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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).)

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

Background: Long-term use of proton pump inhibitors (PPIs) is associated with some safety issues. In this study, data mining was carried out to discover the potential association between renal neoplasms and PPIs., Research Design and Methods: Neoplasms signals of PPIs were detected in the Food and Drug Administration Adverse Event Reporting System from 2014 to 2020 by examining the reporting odds ratio. Adjusted odds ratios were analyzed using logistic regression., Results: Signals were detected with respect to renal hemangioma, acquired or unspecified cystic kidney disease, and papillary and unspecified renal cell carcinoma, of which intervals between adverse effects onset and medication were 7.00 (3.33, 15.67) years, 5.00 (1.70, 10.25) years, and 7.00 (4.72, 12.25) years, respectively. The lansoprazole had the strongest signal. Adjusted odds ratios for PPIs associated with renal cell carcinoma in cases with or without acquired cystic kidney disease or chronic kidney disease were 1.67 [95% confidence interval (CI) 1.46-1.91] and 1.62 (95% CI 1.41-1.87)., Conclusions: Exposure to PPIs was related to the raised risk of renal neoplasms. Careful consideration should be given to the possibility of an increased risk when PPIs are administered.

Background: Crizotinib is a first-generation tyrosine kinase inhibitor used for anaplastic lymphoma kinase (ALK) positive cancers. Simple and complex renal cyst formation is a rare complication of crizotinib use that has been reported previously in the adult population., Case: We report a case of a right renal mass in a 17-year-old with ALK-positive epithelioid inflammatory myofibroblastic sarcoma treated with Crizotinib. After cessation of Crizotinib and initiating Alectenib, a second generation ALK inhibitor, the mass decreased in size and the patient remained asymptomatic without evidence of recurrence at three months of follow-up., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 an anaplastic lymphoma kinase (ALK) inhibitor that was approved for ALK-harboring lung cancer. There have been reports about the development and progression of renal cysts from crizotinib. We report a series of 3 cases of crizotinib-associated renal cysts in patients admitted to our institution, with different kinds of presentation. A monitor for complex renal cysts is warranted in patients receiving crizotinib., (© 2019 S. Karger AG, Basel.)

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.

Treatment with the ALK inhibitor crizotinib has been associated with complex renal cyst formation in patients with non-small cell lung cancer (NSCLC). Using patients treated with crizotinib, we aimed to evaluate the incidence of renal cyst formation, to identify risk factors for cyst formation and to provide a radiological description of cyst characteristics. Patients with ALK-positive NSCLC treated with crizotinib were retrospectively identified from an institutional database. Computed tomography (CT) imaging performed prior to and during crizotinib treatment was retrospectively reviewed to assess the size and complexity of pre-existing cysts, new cysts, and enlarging cysts. Demographic data including age, sex, ethnicity, smoking history and length of treatment were also recorded. Data from 60 patients with NSCLC treated with crizotinib at our institution between 6/5/2009 and 7/1/2015 were collected. 57 had CT imaging before and during treatment. Mean length of imaging follow-up was 18 months. 9 (16%) patients had cysts which enlarged or developed de novo during treatment. 2 (4%) patients developed complex renal cysts (1 of these patients also developed complex hepatic cysts). Female gender (p=0.008) and the presence of renal cysts on baseline scans (p=0.044) were significantly associated with cyst formation or growth. Renal cyst formation or growth occurred in 16% of crizotinib-treated patients. Women and those with pre-existing cysts were at greatest risk. Although the potential causal relationship between crizotinib use and renal cyst formation has yet to be fully defined, it is important for radiologists and clinicians to be aware of this finding., (Copyright © 2017. Published by Elsevier B.V.)

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.

We report the case of a woman with an ALK positive lung adenocarcinoma, who developed bilateral complex renal cysts 17 months after the introduction of treatment with crizotinib. Clinical investigation led to the conclusion that the cysts were due to anticancer drug. Regression of the renal cysts was observed one month after cessation of the crizotinib. This case illustrates that specific and little known toxicities can occur with these novel molecules which have entered use for the management of lung cancer., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

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.)

