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Polar renal scarring in pyelonephritis?

Polar renal scarring in pyelonephritis?


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Why does infection and scarring occurs at poles in Vesicoureteric reflux but not in Obstructive pyelonephritis?

It is said in Robbins that, it is due to polar papillae being flattened or concave unlike convex lateral papillae, but why is it not the case in obstructive pyelonephritis?

Also why polar papillae are not convex?


It's more an issue of the extent of reflux than anything else. If you look at the data on scarring, you'll see that grade III and IV VUR present with lateral scarring as well. So, any pyelonephritis that is associated with gross dilation of the ureter and collecting system will give diffuse scarring. Mild dilation, you'll get scarring where the reverse flow goes first. I can't answer the question about why the reverse flow goes to the poles first. The authors of the paper I linked have their own speculation. Robbins has another. Neither have evidence on the mechanism.


Etiology and Pathophysiology of Pyelonephritis

Escherichia coli is the most frequent cause of pyelonephritis. Its possible virulence factors include the ability to adhere and colonize the urinary tract, an imporant initiating factor in all urinary tract infections (UTIs). The importance of P fimbriae in this adhesion is stressed and the evidence for its importance in pyelonephritis is presented in epidemiologic studies of patients, as well as in animal studies. It appears that both host receptor density and the nonsecretor state is responsible for susceptibility to urinary tract infection. Vesicoureteral ref lux can be responsible for ascending upper tract infection, but infection with P-fimbriated E coli may lead to ascending pyelonephritis without ref lux because of the paralytic effect of lipid A on ureteral peristaltic activity. Renal ischemia leads to renal damage following infection by reperfusion damage due to the release of superoxide. Experimentally, this ischemic damage can be prevented by allopurinol, a xanthine oxidase inhibitor. The acute inflammatory response can produce renal damage because of the respiratory burst of phagocytosis, which while killing phagocytosed bacteria also damages renal tubules. An amelioration of the inflammatory response by treatment with superoxide dismutase or corticosteroids has been shown to modulate renal damage. Vaccination with P fimbriae has been shown experimentally to prevent the initiation of the disease. However, since vaccines are not clinically available, the clinical and animal studies on therapy of acute disease are stressed. Acute pyelonephritis during the first 3 years of life more often produced the renal damage that could lead to end-stage renal disease. Thus, the prevention of end-stage renal disease that may occur from acute pyelonephritis during infancy depends on early diagnosis and rapid and effective antibiotic treatment. This will eradicate the bacteria and stop the destructive reperfusion damage and that associated with the inflammatory response.


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Types of Kidney Disease Leading to Scarring

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Methods

This retrospective study was approved by Institutional Review Board of Ajou University Hospital and the requirement for patient consent was waived. Informed consent for the off-label usage of the US contrast agent was obtained from all patient guardians. The study was conducted according to the guidelines of the Declaration of Helsinki.

Subjects

We retrospectively reviewed pediatric patients (15 years old or younger) who were admitted to our institution for suspected acute pyelonephritis from August 2017 to August 2018 and who underwent both CEUS and DMSA scanning during their hospital stay. Some of these patients underwent CT in the emergency room for prompt diagnosis and management before admission. Patients were diagnosed with UTI if they had fever (≥ 37.8 °C), pyuria, and positive urine culture 9 . Some patients who were pretreated with antibiotics did not fulfill the abovementioned criteria at admission but showed a positive urine culture on a follow-up exam. The need for CEUS was determined by the clinician if the patient suffered from recurrent UTI and/or was suspected to have complications due to acute pyelonephritis. Patients who had any of the following were excluded from the CEUS study: (1) previous history of an allergic reaction to the US contrast agent, (2) left-to-right shunt with congenital heart disease, (3) respiratory distress syndrome, (4) severe pulmonary hypertension, and (5) severe systemic hypertension. Administration of sedation or anesthesia for the imaging studies were recorded.

All renal CEUS studies were performed by one pediatric radiologist. The radiologist reviewed the history and previous imaging studies of each patient before conducting CEUS. First, the patients underwent conventional non-enhanced renal ultrasound using a LOGIQ E9 or LOGIQ E10 (GE Healthcare, Milwaukee, WI, USA) ultrasound machine. Either a curved 1–6 transducer or curved 3–10 transducer was used depending on body size. Second, the patients underwent renal CEUS using either a linear 2–9 or curved 1–6 transducer. The mechanical index was set as low as possible from 0.09 to 0.12 31 . All subjects were administered the SonoVue (Bracco, Milan, Italy) contrast agent through a peripheral IV line. Patients younger than 3 years of age received 0.07—0.1 ml/kg body weight of contrast agent and those older than 3 years received 0.06 ml/kg body weight of contrast agent for each injection according to a previous guideline for pediatric urinary tract CEUS studies 12 . Each injection was immediately followed by a 5-ml normal saline solution flush. The time window was 0–3 min for each kidney following the previous guideline 12 . During the time window, the performer scrolled the transducer to completely cover both kidneys. The longitudinal plane was chosen as the standard view, but the axial plane was also chosen whenever the performer found it necessary to further visualize lesions in the kidneys. Patients were in the supine or oblique lateral position during the study. One injection was done for each kidney. Two different injections were given with a 5-min interval. Between the two exams, we used “flash-replenishment” to remove residual microbubbles from the second kidney. After renal CEUS, all patients were observed for 20 min for any adverse reactions to the contrast agent.

DMSA scan

DMSA scans were performed with a gamma camera (Siemens Orbiter, Erlangen, Germany) after the intravenous injection of an adult-equivalent dose of 37-MBq technetium-99 DMSA with weight-adjustment. Single-photon emission computed tomography was performed 4 h after the isotope was administered for a scan time of 20 min.

