Tag Archive for: NSAID


Urolithiasis around the world

Stone disease is a highly prevalent condition that unites all countries around the world, although surgical management will depend on many factors including availability of different technologies. However, percutaneous nephrolithotomy (PCNL) remains the cornerstone for the management of larger renal stones in all parts of the world, and Rizvi et al. [1] report on a huge cohort of PCNL procedures – 3 402 to be precise from Karachi. This is a single-centre series, over an 18-year period, reporting real-life data and showing a stone clearance rate of ~80%, as assessed by plain abdominal radiograph of the kidneys, ureters and bladder, and ultrasonography (US). Whilst the definition of stone-free and imaging modality used to judge it remains a contentious issue, this paper reflects the excellence of high-volume surgery in specialist centres.

Recently, the BJUI became the affiliated journal for the International Alliance of Urolithiasis (IAU), whose annual meeting takes place in Shaoxing this month. To celebrate this, we are proud to publish a ‘Best of Urolithiasis’ issue, which features some of the top stone papers published in the BJUI over the last few years [2]. Choosing articles for this was quite a task given the quality and whilst we have attempted to recognise submissions that potentially change practice, the geographical diversity of the work shows not only the global nature of stone disease but also the excellent research that is being done worldwide and in different healthcare systems to improve care and outcomes. Of particular importance are randomised trials that are often lacking in surgical areas. One such paper from China addressed the question of US vs fluoroscopy for PCNL access during mini-PCNL [3]. Whilst the truth is that surgeons should use whatever gives the best outcomes, the authors in a very high-volume centre were able to demonstrate the effectiveness of US-only punctures, although a combination may be better in complex stone burdens. Another randomised controlled trial (RCT) of clinical importance was from the USA, where the authors conducted a good quality double-blind RCT of NSAID use before ureteric stent removal under local anaesthesia [4]. Whilst a small study, the incidence of severe pain in the 24 h after stent removal was 55% in the placebo group vs 0% in the NSAID group – as such this simple study should have changed practice for all who perform this procedure.

Other papers worthy of inclusion include a single-centre experience of the conservative management of staghorn calculi, which challenges the dogma that all staghorn stones should be treated [5]. This single-centre series showed a conservative policy could be adopted in highly selected patients. Is this practice changing? Maybe … but it certainly gives an evidence base for stone surgeons in making decisions in very high-risk patients. Manoj Monga and his group recently reported on the accuracy of US for the detection of renal stones [6]. This again is a very important topic and a question that commonly arises. In a series of >500 patients with US-detected stones who subsequently underwent CT scanning, 22% of patients would have been inappropriately counselled about their stone based on US alone. Again, the message is clear … US is a good screening tool but do not rely on it for treatment decisions.

I hope you take the time to check out the virtual issue on urolithiasis and read the other papers I could not mention here. Please continue to send your high-quality stone papers to the BJUI and maybe your submission will feature in our next ‘Best of Urolithiasis’ issue.

Matthew Bultitude, BJUI Associate Editor


Guys and St Thomas NHS Foundation Trust, London, UK




1 Rizvi SA, Hussain M, Askari SH, Hashmi A, Lal M, Zafar MN. Surgical outcomes of percutaneous nephrolithotomy in 3402 patients and results of stone analysis in 1559 patients. BJU Int 2017; 120: 7029


2 BJU International. Virtual Issues Page. Available at: https://bit.ly/BJUI-VIs. Accessed September 2017



4 Tadros NN, Bland L, Legg E, Olyaei A, Conlin MJ. A single dose of non-steroidal anti-inammatory drug (NSAID) prevents severe pain after ureteric stent removal: a prospective, randomised, double-blind, placebo-  controlled trial. BJU Int 2013; 111: 1015


5 Deutsch PG, Subramonian K. Conservative management of staghorn calculi: a single-centre experience. BJU Int 2016; 118: 44450


6 Ganesan V, De S, Greene D, Torricelli FC, Monga M. Accuracy of ultrasonography for renal stone detection and size determination: is it good enough for management decisions? BJU Int 2017; 119: 4649


Renal cell carcinoma in a setting of chronic lithium toxicity

A case of renal cell carcinoma on a background of acquired cystic disease due to chronic lithium toxicity is described. The possible pathogenetic mechanisms that may have lead to the development of the renal cell carcinoma in this setting are explored.