Crizotinib is the first clinically available tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and is associated with the development of complex renal cysts. We now describe a 39-year-old woman who developed infected complex renal cysts during crizotinib treatment. After 10 months of such treatment, she presented with a high fever and low back pain. Computed tomography findings were consistent with complex renal cysts and perilesional inflammation. Interventions including cyst drainage and antibiotic administration contributed to diagnosis and management of the infected cysts.

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.

D-penicillamine, used to treat cystinuria, is known to cause impaired collagen deposition and dysfunction in elastic fibers. D-penicillamine also has been associated with glomerular abnormalities, typically membranous glomerulonephritis. We describe a patient with severe bilateral cystic kidney disease that developed after long-term D-penicillamine use for treatment of cystinuria. The cysts in the kidneys were noted during an evaluation for acute kidney injury. The patient had no evidence of cysts on prior renal imaging at a time when his kidney function was normal. Simultaneously, he presented with multiorgan manifestations of D-penicillamine toxicity, including the skin findings of cutix laxa and elastosis perforans serpiginosa. Consequently, D-penicillamine treatment was discontinued, after which the progression of cystic kidney disease gradually ceased, along with the other systemic manifestations of toxicity. To our knowledge, this is the first report of cystic kidney disease associated with and perhaps caused by long-term d-penicillamine therapy. The proposed mechanism of cyst formation is the malfunction of the extracellular matrix of the kidney by d-penicillamine that leads to an impaired repair process after kidney injury., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Lithium is one of the most effective medications in the treatment of mood disorders. The long-term lithium therapy can alter kidney morphology and function., Objective: To evaluate the relation of Magnetic resonance imaging (MRI) of the kidneys and renal function in patients undergoing chronic lithium therapy., Methods: Thirty five consecutive patients with mood disorders who were undergoing lithium therapy for at least two years were evaluated with a 1.5 tesla MR imaging and renal function tests. The relationship between renal size, the presence, number and location of renal microcyst with renal function were evaluated. The partial correlation analysis was performed to assess correlation between variables., Results: The mean size of kidney was 106.0 mm ± 6.0 and 106.0 mm ± 11.0 in right and left kidneys respectively. The mean number of microcysts in both kidneys was 6.2. There was a positive correlation between duration of lithium treatment and number of renal microcyst (P-value=0.03). Correlation between MRI findings and renal function tests was not statistically significant., Conclusion: The present study revealed that longer duration of lithium therapy can increase number of renal microcysts which is well shown with MR imaging. It seems that increasing renal microcysts may not be consistent with renal function impairment especially in earlier treatment phase. Thus the question arises is that MRI may not be as the first line method for clinicians who aim to assess renal function during long term lithium therapy.

Hyperdense renal cysts, a common condition in autosomal dominant polycystic kidney disease, may be induced by haemorrhage into the cysts. However, hyperdense renal cysts resulting from retention of contrast material after intravenous injection is extremely uncommon because the intravenous administration of contrast material does not induce an increase in the attenuation of renal cysts. We report a case of retention of iodinated contrast material within renal cysts in a patient with autosomal dominant polycystic kidney disease.

Purpose: To describe MR features of the kidney in patients on chronic lithium therapy and to correlate findings with the level of renal impairment., Method: In this retrospective HIPPA compliant study, a search was performed in our institutional clinical and radiological computerized database for subjects with lithium-related kidney disease between August 1, 2009 and May 30, 2010. Four patients (2 male and 2 females, mean age 64.75 ± 3.5) with a total of eight kidneys fulfilled the search criteria. T2-weighted images were used to evaluate the presence, size, and distribution of renal cysts. T1-weighted images were used to evaluate kidney length, parenchymal thickness, and cortico-medullary differentiation (CMD)., Results: All kidneys displayed multiple, very abundant, small size (1-2 mm) cysts. The distribution of the cysts was symmetric in renal cortex and medulla and the number of cysts was similar in both kidneys. Sparse, asymmetrical parenchymal renal cysts >3 mm in diameter were also observed. The size and parenchyma thickness of both kidneys was considered normal in all patients. The CMD differentiation was preserved only in patients with normal laboratory kidney findings (n = 2), but was lost in patients with chronic renal failure., Conclusions: Multi-microcystic kidney disease secondary to long-term lithium therapy can be detected with MR imaging regardless of known renal impairment. Preservation of renal CMD was observed in both patients with normal kidney function. The results of our preliminary study suggest the possible role of MR imaging for the screening of early manifestations of nephropathy in patients undergoing chronic lithium therapy.

