Pyuria Without Casts And Bilateral Kidney Enlargement Are Probable Hallmarks Of Severe Acute Kidney Injury Induced By Acute Pyelonephritis: A Case Report And Literature Review Ⅱ

Discussion 

We experienced a rare case with APN-induced severe AKI that was confirmed by kidney biopsy. Mild AKI from inflammation-related hemodynamics is common in APNs and resolves quickly with treatment. 

However, severe AKI in the absence of coexisting urinary tract obstruction is rare (5). Our case involved a middle-aged man who presented with constitutional symptoms and who was using NSAIDs; his renal function worsened 24 hours after antibiotic therapy with sufficient hydration. Thus, we thought that other causes of AKI (besides APN-induced AKI) should be considered since it has been reported that APN patients without urinary tract obstruction tend to improve within 24 to 48 hours after antibiotic therapy (5).

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The characteristics of adult cases with severe AKI caused by APN without urinary tract obstruction, single kidney, or chronic kidney disease (CKD), that were reported in the relevant English literature from 1969 to 2019 are shown in Table (6-24). Severe AKI was defined as KDIGO stage 2 or 3. However, the AKI stage could not be confirmed due to the limited data that were available in some cases. APN-induced AKI was proven by histopathology or by clinical course with antibiotic therapy. A total of twenty-six cases (T-group) were reported over the approximately 50-year period. Among them, 19 cases were histopathology-proven (H-group). The incidence of AKI stage 3 (serum creatinine  4.0 mg/dL or renal replacement therapy) (2) was 84.6% in the T-group and 89.4% in H-group. Female patients accounted for 61.5% of the patients in the T-group and 63.1% of the patients in the H-group. The mean ages were 53.8 years in the T-group and 55.1 years in the H-group. The analysis of available data showed that the incidence of oliguria was 46.1% in the T-group and 52.5% in the H-group. The rates of pyuria, which was defined as a urine WBC count of >5/high-power field or dipstick positivity for leukocyte esterase (25), and the absence of pathologic casts were 73.0%/78.9% in the T-group and 57.6%/ 68.4% in the H-group, respectively. The incidence of bilateral kidney enlargement on imaging was 61.5% in the Tgroup and 68.4% in the H group. Urine and/or blood were positive for E. coli in 73.0% of the patients in both groups. Both blood and urine were positive for Klebsiella in 15.3% of the patients in the T-group and 21.0% in the H-group. Pregnancy, indwelling catheter, immunocompromised status, and nonsteroidal anti-inflammatory drug (NSAID)/analgesic use were reported as predisposing factors. 

NSAIDs were used in 30.7% of cases in the T-group and 26.3% of the cases in the H-group. A total of 38.4% of the cases in the T-group and 36.8% of the cases in the H-group recovered from AKI; 38.4% of the cases in the Tgroup and 31.5% of the cases in the H-group showed improvement of AKI but developed CKD; 11.5% of the cases in both groups became dialysis-dependent; and 11.5% cases in both groups died. Accordingly, the key characteristics of APN-induced AKI were pyuria without casts and bilateral kidney enlargement. Bilateral kidney enlargement may be caused by interstitial infiltration, edema, and pus casts in the tubules of both infected kidneys. Oligoanuria was frequently associated. NSAID use is a possible risk factor for APN-induced severe AKI. However, the causal relationship between NSAID use and APN-induced severe AKI is not known. NSAIDs can delay the presentation of APN patients due to the temporary alleviation of pain and fever, and thus delay appropriate management. In addition, NSAIDs can reduce the glomerular filtration rate, contributing to the development of APN-induced severe AKI. Our case featured characteristics of APN-induced severe AKI, including NSAID use, oliguria, pyuria without casts, and bilateral kidney enlargement. We did not perform screening for human immunodeficiency virus (HIV) infection, because he did not show any history, symptoms, or laboratory abnormalities suggesting HIV infection. Except for NSAID use, he did not have any other reported predisposing factors for bilateral APN. Interestingly, he was taking tizanidine hydrochloride, a muscle relaxant, that affects the bladder skeletal muscle function, and which can be used to treat bladder dysfunction in patients with multiple sclerosis spasticity (26). There have been no reports of tizanidine-associated APN; however, the present patient should be carefully followed up for symptoms, including overactive bladder.