Authors: Zardawi, Ibrahim; Nagonkar, Santoshi; Patel, Purvish
Corresponding Author: Zardawi, Ibrahim


Lithium salts are widely used in the treatment of affective disorders of the bipolar type. Lithium is a nephrotoxic substance and patients undergoing long-term lithium treatment can present with acute lithium intoxication, chronic renal disease or nephrogenic diabetes insipidus.1,2 Lithium causes structural renal damage with tubular loss, fibrosis, inflammation, glomerular sclerosis and cyst formation.3 Cysts appear to predispose the kidney to renal cell carcinoma and an association between the two conditions has been well documented.4 A case of renal cell carcinoma on a background of acquired cystic disease due to chronic lithium toxicity is described. The possible pathogenetic mechanisms that may have lead to the development of the renal cell carcinoma in this setting are explored.

A 72 year old obese female with an 18 year history of a schizoaffective disorder, presented in March 2011 with painless haematuria. She had been on Lithium for approximately 12 years, from 1993 to 2005. She was diagnosed in 2005 with Type 2 Diabetes Mellitus and in 2008 with chronic kidney disease thought to be due to chronic interstitial nephritis from long term Lithium use. She has been a heavy user of non-steroidal anti-inflammatory drugs but is a non-smoker. Her past medical history included hysterectomy and appendectomy. On examination, she was found to be mildly hypertensive with a blood pressure of 155/90 mm Hg. She was haemodynamically stable with no pallor, bruising, petechiae or purpura and no signs of mucosal bleeding. Her abdomen was soft and non-tender and there were no masses or organomegaly. Her medications at presentation included Aripiprazole 10mg daily, Sodium Valproate 500mg bd, Atorvastatin 20mg daily, Thyroxin 50mcg daily and Telmisartan Hydrochlorothiazide 80/12.5 mg daily.

Investigations revealed a raised blood urea at 16.5 mmol/L (reference range (3.0-10.0 mmol/L) and serum Creatinine of 205 umol/L (reference range 30-100 umol/L). Renal ultrasound showed a mass (4.5x 4.7x 4.5 cm) with cystic and solid components and increased vascularity in the upper pole of the left kidney. No other renal masses were detected but both kidneys contained multiple cysts. A mobile echogenic mass (3.4cm X 2.8 cm in size), thought to be a blood clot, was detected in the bladder. No significant abnormalities were detected on cystoscopy and retrograde ureteroscopy, except for a blood clot which was removed during the procedure. No bladder or ureteric masses or stones were identified. Bladder biopsy showed active (acute and chronic) inflammation but no urothelial dysplasia or malignancy. A left renal tumour, indenting the renal sinus and extending into the renal vein with the presence of thrombosis was detected on Magnetic Resonance Imaging (MRI). Numerous cysts, mostly less that 5mm in diameter were identified in both kidneys. There was no evidence of metastatic disease in the abdomen or pelvis. A left laparoscopic nephrectomy was performed. The patient has been well post nephrectomy with no clinical or radiological evidence of tumour recurrence.

The macroscopic specimen consisted of a kidney with attached peri-nephric fat. The kidney (140x85x40mm) contained numerous cysts up to 30mm in maximum diameter (Fig. 1). A relatively circumscribed, partly necrotic tumour with haemorrhage necrosis, 60 x 55mm was noted in the upper part of the kidney with extension into the renal vein and peri-hilar fat (Fig. 1). Microscopically, the renal tumour was a Fuhrman grade 2 clear cell carcinoma. The tumour had extended into the peri-hilar adipose tissue and the renal vein. The remainder of the kidney showed numerous simple cysts, each lined with a layer of flattened cuboidal cells (Fig. 2). Cysts were present throughout the renal parenchyma with involvement of cortical and medullary tissues.