Inorganic lead compounds are carcinogenic in animals and have carcinogenic potential in humans. In mice, lead (Pb) is a transplacental carcinogen in the kidney. Metallothionein (MT) is a metal-binding protein that can reduce the toxicity of various metals, including Pb, either by direct sequestration or as an antioxidant for metals that generate reactive oxygen species. Although MT appears to reduce Pb carcinogenicity in adult mice it is unknown how MT deficiency may affect Pb carcinogenicity from early life exposure. Thus, groups (n=10) of pregnant MT-I/II double knockout (MT-null) or 129/SVJ MT wild type (WT) mice were exposed to Pb acetate in the drinking water (0, 2000, 4000ppm Pb) from gestation day 8 through birth and during lactation. Maternal drinking water Pb exposure continued to wean at 4 weeks of age and the male offspring were then directly exposed to Pb until 8 weeks of age and observed until 2 years old. High dose (4000ppm) but not low dose (2000ppm) Pb reduced survival in the latter part of the study in both MT-null and WT mice. In MT-null mice, but not WT, early life Pb exposure caused a dose-related increase in testicular teratomas, to a maximum incidence of 28% compared to control (4%). Pb-induced renal cystic hyperplasia, considered preneoplastic, was a prominent occurrence in MT-null mice but nearly absent in WT mice. Pb dose-related increases in renal cystic hyperplasia occurred in adult MT-null with early life exposure with maximal incidence of 52%. Pb-treated MT-null mice also showed dose-related increases in urinary bladder hyperplasia with occasional papilloma that were absent in WT mice. Thus, MT deficiency made mice more sensitive to early life Pb exposure with regard to testes tumors, and renal and urinary bladder preneoplastic lesions., (Published by Elsevier Ireland Ltd.)

Purpose: To evaluate the appearance of lithium nephropathy at magnetic resonance (MR) imaging., Materials and Methods: Sixteen patients with renal insufficiency and clinical and laboratory evidence of nephropathy secondary to therapy with lithium salts were examined with a 1.5-T MR imaging unit with T1-weighted, T2-weighted fast imaging with steady-state precession (true FISP), rapid acquisition with relaxation enhancement, half-Fourier turbo spin-echo, and gadolinium-enhanced (FISP three-dimensional MR angiographic) sequences. Renal size and the presence, number, location and size of parenchymal cysts were analyzed. The cysts in each kidney were defined as rare (fewer than 10 cysts), sparse (between 10 and 30 cysts), abundant (30-60 cysts), or very abundant (more than 60 cysts)., Results: The mean length of both kidneys was 104 mm +/- 9 in seven cases, and one or both kidneys were less than 90 mm in length in nine cases. Renal microcysts measuring from 1 to 2 mm were detected in all patients. They were either very abundant (n = 12), abundant (n = 2), or sparse (n = 2). The cysts were located with equal abundance in both the cortex and the medulla in 11 cases and were predominantly located in the renal cortex in five cases. No renal artery stenosis was present., Conclusion: Microcysts secondary to long-term lithium therapy can be detected with MR imaging., (Copyright RSNA, 2003)

The study investigates relationship between simple renal cyst enlargement studied by ultrasonography and anti-hypertensive treatment. To this purpose we enrolled 42 patients with newly diagnosed hypertension affected by simple renal cysts. Fourteen were randomly assigned to treatment with ACE-Inhibitors (group 1), twelve to diuretics (group 2) and sixteen to Ca-Antagonists (group 3). Patient performed a basal ultrasonography to evaluate basal cyst dimension before starting anti-hypertensive treatment. Following 12 months of the anti-hypertensive regimen, a new echograph was performed to evaluate changes in cyst size. A control group consisting of 15 patients with normal blood pressure and simple renal cysts was enrolled (group 0). An enlargement of cysts was detected in all patients. However, the enlargement observed in patients treated by Ca-Antagonists was significantly greater than that observed in the other groups (p<0.05). Our study supports the hypothesis that Ca-Antagonists may favor cyst enlargement by enhancing cyclic AMP production. In fact, cAMP and cAMP agonists stimulate fluid secretion by lining cells of the cyst wall, inducing cyst enlargement.

