Most commonly, encrusted uropathy is encountered in patients with predisposing conditions [Table 1; (3–6)], but a rare case has been described in a patient without apparent underlying risk factors (7).

While encrusted cystitis was first described in 1914 (1), the first cases of encrusted pyelitis were reported only 80 years later, in renal transplant recipients (8). These patients are more frequently affected than the general population because they often present a combination of predisposing factors comprising immunosuppressed status, long-term hospitalization, frequent antibiotic treatment, bladder and ureteral catheterization and a history of urological procedures, which may have led to the formation of fistulas, lymphoceles, and urethral or ureteral damage or stenosis. Particularly surgical reinterventions and long-term (>1 month) vesical and ureteral catheterization have been identified as important risk factors for the development of encrusted uropathy in this population (9, 10).

The incidence of encrusted pyelitis (EP) and encrusted cystitis (EC) in renal transplant recipients is estimated at 0.26–2.13% and 0.61%, respectively (9, 11), the time between renal transplantation and the diagnosis of encrusted uropathy ranging from 5 to 84 months with a mean of 24 months (9). Incidence rates of EC and EP in non-transplant patients are unknown. Although the condition remains rare, the number of reported cases has increased during the last three decades and is likely to augment even further due to increasing numbers of urological procedures, urological instrumentation and renal transplantation in older and more debilitated patients, as well as the increasing use of immunosuppressive therapies. Additionally, the detection and identification of Corynebacterium urealyticum (CU), the main causative agent of EC and EP has improved substantially, resulting in an increased reporting of CU bacteriuria, symptomatic urinary tract infection and encrusted uropathy. Actually, Sánchez-Martin et al. (5) described a 300% increase in positive CU urine cultures between 2009 and 2014.

CU is a skin commensal, colonizing 25% of hospitalized and 37% of institutionalized patients and is mainly detected in the groin area (15). Women are more frequently colonized than men (43 vs. 18%). In the normal population the cutaneous colonization rate is 0–12% (16–18). CU colonization and subsequent infection is hence predominantly hospital-acquired, with bacterial spread between patients by direct contact or airborn (19). One report even described a nosocomial outbreak in 15 patients (20). Two large case series reported 78–100% of CU bacteriuria cases to be hospital-acquired (3, 4), with time between hospital admission and bacteriuria ranging from 4 days to 6 months with a mean of 27 days (3). Skin colonization is hypothesized to be facilitated by the use of broad-spectrum antibiotics, after which urological procedures promote introduction of CU in the urinary tract. The bacterium has a special tropism for the urinary tract with strong adherence to the urothelium (21), urinary and nephrostomy catheters (22, 23), easy penetration and embedment in the mucosa (3) and biofilm formation (24, 25). In fact, in 71% of patients with positive CU urine culture, the same bacterial strain can be detected in inguinal skin culture (16), with identical antibiotic resistance patterns in skin and urinary isolates (16, 26). In a series of renal transplant recipients, skin colonization was reported as an independent risk factor for the development of CU bacteriuria (27). Additionally, hospitalization and its associated antibiotic use drive the development of antibiotic resistance (26).

The prevalence of CU bacteriuria depends on the population screened and the culture media used. In non-selected populations using non-selective media, prevalence rates of 0.04–0.20% have been reported, while the use of selective media increases the rate to 1.17% (28, 29). In selected populations detection rates augment even further, with a reported prevalence of 1.32% in hospitalized patients using non-selective media, compared to 4.64% using selective media (30). The highest rates have been described in renal transplant recipients: 1.8–10.0% vs. 9.8% with the use of non-selective media and selective media, respectively (9, 27). In one series, CU bacteriuria accounted for 3.8% of all positive urine cultures (4).