Lithium salts are widely used in the treatment of affective disorders of the bipolar type. A frequent side effect of long-standing lithium treatment is kidney damage. Compared with the general population, patients on long-term Lithium salts are 6 times more likely to develop chronic renal failure. In a recent Swedish study, plasma creatinine levels of >150 µmol/L (normal range 30-100 µmol/L) were detected in 12% of patients on long-term lithium treatment and renal replacement therapy was required in 5.3% of the lithium treated population.5 Patients undergoing long-term lithium treatment can present with acute lithium intoxication, chronic renal disease or nephrogenic diabetes insipidus.1,2 Lithium causes structural renal damage with tubular loss, fibrosis, inflammation, glomerular sclerosis and cyst formation.3,4

Cysts appear to predispose the kidney to renal cell carcinoma and an association between the two conditions has been well documented.5 The patient presented here, is obese, had been on lithium for 12 years and has misused non-steroidal anti-inflammatories for a long period of time. The above combination is important when considering renal cell carcinoma in this setting because a relationship, albeit indirect, can be established between these medications and renal cell carcinoma. Renal biopsy from patients on long-term lithium treatment often shows chronic interstitial nephritis with associated tubular atrophy, cortical and medullary fibrosis, glomerular sclerosis, tubular dilatation and cyst formation.6,7 This patient had numerous renal cysts and macroscopically these cysts were indistinguishable from the cysts of adult polycystic kidney disease. These cysts, which were deemed to be acquired (acquired cystic disease), were attributed to lithium toxicity.

Renal cell carcinoma is a group of malignancies that arise from the renal tubular epithelium. Although smoking, obesity and hypertension are the main risk factors for renal cell cancer in both sexes, exposure to environmental chemicals and prolonged intake of phenacetin-containing analgesics also play a role in the aetiology of renal cell carcinoma.8 An association between renal cell carcinoma and acquired and hereditary cysts has been well documented.9 The majority of renal neoplasms in the setting of acquired cystic kidney disease have been in patients on chronic haemodialysis for several years. Tumours also occur in patients with chronic renal failure who have not been dialysed. The number of cysts is important for establishing a diagnosis of renal cell carcinoma associated with acquired cystic disease. At least 5 cysts are necessary for a diagnosis of acquired cystic disease.8 This patient, who had not been dialysed, fulfils the criteria for acquired renal disease. Although renal tumours are found in 25% of patients with acquired cystic disease, not all lesions are histologically malignant and only 5% metastasise. This observation is different to the findings in this case, which is a high stage tumour with a large tongue of tumour extending into the main renal vein. In some cases of acquired cystic disease, atypical proliferative epithelial changes, harbouring cytogenetic abnormalities, representing early neoplastic transformation have been found. Some clear cell renal cell carcinomata arising in the setting of acquired cystic disease has been shown to have von Hipple-Lindau (VHL) gene mutations.8 The cysts in this patient are simple and there is no epithelial hyperplasia or atypia, therefore no precancerous proliferative changes are demonstrable morphologically. It is worthwhile remembering that renal cell carcinomas are rare in adult polycystic kidneys and probably occur with no more greater frequency than might be expected based on the prevalence of the two conditions.8

A small but consistent excess of renal cell carcinoma has been established with exposure to phenacetin-containing analgesics which also cause cancer of the renal pelvis.8 This patient has abused many types of analgesics for a long period of time and had often consumed large quantities of these analgesics.

