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Background: Crizotinib, an oral first-generation tyrosine kinase inhibitor (TKI), is superior to systemic chemotherapy for the treatment of non-small cell lung cancer (NSCLC) with positive rearrangement of anaplastic lymphoma kinase (ALK). However, an increased incidence of renal and hepatic cysts has been reported in the patients on crizotinib treatment., Case Presentation: Here, we describe a case of a 71-year-old Chinese women developed multiple cystic lesions in kidney and liver during crizotinib treatment for the primary and metastatic NSCLC. The renal and hepatic cysts were noted by CT scan 3 months after crizotinib treatment, which were spontaneously and significantly regressed after stopping crizotinib., Conclusions: Based on literature review and our experience in this case report, we concluded that crizotinib-associated renal cyst (CARCs) has features of malignancy and abscess in radiographic imaging, and thus, pathological confirmation is necessary to avoid inappropriate treatment decision. In addition, to benefit the patients with progress-free survival (PFS), switching from crizotinib to alectinib is recommended for the treatment of NSCLC patients who developed CARCs., (© 2024. The Author(s).)

The oral small-molecule tyrosine kinase inhibitor (TKI), crizotinib has been approved as a first-generation anaplastic lymphoma kinase (ALK) inhibitor in treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). Recently, development of complex renal cysts has been reported with crizotinib usage, highlighting the importance of accurate differentiation between complex renal cysts and new metastasis in NSCLC. Here we describe a case study with confirmed EGFR wild-type and ALK-rearranged lung adenocarcinoma who developed complex renal cysts combined with hemorrhage during crizotinib treatment, with no abnormal clinical symptoms or kidney functions observed. Interestingly, without crizotinib treatment termination or reduction, the complex hemorrhagic renal cysts regressed with self-limiting and healing. The combined usage of ultrasound, CT and MRI techniques in the presented case allowed proper monitoring of the internal changes within complex renal cysts. The patient provided written informed consent authorizing publication of clinical case. Thus, better understanding of the imaging features of crizotinib-related renal cysts combined with hemorrhage would avoid misdiagnoses as a new metastatic renal mass or the aggravation of the primary disease, therefore avoiding further invasive investigation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Crizotinib is highly effective against anaplastic lymphoma kinase-positive and c-ros oncogen1-positive non-small cell lung cancer. Renal dysfunction is associated with crizotinib therapy but the mechanism is unknown. Here, we report a case of anaplastic lymphoma kinase positive non-small cell lung cancer showing multiple cysts and dysfunction of the kidneys during crizotinib administration. We also present results demonstrating that long-term crizotinib treatment induces fibrosis and dysfunction of the kidneys by activating the tumor necrosis factor-α/nuclear factor-κB signaling pathway. In conclusion, this study shows the renal detrimental effects of crizotinib, suggesting the need of careful monitoring of renal function during crizotinib therapy.

Crizotinib, which is effective in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer, is sometimes associated with the generation of complex renal cysts. A 56-year-old man with ALK positive adenocarcinoma received crizotinib. Ten months after the introduction of crizotinib, a cystic lesion developed from his right kidney to the iliopsoas muscle, accompanied by fever, anemia, and hypoproteinemia. After 17 months of treatment, crizotinib was switched to alectinib, followed by the recovery of hypoproteinemia and systemic inflammation. Switching to alectinib may be beneficial in patients demonstrating crizotinib-associated complex renal cysts with systemic inflammation and exhaustion.

Background: Novel therapeutic agents recently introduced for the treatment of cancer have several unusual side effects. An increased incidence of renal cystic lesions, often with features concerning for malignancy or infection, has been reported in patients with anaplastic lymphoma kinase (ALK) - rearranged advanced non-small cell lung cancer (NSCLC) treated with Crizotinib. Many of these lesions undergo spontaneous resolution despite developing complex features on imaging. We assess the incidence and patterns of evolution of Crizotinib Associated Renal Cysts [CARCs] at our institute and provide histopathology correlation of their benign nature., Methods: A retrospective analysis of renal lesions in computerised tomography (CT) scans of 35 patients with advanced ALK-rearranged NSCLC who had been prescribed crizotinib at our institution was performed by three radiologists, who analysed the evolution of these lesions, particularly for pre-defined significant and complex changes., Results: Of 26 patients eligible for this analysis, 4 (15%) had cysts at baseline that remained stable on crizotinib treatment while 11(42%) developed significant change in 28 renal cysts. Commonest pattern of cyst evolution was enlargement from baseline followed by spontaneous regression (17/28 lesions) while other patterns noted were stable lesions, regression from baseline and ongoing enlargement. The median maximum size reached was 23 mm (range 9 - 67 mm) after a median of 178 days (160 to 1342) on crizotinib. Complex change occurred in 12 cysts, in 7/26 (27%) patients and within 60 days of starting Crizotinib in 10 cysts. Imaging features were falsely concerning for malignancy or abscess in 4/26 patients., Conclusion: Most CARCs resolve spontaneously, or have a benign evolution despite enlargement and other features concerning for malignancy or infection on imaging. This unusual manifestation of chemotherapy should be recognised, particularly by radiologists, so that inappropriate treatment decisions are avoided.

