|Year : 2023 | Volume
| Issue : 1 | Page : 46-53
Emphysematous pyelonephritis and diabetes mellitus: A clinical perspective
Charan Bale1, Sunil Mhaske2, Vedavati B Purandare3, Akshay Kulkarni4, Abhijit Chavan4, Nishant Vyas5, Bharat Purandare6
1 Department of Nephrology, Dr. D. Y. Patil Medical College, Hospital and Research Center, Pune, Maharashtra, India
2 Department of Urology, Dr. D.Y. Patil Medical College and Research Hospital, DPU, Pune, Maharashtra, India
3 Department of Medicine, Chellaram Diabetes Institute, Pune, Maharashtra, India
4 Department of Nephrology, Dr. D. Y. Patil Medical College and Research Centre, D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
5 Department of Immunology, Logical Life Sciences Pvt. Ltd., Pune, Maharashtra, India
6 Department of Infectious Disease, Deenanath Mangeshkar Hospital and Research Center, Pune, Maharashtra, India
|Date of Submission||24-May-2022|
|Date of Decision||16-Oct-2022|
|Date of Acceptance||28-Oct-2022|
|Date of Web Publication||18-Jan-2023|
Dr. D. Y. Patil Medical College and Research Centre, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
Emphysematous urinary tract infections (UTIs) are lower or upper UTIs associated with gas formation. Emphysematous pyelonephritis (EPN) is a rare disease but is highly prevalent in patients with diabetes and even higher among female patients with diabetes. Earlier, the mortality rate of EPN was 60%–80%, but now, it has been reduced to 20% to 25% due to the availability of good antimicrobial agents and timely treatment. Our objective of this article is to elucidate the pathogenesis of EPN including gas-forming mechanism; discuss clinical features, radiological classification, and prognostic factors; in addition, compare the modalities of management of EPN and outcome among the various radiological classes.
Keywords: Diabetes mellitus, emphysematous pyelonephritis, fimbriae, percutaneous drain, renal emphysema, urinary tract infections
|How to cite this article:|
Bale C, Mhaske S, Purandare VB, Kulkarni A, Chavan A, Vyas N, Purandare B. Emphysematous pyelonephritis and diabetes mellitus: A clinical perspective. Chron Diabetes Res Pract 2023;2:46-53
|How to cite this URL:|
Bale C, Mhaske S, Purandare VB, Kulkarni A, Chavan A, Vyas N, Purandare B. Emphysematous pyelonephritis and diabetes mellitus: A clinical perspective. Chron Diabetes Res Pract [serial online] 2023 [cited 2023 Feb 5];2:46-53. Available from: https://cdrpj.org//text.asp?2023/2/1/46/368023
| Introduction|| |
Emphysematous pyelonephritis (EPN) is an infection of the kidney characterized by necrosis, gas formation in the renal parenchyma, and in severe cases, sepsis and renal dysfunction. It has a well-known association with uncontrolled diabetes mellitus. Since the reporting of the first case of EPN in 1898, many hypotheses have been put forward to explain the formation and accumulation of gas in the renal parenchyma, collecting system, and/or perinephric tissue. The purpose of this review is to understand how diabetes mellitus leads to homing of infections in the urinary system and what are the gaps in the area for future research.
| Diabetes Mellitus and Emphysematous Pyelonephritis|| |
EPN is a rare and acute condition of the kidney which is characterized by hostile and necrotizing infection. The main region of the kidney which is affected in EPN is renal parenchyma. In many cases, surrounding tissues are also affected. The renal parenchyma is found to have the presence of gas in cases of EPN. Most of the literature also mentions the presence of gas in the collecting system and/or perinephric tissue., Approximately 90% of the cases of EPN are associated with uncontrolled diabetes mellitus and 20% of cases are associated with obstruction in the urinary tract. Either of the kidneys can be affected, but rarely both kidneys are simultaneously affected.
| Prevalence of Emphysematous Pyelonephritis|| |
EPN is a rare disease, but highly prevalent in patients with diabetes and even higher among females with diabetes. However, the infection caused by Candida spp. has been reported more in males than females. A relatively rising number of EPN is being reported. In one of the largest single retrospective series, which included 48 patients in Taiwan who were diagnosed with either EPN or emphysematous pyelitis, 96% had diabetes mellitus and 22% had urinary tract obstruction.