Aims: The effect of oral adsorbent, AST-120, on the experimental renal disease induced by adriamycin, uninephrectomy and high protein diet proposed as a model of acquired cystic disease of the kidney was investigated., Methods: 3 mg of adriamycin was injected into the tail vein of rats and 4 weeks later right-side nephrectomy was performed, 2 weeks thereafter 26 rats with urinary protein excretion between 100 and 358 mg/day were selected from 60 rats. Two groups, 13 rats in each group, namely the AST-120-treated group and control group, both of which had equal renal damage before the administration of AST-120 or placebo. AST-120 (0.4 g/100 g BW/day) was administered for 19 weeks., Results: Serum creatinine and BUN in the AST-120-treated group were significantly lower (serum creatinine: 3.3 +/- 2.1 vs. 7.1 +/- 2.7 mg/dl, p < 0.003) and creatinine clearance was higher (0.62 +/- 0.49 vs. 0.29 +/- 0.30 ml/min, p < 0.05) at the final examination than in the control group. Survival rate which was examined using another set of 9 rats was higher in AST-120-treated rats than in AST-120-untreated rats. Serum indoxyl sulfate was significantly lower at all times after using AST-120 in the AST-120-treated group than in contrast to the control group. Histological examination revealed less severe interstitial and cystic changes in the AST-120-treated group. This suggests that AST-120 can prevent or retard the development of acquired renal cystic disease in this model. Aortic calcification tended to be less severe in the AST-120-treated group because of less serum Ca x P products., Conclusion: The AST-120-treated group significantly decreased serum creatinine and increased creatinine clearance with less severe renal cystic changes in this model during the later weeks of administration of AST-120 or at death, accompanied with the tendency of less severe aortic calcification., (Copyright 2002 S. Karger AG, Basel)

The growing use of creatine as a potential ergogenic aid among active individuals has raised concern regarding its effects on the kidney, particularly among those individuals with compromised renal function. The object of this study is to investigate the effects of oral creatine supplementation in an accepted animal model of renal cystic disease. Han:Sprague-Dawley (SPRD)-cy rats with cystic kidney disease were administered a creatine supplement at a loading dose of 2.0 g/kg of diet for 1 week, followed by 5 weeks during which the dose was one fifth this amount, mimicking typical human consumption on a body-weight basis. Cystic kidney disease progression was assessed by measuring kidney size and fluid content and determining cyst scores. Renal function was assessed by measuring serum urea and creatinine concentrations and creatinine clearance. Creatine supplementation resulted in greater cyst growth and worsened renal function in the Han:SPRD-cy rat, evidenced by greater kidney weights (2.87 +/- 0.08 versus 2.61 +/- 0.09 g/100 g of body weight; P: = 0.0365), renal fluid contents (89.22 +/- 0.41 versus 87.38 +/- 0.48 g/100 g of kidney weight; P: = 0.0057), cyst scores (0.49 +/- 0.02 versus 0.40 +/- 0.03; P: = 0.0167) and serum urea concentrations (23.96 +/- 0.92 versus 20.65 +/- 1.06 mmol/L; P: = 0.0230), and lower creatinine clearances (0.125 +/- 0.098 versus 0.162 +/- 0.011 mL/min/100 g of body weight; P: = 0.0159). These results indicate that creatine supplements may exacerbate disease progression in an animal model of cystic renal disease. Although systematic research of the effects of creatine supplementation in humans with compromised renal function is awaited, it follows that creatine should be used with particular caution in individuals with or at risk for renal disease.

