- Pictorial Review
- Open Access
Chemotherapy-related complications in the kidneys and collecting system: an imaging perspective
© The Author(s) 2015
- Received: 19 January 2015
- Accepted: 16 June 2015
- Published: 11 July 2015
Nephrotoxicity is a common adverse effect of many chemotherapeutic agents. The agents most commonly associated with chemotherapy-associated nephrotoxicity are methotrexate, semustine, streptozocin, mithramycin, and cisplatin. Certain chemotherapeutic agents have adverse effects on the kidneys and urothelium that can be visualized radiographically, including cystic change, interstitial nephritis, papillary necrosis, urothelial changes, haemorrhagic cystitis, acute tubular necrosis, and infarction. This review focuses on imaging features identifying complications of chemotherapy in the kidneys and collecting system and provides didactic cases to alert referring clinicians.
• Nephrotoxicity is a common adverse effect of many chemotherapeutic agents.
• Chemotherapies have adverse renal and urothelial effects that can be visualized radiographically.
• Crizotinib use can result in the development of complex renal cysts.
- Biologic agents
- Renal cysts
- Drug-associated adverse effects
Table summarizing adverse effects in the kidneys and collecting system visible on imaging and associated cancer therapies
Complex renal cysts
US- Ovoid, anechoic cysts with clearly demarcated walls, no septa or calcifications, near water density
CT- Bosniak III-IV complex cysts
Urography- Enlarged kidneys, dense persistent nephrogram
FENa> 1 %
US- Enlarged kidneys
CT- Renal edema and enlargement, streaky parenchymal low-attenuation areas
Renal papillary necrosis
↑ Plasma creatinine
Urography- Irregular contour of the renal papillae and widening of the fornixes, “ball on a tee sign”
US- Multiple cystic spaces in the medullary region arranged around the renal sinus, non-shadowing soft tissue masses within the ureter
CT- Excavation of the calyces, regression of the papillae, blunting of the calyces, detached papillae in the ureter
↑ Lactate dehydrogenase
Urography- Absence of contrast material in infarcted parenchyma
Combination Cisplatin and Gemcitabine Regimens
US- Heterogeneity of parenchyma
CT- Low attenuation, wedge shaped areas in the cortex, “rim sign”
Acute tubular necrosis
Urography- Renal enlargement with prolonged opacification of the renal parenchyma, increase in density of the pyramids
US- Cortical echogenicity
CT- Contrast retention in the parenchyma, “rim sign”
↓ Urine osmolality
↓ Urine/plasma creatinine ratio
Urine sediment: renal tubular epithelial cells, epithelial cell casts, and muddy brown granular casts
Intravesical Mitomycin C
Urography- Small bladder with thickened walls, calcifications within the walls may be present
CT- Diffuse or focal irregular bladder wall thickening, decreased bladder volume and perivesical fat, edema
MRI- High T2 signal within the bladder wall
CT- Bladder wall thickening
Complex renal cysts
The development of complex renal cysts associated with crizotinib treatment is well documented in the literature. Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor used in the treatment of ALK positive metastatic non-small cell lung cancer (NSCLC). Lin et al. explored the presence of complex renal cysts in patients enrolled in prospective clinical trials for crizotinib treatment. In the 32 patients included in the study, 13 % developed new complex renal cysts and 22 % had significant renal cyst change following initiation of crizotinib treatment. After cessation of crizotinib treatment, the cysts were found to regress significantly . In a similar retrospective study, Schnell et al. reported that of 17 patients found with complex renal cysts associated with crizotinib use, 11 required hospitalization due to the cysts, with seven having cystic invasion into adjacent structures in the form of inflammatory cystic masses. The majority of patients were asymptomatic, but a small number presented with flank pain or fevers .
Urography cannot be used to definitively diagnose complex cysts as they present as indiscernible masses when this technique is used . Sonographically, cysts associated with crizotinib have been described as ovoid, anechoic with internal echoes, near-water density, with smooth clearly demarcated walls and acoustic enhancement behind the cysts, and without septa or calcifications . On ultrasound (US), diagnosis of cysts may be complicated by a number of factors. Vascular malformations or aneurysms could be mistaken for cystic disease if real-time studies do not demonstrate pulsations or large feeding vessels are not delineated. In addition, peripelvic cysts often contain artificially created echoes due to their proximity to structures of the collecting system and need to be confirmed on computed tomography (CT) .
Interstitial nephritis refers to inflammation of the renal interstitium. Histologically, this is characterized by interstitial infiltration by lymphocytes, monocytes, and granulomas. Symptoms may include oliguria and less commonly, hematuria. Patients may also have nonspecific symptoms of fever, rash, and loin pain, but in many cases patients are asymptomatic . Interstitial nephritis can be associated with a decline in creatinine clearance, eosinophilia, eosinophiluria, and proteinuria. Multiple chemotherapy regimens have been associated with interstitial nephritis, most notably ipilimumab. In ipilimumab-induced interstitial nephritis, patients are treated with prednisone and quickly return to their baseline kidney function .
Renal papillary necrosis
Renal papillae are present at the apex of the renal pyramid at the site where urine is discharged from the renal tubules. Papillary necrosis occurs secondary to ischemia and can be triggered by a number of factors, the most common ones being analgesic nephropathy, diabetes, sickle cell disease, and infection. Histologically, renal papillary necrosis (RPN) appears as coagulative necrosis, characterized by a pale centre with surrounding inflammatory cells . Symptoms of RPN most commonly include fevers, chills, flank pain, and hematuria. Sloughed papillae can cause ureteral obstruction and hydronephrosis, further worsening renal function. The platinum based agents, cisplatin and nedaplatin, are associated with RPN . Care needs to be taken in interpretation of this pathological outcome as it can be difficult to determine whether the cause is the chemotherapy itself or chronic analgesic use since cancer patients are often on powerful analgesic regimens.