With men accounting for 55–76% of positive CU urine cultures (3–5, 16), CU bacteriuria has a clear male predilection, in contrast to CU skin colonization rates (15), likely reflecting the higher frequency of urological procedures and manipulations in males. The mean age of patients developing CU bacteriuria is 58–68 years (3–5, 16) and risk factors include prolonged hospitalization, reported in 73–75% of patients, previous urological disease in 50–64%, urological manipulation in 55–83% (bladder catheterization in 55–77%), previous urinary tract infection in 42–61%, immunosuppressed status in 27–41%, chronic debilitating disease in 48–52% and antibiotic use during the previous 3 months in 73–93% (3, 4, 16, 21). In a series of renal transplant recipients, other than CU skin colonization, independent risk factors for the development of CU bacteriuria were antibiotic treatment in the previous month and history of nephrostomy (27).

Spontaneous eradication of CU from the urine has been reported in 35–41% of patients (3, 16), while in another series 15% of patients showed resolution after vesical catheter change (4). Fifty-two to seventy-six percent of patients with positive urine culture, however, develop symptomatic urinary tract infection, comprising acute and chronic cystitis, chronic prostatitis, and pyelonephritis (3, 4, 16, 31). A case of renal cyst infection has been described (32).

Although the bacterium mainly causes urinary tract infections, CU has also been described as the rare cause of wound and soft tissue infections (31, 33–35), osteomyelitis and orthopedic device-related infections (35, 36), bacteremia (34, 37–43), pneumonia (44), pericarditis (45), endocarditis (46), mediastinitis (41), and peritonitis (40), mainly in patients with underlying urological disease or other risk factors. While CU previously was considered as a non-pathogenic commensal, the bacterium is now clearly recognized as a cause of significant urinary tract and other infections. In fact, urinary presence of CU even if colony-forming units (CFU) < 100,000/mL should always be considered as pathological.

In 4–16% of patients with CU bacteriuria, encrusted urological disease develops (3–5, 16, 27). This occurs mainly in those with a suitable urothelial environment [“vesical ground” (29)], damaged by inflammation, malignancy, ischemia or urological instrumentation, creating an ideal territory for struvite encrustations. The time between urological instrumentation or intervention and diagnosis of encrusted urological disease can range from a few days to 3 years (18). Again, a male predominance (66–75%) has been reported in most series of encrusted uropathy (4, 9), with a mean age of 50–71 years (4, 9).

The pathogenic role in struvite (magnesium ammonium phosphate, NH₄MgPO₄.6H₂O) formation has been demonstrated in vivo and in vitro for CU (47) and for other urease-producing bacteria like Ureaplasma urealyticum (48, 49) and Proteus vulgaris (47). Struvite formation is primarily caused by the bacterial urease activity (50), which generates a high urinary pH, a requisite for struvite production [Figure 1; (51)]. Elliot et al. (52) described a minimum urinary pH of 7.1 to be required for pathogenesis, although lower values have been described in some patients with encrusted uropathy (5) and struvite urolithiasis (53). Actually, urease hydrolyses urea to CO₂ and ammonia (NH₃), resulting in alkaline urine due to its binding with H⁺ ions resulting in the formation of ammonium (NH4+). The high urinary pH favors the conversion of CO₂ to bicarbonate with subsequently carbonate formation and facilitates the supersaturation of magnesium ammonium phosphate and carbonated apatite [carbapatite, Ca₁₀(PO₄)₆CO₃], leading to struvite and carbonated apatite crystal formation, which can cause free stone formation and/or urothelial encrustations. In the presence of hyperuricosuria, ammonium urate can be formed as well. Increased urinary pH, increased ammonium concentration, decreased urea concentration and struvite crystal formation occur as quickly as 24 h after incubation of the urine with CU and even as fast as 7 h after incubation with Proteus vulgaris in experimental models (47). Additionally, the increased ammonium concentrations cause cytotoxic damage to the protective mucosal glycosaminoglycan layer, expediting strong urothelial bacterial adherence, inflammation and crystal deposition (54). As opposed to carbonated apatite, which can be formed by other lithogenic processes, the presence of struvite is pathognomonic for infection with urease-producing bacteria.