A 57-year-old man on chronic hemodialysis presented marked bilateral renal enlargement due to acquired cystic kidney disease (ACKD). He had been on hemodialysis for less than 3 years only (14 months prior to receiving a functional renal transplant which lasted 8 years, followed by 18 additional months of dialysis), before the diagnosis of ACKD was made following an episode of flank pain with gross hematuria. The marked changes in kidney appearance during this 11-year period were documented by serial ultrasound examination showing the kidneys to be of near-normal size before the start of dialysis (> or =10 cm in 1986), then shrunken and contracted 5 years later while having a functioning renal transplant (<5 cm in 1991), and markedly enlarged reaching the size of adult polycystic kidney disease after returning to dialysis (>13 cm in 1997). Since the risk of ACKD increases with duration of dialysis, we sought additional predisposing factors in this unusual case and found that 2 years after renal transplantation, the patient was diagnosed with breast cancer for which he was treated with surgical excision and tamoxifen. Based on ultrasound evidence that the tamoxifen treatment preceeded the appearance of the renal cystic changes, we wonder whether this drug may have played a role in the rapid development of ACKD.

Objective: The purpose of this study is to emphasize the high risk of renal failure and severe morphologic changes related to prolonged prenatal exposure to indomethacin., Study Design: Referred renal specimens from six anuric neonates exposed in utero to indomethacin were studied. Clinical charts were retrospectively reviewed. Indomethacin dosages varied from 150 to 400 mg daily, and the drug was given for a 2- to 11-week period, until birth., Results: All infants died in anuria, 4 of them after 7 to 39 days on peritoneal dialysis. In 5 infants cystic dilatations of superficial nephrons were associated with ischemic changes of the deep cortex. By immunohistochemical analysis intrarenal renin content was increased in 4 of 5 patients., Conclusion: Long-term indomethacin treatment during pregnancy may lead to the development of renal failure and irreversible renal damage with cystic dilatation of developing nephrons in an exposed fetus. Prior stimulation of the renin-angiotensin system may favor this complication.

1. Phthalate esters are known to cause hepatic peroxisome proliferation in rodents and, after prolonged administration, hepatocarcinogenesis. Peroxisome proliferators as a group are hepatocarcinogenic. The mechanism is not known but it does not appear to involve a direct genotoxic element. 2. DEHP and DBP have been shown to cause renal cysts in rodents and they also produce renal peroxisome proliferation. There are no data to causally link the two phenomena. 3. Although renal cysts have been noted in haemodialysis patients and haemodialysis is a route of exposure to DEHP, there are no data to suggest a cause and effect relationship. 4. More studies are needed on the mechanism of renal cystogenesis.

Subchronic feeding of 2-amino-4,5-diphenylthiazole (DPT) to rats results in the development of renal cysts and has been used as a model system to study polycystic kidney disease. Because previous studies revealed changes in renal enzymes following DPT administration, a possible direct effect of DPT and its phenolic metabolites on catalase and a related enzyme, epoxide hydrolase, was examined. Experiments with three in vitro systems (suspensions of rabbit renal tubules, rat kidney homogenates, and commercially obtained bovine liver catalase) revealed direct inhibition of catalase activity by the diphenolic metabolite (diOH- DPT: 2-amino-4,5di(4'-hydroxyphenyl)-thiazole), the known renal cystogen nordihydroquaiaretic acid (NDGA) 2-amino-4(4'-hydroxyphenyl),5-phenyl-thiazole (4OH-DPT), and the known catalase inhibitor 3-amino-1,2,4-triazole; DPT did not inhibit catalase activity. Following oral administration to rats of the DPT congeners, 4OH-DPT caused the greatest decrease in both renal catalase and cytosolic epoxide hydrolase activities and the shortest time to onset of cystic lesions. In vitro, mouse liver cytosolic epoxide hydrolase activity was substantially inhibited by 4OH-DPT and dioH-DPT, and NDGA, but not by 2-amino-4-phenyl,5-(4'-hydroxyphenyl)-thiazole (5OH-DPT) or DPT itself. Microsomal epoxide hydrolase (mEH) activity was inhibited by 4OH-DPT, unaffected by DPT or dioH-DPT, and stimulated 2-fold by 5OH-DPT. Finally, mEH activity was substantially higher in samples of normal human kidney than in samples of kidney derived from a patient with autosomal recessive polycystic kidney disease; no differences were observed in cEH activity in these samples. Although the role of altered catalase and epoxide hydrolase activities in cystogenesis is unknown, DPT-induced cyst formation is associated with loss of these enzyme activities in kidney tissue. To our knowledge, this is the first report of an in vivo diminution of cytosolic epoxide hydrolase activity by xenobiotics.