Renal infarction presents with persistent pain often resistant to analgesia, nausea and vomiting, proteinuria, hematuria, and elevated lactate dehydrogenase . In the literature, it has been reported with use of methotrexate and combination regimens of cisplatin and gemcitabine [18, 19]. In a case series with 44 patients with long-term follow-up for renal infarction, 61 % of patients regained normal renal function while the remaining patients alive at follow-up had progressed to irreversible kidney dysfunction .
Acute tubular necrosis
ATN refers to acute renal failure caused by an ischemic or toxic insult to the tubular epithelial cells. This results in epithelial cell detachment from the basement membrane causing tubular dysfunction. It presents with a decrease in GFR, urine osmolality, and urine/plasma creatinine ratio. Urine sediment is characterized by renal tubular epithelial cells, epithelial cell casts, and muddy brown granular casts . ATN is associated with cisplatin and ifosfamide treatment [27, 28]. Patients may return to baseline kidney function following ATN; however, some patients develop an irreversible decline in function. Risk factors for permanent injury include age over 65 years, atheroembolic disease, and preexisting chronic kidney disease. ATN that develops in the hospital setting is associated with a high mortality rate [29, 30].
Effects of chemotherapeutic agents on cross-sectional imaging of the collecting systems
Chemotherapy-induced cystitis is characterized by epithelial proliferation following chemotherapy treatment. A study looking at 17 cases of both chemotherapy- and radiation-induced cystitis histologically characterized the cystitis as epithelial proliferation within the lamina propria with mild to moderate nuclear pleomorphism without mitoses. Pseudoinvasive urothelial nests wrapping around vessels, haemorrhage, fibrin, deposition, and acute and chronic inflammation were also present in all cases. All patients presented with hematuria with the presentation of symptoms occurring anywhere from mid-chemotherapy treatment to as far as 60 days following treatment cessation in patients with chemotherapy-induced cystitis. All patients available for follow-up at 9 months had an improvement in their hematuria and 71 % had negative cystoscopies at this time. No patients went on to develop bladder cancer . Chemotherapy cystitis is associated with intravesical use of mitomycin C .
Radiologic findings of chemotherapy-induced cystitis are nonspecific and cannot be distinguished from other causes of cystitis. On intravenous urography and cystography, the bladder may be small with thickened walls. Rarely, calcifications can be present within the wall . On CT imaging, acute chemotherapy-induced cystitis may present with diffuse or focal irregular bladder wall thickening, decreased bladder volume and perivesical fat, and oedema. Increased contrast enhancement of the bladder wall is not usually present . On MRI, there is high T2 signal intensity within the bladder wall, which is suggestive of inflammation . Increased signal intensity of the mucosa may also be seen on T1-weighted images and is likely attributable to mucosal haemorrhage .
Hemorrhagic cystitis is inflammation of the bladder that is characterized by mucosal hyperemia, ulcerations, haemorrhage, and necrosis. Symptoms consist of hematuria, frequency, dysuria, burning, urgency, incontinence, and nocturia . Hemorrhagic cystitis is highly associated with oxazaphosphorine compounds, especially cyclophosphamide and ifosphamide . Busulfan  and cabazitaxel  are also implicated. Mesna and continuous bladder irrigation and hyperhydration have been shown to be effective in preventing cyclophosphamide-induced hemorrhagic cystitis [42, 43]. Hemorrhagic cystitis caused by chemotherapeutic agents is generally reversible following cessation of the offending agent.
Cancer therapy has been moving in the direction of targeted therapies. As evidence surfaces for these novel agents, many are found to have renal toxicities. Antiangiogenic compounds such as bevacimumab, sunitinib, and sorafenib, which inhibit the VEGF pathway, are associated with proteinuria, increased levels of creatinine, and hypertension. MET inhibitors in phase II trials have also been found to be associated with proteinuria and hypertension. The EGFR inhibitors, erlotinib, cituximab, and gefitinib, and the HER2 inhibitors, trastuzumab and lapatinib, have not been associated with any renal toxicities.
Adverse effects associated with newer targeted agents visible radiographically include interstitial nephritis reported with sorafenib treatment and tubular necrosis reported with imatinib treatment .
Chemotherapy is vital in the treatment of cancer. However, its inherent toxicity often has unintended adverse effects. The kidney and collecting system are commonly involved due to their role in filtration and elimination. Chemotherapy can cause various changes including complex renal cysts, interstitial nephritis, urothelial irritation, acute and chronic tubular necrosis, and renal infarction, among others. Aside from complex renal cysts associated with crizotinib use, the pathologies elaborated on in this manuscript are often symptomatic and can negatively impact renal or collecting system function. Therefore, if imaging suggestive of these pathologies arises, renal function tests need to be performed and regimens adjusted accordingly. With complex cysts secondary to crizotinib use, regression occurs spontaneously following treatment. However, if patients are symptomatic or if invasion into surrounding structures is noted on imaging, then further evaluation and medication adjustments need to be made. Familiarization with imaging features consistent with post-chemotherapy changes to the kidneys and urothelium and subsequent recognition and reporting will improve clinical monitoring of patients, early detection of chemotherapy-associated complications, and will ultimately result in improved patient care and outcomes through modification, interruption, or suspension of therapy.
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