Owing to its rarity, there is little information on the number of cases noted every year.
Earlier, the mortality rate of EPN was 60%–80%, but now, it has been reduced to 20%–25%. This trend is similar to other infections of the urinary tract in patients with diabetes (e.g., emphysematous pyelitis).
| Etiology and Risk Factors|| |
The main underlying cause of EPN is Coliform, Gram-negative, anaerobic bacteria such as Escherichia coli that are responsible for more than 60% of the EPN cases. Other organisms that have rarely been shown to cause EPN are Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Clostridium, Streptococcus spp., Bacillus pyocyaneus, Aerobacter aerogenes, Staphylococcus albus, Candida spp., Entamoeba histolytica, Aspergillus fumigatus, and Cryptococcus spp.,,
E. coli, which is the most prevalent pathogen that causes EPN is found to have elevated levels of uropathogenic-specific protein, which gives the pathogen its virulence. Hence, the cause of EPN in diabetes usually involves both kidneys (a disease condition originating from infections or allergies). Most of the organisms that cause EPN in patients with diabetes are also responsible for causing urinary tract infections (UTIs) in individuals without diabetes.
Diabetes mellitus is the prime risk factor for EPN. Immunocompromise in patients with diabetes is more likely to develop EPN. Some cases have reported EPN without diabetes mellitus.
Other than diabetes, HIV infection, obstructive uropathy, liver cirrhosis, polycystic kidney, chronic kidney disease, postkidney transplant, use of urethral instruments, and excessive alcoholism are other risk factors.,,
In the case of UTI, genes affecting innate immune response contribute to the pathogenesis of the infection. A deletion in the gene of chemokine receptor and polymorphism in TLR4, which is involved in the normal functioning of neutrophils, leads to an increased susceptibility toward UTIs and pyelonephritis.
The work of Thomas Miller on mouse models was conclusive of the fact that genetics play a major role in host susceptibility to renal infections such as EPN or acute pyelonephritis. Renal infections have been linked to both autosomal dominant genes and autosomal recessive genes. Either the host immune response is suppressed, which prevents self-tissue destruction (dominant gene) or there is an initiation of lesion formation (recessive trait). The genetic factors also control the severity of the infection by regulating the host's immune response.
Normally, the immune system efficiently keeps the urinary tract sterile, but in patients with diabetes, the immune system is suppressed. The virulent factors of pathogens such as P fimbriae, type 1 fimbriae, and host receptors such as TLRs and integrins induce the production and secretion of interleukin-8 (IL-8) and IL-6 from epithelial cells in EPN patients and initiate the activation of the innate immune response.
Impaired neutrophil recruitment to the site of infection leads to the progression of UTI, suggesting a higher susceptibility of the host to pathogens., This indicates a defect in the chemokine (IL-8) secretion by the epithelial cells to signal the recruitment of neutrophils in susceptible hosts. A study conducted by Frendéus et al., on mouse models, showed the recruitment of neutrophils but impairment in crossing the epithelial barrier due to mutation in the IL-8 receptor (CXCR2). The accumulated neutrophils caused damage to the surrounding host cells instead of pathogens. These immunodeficient mice were unable to get rid of the pathogens from the kidneys.
P fimbriae, an appendage of the pathogen, are a highly potent activator of innate immune response (TLR4 signaling).
IRF-3 signaling cascade is another immune component important for driving an efficient immune response against uropathogens. Similarly, genetic defects in Tlr5 and Tlr11 have been reported to be associated with impaired immune response.,
CXCR1 expression also controls the host's susceptibility to pyelonephritis.
High glucose levels in patients with diabetes negatively regulate the functioning of neutrophils, macrophages, natural killer cells, and the complement system. Although previous studies have indicated insignificant involvement of acquired immunity in EPN, more recent studies have highlighted the importance of innate immunity as well.
| Classification|| |
Some experts categorize renal emphysema into two types of disorders: EPN (presence of gas in renal parenchyma) and emphysematous pyelitis (presence of gas in collecting system). Other than the region of gas formation, there is not much difference between these two. Many clinicians have tried to classify EPN; the following two of them are widely accepted.
