathogenesis of XGP is related to repeated cycles of infection, inflammation, and attempted healing (Fig. 4). Continued obstructive uropathy perpetuates the disease, leading to further cycles of infection, inflammation, and worsening of XGP until the renal parenchyma is destroyed.
Fig. 4The pathogenesis of XGP is likely related to an ongoing cycle of obstructive uropathy predisposing to repeated infection and inflammation resulting in worsening XGP.
Occasionally, the sole presenting symptoms are the manifestations of its extrarenal complications. Patients may present with signs and symptoms of disease spread to distant tissues. These include the liver, spleen, diaphragm, pleural space, chest wall, abdominal wall, gluteus, and skin (Table 3).
D25 unusual infections: case reports: pulmonary empyema with thoracic compression resulting from direct invasion of xanthogranulomatous pyleonephritis.
For instance, cutaneous fistula tracts have been misdiagnosed as superficial abscesses and treated with simple drainage and antibiotics, thus delaying diagnosis. These late signs and symptoms have the potential to direct clinical attention away from possible XGP until further workup is obtained.
Table 3Extrarenal Manifestations
Study
Abscess
Symptoms
Ho et al
Splenic
Abdominal pain, fevers, chills
Ghoz et al
Psoas
Abdominal pain, nausea, fatigue, altered mental status
In patients with a high clinical suspicion for XGP, pertinent laboratory studies include a complete blood count, urinalysis with urine cytology, and blood and urine cultures. According to one study, laboratory findings include leukocytosis (41%), pyuria (57%), anemia (63%), and elevated erythrocyte sedimentation rate (94.4%).
The presence of xanthoma cells in urine cytology, while poorly sensitive (present in 30.76% of cases in one series), is a more specific finding for XGP, as these would not typically be seen with renal cell carcinoma, which presents similarly on imaging.
Urine cultures are most commonly positive for Proteus mirabilis or Escherichia coli. However, cultures may be sterile in some cases, likely due to prior antibiotic use, with one series of XGP cases demonstrating 9 out of 34 cultures without growth.
Workup for suspected XGP should include CT of the abdomen. The classic radiologic presentation of diffuse XGP is a “bear paw sign,” or enlargement of the kidney with several discrete hypodense, rim-enhancing concentric cavities. These hypodense cavities appear as the digits of the “bear paw” on CT scan and correspond to the xanthogranulomatous inflammation of the renal calices.
The usage of IV contrast greatly increases enhancement at the borders of the affected kidney's hypodense cavities, assisting in delineating the extent of the disease and in assessing for any extrarenal fistulous tracts or abscesses.
Xanthogranulomatous pyelonephritis: a narrative review with current perspectives on diagnostic imaging and management, including interventional radiology techniques.
Focal XGP is characterized by partial involvement of the kidney by hypodense, cyst-like masses. There can be thickening of the Gerota's fascia but without perirenal involvement. Diffuse XGP, on the other hand, is characterized by multiple hypodense areas with thinning of the renal parenchyma, poorly visible contrast-material excretion (indicating poor renal function), and perinephric fat enhancement.
On PET/CT, the imaging features of XGP are nonspecific and cannot differentiate XGP from other inflammatory or neoplastic disorders.
Xanthogranulomatous pyelonephritis: a narrative review with current perspectives on diagnostic imaging and management, including interventional radiology techniques.
Xanthogranulomatous pyelonephritis: a narrative review with current perspectives on diagnostic imaging and management, including interventional radiology techniques.
The role of interventional radiology may be helpful in select cases, ranging from renal biopsy in cases of uncertain diagnosis to pre-operative percutaneous drainage of fluid collections in order to obtain culture data for appropriate antibiotic therapy and facilitate surgery.
Xanthogranulomatous pyelonephritis: a narrative review with current perspectives on diagnostic imaging and management, including interventional radiology techniques.
The diagnosis of XGP may result from presentations across the clinical spectrum, ranging from asymptomatic radiologic findings to more fulminant complications. The staging of XGP is an anatomic rather than clinical classification, and the lack of any particular clinical findings does not preclude insidious progression of the disease. In the setting of chronic obstructive uropathy, recurrent UTIs, and other risk factors, XGP should be an important diagnostic consideration. Definitive diagnosis is made by histologic examination of specimens.
The differential diagnosis of XGP includes renal carcinoma, abscess, tuberculosis, lymphoma, angiolipoma, leiomyosarcoma, megalocytic interstitial nephritis, malakoplakia, or Wilms tumor.
Renal cell carcinoma and renal abscess deserve particular mention as pathologies that must be ruled out. XGP can be differentiated histologically from renal cell carcinoma through the presence of granulomatous cavities and through immunohistochemical analysis.