The risk of renal cell carcinoma increases steadily with increasing body mass index (BMI).10 The incidence of renal cell carcinoma in obese people with a BMI of >29 kg/m2 is double that of normal individuals. In Europe one quarter of kidney cancers in both sexes are attributable to excess weight, particularly in women8. A real association would be supported by oestrogen-mediated carcinogenesis that is documented in animal models. Conversely, it could be a confounding effect of excess body weight that is often increased in women who have had many children. Our patient’s BMI is close to 30 kg/m2. The mechanism by which obesity predisposes to renal cell cancer in humans is unclear, although hormonal factors are thought to play a role. An alternative explanation is that hypertension or metabolic complications of obesity may result in kidney damage that increases susceptibility to carcinogens or promoting agents. The association with obesity persists after controlling for other risk factors, such as a history of hypertension or kidney disease and intake of meat, fat or protein.10

The incidence of renal cell carcinoma is significantly increased in people with a history of hypertension that is independent of obesity and tobacco smoking.9 The association with the use of diuretics instead is likely to be due to the associated hypertension.

Lithium is commonly used in the treatment of bipolar mental illness. It is nephrotoxic and long-term use of lithium can lead to chronic renal failure through tubular damage with cyst formation. Kidneys with multiple cysts are at risk of renal cell carcinoma. In this case, it is difficult to determine if long term Lithium use is responsible for the renal cell carcinoma as other contributing factures to renal cell carcinoma, such hypertension, obesity and analgesic abuse are also present. Despite this, patients on long-term lithium therapy should undergo regular renal function and imaging tests.

1. Hansen HE. Renal toxicity of lithium. Drugs 1981; 22: 461–476.
2. Timmer RT, Sands JM: Lithium intoxication. J Am Soc Nephrol. 1999;10: 666–674.
3. Hansen HE, Hestbech J, Olsen S, Amdisen A. Renal function and renal pathology in patients with lithium-induced impairment of renal concentrating ability. Proc Eur Dial Transplant Assoc. 1977;14:518-527.
4. Bendz H, Schön S, Attman PO, Aurell M. Renal failure occurs in chronic lithium treatment but is uncommon. Kidney Int. 2010;77:219-224.
4. Hurst FP, Jindal RM, Fletcher JJ, Dharnidharka V, Gorman G, Lechner B, Nee R, Agodoa LY, Abbott KC. Incidence, predictors and associated outcomes of renal cell carcinoma in long-term dialysis patients. Urology. 2011;77:1271-1276.
6. Markovitz GS, Radhakrishnan J, Kammbham N, Valeri AM, Hines WH, D’Agati VD. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 2000; 11:1439–1448.
7. Farres MT, Ronco P, Saadoun D, Remy P, Vincent F, Khalil A, Le Blanche AF. Chronic Lithium Nephropathy: MR Imaging for Diagnosis. Radiology 2003; 229:570–574.
8. WHO classification of tumours: Pathology and genetics of tumours of the urinary system and male genital organs. Edited by Eble JN, Sauter G, Epstein JI, Sesterhenn IA. IARC press, Lyon 2004.
9. McCredie M, Stewart JH, Day NE. Different roles for phenacetin and paracetamol in cancer of the kidney and renal pelvis. Int J Cancer. 1993;53:245-249
10. Chow WH, McLaughlin JK, Mandel JS, Wacholder S, Niwa S, Fraumeni JF (Jr). Obesity and risk of renal cell cancer. Cancer Epidemiol Biomarkers Prev 1996;5:17-21.
11. Setiawan VW, Daniel O. Stram DO, Nomura AMY, Kolonel LN and Brian E. Henderson BE. Risk Factors for Renal Cell Cancer: The Multiethnic Cohort. Am. J. Epidemiol. 2007; 166: 932-940.








Figure 1. Numerous cysts in the kidney (left panel) with part of a tumour in the right upper corner of the kidney. A large haemorrhagic tumour in the upper pole of the kidney (right panel) with renal vein invasion by tumour (arrow).











Figure 2. Kidney with simple cysts, tubular atrophy and interstitial fibrosis with mild inflammation (left panel) and clear cell renal cell carcinoma within the renal vein, as arrowed in the right panel.


Date added to bjui.org: 02/12/2012

DOI: 10.1002/BJUIw-2012-062-web


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