The first classification was put forward by Wan et al. They classified it as type I – renal necrosis, accumulation of gas but no fluid and type II – accumulation of gas and fluid in renal parenchyma. Wan et al. made another attempt at classifying EPN. Type I consists of parenchymal destruction with either absence of abscess or the presence of gas. Type II consists of renal or perirenal abscess with gas in the collecting system.
The next attempt was made by Huang and Tseng, in which they classified EPN into four main classes: Class I – gas in the collecting system only, Class II – gas in renal parenchyma only, Class IIIa – an extension of gas or abscess to perinephric space, Class IIIb – an extension of gas or abscess to pararenal space, and Class IV – bilateral EPN or solitary kidney with EPN.
| Pathogenesis|| |
The pathogenesis of EPN is not fully understood. However, some of the aspects that are currently known are discussed below.
Pathogens like E. coli gain access to the urethral opening and ascend the urethra and reach the kidney [Figure 1]a and [Figure 1]b. Pathogens bind to the superficial epithelial cells (facet cells). This interaction is mediated by type 1 pili-dependent anchorage. Type 1 pili are encoded by pathogens that mediate the binding of bacteria to the host cell. Another important molecule for the attachment of pathogen to the epithelial cell surface is globo-series glycolipids present on host cells. These groups of glycolipids are also present on red blood cells and represent the P1 blood group; studies have shown higher susceptibility of the P1 blood type toward the attachment of pathogens.
|Figure 1: Pathogenesis of EPN. (a) Pathogens like Escherichia coli gain access to urethral opening and ascend to bladder then kidney causing infection. (b) Escherichia coli adheres to the host cell by type 1 pilli. The host cell engulfs the bacteria which starts dividing in host cell, forming IBCs. The IBCs are shed in the urine after expulsion from the host cells. In other host cells, the infections persist causing evasion. This leads to activation of host's immune response via TLRs and ILs. Created by BioRender.com. EPN: Emphysematous pyelonephritis, IBC: Intracellular bacterial community, IL: Interleukin|
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P fimbriae bind to glycosphingolipids (galactosylceramide and globotriaosylceramide) which are present in all the tissue of the urethra and kidney. This interaction is thought to be unique to cells and tissues of the urinary tract. Mannose-resistant adhesins on pathogens also play a crucial role in the binding process.
The adhesive capacity of the pathogen is important in the persistence of bacteria in the tissues of the kidney. The host's capacity to clear the bacteria is related to the ability of host cells to respond to lipopolysaccharides which exert a mitogenic effect. Followed by interaction by type 1 pili, the bacteria are engulfed in the epithelial cells. In response, the epithelial cells activate the mechanism of the expulsion of the pathogens. An immune response is initiated by the host at this stage. In the urinary bladder, the pathogens replicate in the cell and form intracellular bacterial communities which are shed off by the superficial layer. This step is advantageous for the host as thousands of bacteria are shed off in urine and then excreted out. However, the infection advances further at a faster rate and ascends to the kidney. Complicated UTIs lead to infection of the upper urinary tract by ascending from the urethra to the bladder to kidneys. This mechanism which is true for UTIs is most likely to be true for EPN as well.
The gas formation in EPN is believed to be linked to the glucose metabolism in patients with diabetes. A high amount of glucose in nearby tissues acts as substrates for bacteria which metabolizes or ferments glucose and carbon dioxide (14.4%), hydrogen (H2) (12.8%) gases are formed. Hence, the glycemic control in the host is the deciding factor for the amount of gas formation in the kidney. Another substrate for bacteria could be necrosis of kidney tissue. Along with carbon dioxide and H2, traces of nitrogen (63.5%), oxygen (6.3%), methane (0.06%), and ammonia (NH3) (0.05%) were also found.
Mixed acid fermentation and butyric acid fermentation of glucose involve the formation of H2 gas. The formation of NH3 is likely to be the result of the degradation of necrotic cells and tissues by pathogens.