Xanthogranulomatous pyelonephritis in a renal allograft associated with xanthogranulomatous diverticulitis: report of the first case and review of the literature.
Nevertheless, inadequate sampling (such as through fine-needle aspiration) can result in misdiagnosis if the particular sample is poor in granulomatous inflammation.
The major risk factors of XGP (obstructive uropathy, recurrent UTIs, etc.) are often recognized in lieu of the disease itself until XGP either becomes more apparent on imaging findings or the disease process has significantly advanced. Patients have historically undergone total nephrectomy for suspected non-XGP diagnoses such as RCC or pyonephrosis (infection confined to the renal collecting system), only to be found to have XGP upon histologic examination of surgical specimens. In a review of 187 nephrectomies, the most common preoperative diagnosis was RCC at 42%, followed by XGP at 31%.
The rare nature of the disease has led to highly variable reports of the prevalence of XGP. Although Korkes et al demonstrated 19.2% XGP in a sample of 214 nephrectomies, other studies indicate a prevalence ranging from 0.6% to 4% of chronic pyelonephritis cases.
The source of this variability includes differing patient populations, small sample size, and era of investigation, with higher diagnosis rates expected with advances in CT imaging. Although XGP is an overall rare entity, it may be significantly more common in populations with risk factors, thus emphasizing the importance of patient history and imaging findings, maintaining a broad differential diagnosis, and considering XGP.
These findings correlate with our clinical experience with XGP. Our patients were not diagnosed with XGP until well into their disease course. If available, serial abdominal CT scans should be analyzed to ascertain risk factors such as long-standing nephrolithiasis, and to track findings suspicious for development of XGP such as gradually increasing hydronephrosis.
Management
Due to the accompanying inflammation which obscures surgical planes and destroys renal function, management of XGP is generally through nephrectomy. The controversy involves partial versus total nephrectomy, and the robotic/laparoscopic approach versus the classical open method. These controversies were reinforced by our literature review.
Management for focal XGP with antibiotics and drainage alone is rare. Kundu et al reported 5% of their cases being successfully treated with partial nephrectomy.
However, the vast majority of XGP cases involve significant destruction of the affected kidney with concomitant obliterations of surgical planes. NM renal scan demonstrates little meaningful renal function in the affected kidney in up to 80% of cases.
Xanthogranulomatous pyelonephritis: a narrative review with current perspectives on diagnostic imaging and management, including interventional radiology techniques.
This lack of salvageable function obviates the need for a more technically demanding partial nephrectomy. The open, total nephrectomy approach has been the traditional standard of care. To some degree, this approach has persevered.
Previously, nearly all cases of XGP were treated through nephrectomy. The laparoscopic approach was first described by Clayman et al in 1991 and has been increasingly utilized.
It is unclear whether the tendency toward robotic or laparoscopic approach is data driven. It may be a byproduct of several trends, including proliferation of robotic surgery devices and increased training in robotic surgery among new surgical graduates.
Asali et al performed an analysis of the laparoscopic approach to XGP.
They demonstrated a 96% success rate (26/27) with one case requiring conversion to open procedure. In a recent analysis of 40 surgeries by Barboza et al, there was no statistically significant difference in the rate of complications between open and laparoscopic surgery.
The minimally invasive approach was associated with fewer blood transfusions, shorter hospital stay, and lower likelihood of ICU admission. However, it was noted that 3 out of the 40 cases required conversion to open nephrectomy due to intraoperative complications. There was some obvious selection bias present - patients who were selected for the open technique generally had hostile anatomy due to more complicated, advanced XGP. While the laparoscopic approach was associated with a longer operative time, the postoperative recovery was significantly faster; the mean length of stay of the laparoscopic group was less than half the time of the open group in multiple studies.
Conversely, investigators such as Korkes et al have emphasized that the laparoscopic approach results in a high conversion rate; this is attributed to predominance of inflammation in higher stage XGP resulting in difficult anatomy and subsequent complications.
The importance of an accurate preoperative diagnosis is essential for the best possible outcomes. The intraoperative conversion to open nephrectomy from the minimally invasive approach prolongs operative times. Rather than embarking on an open approach from the onset in these hostile cases, the conversion increases operative time and accompanying complications.
Predictive factors for laparoscopic success have been poorly studied. In one analysis of intraoperative data, factors that were associated with higher rates of conversion included significant hydronephrosis, the time to control renal vessels, and right-sided nephrectomies.
Further studies in this area regarding the pre-operative condition of the patient will help predict laparoscopic success.
A balanced, practical approach suggests that a laparoscopic approach should be attempted if the surgeon is experienced with laparoscopic nephrectomy and the inflammation remains contained within the Gerota's fascia (up to the focal or diffuse stage). However, Guzzo admitted that the laparoscopic approach in the setting of XGP is often difficult, requires advanced laparoscopic skills, and should be offered to “highly selected patients.”