Single-phase enhanced abdominal CT was performed with a 128 MDCT scanner (SOMATOM Definition Edge, Siemens Healthcare, Erlangen, Germany). The scan parameters were as follows: 100 kVp, 80 mAs with automatic tube current modulation (reference mA), rotation time 0.5, and pitch 1.2. Automatic tube current modulation systems adapt the tube current according to each patient’s attenuation characteristics. The image quality metric is specified in the form of either image noise or reference mAs and we set the reference mAs as 80 mAs 32 . Images were reconstructed at 3 mm slice thickness. Intravenous contrast Bonorex Iohexol 300 (Central Medical Services, Seoul, Korea) was administered at an average dose of 1.5–2 ml/kg body weight. The nephrogenic phase was acquired 60–90 s after the contrast was injected depending on patient age, acquisition time, contrast amount, and injection speed 33 .

Image analysis

All the reviewers were blinded to prior interpretations and prior imaging studies.

CEUS movie files consisting of one clip for each kidney were generated by a radiologist. The analyzed movie file had a renal CEUS time window of 1–2 min instead of the whole 3 min of the original file as the late parenchymal phase has been reported to be the best phase for pyelonephritis 28 . To evaluate inter-observer variability, the movie clips were randomly displayed and interpreted by two faculty radiologists. Radiologist 1 was a pediatric radiologist and Radiologist 2 was an abdominal radiologist, both with 9 years of experience in radiology and 2 years of experience in CEUS. The radiologists were blinded to other imaging findings and clinical information. Decreased cortical perfusion was considered to indicate acute pyelonephritis. Each radiologist documented the presence of acute pyelonephritis (absent or present) and its location (right or left kidney). Radiologist 1 repeated assessments two weeks later to evaluate intra-observer variability. The presence or absence of abscess was also determined and recorded. A renal abscess was diagnosed when there was a hypoechoic lesion without enhancement during the CEUS study 28 .

CT images were interpreted by Radiologist 1. A typical wedge-shaped cortical area of decreased enhancement was considered to indicate acute pyelonephritis 10 . Again, the presence of acute pyelonephritis and its location (right or left kidney) was documented. The presence or absence of renal abscess was also documented. A renal abscess was diagnosed when there was a well-defined low attenuating mass with wall enhancement 34 .

DMSA scan reports, which were wrote up by one of the nuclear physicians in our institution, were used for this study. The International Radionuclide Nephrourology consensus criteria were used to interpret DMSA scans and the scans were deemed positive if there were any cortical defects 35 .

Statistics

Reports from DMSA scans and CT served as reference standards for the agreement analysis. Sensitivity, specificity, PPV, and NPV were calculated for CEUS with the DMSA scan as the reference standard and CEUS with CT as the reference standard. The generalized kappa value was used to assess agreements for inter- and intra-observer variability. Agreements for inter- and intra-observer variability were categorized as follows: 0.81–0.99, almost perfect agreement 0.61–0.80, substantial agreement 0.41–0.60, moderate agreement 0.21–0.40, fair agreement 0.01–0.20, slight agreement, and < 0.01, poor or less than chance agreement 36 . A p value of less than 0.05 was considered statistically significant. SPSS v.25.0 (SPSS, Chicago, IL, USA) was used for analysis.


Contents

Signs and symptoms of acute pyelonephritis generally develop rapidly over a few hours or a day. It can cause high fever, pain on passing urine, and abdominal pain that radiates along the flank towards the back. There is often associated vomiting. [9]

Chronic pyelonephritis causes persistent flank or abdominal pain, signs of infection (fever, unintentional weight loss, malaise, decreased appetite), lower urinary tract symptoms and blood in the urine. [10] Chronic pyelonephritis can in addition cause fever of unknown origin. Furthermore, inflammation-related proteins can accumulate in organs and cause the condition AA amyloidosis. [11]

Physical examination may reveal fever and tenderness at the costovertebral angle on the affected side. [12]

Most cases of community-acquired pyelonephritis are due to bowel organisms that enter the urinary tract. Common organisms are E. coli (70–80%) and Enterococcus faecalis. Hospital-acquired infections may be due to coliform bacteria and enterococci, as well as other organisms uncommon in the community (e.g., Pseudomonas aeruginosa and various species of Klebsiella). Most cases of pyelonephritis start off as lower urinary tract infections, mainly cystitis and prostatitis. [9] E. coli can invade the superficial umbrella cells of the bladder to form intracellular bacterial communities (IBCs), which can mature into biofilms. These biofilm-producing E. coli are resistant to antibiotic therapy and immune system responses, and present a possible explanation for recurrent urinary tract infections, including pyelonephritis. [13] Risk is increased in the following situations: [9] [14]

  • Mechanical: any structural abnormalities in the urinary tract, vesicoureteral reflux (urine from the bladder flowing back into the ureter), kidney stones, urinary tract catheterization, ureteral stents or drainage procedures (e.g., nephrostomy), pregnancy, neurogenic bladder (e.g., due to spinal cord damage, spina bifida or multiple sclerosis) and prostate disease (e.g., benign prostatic hyperplasia) in men
  • Constitutional: diabetes mellitus, immunocompromised states
  • Behavioral: change in sexual partner within the last year, spermicide use
  • Positive family history (close family members with frequent urinary tract infections)