The formation of gas in the kidneys of EPN patients is also attributed to renal hypoperfusion, which prevents gas elimination from the parenchyma [Figure 2]a and [Figure 2]b.
|Figure 2: (a) Locations of gas accumulation in kidney in EPN. (b) Factors contributing to the formation of gas (high blood and tissue glucose levels, suppressed immune response, necrotic cells, renal ischemia and gas forming pathogens like Escherichia coli). Created by BioRender.com. EPN: Emphysematous pyelonephritis|
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In conclusion, high blood and tissue glucose, gas-forming pathogens, and suppressed immune response, presence of obstruction in the urinary tract likely promote gas formation.
| Clinical Features|| |
Patients present with mild fever, nausea, vomiting, lethargy, pyuria, flank pain, and/or general malaise. All the patients report having a large number of leukocytes detected in urine, ranging from 12,000 to 24,000 cells/mm3. Along with foul-smelling gas, several cases have reported drainage of pus or abscess from the kidneys. Thrombocytopenia, confusion, impaired consciousness, sepsis, and acute kidney injury are predictors of poor outcomes and require special attention for the treatment.,
Experts have discovered a honeycomb pattern of gas in renal parenchyma. The formation of gas is reported to be earliest in and around the papilla because the vasculature is diminished in the area. In many cases, gas has also been detected in the hepatic and renal veins., In computed tomography (CT) images, the gas appears as a shadow in the kidneys, which might change its position with the movement of the patient. On the other hand, gas in specific regions, such as the perinephric region, is not associated with poor outcomes. On surgery, gas escape is evident with a hissing sound and foul smell, and both the kidneys are equally affected.,,,,
In a study, a low platelet-to-leukocyte ratio was found to be associated with sepsis in EPN patients and death. Huang and Tseng reported that Class IV EPN had highest prevalence of severe symptoms and the worst prognosis. In a study by Mohsin et al., the patients were classified as class 3A & 3B which carries the worse prognosis, which again may explain the high mortality. The gravity of the prognosis increases with each class, with class 4 being the worse. Another poor outcome is recorded by Wan et al. in their type 2 EPN.
| Diagnosis|| |
EPN requires imaging techniques for accurate diagnosis. Ultrasonography, CT scan, or X-ray (excretory urography) is usually used for diagnosis., Although many experts use ultrasonography, it has been evident that it is difficult to distinguish between bowel gas and gas in the kidney in patients with diabetes and obesity ultrasonography. Hence, a CT scan has been considered gold standard diagnostic and imaging method for EPN as it is sensitive and reveals the distribution of gas in the kidney. Staging is also possible with CT scan [Figure 3] to provide a real-time and faster diagnosis, by Brown et al. Early diagnosis is extremely important for treating patients. To confirm the presence of the pathogen and its species and pus in the urine, urine culture is also routinely done in the diagnosis of EPN.
|Figure 3: NCCT images abdomen and pelvis shows right kidney enlarged with destruction of parenchyma, renal parenchyma replaced with gas. Class 2 EPN (Huang Tseng CT classification). EPN: Emphysematous pyelonephritis, CT: Computed tomography, NCCT: Noncontrast computed tomography|
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| Management of Emphysematous Pyelonephritis|| |
Empiric antibiotic treatment has been shown to reduce mortality in cases where Gram-negative infections prevail. Such therapy should be broad spectrum (based on local antibiograms) and individualized (attuned to patient characteristics and antimicrobial resistance), taking into account the severity of the infection and patient vulnerability.,
Preferred single-agent options for treating EPN, effective against the highest percentage of bacterial isolates, are third- or fourth-generation cephalosporins (e.g., ceftazidime) and carbapenems. Alternate empiric regimens include a combination of amikacin and third-generation cephalosporin, given the very low overall resistance rates among E coli, Klebsiella pneumoniae, and P. mirabilis. Aminoglycosides must be used with care in patients with impaired renal function. The addition of gentamicin may be inappropriate and ineffective in this setting.