Antibiotics are an adjunct for the treatment of XGP. The choice of antibiotic depends on the organism cultured and antimicrobial susceptibility results; most commonly a urinary tract organism of the Enterobacterales family such as Proteus mirabilis or Escherischia coli. Broad-spectrum antibiotics as used for pyelonephritis are appropriate for XGP. Previously studied examples include extended-spectrum penicillins, third-generation cephalosporins, carbapenems, or fluoroquinolones, with extended-spectrum penicillins and third-generation cephalosporins being most commonly used.
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
Although XGP is closely associated with chronic obstructive nephrolithiasis, further studies are needed to determine whether treatment of nephrolithiasis would halt the progression of the disease. Several factors indicate that this may be the case. First, focal XGP has been cured by partial nephrectomy alone. This suggests that the disease process does not inevitably spread to the rest of the kidney provided the diseased portion is removed.
Second, several cases have been reported of focal XGP which was successfully treated with the treatment of nephrolithiasis and antibiotic therapy alone. This could imply that the disease process is tied to nephrolithiasis and is potentially reversible.
Pyélonéphrite xanthogranulomateuse pseudotumorale: diagnostic par la biopsie percutanée et succès du traitement conservateur [Pseudotumoral xanthogranulomatous pyelonephritis: diagnosis with percutaneous biopsy and success of conservative treatment].
The similarity between XGP and RCC on imaging always makes a nephron-sparing approach potentially hazardous. Missing a potential malignancy has sinister implications which may necessitate a preoperative kidney biopsy and postoperative surveillance imaging if a partial nephrectomy is performed.
Recognizing that XGP involves a chronic inflammatory process with various molecularly expressed proteins and cytokines, the therapeutic role of biologic immunomodulating agents should be investigated. Further research on the cell and molecular pathogenesis of the disease may potentially reveal a role for these agents, either in prevention of disease progression or as an adjunctive therapy to the nephron-sparing approach.
One of our patients had imaging findings two years ago demonstrating nephrolithiasis and mild hydronephrosis; this implied an indolent disease course. It can be surmised that a urologic intervention (i.e., stone removal) may have prevented the destruction of the kidney leading to XGP. Clinicians should be vigilant that patients with recurrent UTIs and small changes in imaging showing nephrolithiasis and hydronephrosis need attention. These patients need surveillance and sometimes early urologic intervention to prevent the sequelae which cascade toward XGP. Complications of delayed diagnosis and/or treatment include the following: fistula formation, abscess, and increased perinephric adhesions. These all can result in subsequent management challenges, necessitating resection of affected tissues, lysis of adhesions, and closure of fistulas.
Conclusion
Xanthogranulomatous pyelonephritis is a rare complication of pyelonephritis in the setting of chronic urologic obstruction. It is difficult to diagnose as it often remains asymptomatic, and the clinical and imaging findings can be mistaken for other pathologies. If suspected, diagnosis should be made through a combination of CT scan and laboratory markers. Early diagnosis and accurate staging of the disease facilitate less-invasive surgical options and reduces complications. Further research into the disease process is warranted, particularly the potential for preventing disease evolution or halting disease progression at an early stage.
Author contributions
Timothy Jang was responsible for writing the manuscript and performing literature review.
Trevor McKoy obtained patient data and assisted with writing the manuscript.
Jonathan Hakim edited portions of the manuscript and assisted with literature review.
Hari Polenakovik conceived this review article and assisted with literature review.
We have no conflicts of interest to disclose as well as no financial support to disclose.
Declaration of Competing Interest
The author has no financial or other conflicts of interest to disclose.
References
Siddappa S
Ramprasad K
Muddegowda MK.
Xanthogranulomatous pyelonephritis: a retrospective review of 16 cases.
Xanthogranulomatous pyelonephritis in a renal allograft associated with xanthogranulomatous diverticulitis: report of the first case and review of the literature.
D25 unusual infections: case reports: pulmonary empyema with thoracic compression resulting from direct invasion of xanthogranulomatous pyleonephritis.
Xanthogranulomatous pyelonephritis: a narrative review with current perspectives on diagnostic imaging and management, including interventional radiology techniques.
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.
Pyélonéphrite xanthogranulomateuse pseudotumorale: diagnostic par la biopsie percutanée et succès du traitement conservateur [Pseudotumoral xanthogranulomatous pyelonephritis: diagnosis with percutaneous biopsy and success of conservative treatment].
00465-7&id=gr1.jpg){kind=link}
00465-7&id=gr2.jpg){kind=link}
00465-7&id=gr3.jpg){kind=link}
00465-7&id=gr4.jpg){kind=link}