Laboratory examination Edit

Analysis of the urine may show signs of urinary tract infection. Specifically, the presence of nitrite and white blood cells on a urine test strip in patients with typical symptoms are sufficient for the diagnosis of pyelonephritis, and are an indication for empirical treatment. Blood tests such as a complete blood count may show neutrophilia. Microbiological culture of the urine, with or without blood cultures and antibiotic sensitivity testing are useful for establishing a formal diagnosis, [9] and are considered mandatory. [15]

Imaging studies Edit

If a kidney stone is suspected (e.g. on the basis of characteristic colicky pain or the presence of a disproportionate amount of blood in the urine), a kidneys, ureters, and bladder x-ray (KUB film) may assist in identifying radioopaque stones. [9] Where available, a noncontrast helical CT scan with 5 millimeter sections is the diagnostic modality of choice in the radiographic evaluation of suspected nephrolithiasis. [16] [17] [18] All stones are detectable on CT scans except very rare stones composed of certain drug residues in the urine. [19] In patients with recurrent ascending urinary tract infections, it may be necessary to exclude an anatomical abnormality, such as vesicoureteral reflux or polycystic kidney disease. Investigations used in this setting include kidney ultrasonography or voiding cystourethrography. [9] CT scan or kidney ultrasonography is useful in the diagnosis of xanthogranulomatous pyelonephritis serial imaging may be useful for differentiating this condition from kidney cancer. [10]

Ultrasound findings that indicate pyelonephritis are enlargement of the kidney, edema in the renal sinus or parenchyma, bleeding, loss of corticomedullary differentiation, abscess formation, or an areas of poor blood flow on doppler ultrasound. [21] However, ultrasound findings are seen in only 20% to 24% of people with pyelonephritis. [21]

A DMSA scan is a radionuclide scan that uses dimercaptosuccinic acid in assessing the kidney morphology. It is now [ when? ] the most reliable test for the diagnosis of acute pyelonephritis. [22]

Classification Edit

Acute pyelonephritis Edit

Acute pyelonephritis is an exudative purulent localized inflammation of the renal pelvis (collecting system) and kidney. The kidney parenchyma presents in the interstitium abscesses (suppurative necrosis), consisting in purulent exudate (pus): neutrophils, fibrin, cell debris and central germ colonies (hematoxylinophils). Tubules are damaged by exudate and may contain neutrophil casts. In the early stages, the glomerulus and vessels are normal. Gross pathology often reveals pathognomonic radiations of bleeding and suppuration through the renal pelvis to the renal cortex. [ citation needed ]

Chronic pyelonephritis Edit

Chronic pyelonephritis implies recurrent kidney infections and can result in scarring of the renal parenchyma and impaired function, especially in the setting of obstruction. A perinephric abscess (infection around the kidney) and/or pyonephrosis may develop in severe cases of pyelonephritis. [23]

Abscess around both kidneys [24]

Abscess around both kidneys [24]

Chronic pyelonephritis with reduced kidney size and focal cortical thinning. Measurement of kidney length on the US image is illustrated by ‘+’ and a dashed line. [20]

Xanthogranulomatous pyelonephritis Edit

Xanthogranulomatous pyelonephritis is an unusual form of chronic pyelonephritis characterized by granulomatous abscess formation, severe kidney destruction, and a clinical picture that may resemble renal cell carcinoma and other inflammatory kidney parenchymal diseases. Most affected individuals present with recurrent fevers and urosepsis, anemia, and a painful kidney mass. Other common manifestations include kidney stones and loss of function of the affected kidney. Bacterial cultures of kidney tissue are almost always positive. [25] Microscopically, there are granulomas and lipid-laden macrophages (hence the term xantho-, which means yellow in ancient Greek). It is found in roughly 20% of specimens from surgically managed cases of pyelonephritis. [10]

In people who experience recurrent urinary tract infections, additional investigations may identify an underlying abnormality. Occasionally, surgical intervention is necessary to reduce the likelihood of recurrence. If no abnormality is identified, some studies suggest long-term preventive treatment with antibiotics, either daily or after sexual activity. [26] In children at risk for recurrent urinary tract infections, not enough studies have been performed to conclude prescription of long-term antibiotics have a net positive benefit. [27] Drinking cranberry juice does not appear to provide much if any benefit in decreasing urinary tract infections. [28]

In people suspected of having pyelonephritis, a urine culture and antibiotic sensitivity test is performed, so therapy can eventually be tailored on the basis of the infecting organism. [5] As most cases of pyelonephritis are due to bacterial infections, antibiotics are the mainstay of treatment. [5] The choice of antibiotic depends on the species and antibiotic sensitivity profile of the infecting organism, and may include fluoroquinolones, cephalosporins, aminoglycosides, or trimethoprim/sulfamethoxazole, either alone or in combination. [15]

Simple Edit

A 2018 systematic review recommended the use of norfloxacin as it has the lowest rate of side effects with a comparable efficacy to commonly used antibiotics. [29]

In people who do not require hospitalization and live in an area where there is a low prevalence of antibiotic-resistant bacteria, a fluoroquinolone by mouth such as ciprofloxacin or levofloxacin is an appropriate initial choice for therapy. [5] In areas where there is a higher prevalence of fluoroquinolone resistance, it is useful to initiate treatment with a single intravenous dose of a long-acting antibiotic such as ceftriaxone or an aminoglycoside, and then continuing treatment with a fluoroquinolone. Oral trimethoprim/sulfamethoxazole is an appropriate choice for therapy if the bacteria is known to be susceptible. [5] If trimethoprim/sulfamethoxazole is used when the susceptibility is not known, it is useful to initiate treatment with a single intravenous dose of a long-acting antibiotic such as ceftriaxone or an aminoglycoside. Oral beta-lactam antibiotics are less effective than other available agents for treatment of pyelonephritis. [15] Improvement is expected in 48 to 72 hours. [5]