The complete genome of 2 CU strains has been sequenced (55, 56), providing insight into the pathogenicity of CU (57). Its strong urease activity might be promoted by the absence of potential transcription regulator genes at the urease gene locus, located at cluster ureABCEFGD. Biofilm formation is presumed to be regulated by surA and surB genes which encode for cell surface proteins. It is assumed that urothelial adherence occurs through a surface-anchored proteinaceous pilus, encoded by genes at the SpaDEF cluster. Additionally, the rpfC gene is implicated in the resuscitation of inert bacteria and the proliferation of non-dormant, viable bacteria. Finally, horizontal gene transfer of resistance genes located on mobile genetic elements has been reported to be the primordial cause of antibiotic multiresistance.

Strong immunohistochemical staining of the osteogenic markers osteocalcin, osteonectin and osteopontin on affected bladder tissue which disappeared after treatment, has been described in a case of EC, suggesting the involvement of an osteogenic process in the pathogenesis of encrusted uropathy (58). Additionally, the implication of osteopontin in the adhesion of calcium oxalate crystals to renal epithelial cells has been reported (59). Its potential role in urothelial struvite crystal adhesion has not yet been examined.

Abdominal X-ray may reveal urinary tract calcifications, mainly of the bladder, but thin and occasionally radiolucent encrustations (72) are frequently missed. Accompanying staghorn calculi may be visualized. Just like for abdominal X-ray, the sensitivity for diagnosing encrusted uropathy is limited for ultrasound. In EC, thickening or irregular lining of the bladder with calcifications may be visualized while in EP hyperechogenic material in the collecting system, sometimes in association with staghorn stones, can be found. Uni- or bilateral ureterohydronephrosis can be detected. Non-enhanced CT-scan of EP shows calcifications of the renal collecting system, detected as high-density lesions, ranging from regular, thin, linear calcifications to edgy, bulky, irregular plaques. Micro-abscesses and free stones can be present. Urinary tract wall thickening, perinephric and/or periureteral inflammatory fat stranding and unilateral or bilateral ureterohydronephrosis may be demonstrated. In EC, a thickened, edematous bladder mucosa with encrustations and necrosis may be detected. Non-enhanced CT-scan has a high sensitivity and specificity and is the gold standard imaging modality for diagnosing encrusted uropathy (72) and is particularly useful for diagnosing EP (Figure 3).

Cystoscopic examination typically reveals a fragile, inflammatory, or hemorrhagic mucosa with ulcerations covered with white to yellow-tanned fragile encrustations. Vesical edema may impair the visualization of the ureteral orifices. The encrustations, which may resemble neoplastic lesions, may vary in size and adherence to the urothelium, ranging from small superficial fragments to large calcified encrustations deeply embedded in the bladder mucosa and are predominantly found at the trigone, ureteral orifices, bladder neck and sites of previously damaged urothelium. In EP, endourological examination can demonstrate calcified encrustations sometimes extremely closely adhered to the renal collecting system and ureters with accompanying mucosal inflammation (73). Associated staghorn stones may have a glue-like consistency (74).

Macroscopically a kidney affected by EP shows clear urothelial thickening with closely adherent, superficial calcifications (72). Parenchymal abscesses can be present. In EC, the bladder mucosa can show a thin layer of fibrin mixed with calcified necrotic debris.

Microscopic histopathological examination of tissue affected by EC/EP typically reveals 3 distinct layers (3, 9, 18). The first superficial layer consists of ulceronecrotic urothelial tissue with calcified encrustations (Figure 4) which can be demonstrated by Von Kossa stain. In zones of non-affected urothelium, there is an increased cellularity with occasionally development of degenerative lesions like squamous metaplasia. A second layer, located at the lamina propria, reveals an edematous, inflammatory infiltrate with presence of lymphocytes, plasmacytes and polymorphonuclear cells, forming a thick conglomerate, sometimes leading to granuloma formation. Occasionally eosinophils, mastocytes, fibroblasts, and histiocytes can be found. Small blood vessels are subject to thrombosis, causing necrotic areas at the superficial layer, creating a nidus for crystal deposition. Ischemia and inflammation also trigger neovascularization with increased vascular proliferation. Microabcesses with bacterial microcolonies can be present. The third and most peripheral layer corresponds to the muscularis. It usually has normal histological findings but can be the site of secondary fibrotic changes. There is very scarce knowledge about the renal parenchymal histopathological changes caused by encrusted uropathy. Severe chronic damage due to chronic pyelonephritis may be observed (Figure 5). In one case, cast formation with severe tubular damage and interstitial nephritis was described (75).