Some of the abovementioned features of APN-induced severe AKI seem to resemble other causes of AKI, including AIN, acute tubular necrosis (ATN), and rapidly progressive glomerulonephritis (RPGN). All of these conditions can cause AKI with bilateral kidney enlargement (27, 28). The common clinical manifestations of AIN are nonspecific, including asthenia, anorexia, nausea, and vomiting. Laboratory data show AKI with or without oliguria, microscopic hematuria, non-nephrotic proteinuria, and pyuria (29, 30). Unlike APN, AIN can be associated with WBC casts and non-pigmented granular casts in urine (29). Patients with ATN also present with nonspecific clinical symptoms. Unlike APN, pigmented "muddy brown" granular casts or tubular epithelial cell casts, usually with microscopic hematuria and mild proteinuria, are found. However, casts can be absent (29). Patients with RPGN due to crescentic glomerulonephritis show loin pain, which is not uncommon (31). Leukocytosis, anemia, and elevated inflammatory marker levels are usually found. A urinalysis reveals modest proteinuria, microscopic hematuria, and RBC and WBC casts, unlike APN. Pyuria is also a common urine finding (32). Rarely, urine findings may be minimal, and the absence of active urine sediment does not exclude a diagnosis of RPGN. The rate of progression to renal failure is variable, ranging from hours to months.

When the characteristics of AIN, ATN, and RPGN are compared, pyuria without pathological casts may be a hallmark of APN-induced severe AKI. Isolated pyuria is unusual since inflammatory reactions in the kidney or collecting system are also associated with hematuria. The presence of WBCs with bacteria is indicative of pyelonephritis. However, if patients have used medicines, such as NSAIDs, which can induce AIN or ATN (33, 34), it is difficult to discriminate drug-induced AKI from APN-induced AKI, as in our case. Moreover, in AKI patients with constitutional symptoms and nonspecific urinalysis results, the possibility of RPGN cannot be excluded. A definite diagnosis of APN-induced AKI requires a kidney biopsy. However, in certain patients, kidney biopsy cannot always be smoothly and quickly performed due to illness. If AKI patients have infectious signs, pyuria without casts, and bilateral kidney enlargement, after starting antibiotic therapy and withdrawing suspected medicines, a kidney biopsy can be postponed until other information, including the results of PRGN-related laboratory data and the efficacy of antibiotic therapy over another several days, can be obtained. In summary, the key characteristics of APN-induced severe AKI include bilateral kidney enlargement with pyuria without casts. Oligoanuria was frequently associated with APN-induced severe AKI, and NSAIDs may be a possible risk factor. Prompt antibiotic treatment based on the clinical characteristics of APN-induced AKI is essential to improve renal outcomes.

References 

1. Czaja CA, Scholes D, Hooton TM, Stamm WE. Population-based epidemiologic analysis of acute pyelonephritis. Clin Infect Dis 45: 273-280, 2007. 

2. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2: 19-36, 2012. 

3. Iványi B, Ormos J, Lantos J. Tubulointerstitial inflammation, cast formation, and renal parenchymal damage in experimental pyelonephritis. Am J Pathol 113: 300-308, 1983. 

4. Piccoli GB, Consiglio V, Colla L, et al. Antibiotic treatment for acute 'uncomplicated' or 'primary' pyelonephritis: a systematic, 'semantic revision'. Int J Antimicrob Agents 28 (Suppl1): S49-S 63, 2006. 

5. Johnson JR, Russo TA. Acute Pyelonephritis in Adults. N Engl J Med 378: 48-59, 2018. 

6. Bailey RR, Little PJ, Rolleston GL. Renal damage after acute pyelonephritis. Br Med J 1: 550-551, 1969. 

7. Trivedi HL, Kumar S, Minielly JA. Renal cortical microabscesses as the cause of reversible acute renal failure. Urology 9: 177-179, 1977. 

8. Adler SN. Nonobstructive pyelonephritis was initially seen as acute renal failure. Arch Intern Med 138: 816-817, 1978. 

9. Baker LR, Cattell WR, Fry IK, Mallinson WJ. Acute renal failure due to bacterial pyelonephritis. Q J Med 48: 603-612, 1979. 

10. Olsson PJ, Black JR, Gaffney E, Alexander RW, Mars DR, Fuller TJ. Reversible acute renal failure secondary to acute pyelonephritis. South Med J 73: 374-376, 1980.