Complicated Edit

People with acute pyelonephritis that is accompanied by high fever and leukocytosis are typically admitted to the hospital for intravenous hydration and intravenous antibiotic treatment. Treatment is typically initiated with an intravenous fluoroquinolone, an aminoglycoside, an extended-spectrum penicillin or cephalosporin, or a carbapenem. Combination antibiotic therapy is often used in such situations. The treatment regimen is selected based on local resistance data and the susceptibility profile of the specific infecting organism(s). [15]

During the course of antibiotic treatment, serial white blood cell count and temperature are closely monitored. Typically, the intravenous antibiotics are continued until the person has no fever for at least 24 to 48 hours, then equivalent antibiotics by mouth can be given for a total of two–week duration of treatment. [30] Intravenous fluids may be administered to compensate for the reduced oral intake, insensible losses (due to the raised temperature) and vasodilation and to optimize urine output. Percutaneous nephrostomy or ureteral stent placement may be indicated to relieve obstruction caused by a stone. Children with acute pyelonephritis can be treated effectively with oral antibiotics (cefixime, ceftibuten and amoxicillin/clavulanic acid) or with short courses (2 to 4 days) of intravenous therapy followed by oral therapy. [31] If intravenous therapy is chosen, single daily dosing with aminoglycosides is safe and effective. [31]

Fosfomycin can be used as an efficacious treatment for both UTIs and complicated UTIs including acute pyelonephritis. The standard regimen for complicated UTIs is an oral 3g dose administered once every 48 or 72 hours for a total of 3 doses or a 6 grams every 8 hours for 7 days to 14 days when fosfomycin is given in IV form. [32]

Treatment of xanthogranulomatous pyelonephritis involves antibiotics as well as surgery. Removal of the kidney is the best surgical treatment in the overwhelming majority of cases, although polar resection (partial nephrectomy) has been effective for some people with localized disease. [10] [33] Watchful waiting with serial imaging may be appropriate in rare circumstances. [34]

Follow-up Edit

If no improvement is made in one to two days post therapy, inpatients should repeat an urine analysis and imaging. Outpatients should check again with their doctor. [35]

There are roughly 12–13 cases annually per 10,000 population in women receiving outpatient treatment and 3–4 cases requiring admission. In men, 2–3 cases per 10,000 are treated as outpatients and 1– cases/10,000 require admission. [36] Young women are most often affected. Infants and the elderly are also at increased risk, reflecting anatomical changes and hormonal status. [36] Xanthogranulomatous pyelonephritis is most common in middle-aged women. [25] It can present somewhat differently in children, in whom it may be mistaken for Wilms' tumor. [37]

According to a 2015 meta analysis, vitamin A has been shown to alleviate renal damage and/or prevent renal scarring. [38]

The term is from Greek πύελο|ς pýelo|s, "basin" + νεφρ|ός nepʰrós, "kidney" + suffix -itis suggesting "inflammation". [ citation needed ]

A similar term is "pyelitis", which means inflammation of the renal pelvis and calyces. [39] [40] In other words, pyelitis together with nephritis is collectively known as pyelonephritis. [ citation needed ]


Could Pyelonephritic Scarring Be Prevented by Anti-Inflammatory Treatment? An Experimental Model of Acute Pyelonephritis

Objectives. This study aimed to demonstrate if the addition of anti-inflammatory treatment to antibiotic therapy shows any superiority to the treatment with antibiotic only. Methods. Forty-nine Wistar rats were divided into 7 groups. Pyelonephritis was performed by E. coli injection to upper pole of kidneys except control group. Group 2 was not treated. Ceftriaxone, ketoprofen, “ceftriaxone + ketoprofen,” methylprednisolone, and “ceftriaxone + methylprednisolone” were given in the groups. The technetium-99m-dimercaptosuccinic acid scintigraphies were performed in 3rd day to detect pyelonephritis and 10th week to detect renal scarring. All kidneys were also histopathologically evaluated. Results. When 3rd day and 10th week scintigraphies were compared, initial 2.00 ± 0.30 point pyelonephritis score resulted in 0.71 ± 0.36 renal scar score in “ceftriaxone + ketoprofen” group (

). Initial 2.00 ± 0.43 point pyelonephritis score resulted in 0.86 ± 0.26 renal scar score in “ceftriaxone + methylprednisolone” group (

). Renal scar score was declined in “ceftriaxone + ketoprofen” group and “ceftriaxone + methylprednisolone” group compared with no-treatment group on 10th week of the study (

, ). On histopathological evaluation, it was seen that renal scar prevalence and expansion declined significantly in “ceftriaxone + ketoprofen and ceftriaxone + methylprednisolone” ( , ). Conclusion. It was evidenced that ceftriaxone treatment in combination with ketoprofen or methylprednisolone declined scar formation in scintigraphic and histopathologic examinations of the kidneys.

1. Introduction

Urinary tract infection (UTI) in infants and children is a relatively common problem, with potentially serious consequences.

Technetium-99m-dimercaptosuccinic acid (DMSA) renal scintigraphy is considered the most sensitive test for the diagnosis of renal involvement and the subsequent development of renal scarring [1, 2].

It may still cause renal scar formation in up to 40% of cases, leading to hypertension, proteinuria, and end-stage renal disease in children [3]. Most important role belongs to acute inflammatory response in scar generation [3, 4].