Microbiological detection of CU is difficult, as it is a slow-growing bacterium for which prolonged incubation (during 48–72 h) in 5% CO₂ on blood agar or cysteine lactose electrolyte deficient agar or on selective, enriched media is required, while conventional urine cultures generally are discarded if negative after 24 h of incubation. Initially negative conventional urine cultures with pyuria should hence raise the suspicion of encrusted uropathy and prompt the use of enriched culture media and/or prolonged incubation time, especially if struvite crystals can be detected or if the urine is alkaline.

If selective media, enriched with antibiotics impairing the growth of normal urine flora, are used, there is a 4–31 times higher urinary CU detection rate compared to the use of non-selective media (27, 28, 30). Frequently used selective media are those enriched with fosfomycin, aztreonam, polymyxin B, and amphothericin B (27, 30), those enriched with ticarcillin, fosfomycin, cefotaxime, and 5-fluorocytosine (16, 28) or those enriched with colistin and aztreonam. Rare cases of CU bacteriuria detected by conventional media but missed on selective media in case of beta-lactam sensitive strains have been described (16, 28).

Depending on the media used, simultaneous detection of other more easily identifiable bacteria has been reported in 6–57% of CU bacteriuria cases (4, 16, 27, 30). Additionally, CU can be cultured from bladder mucosa, encrustations, debris, or kidney stones (6, 16).

The bacteria grow as small whitish, opaque, smooth, convex, circular, non-motile and non-hemolytic colonies, which could traditionally be identified as CU with biochemical methods based on its urease activity and its lipophilic and asaccharolytic qualities (76). Additionally, they are catalase-positive, oxidase-negative, and nitrate-negative. Currently, however, identification of cultured bacteria is performed by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF) (77), based on the bacterial protein composition. Although improvements have been made during the last decades, culturing and correct identification of CU remains challenging. Currently, molecular techniques like polymerase chain reaction (PCR) amplification and 16S rRNA gene sequencing (78, 79), RNA polymerase beta-subunit-encoding (rpoB) gene sequencing (80) and restriction fragment length polymorphism (81) are available for its detection and identification.

Alternatively, the involvement of urease-producing bacteria can be confirmed by the discovery of struvite crystals during crystalluria examination, which are detected frequently in patients with encrusted uropathy (4, 9, 29, 62). The detection of struvite crystals is pathognomonic for the presence of urease-producing bacteria but not for encrusted uropathy, as 27–70% of patients with CU bacteriuria without encrusted uropathy also have detectable struvite crystals (3, 4, 16, 27). Carbonated apatite crystals can also be observed (16) but are, as opposed to struvite crystals, not pathognomonic for the presence of urease-producing bacteria.

Chemical, crystallographic, or infrared spectrophotometric analysis of encrustations or kidney stones reveals the predominant presence of struvite (30–85%) and carbonated apatite (10–35%), accompanied by some minor compounds like ammonium urate, calcium oxalate, proteins, amorphous calcium phosphate, or uric acid (16, 73, 74, 82). In an experimental model, Ureaplasma urealyticum infection not only produced struvite but also whitlockite crystals (Ca₉(Mg,Fe²⁺)(PO₄)₆PO₃OH) (48), a component associated with infection-associated nephrolithiasis (83), but not yet described as a compound of encrustations in human encrusted uropathy.