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.

Chronic intoxication with diphenylamine (DPA), which causes a cystic kidney disease in the rat and the guinea-pig, caused degeneration of the renal tubular epithelium in the chicken. This was similar to but much more serious than that preceding the formation of cysts in the rodents, but did not actually result in cyst formation, probably because of the high mortality rate observed in the birds even at this early stage. In the chicken until now it had been possible to obtain a pattern of renal cysts only with polychlorinated biphenyls (PCB) which also induce the "chick oedema" syndrome. The renal lesions due to DPA in the chicken were similar to those produced by PCB, but were not accompanied by oedema, which suggests that "chick oedema" caused by PCB is not due to renal insufficiency. The differences in the renal lesions noted in the various animal species give credit to the hypothesis that DPA may have two effects on the tubular epitelium, one stimulating cell proliferation and one leading to degeneration. Cysts may be formed only in those species in which there is cell proliferation.

We studied the renal lesions induced by transplacental administration of n-ethylnitrosourea (ENU) in the rat. In the 231 offspring we observed, 40 nephroblastomas (17.3%), 7 clear cell epithelial tumors and clear cell cystadenomas (3.0%), 183 simple cysts (79.2%), and 2 mesenchymal tumors (0.8%). Nephroblastomas showed a wide spectrum of histological appearance, and many were located in the deep renal cortex, with occasional intra-pelvic-protrusion. They showed both infiltrative and focal expansile growth without definite capsule formation. Nephroblastomas were usually unilateral, but multicentric and bilateral lesions were found in some cases. The earliest nephroblastoma was found at 4 weeks, earlier than generally described. Some of the nephroblastomas were heterotransplantable to athymic nude mice and serial transplantation was achieved in one instance. These experiments have induced a wide variety of renal tumors and tumor-like conditions, comparable to the different types of renal lesions observed in children, and may provide a useful model for the study of the pathogenesis of embryonal tumors in man.

Because of difficulty in obtaining cystic human kidneys for functional and morphologic study, animal models are receiving increasing attention. Most prominent among them is the renal cystic disease that is induced in rats through feeding of the antioxidant, diphenylamine, The present study examined the morphology of adult polycystic and medullary cystic kidney disease in man using scanning electron microscopy and compared them with diphenylamine-induced cystic kidney disease in rats. Diphenylamine nephropathy was induced by feeding rats 1 per cent diphenylamine for 12 to 18 months. All types of cystic disease showed changes in the renal corpuscles, including dilation of Bowman's space, podocyte fusion and degeneration, and basement membrane thickening. Cysts were noted along the entire nephron in polycystic and diphenylamine-induced cystic disease but only along the collecting ducts in medullary cystic disease. Cysts in polycystic disease were large and lined by flattened epithelium. Collecting duct cysts in diphenylamine cystic disease were lined by cells of irregular size and shape suggestive of cell hypertrophy and/or hyperplasia, whereas cysts of medullary cystic disease were lined by flattened epithelium except where the nephron entered or left the cyst. Cast material was generally found in the cysts of diphenylamine-induced and polycystic kidney disease but not medullary cystic disease. Atrophic glomeruli and tubules were found in all three diseases. Complete tubular obstruction was found in none; however, larger cysts frequently impinged on adjacent tubules and narrowed their lumina. The results of this study show that, in the terminal stages, cellular as well as gross morphologic differences exist between polycystic and medullary cystic kidney disease and that diphenylamine-induced cystic disease more closely resembles human polycystic than medullary cystic kidney disease.