Various anti-inflammatory treatments were experimental in order to prevent scar generation due to the importance of host origin cytokine in inflammation. Therefore, ongoing research projects are underway to find an agent that can prevent renal scarring and subsequent complications. Inhibition of acute inflammation in experimental studies by steroids [3, 5], anti-inflammatory agents [6, 7], melatonin [8], pentoxifylline [9], vitamin A [10], vitamins A and E [11], vitamins C and E [12], vitamin E [13], mesenchymal stem cell [14], methylene blue [15], dapsone [16], ulinastatin [17], and montelukast [18] have been reported to reduce kidney damage after infection.

It was thought that both ketoprofen and methylprednisolone may block such mechanisms which give acute inflammatory response, at various stages to prevent renal scar generation. This study aimed to demonstrate if the anti-inflammatory treatment in combination with antibiotic treatment shows any superiority to antibiotic treatment alone.

2. Material and Methods

2.1. Animals

In this study, 49 Wistar rats weighing between 150 and 200 g were used. Animals were housed in specific pathogen-free conditions at room temperature (

) using a 12/12-hour light/dark cycle and provided with commercially available rat chow and tap water ad libitum. All of the rats were 8–10 weeks old. Karadeniz Technical University animal ethics board approved number is “02.370.”

2.2. Bacteria

The Escherichia coli strain UTI 36, isolated from a previous patient with confirmed acute pyelonephritis and phenotyped for the presence of P-fimbria and hemolysin production, was grown overnight on Luria Bertani (LB) agar. Before infection, a single colony of bacteria was inoculated onto LB broth and grown at 37°C with shaking to the stationary phase, after which the organisms were centrifuged and washed twice in phosphate-buffered saline. A solution containing approximately

organisms/mL was prepared. Antibiotic sensitivities were assayed using Kirby-Bauer disks impregnated with ceftriaxone.

2.3. Experimental Infection

All animals were anesthetized by intramuscular injection of ketamine hydrochloride at 80 mg/kg (Ketalar, Parke-Davis). The kidney was exposed through a midline abdominal incision, and 0.1 mL of bacterial solution ( colony-forming units/mL) was then injected to upper pole.

2.4. Scintigraphic Imaging

In the 3rd day (48–96th hours) of the study, the technetium-99m-dimercaptosuccinic acid (DMSA) renal scintigraphies of all rats including the control group were taken and the rats were classified according to the presence and expansion of pyelonephritis (Figures 1(a), 1(b), and 1(c)). Furthermore, the DMSA renal scintigraphies of all rats were taken a second time at the 10th week of the study and their kidneys were classified according to the presence and expansion of renal scarring (Figures 1(d), 1(e), and 1(f)).


(a)
(b)
(c)
(d)
(e)
(f)
(a)
(b)
(c)
(d)
(e)
(f) (a) DMSA kidney scintigraphy that indicates normal activity retention in the 3rd day in control group (pyelonephritis score: 0). (b)DMSA kidney scintigraphy in the 3rd day in ceftriaxone group (pyelonephritis score: 1). (c) DMSA kidney scintigraphy in the 3rd day in ceftriaxone-ketoprophen group (pyelonephritis score: 3). (d) DMSA kidney scintigraphy in the 10th week in no-treatment group (scar score: 2). (e) DMSA kidney scintigraphy in the 10th week in ceftriaxone group (scar score: 1). (f) DMSA kidney scintigraphy in the 10th week in Ceftriaxone − Ketoprophen Group (scar score: 0).

Scar or pyelonephritis score was assessed using a renal damage score. Each renal unit was divided into three equal zones, and lesions were graded based on percent of affected cortex. Renal scars were each graded by DMSA scan from 0 to 3 according to the extent of pyelonephritic lesions of varying severity involvement as follows: 0, if no damage 1, if less than 33% damage 2, if between 33 and 66% damage 3, if more than 66% damage [5].

2.5. Experimental Groups

The rats were divided equally into seven groups each containing seven rats. In control group, sham operated group (Group 1) consisted of healthy rats. Pyelonephritis was induced by injection of E. coli to other rats as mentioned above. In no-treatment group (Group 2), the rats had pyelonephritis but did not receive any treatment. Treatments began 72 hours after bacterial inoculation in the other groups. The rats in ceftriaxone group (Group 3) were treated only with ceftriaxone (i.m) at a dose of 50 mg/kg once daily for 10 days. In ketoprofen group (Group 4), ketoprofen injections were done at a dose of 2 mg/kg for 3 days. Two rats with no indication about infection in 3rd day scintigraphic examination in group 4 were excluded from the study. The rats in “ceftriaxone plus ketoprofen” group (Group 5) were treated with 50 mg/kg ceftriaxone for 10 days and 2 mg/kg ketoprofen for 3 days before 30 minutes of ceftriaxone administration. The rats in methylprednisolone group (Group 6) were given 30 mg/kg methylprednisolone for 3 days. The rats in “ceftriaxone plus methylprednisolone” group (Group 7) were given 50 mg/kg ceftriaxone for 10 days and 30 mg/kg methylprednisolone for 3 days before 30 minutes of ceftriaxone administration.

2.6. Histopathologic Examination

After routine processing, each half renal unit was divided into three equal zones (upper, middle, and lower), and five sections were obtained from anterior zone and five from posterior zone. The sections were obtained through the renal cortex to the collecting system. The sections were stained with hematoxylin-eosin and Masson’s trichrome. A pathologist, who was unaware of the group designations, evaluated the specimens. Two main histopathologic changes were regarded as microscopic criteria: the inflammatory response (interstitial mononuclear inflammatory cell infiltration) and cicatrization (interstitial fibrosis-tubular atrophy). These changes were scored semiquantitatively for comparison purposes. The two criteria were each graded from 0 to 3 according to the extent of parenchymal involvement: 0, if none was involved 1, if less than 5% of the parenchyma was involved 2, if more than 5% and less than 10% of the parenchyma was involved and 3, if more than 10% of the parenchyma was involved [8].