Table 2 provides an overview of the conditions to be considered in the differential diagnosis of encrusted uropathy.

CU is an extremely multi-resistant bacterium, with complete bacterial eradication being hampered additionally by biofilm formation (24) and viability of residual bacteria within encrustations and stones. The recommended antibiotics are the glycopeptides vancomycin and teicoplanin (17, 84–86), to which the bacterium is uniformly sensitive and whose efficacy is not influenced by the urinary pH (87). Vancomycin should be administered intravenously with recommended trough levels 25–30 mcg/mL with continuous infusion and 15–20 μg/mL with intermittent administration. The possibility of intramuscular administration of teicoplanin can ensure long-term antibiotic treatment at home and limit the duration of hospitalization. Recommended dosing for intravenous and intramuscular teicoplanin is a loading dose of 1.6 g on the first day of treatment, followed by approximately 800 mg daily for through levels >30 μg/mL. Additionally, CU is consistently sensitive to linezolid (86, 88). There is a variable activity of quinolones, with fewer resistant strains with the use of the newer quinolones, although increasing resistance has also been demonstrated with use of the latter (26, 85, 89, 90). Additionally there is a variable activity of tetracyclines (26, 84, 85) and rifampin (26, 43, 84) and a reasonable activity of fusidic acid (43, 84, 91). CU is however highly resistant to penicillins, cephalosporins, carbapenems, lincosamides, aminoglycosides, macrolides, ketolides, sulphonamides, nitrofurantoin, fosfomycin, chloramphenicol, and trimethoprim-sulfamethoxazole (24, 40, 84–86, 92).

In order to fully eradicate the infection, the encrustations should be completely removed, which frequently requires repeated urological interventions. In EC, removal of encrustations can be performed by transurethral resection, although vesical edema may complicate the procedure. In cases of prostatic involvement repeated transurethral resection of the prostate (TURP) is often necessary. In EP, extracorporeal lithotripsy is not efficacious due to close urothelial adherence of the encrustations. For the same reason and due to fibrosis and edema, endourological treatment with fragmentation of encrustations is frequently difficult and should be performed with extreme caution, as it might be complicated by hemorrhage. Additionally, the development of ureteral stenosis might complicate an endourological approach. A surgical or percutaneous approach for the treatment of EP can be considered but again may be strenuous and complicated by renal hemorrhage (73). In cases where urological removal of encrustations is incomplete, impossible or considered too hazardous, a conservative approach can be considered by means of urinary acidification in combination with prolonged antibiotic therapy (61).

Urinary acidification removes residual encrustations and inhibits further encrustation formation by preventing struvite and carbonated apatite supersaturation. At urinary pH < 5.5 the solubility of struvite increases significantly (93). Acidification of the urine can be performed by oral compounds or local acidification solutions. Many oral acidification formulas have been proposed and tested in experimental models (48, 94–103), but the most efficacious and the most commonly used compound in clinical practice is acetohydroxamic acid. With a molecular structure resembling urea, acetohydroxamic acid irreversibly inhibits urease, leading to increased urea concentration, reduced ammonia concentration and reduced urinary pH, hence preventing struvite crystal formation (104). Additionally, some minor bacteriostatic activity has been described (87, 104). In encrusted uropathy the available evidence is limited to case reports and case series, but in infection-induced nephrolithiasis, the efficacy of acetohydroxamic acid on stone growth reduction has been demonstrated in three randomized double-blind placebo-controlled trials (105–107). Adverse events, however, develop frequently, in 45–78% of patients, requiring cessation of therapy in 10–22% (105–107). The most frequently encountered side effects are nausea, psychoneurological symptoms like tremor and headache and musculocutaneous symptoms including myalgia, leg swelling, rash and alopecia, which all resolve upon dose reduction. Additionally, thrombophlebitis and haemolytic anemia, reversible upon temporary withdrawal of the therapy and occurring more frequently with daily dosage ≥1,500 mg and in patients with renal insufficiency, have been reported (105, 107, 108). For this reason, the recommended dosage of acetohydroxamic acid of 15 mg/kg should not exceed 1,000 mg daily, its use is contraindicated in severe renal insufficiency (serum creatinine > 3 mg/dL) and dosage reduction should be implemented in mild and moderate renal insufficiency. Close monitoring of all patients is highly recommended. Additionally, the compound is proven to be teratogenic in animals (109, 110), requiring effective contraception in females of childbearing age. Alternatively, although less effective, propionohydroxamic acid (111, 112), ammonium chloride (6, 113), vitamin C (11), cranberry juice (75), and hydroxyurea (114) have been used as oral acidifying agents. Finally, the effectiveness of l-methionine for long-term oral urinary acidification has very recently been reported in one case of encrusted uropathy by Sabiote et al. (115).