An apparent causal association between crizotinib treatment and renal cyst development emerged during clinical trials in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Serious adverse event (SAE) reports of renal cysts from a safety database of 1375 patients from four clinical trials were reviewed. A blinded, retrospective, independent radiologic review (IRR) was performed using scans from patients on study for ≥ 6 months in three clinical trials; risk factors for renal cyst development were assessed. Among 17 patients with renal cysts reported as SAEs, evidence of invasion into adjacent structures was noted in seven patients, with no evidence of malignancy found. These patients generally did not require dose reductions, none required permanent crizotinib discontinuation due to this AE, and most continued treatment with clinical benefit. In the blinded IRR, among 255 crizotinib-treated patients, 22%, 3%, and 2% had preexisting simple cysts, complex cysts, or both, respectively. At the 6-month tumor assessment, 9% of all patients had acquired new cysts, and 2% of patients with preexisting cysts had developed new cysts and enlargements (>50%) of preexisting simple cysts. Asians appeared to have an increased risk of developing new cysts on treatment; Koreans in particular had 5.18 times higher odds of developing cysts than non-Asians (95% confidence interval, 1.51-17.78; P = 0.05). Crizotinib treatment appears to be associated with an increased risk of development and progression of renal cysts in patients with ALK-positive NSCLC. While close monitoring is recommended, dosing modification was not generally necessary, allowing patients to remain on crizotinib treatment., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: The development of complex renal cysts after crizotinib treatment for non-small-cell lung cancer (NSCLC) is a reported side effect. However, its occurrence and characteristics have not been reported., Methods: Medical records and computed tomography images of crizotinib-treated patients in three prospective clinical trials were reviewed. The size and Bosniak category of the renal cysts before and after crizotinib treatment were determined. Patients' clinical characteristics, tumor stage, treatment response, renal function, and outcomes were analyzed., Results: During December 2010 to March 2013, we enrolled 32 patients who received crizotinib. There were 23 patients who had renal cysts before crizotinib. The median follow-up time was 493 days. Seven patients (22%, six with baseline renal cyst and one without baseline renal cyst) had significant renal cyst change. Four (13% of all) had new complex renal cysts. The median time from crizotinib treatment to first recognization of significant renal cyst change was 77 days. After stopping crizotinib, complex renal cysts regressed significantly. Patients with significant renal cyst change received more previous anticancer therapy (median, 5 lines versus 3 lines, p = 0.04) and received crizotinib for longer duration (median, 956 days versus 248 days, p = 0.007) compared with those without significant renal cyst change., Conclusions: Change of renal cysts after crizotinib treatment is not uncommon. Development of complex renal cysts reverses after stopping crizotinib.

To delineate changes in the development and regression of renal cystic disease, sequential studies were done in rats fed 2-amino-4,5-diphenyl thiazole (DPT). Kidneys were perfusion fixed with either aldehyde fixative alone or with the addition of ruthenium red (RR). Tissues were processed for light and electron microscopy. Light microscopy sections were stained with alcian blue and eosin and hematoxylin. Initially, cellular proliferation and, later, cystic transformation of collecting tubules were observed. The structural changes in tubular cells preceded alterations in the basement membrane and consisted of an increase in smooth and rough endoplasmic reticulum and free polyribosomes, prominence of Golgi complexes, and an increased number of lysosomes. These findings are suggestive of changes in the biosynthetic, secretory, and degradative mechanisms of the cell. With time, the tubular basement membranes became progressively thicker and laminated with concomitant loss of alcian-blue- and RR-staining. When DPT-treated animals with renal cystic disease were placed on a normal diet, tubular cell and basement membrane morphology and alcian-blue- and RR-staining returned to normal and cystic changes regressed. These findings are compatible with altered synthesis and degradation of tubular basement membranes in this model of cystic disease.