2.7. Sacrifice of Animals

The rats in were sacrificed under anesthesia, ten weeks after bacterial inoculation to determine the extent of renal scar formation.

2.8. Statistical Analysis

SPSS (statistical package for social science) for Windows was used for statistical analyses.

was regarded as significant. DMSA scintigraphic scores of 3rd day and 10th week are compared with using “Wilcoxon” test. No-treatment group and other groups were compared with “Kruskal Wallis” test on the base of 10th week DMSA scintigraphic results. No-treatment group and other groups were compared with “Mann Whitney U” test on the base of histopathological results.

3. Results

Table 1 shows the result of DMSA kidney scintigraphy (Figures 1(a)–1(f)) of the 3rd day pyelonephritic scores and of the 10th week renal scarring scores.

When the rats were evaluated in terms of the DMSA renal scintigraphy findings, it was found that in the no-treatment group the pyelonephritic involvement score decreased from in the 3th day to

scar score at the end of the 10th week. ( ).

In the group which received only ceftriaxone treatment, the pyelonephritic involvement score was found in 3th day and renal scar score at the end of the 10th week. ( ).

In the group which received “ceftriaxone plus ketoprofen” treatment, the pyelonephritic involvement score decreased from in the 3th day to renal scar score at the end of the 10th week. ( ).

In the group which received “ceftriaxone plus methylprednisolone” treatment, the pyelonephritic involvement score decreased from in the 3rd day to renal scar score at the end of the 10th week ( ).

Table 2 shows no-treatment group compared with other groups on the base of the 10th week DMSA scintigraphic results.

Scar scores were low in the “ceftriaxone plus ketoprofen” and “ceftriaxone plus methylprednisolone” groups when compared with no-treatment group ( , , resp.) as shown in Table 2. Scar score in ceftriaxone treated group was not significant compared to no-treatment group. ( ).

After the histopathological evaluation, when the no-treatment group was compared with other groups in terms of the presence and expansion of renal scars, a statistically significant decrease was observed in the presence and expansion of renal scars in the “ceftriaxone plus ketoprofen” and “ceftriaxone plus methylprednisolone” groups ( , , resp.) (Figures 2(a)–2(d)) (Table 3). Only ceftriaxone treated group is not significantly different compared to no-treatment group ( ).


(a)
(b)
(c)
(d)
(a)
(b)
(c)
(d) (a) Control group kidney tissue which does not indicate any pathological finding in renal parenchyma (H.E

100). (b) 2nd degree inflammation in renal parenchyma, no-treatment group (HE

40). (c) 2nd degree scar in renal parenchyma, no-treatment group (M.T

4. Discussion

Pyelonephritis, an acute infectious disease of kidney parenchyma, now being considered common and serious, bacterial infection that occurs in infancy and early childhood. Renal scarring is a frequent outcome of acute pyelonephritis in children, reported in up to 65% of patients with pyelonephritis. The development of scars in early life, particularly in patients with VUR, has been correlated with the development of hypertension [19], preeclampsia, proteinuria, renal insufficiency, and end-stage renal disease. Of all patients with endstage renal disease, chronic pyelonephritis has been reportedly the cause in 10 to 25% of children, 7–17% in the world, and 23.6% in our country. Antibiotic treatment is important but not minimizing renal damage and scarring alone.

Escherichia coli is the most common organism present up to 80% in UTI as we used in our study, although other enteric organisms such as Klebsiella spp. and enterococci, as well as Staphylococci, have been identified [20]. Bacterial inoculation in the tissue, ischemia reperfusion damage, and lysosomal lytic enzyme retention cause renal scar by means of endoxines, cytokines, and chimiotaxy [4]. Cytokines play a major role in renal scar formation [3].

It has been reported that renal damage after acute pyelonephritis is more closely related to the extent of the inflammatory process associated with infection than the actual bacterial growth in kidney [21, 22]. The inflammatory response following bacterial inoculation is characterized by recruitment of activated neutrophils and lymphocytes to renal tissue and the release of antibacterial substances such as free radical species and lysosomal enzymes [23]. Therefore, anti-inflammatory treatment is believed to be effective in preventing renal scarring. [5–7, 24, 25]. Glucocorticoids are widely used for the suppression of inflammation [26].

Previous experimental studies reported that technetium-99m-dimercaptosuccinic acid (Tc-99m-DMSA) renal scintigraphy is highly sensitive and reliable for the detection of acute pyelonephritis when performed during the acute phase of infection and renal scaring when performed after recovery. DMSA scintigraphy is considered the most sensitive test for the diagnosis of renal involvement and the subsequent development of renal scarring [1, 2]. The renal cortical changes are acceptably detected by Tc-99m-DMSA renal scintigraphy. In our study, DMSA scan findings were comparable with histopathological results.