Oral urinary acidification can be sufficient in cases of limited and thin encrustations. If encrustations are extensive, additional topical acidification is necessary, especially at the start of treatment. Many solutions have been used (5, 6, 11, 18, 116–118), sometimes in association with topical antibiotics (3, 5). The use of 10% hemiacidrin solution has been prohibited by the FDA in the past after the reports of 6 deaths, probably due to urosepsis. Currently, the most frequently used solutions are Suby-G solution (citric acid 32.3 g, sodium carbonate 4.4 g, magnesium oxide 3.8 g, distilled water 1,000 mL) and Thomas' C24 solution (sodium gluconate 27 g, citric acid 27 g, malic acid 27 g, distilled water 1,000 mL) (18). Besides their acidifying capacities (the approximate pH of these solutions is 4), which increase the solubility of struvite, these solutions have bactericidal properties and can induce calcium citrate complex formation with subsequent prevention of struvite and carbonated apatite crystal formation. Continuous bladder acidification can be performed through a 22F 3-way Foley catheter or through a suprapubic catheter with outflow through a 2-way Foley catheter in EC. In EP, irrigation with an acidifying solution can be accomplished through a percutaneous nephrostomy catheter with outflow through ureteral and bladder catheters or through a secondary nephrostomy catheter. An aseptic technique should be used to prevent infection. In order to limit pain and intraparenchymal solution diffusion, precautionary measures should be taken: free inflow and outflow of the solution should be maintained, the daily amount of applied irrigation fluid should be limited to 1–2 L and the intrapelvic pressure should be <25 cm H₂O (61), for which the height of the irrigation fluid container in relation to the patient should be carefully determined. It is recommended to start the irrigation at 10–20 mL/h and to increase the irrigation rate to a maximum of 50 mL/h according to the patient's tolerance. In general, topical acidification is well-tolerated, although pain, mild metabolic acidosis, fungal urinary tract infection, low-grade fever and pelvic edema can develop (61, 73). Additionally, there is a risk of hypermagnesemia due to Suby-G application. A recent case reported the use of intravesical dimethylsulfoxide, a weak acid with anti-inflammatory action which has been approved for interstitial cystitis and painful bladder syndrome, as add-on to transurethral removal of encrustations in the treatment of encrusted cystitis (119).

The optimal duration of treatment is not well established but depends on the severity of the encrustations and the condition's evolution under treatment. Mostly several weeks to a few months of treatment is necessary. Urological treatment of encrustations and urinary acidification should always be preceded by antibiotic treatment. Oral acidification can be sufficient in case of thin or few residual encrustations, while topical acidification is necessary in case of large encrustations, especially in the beginning of the treatment, which later can be switched to oral acidification when only small encrustations are remaining. In case of renal insufficiency with serum creatinine > 3 mg/dL, oral acidification is contraindicated. Monitoring of the efficacy of treatment and treatment duration determination is performed by repeated CT-scan, urine cultures, urinary pH testing and crystalluria examination. Treatment with antibiotics and urinary acidification should continue until there is complete resolution of encrustations on imaging, disappearance of struvite crystals, normalization of urine pH and sterilization of the urine.