Several international guidelines currently recommend fluoroquinolones as the empiric treatment of choice for UTI., Resistance of uropathogens to fluoroquinolones is increasing, which is a major clinical concern. Risk factors for fluoroquinolone-resistant E coli infection include recent hospitalization, prior fluoroquinolone use, and urinary catheter placement. Indiscriminate use of fluoroquinolones for complicated or catheter-related UTIs may even undermine the susceptibility of respiratory pathogens to these agents.,,,
Percutaneous drain (PCD) helps to preserve the function of the affected kidney in about 70% of cases. PCD should be performed on patients who have localized areas of gas and in whom functioning renal tissue is believed to be present. Endoscopic drainage is preferable in Type 1 EPN and vitally stable patients.
A pigtail drain, at least 14 Fr. in size, should be inserted, either with ultrasonography or CT guidance. CT guidance has a better success rate when compared with ultrasonography.
Multiple abscesses are not a contraindication for PCD, as more than one catheter can be used to drain all loculations. The abscess, which is technically easier to access and would significantly reduce the pressure on the viable kidney tissue, should be targeted first with PCD.
During the last decade, there has been a gradual shift toward a nephron-sparing approach with PCD, with or without elective nephrectomy at a later stage.
Significant advances in percutaneous drainage such as ultrasound and CT-guided drainage, have made it possible to have percutaneous drainage as a treatment option for EPN, which was first shown by Hudson et al.
Subsequent case studies have shown patients being successfully treated with PCD when used in addition to medical management, with a significant reduction in mortality rates.
In an analysis of 48 cases, Huang and Tseng concluded that Class 1 and Class 2 EPN could be managed with percutaneous drainage and antibiotics; there was a 61% failure rate and 19% mortality rate in Class 3A after drainage; in Class 3B, there was a failure rate of 75% and a mortality rate of 29% after drainage.
This approach could also be used in patients with class 3 or 4 EPN who have fewer than two risk factors (e.g., thrombocytopenia, elevated serum creatinine levels, altered sensorium, and shock).
Any obstruction found in imaging studies should be relieved with either percutaneous drainage or stent placement. However, in the presence of two or more risk factors, nephrectomy gives better results.
In a meta-analysis of the management strategies, the most successful management was medical management with drainage (80%–100%), which was also associated with the lowest mortality at 13.5% (P < 0.001).
Gas in the renal parenchyma or dry-type EPN should be treated immediately with nephrectomy. Nephrectomy in patients with EPN can be simple, radical, or laparoscopic. A simple nephrectomy can be carried out with a mortality rate as low as 5%. Laparoscopic nephrectomy can be successfully performed in these patients and has the advantage of providing a shortened recovery period and hospital stay.,
Mortality rates were 15%–20% in two series in which nephrectomy was the treatment of choice in EPN,, while in a study by Huang and Tseng, nephrectomy had a 10% mortality rate.
Recent advances and future implications
Langermann et al. have put forward immunization of diabetes patients with FimH adhesin type 1 fimbriae which will prevent EPN. Proteins from pathogens such as type 1 fimbriae can be a suitable vaccine candidate for mouse models and clinical trials. It was recently reported that immunization with the FimH adhesin of type 1 fimbriae protects mice from UTIs. Thus, proteins from the F1C fimbriae may be used as a novel vaccine candidate to confer protection against pyelonephritis caused by non-P-fimbriated E. coli strains.
- Various hypotheses have been put forth in the development of EPN, but the exact pathogenesis is yet to be understood
- As the clinicians get bacterial culture reports in 48–72 h, there could be delay in the initiation of organism-specific antibiotics due to a lack of efficient diagnostic tests. Some rapid ways to get these reports might improve patient care. Usually, broad-spectrum antibiotic is initiated in EPN patients, but in the era of multi-drug/pan-resistant microbes, early sensitivity reports will help to hit the target early
- Additional multicenter studies comprising, a large sample size will help us a better understanding of the disease
- Genotypic evaluation with phenotypic correlation will aid us in the desired understanding of EPN.
| Conclusion|| |
EPN though a rare condition in clinical practice, needs a high index of suspicion in patients with diabetes mellitus. Early diagnosis and prompt aggressive treatment are the keys to manage EPN. A multidisciplinary approach is imperative. The standard treatment protocol of EPN includes long-term antibiotic therapy (intravenous and/or oral), percutaneous drainage, double J catheter insertion, or nephrectomy.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]