Recent experimental studies demonstrate that oxygen-free radical scavengers and antioxidants can reduce tissue damage and renal scaring during acute and chronic pyelonephritis. Antioxidant vitamins [3, 9] increase tissue protection from oxidative stress. Bennett et al. showed that vitamins A and E suppressed renal inflammation in pyelonephritis [11]. Kanter et al. showed that vitamin C treatment alone or with vitamin A may prevent endotoxin-induced renal damage [27]. Imamoǧlu et al. measured the level of tissue malondialdehyde in an experimental pyelonephritis model in rats and showed that combined with antibiotics and melatonin it may decrease the inflammation [8]. From the report by Yagmurlu et al., it is showed that anticytokine activity of pentoxifylline could be the other mechanism for the prevention of renal scarring due to pyelonephritis, though this study did not include cytokine measurements [9]. The preventive effect of dapsone which has a scavenging activity on active oxygen species on renal scarring was found to effectively prevent renal scarring by Mochida et al. [16]. Caffeic acid phenethyl ester (an active component of propolis from honeybee hives, which has antioxidant, anti-inflammatory, and antibacterial properties) administration reduced significantly decreased E. coli-induced lipid peroxidation as showed by Celik et al. [20]. Cyclophosphamide due to effect of neutropenia and inhibition leukocyte migration of colchicine was used to leukocyte modulation and found that they can prevent renal scarring by Matsumoto et al. But it is not useful because of serious side effects of this agent [28]. In a study by Patel et al. the degree of renal dysfunction and inflammation caused by ischemia-reperfusion was significantly reduced in 5-lipoxygenase knockout mice as compared to wild type mice. Moreover, administration of 5-lipoxygenase inhibitor before ischemia-reperfusion significantly reduced the degree of renal dysfunction and injury [29]. Mesenchymal stem cells (rMSC) were shown to have therapeutic value in alleviating pyelonephritis-associated histopathologic changes in rats [14]. Nevertheless, in real clinical practice, the beginning of the infectious process is silent and cannot be used for antioxidant treatment [13]. Haraoka et al. confirmed the active role of inflammation in renal scarring by demonstrating that prednisolone was sufficient to prevent renal scar formation in rats with APN receiving delayed antibiotics treatment [22]. Surgery performed vezicouretheral reflu on pigs was created as an experimental pyelonephritis model. Pohl et al. investigated the effect of preventing the renal scarring of oral prednisolone [5]. Also, in a study by Sharifian et al. it was concluded that the administration of dexamethasone could possibly prevent the formation of kidney scar [3]. As similar to our study, combined antibiotic with ibuprofen, an inhibitor of cyclooxygenase, and neutrophil chemotaxis was expected to decrease renal scar formation resulting from inflammation by Huang et al. [7].

In this study, it was found that ceftriaxone treatment in combination with ketoprofen or methylprednisolone decreased renal scar development in pyelonephritis. Although there was some decrease in scar expanse compared to the expansion of the pyelonephritic involvement in only ceftriaxone treatment group, this value was not statistically significant. The rats which received no treatment developed scars whose expansion was proportionate to the expansion of the pyelonephritic involvement.

Compared to previous studies, in all infected rats, pyelonephritis was verified via DMSA and scar verified both DMSA and histopathologic examination. In accordance with the aforementioned studies, our results show that adding ketoprofen or methylprednisolone to ceftriaxone treatment declines scar formation in experimental pyelonephritis. Ceftriaxone treatment is not effective as ceftriaxone plus anti-inflammatory treatment to prevent renal scarring.

Ketoprofen is a nonsteroidal anti-inflammatory drug used for six-month and older infants as analgesic and antipyretic drug approved by Food and Drug Administration and promising good results when used as anti-inflammatory therapy to prevent renal scarring for febrile pyelonephritic children as well as antipyretic effect.

Our study is the first study that showed scar by both DMSA and histopathological examination. The results were consistent with the literature. We hope this information will have potential use in minimizing the renal scarring associated with pyelonephritis in children.

5. Conclusion

Our results provide ceftriaxone with ketoprofen OR methylprednisolone can effectively decrease cellular damage and prevent long-term complications in acute pyelonephritis.

In conclusion, the study showed both histopathologically and with DMSA renal scintigraphy in an experimental pyelonephritis model on rats that the addition of ketoprofen or methylprednisolone to ceftriaxone treatment decreases scar development. The study is the first in the literature in which pyelonephritis was proven by DMSA and pyelonephritic scar was shown both histopathologically and with DMSA. There are few studies on this topic in the literature and our findings are congruent with the literature.

Given the fact that the most common causes of pediatric end stage renal disease in Turkey that develop renal scars are mainly pyelonephritis, the importance of studies and attempts towards the prevention of scars in pyelonephritis is apparent. According to the findings of the study, the addition of ketoprofen or methylprednisolone to ceftriaxone treatment is seen as an intervention that will contribute to the realization of this aim. It is hoped that this study will pioneer the clinical studies to be conducted for the aim of preventing scar development.

Disclosure

Preliminary results of this study are orally presented in the 44th annually scientific meeting of ESPN, Dubrovnik.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

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Copyright

Copyright © 2014 Elif Bahat Özdoᇺn et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Difference Between Pyelitis and Pyelonephritis

Pyelitis and Pyelonephritis

Pyelitis and pyelonephritis are inflammatory diseases affecting the kidneys. Pyelitis is a condition which affects renal pelvis which is a part of the kidney and causes inflammatory changes in the lining of the renal pelvis. Pyelonephritis, in contrast, is an inflammation of the main renal tissue (parenchyma, calyces) and the renal pelvis.