Studies were performed to characterize conditions in rat kidneys whose nephrons were made cystic by feeding 2% nordihydroguaiaretic acid (NDGA) to the animals. Using two micropipettes, we monitored intratubular hydrostatic pressures while perfusing single surface nephrons in NDGA-exposed (5 to 7 weeks) and normal rat kidneys. The introduction of 50 nl of Ringers solution labeled with 3H-inulin at a flow rate of 25 nl/min was associated with a significant mean (+/- SEM) increase (167 +/- 61%; P less than 0.02) in pressure in cystic but not in nondilated (-0.5 +/- 27.2%) or normal (31 +/- 23%) nephrons, respectively. The relative amount of 3H-inulin excreted in 40 min from cystic (4.0 +/- 2.0%) was less than that excreted from either nondilated (19 +/- 7%; P less than 0.05) or normal (105 +/- 26%; P less than 0.01) nephrons. Intralumenal pressures in nondilated but not other nephron groups correlated with urinary flow rates (r = 0.51; P less than 0.02). Single nephron filtration rates and tubular-fluid-to-plasma 3H-inulin rations in additional rats were similar among all groups of tubules. Concluding that these data reflected increased resistance to outflow from cystic nephrons, we examined these and additional NDGA-exposed (1 to 24 weeks) kidneys. 3H-thymidine radioautography demonstrated maximum collecting tubular cell hyperplasia (13% labeling) at 2 to 3 weeks of NDGA-exposure. Microscopy and microdissection demonstrated tiny mural polyps along outer medullary segments of collecting tubules. Thirteen tubules were traced to their outlets; polyps impinging on outflow lumens were found in all 13 instances. We conclude that partial nephron obstruction exists in NDGA-exposed kidneys and that obstruction is a likely contributor to cyst formation in this model.

The ability of prednisolone, prednisolone tertiary butyl acetate, and tertiary butyl acetate to induce cysts in the kidneys of 8-day-old rats has been examined following single intramuscular injection of the chemicals into newborn rats. The results indicate that only prednisolone tertiary butyl acetate-treated rats developed cysts to any marked extent. The daily injection of potassium chloride (from Day 2 to Day 7) into the prednisolone tertiary butyl acetate-treated rats prevented the formation of cysts. Similar injection of potassium bicarbonate failed to provide protection. Serum and urine electrolyte (potassium, sodium, and chloride) concentrations were also studied on the day of necropsy. The steroid-treated rats did not develop the hypokalemia observed by previous workers. Changes in electrolyte concentrations were noted in a number of instances, but these could not be causally related to cyst formation.

The influence of environment on renal cyst growth was assessed in experiments utilizing 56 germ-free and 32 conventional male Sprague-Dawley rats fed 2% nordihydroguaiaretic acid (NDGA). Among three groups of six germ-free rats allowed ad lib intake of NDGA for six weeks and deconditioned (placed into the ambient laboratory environment) at the start, at the midpoint, or not at all, cyst formation and interstitial changes (both severe) were noted only among animals deconditioned at the midpoint. Among 14 germ-free rats that were offered 0.4 g NDGA daily, deconditioned after two weeks, and sacrificed 0 to 15 days thereafter, nephron dilation and thymidine uptake by renal tubular epithelium appeared within one to three days and correlated in magnitude with each other and with the duration of the contamination interval. Deconditioning, a prior period of four or more days of exposure to NDGA in the germ-free state, the duration of the contamination period, and the presence of cecal flora were identified as prerequisites to accelerated cyst formation in this model, while the dose of ingested NDGA, the presence of bacteria within the kidney, an action of bacteria on NDGA within the colon, and the type(s) of organisms colonizing the host were not. These findings provide experimental evidence that environmental circumstance can modulate the expression of renal cystic disease.

Standard micropuncture and microdissection techniques were used to examine the function and structure of nephrons in rats whose kidneys were made cystic by dietary exposure to diphenylamine. Heterogeneity characterized the lesion, with dilation and frank cyst formation occurring in 5-30% of nephrons. Elevated intraluminal hydrostatic pressures, occurring in the absence of increased glomerular filtration or decreased net water reabsorption, were recorded in dilated, but not in nondilated nephrons. Structural studies demonstrated communication of dilated nephrons with cysts, concretions of debris within tubular lumens, evidence of extrinsic pressure by cysts on adjacent tubules, and apparent luminal narrowing of some proximal tubules. These observations were used to explain prolonged loop of Henle transit times and occasional failure to detect [3H]inulin excretion after microperfusion into dilated tubules. It was concluded that the elevated hydrostatic pressures in the dilated nephrons of diphenylamine-exposed kidneys were the consequence of variably severe and frequently incomplete tubular occlusion. These findings support the hypothesis that cyst formation is a consequence of partial obstruction and elevated intratubular pressure in this model and perhaps in other susceptible mammalian kidneys.

The herbicide 2,4,5-trichlorophenoxyacetic acid is teratogenic and fetocidal in two strains of mice when administered either subcutaneously or orally and in one strain of rats when administered orally. The incidences of both cystic kidney and cleft palate were increased in the C57BL/6 mice as well as the incidence of cleft palate in the AKR mice. The incidence of cystic kidney was also increased in the rats. In addition, an increase in the ratio of liver weight to body weight in the mouse fetus and the occurrence of hemorrhagic gastrointestinal tract in the rat fetus suggest that this compound also has fetotoxic properties.