This paper presents a structural and morphometric study of the basement membrane underlying the parietal epithelium of cysts developed in the rabbit kidney after a single postnatal injection of methylprednisolone acetate. This epithelium consists of podocyte-like cells named parietal podocytes. Our results show that the parietal podocytes synthesize their own basement membrane in vivo. However, the different laminae of this membrane present differences in structure and thickness when compared to the analogous layers of both the normal glomerular and parietal basement membranes. Differences between the different zones of the parietal podocytic basement membrane are also observed, depending upon the structure that surrounds the cyst (capillaries, interstitial cells or loose connective tissue). A lamina lucida, analogous to the lamina lucida interna of the glomerular basement membrane, is formed only in segments of the parietal podocytic basement membrane in close contact with endothelial or interstitial cells. The thickness of the lamina lucida externa of the parietal podocytic basement membrane appears regulated by the presence of interstitial cells and capillaries. In the zones in contact with capillaries, the lamina densa of the parietal prodocytic basement membrane appears thinner than in other segments. This fact, together with structural observations, suggests that the formation of a single basement membrane, interposed between the parietal podocytes and the endothelium, does not take place by fusion of the two basement membranes but by previous removal of the capillary basement membrane. In areas where the parietal podocytic basement membrane is in contact with loose connective tissue, a lamina fibroreticularis is observed. All these data indicate that the formation of the basement membrane by the parietal podocytes is influenced by nonpodocytic cells. Around the glomerular cysts, a tardy formation of capillaries is observed. Parietal podoytes can be hypothesized to synthesize an angiogenic factor that may be implicated in the process of angiogenesis.

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.

A new experimental model of glucocorticoid-induced tubular cyst formation has been developed in metanephric organ culture. The addition of cortisol (1.4 X 10(-5) M) to chemically defined serum-free culture medium produces cystic changes during in vitro nephrogenesis . The model isolates the role of glucocorticoids in experimental cyst formation.

From a review of renal development and experimental cystic disease, the following observations can be made: 1. The previous theories developed to explain cystic renal disease (nonunion, failure of regression, and obstruction to urine flow) do not adequately fit with the numerous recent observations made in studies of most experimental models or in human renal cystic disease. 2. The most acceptable theory to date for most types of renal cystic abnormalities (except those due to known obstruction of urine flow) is that abnormalities of the tubular supporting wall occur, probably as a result of toxic or metabolic injury to the tubular cells of the wall and the related interstitial tissues, which are exposed to the highest concentrations of these compounds. This theory would also help explain the etiology of cystic renal diseases in man and should lead to attempts to isolate toxic factors or enzyme abnormalities in susceptible families and in early cases. 3. Induction of cystic abnormalities through a variety of experimental manipulations and drugs reveals impressive strain, sex, and species variability, and these differences should be more carefully examined. 4. The same chemical that induces a cystic change in the mature, fully developed kidney may cause changes which are quite different (location, severity, etc.) in both the fetal and newborn kidney, in which continual nephrogenesis is occurring. 5. Many of the previous explanations of cystic changes require careful reinterpretation of the findings (to reconcile certain differences), and confirmatory studies should be performed to help piece together some of the puzzling observations noted, such as the cystic changes seen with adrenocorticosteroids, and their relationship to potassium depletion.

The long-term pathologic effects of the antitumor drug, cis-diamminedichloroplatinum II (CP) on the structure of the rat kidney were investigated. Light microscopy and transmission and scanning electron microscopy were used to characterize the morphologic changes 2 weeks, 4 weeks, and 6 months after the intraperitoneal injection of CP to rats. At all time intervals examined, the S3 segment of the proximal tubule located in the outer stripe of the medulla showed the most consistent pattern of injury. Two weeks after CP, the proximal tubules located in the outer stripe region as well as in the medullary rays were widely dilated and lined by low-lying epithelial cells, many of which contained large atypical nuclei. Many tubules still showed evidence of necrosis, whereas other tubules appeared to be undergoing atrophic changes. After 4 weeks, proximal tubular dilation continued resulting in the formation of numerous microcysts in the region of the outer stripe. These changes appeared to progress, and after 6 months large cysts (mean diameter 2152 +/- 1241 micrometer) were identified which involved the entire outer stripe, with many of these cysts extending to the subcapsular cortex. The kidneys at this time period showed a pattern of chronic renal injury in the outer stripe, and this damage was now also observed in the cortex. In several animals, small foci of abnormal foam cells surrounded by a basal lamina could be identified. We conclude that CP has a pronounced long-term effect and causes cyst formation in the rat kidney.