Difference in causes:

Inflammation of the pelvis (pyelitis) is most commonly the result of infection by bacteria and the condition is usually short lived. It is often neglected, and thus spreads to the deeper tissues of the kidney affecting calyces and parenchyma which is then known as pyelonephritis. Pyelitis is commonly caused by a bacterial infection that spreads up the urinary tract beginning from the urethra. Urinary tract infection is the most common cause, produced by organisms such as E. coli. Other organisms such as pseudomonas and klebsiella may also cause urinary tract infections. Cases of Pyelonephritis start as a lower urinary tract infection, mainly cystitis or a bladder inflammation. Other causes of pyelonephritis include kidney stones that produce obstruction and stasis of urine outlet and act as a foci for infection urinary tract catheterization, structural abnormality in the urinary tract, vesicoureteral reflux which is the most common cause in children younger than 6 years (urine from the bladder flowing back into kidney), pregnancy, diabetes, enlarged prostate, cancer of prostate, neurogenic bladder, polycystic kidney, kidney tuberculosis causing renal tissue damage and recurrent urinary tract infection.

Difference in presentation:

Pyelonephritis is classified into acute pyelonephritis and chronic pyelonephritis. In acute pyelonephritis, there is a sudden localized inflammation of the renal pelvis and collecting tubules of the kidney and the kidney’s filtration function and the blood vessels are still preserved. Chronic pyelonephritis refers to long-standing infection due to recurrent kidney infections results in scarring of renal tissue and impaired kidney function.

Symptoms of pyelitis and pyelonephritis are similar but symptoms of pyelitis are less severe as compared to pyelonephritis. Common symptoms are pain while urination, burning pain while urination, blood in urine, cloudy urine with increased frequency of urination and decreased urinary output, associated with pain in the back at the renal angle, erratic pattern of fever with chills, nausea, vomiting , general malaise and weakness. Children may present with fever alone or associated with vomiting, convulsion, irritability, abdominal distension and weakness. Symptoms may develop over few hours to one day.

Diagnosis is generally based on history and medical examination. Urine analysis may show pus and blood cells with urine culture positive for bacteria. Ultrasonography and CT scan for kidney stones or structural abnormalities such as polycystic kidney or vesico-ureteric reflux. DMSA radionuclide scan is the most reliable test for diagnosis of acute pyelonephritis. Renal function tests might show increased levels of serum creatinine and blood urea nitrogen.

Treatment is the same for both and includes intravenous hydration, lots of water orally, antibiotics oral or intravenous. Choice of antibiotics depends on the organism and antibiotic sensitivity test performed on the urine culture. Antibiotics are given for 10 to 14 days. A surgery called as Percutaneous nephrostomy or a ureteral stent placement may be indicated to relieve obstruction caused by stone. In severe cases, nephrectomy that is removal of kidney is suggested.

Pyelitis is the inflammation of renal pelvis which is a part of a kidney from where the kidney empties into the ureter whereas pyelonephritis includes inflammation of the entire kidney. Signs and symptoms are generally same. The two conditions are generally caused due to an ascending urinary tract infection. Treatment includes antibiotic therapy along with lots of liquids to hydrate.


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Research output : Contribution to journal › Article › peer-review

T1 - Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis

N1 - Funding Information: This work was supported by the Office of Extramural Research, National Institutes of Health grants P50-DK064540 to D.A.H., T32-AI007172 to P.D.O. and F30-DK104446 to P.D.O. L.K.M. is supported by the Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study and a National Science Foundation Graduate Research Fellowship (DGE-1143954). Publisher Copyright: © 2017. Published by The Company of Biologists Ltd.

N2 - We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment. We recently published a novel mini-surgical bladder inoculation technique, with which male C3H/HeN mice develop robust ascending pyelonephritis, highly prevalent renal abscesses and evidence of fibrosis. Here, we devised and optimized an antibiotic treatment strategy within this male model to more closely reflect the clinical course of pyelonephritis. A 5-day ceftriaxone regimen initiated at the onset of abscess development achieved resolution of bladder and kidney infection. A minority of treated mice displayed persistent histological abscess at the end of treatment, despite microbiological cure of pyelonephritis a matching fraction of mice 1 month later exhibited renal scars featuring fibrosis and ongoing inflammatory infiltrates. Successful antibiotic treatment preserved renal function in almost all infected mice, as assessed by biochemical markers 1 and 5 months post-treatment hydronephrosis was observed as a late effect of treated pyelonephritis. An occasional mouse developed chronic kidney disease, generally reflecting the incidence of this late sequela in humans. In total, this model offers a platform to study the molecular pathogenesis of pyelonephritis, response to antibiotic therapy and emergence of sequelae, including fibrosis and renal scarring. Future studies in this system may inform adjunctive therapies that may reduce the long-term complications of this very common bacterial infection.

AB - We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment. We recently published a novel mini-surgical bladder inoculation technique, with which male C3H/HeN mice develop robust ascending pyelonephritis, highly prevalent renal abscesses and evidence of fibrosis. Here, we devised and optimized an antibiotic treatment strategy within this male model to more closely reflect the clinical course of pyelonephritis. A 5-day ceftriaxone regimen initiated at the onset of abscess development achieved resolution of bladder and kidney infection. A minority of treated mice displayed persistent histological abscess at the end of treatment, despite microbiological cure of pyelonephritis a matching fraction of mice 1 month later exhibited renal scars featuring fibrosis and ongoing inflammatory infiltrates. Successful antibiotic treatment preserved renal function in almost all infected mice, as assessed by biochemical markers 1 and 5 months post-treatment hydronephrosis was observed as a late effect of treated pyelonephritis. An occasional mouse developed chronic kidney disease, generally reflecting the incidence of this late sequela in humans. In total, this model offers a platform to study the molecular pathogenesis of pyelonephritis, response to antibiotic therapy and emergence of sequelae, including fibrosis and renal scarring. Future studies in this system may inform adjunctive therapies that may reduce the long-term complications of this very common bacterial infection.