Issues n.1 - 2011


n.1 - 2011

Crystal/cell interaction and nephrolithiasis

Saeed R. Khan


Crystals of calcium oxalate (CaOx), the major constituents of most urinary stones, are injurious to cells, create oxidative stress and evoke an inflammatory response. Renal injury results in cell damage. The damaged and dead cells are released into the urine and are capable of promoting crystal nucleation at much lower supersaturations. Damaged cell membranes also provide sites for crystal attachment and eventual retention within the kidneys. Renal epithelial damage may assist in movement of crystals from the intratubular to interstitial location and perhaps in the formation of apatitic Randall’s plaques. Inflammatory response may be responsible for Randall’s plaques ulceration to the renal papillary surface.

Treatment of small lower pole calculi – SWL vs. URS vs. PNL?

Thomas Knoll, Andrea Tasca, Noor P. Buchholz


According to current guideline recommendations extracorporeal shock wave lithotripsy (SWL) remains the first choice treatment for small and mid-sized renal calculi. However, the results of SWL treatment for lower pole stones can be disappointing whilst more invasive endoscopic modalities, such as flexible ureterorenoscopy (fURS) and percutaneous nephrolithotomy (PNL) are often considered more effective. This article summarizes a point-counterpoint discussion at the 9th eULIS symposium in Como, Italy, and discusses the potential advantages and disadvantages of the different therapeutic approaches.

Ureteral stones: SWL treatment

Gianpaolo Zanetti


When stone removal is indicated SWL (Shock Wave Lithotripsy) and ureteroscopy (URS) are the two most commonly offered interventional procedures and they are both acceptable as first-line treatment. The choice of the procedure depends on several factors, including local experience, patient preference, available equipment, and associated costs. The meta-analysis by the EAU/AUA Guideline Panel in 2007 analysed SWL stone-free results for three locations in the ureter (proximal, mid, distal) and reported an overall stone-free rate for proximal ureteral stones of 82%, with no difference in stone-free rate from URS results. However, for stones < 10 mm SWL, at 90%, had a higher stone-free rate than URS and even for mid and distal ureter it reached a stone-free rate of 84% and 86% respectively. It does appear that SWL may be more effective in the paediatric subset than in the overall population, particularly in the mid and lower ureter with a stone free rate of 82% and 80% respectively. In fact, children appear to pass stone fragments after SWL more readily than adults. SWL is a safe method to treat ureteral stones and serious complications occur very rarely when proper indications are followed. A few published studies addressed the role of SWL in acute renal colic. The available data suggest that is a safe procedure, with an overall success of 70-80% and a need for further intervention in 2-20%. In choosing the optimal therapy for an individual patient, several factors that might affect the outcome should be considered to identify the best candidate for SWL. A superior success rate for proximal ureteral stones was reported in the EAU/AUA meta-analysis but stone size over 10 mm appears negatively correlated with the stone-free rate. About composition, calcium oxalate monohydrate, brushite, cystine and matrix are unfavourable compositions for SWL. Finally, impacted stones are often more resistant to fragmentation. Whether hydronephrosis affects the outcome of SWL remains controversial. A body mass index of over 30 has been found to be an independent factor in predicting failure of SWL treatment in ureteral stones. A number of treatment strategies have been proposed to increase SWL efficacy: a promising suggestion to improve SWL outcome is to reduce the shock wave rate. There have also been attempts to improve shock wave efficiency of stone fragmentation with new shock wave lithotriptor devices. But although these innovation are promising, no advantage in stone-free rate or retreatment rate have yet been proven. Acoustic coupling is a key factor affecting the efficacy of shock wave lithotripsy. An accurate pre-treatment assessment of stone burden and composition with unenhanced CT scan provides useful information to discern which treatment strategy should be favoured and may reduce SWL failure. The real cost for SWL and URS varies considerably from one centre to another, as a result of different internal organisations and also due to the principles of reimbursement from the health care system.

Conclusions: SWL is the first treatment choice for stones smaller than 1 cm in the proximal ureter. With a lower grade of invasiveness and the possibility to complete the treatment with only analgesics and sedation on an outpatient basis, SWL still appears an excellent alternative for removing ureteral stones and these properties compensate for the higher need for repeated treatments. An accurate pre-treatment assessment of stone and clinical factors to select the best candidates for SWL could improve the stone-free rate and reduce retreatments.

Predicting five-year recurrence rates of kidney stones: An artificial neural network model

Renata Caudarella, Lucio Tonello, Elisabetta Rizzoli, Fabio Vescini


Objective: Due to high recurrence rates of urolithiasis, many attempts have been performed to identify tools for predicting the risk of stone formation. The application of Artificial Neural Networks (ANNs) seems to be a valid candidate for reaching this endpoint. The aim of this study was to find a set of parameters able to predict recurrence episodes immediately after clinical and metabolic evaluation performed at the first visit in a 5-year window.

Material and methods: Data were collected from 80 outpatients who presented idiopathic calcium stone disease both at baseline and after 5 years; patients underwent treatment including both general measures and medical therapy. After 5 years, patients were classified into two subsets, namely SSFs (without recurrence episodes), consisting of 45 subjects (56.25%) and RSFs, with at least one episode of recurrence after the baseline, consisting of 35 subjects (43.75%). Helped by conventional statistics (One-way ANOVA and three Discriminant Analyses: standard, backward stepwise and forward stepwise), an Artificial Neural Network (ANN) approach was used to predict recurrence episodes.

Results: An optimal set of 6 parameters was identified from amongst the different combinations in order to efficiently predict the outcome of stone recurrence in approximately 90% of cases. This set consist of serum Na and K as well as Na, P, Oxalate and AP(CaP) index from urine. The results obtained with ANN seem to suggest that some kind of relationship is present between the identified parameters and future stone recurrence. This relationship is probably very complex (in the mathematical sense) and non-linear. In fact, a Logistic Regression was built as a comparative method and performed less good results at least in terms of accuracy and sensitivity.

Conclusions: The application of ANN to the database led to a promising predicting algorithm and suggests that a strongly non-linear relationship seems to exist between the parameters and the recurrence episodes. In particular, the ANN approach identifies as optimal parameters serum concentration of Na and K as well as urinary excretion of Na, P, Oxalate and AP(CaP) index. This study suggest that ANNs could potentially be a useful approach because of their ability to work with complex dynamics such as recurrent stone formation seems to have.

Prognostic estimation of chemical composition of recurrent urinary stones

Olga Konstantinova, Oleg Apolikhin, Andrei Sivkov, Nikolai Dzeranov, Elana Yanenko


We conducted a retrospective study of the course of recurrent urolithiasis in 127 patients (63 women, 64 men aged from 27 to 58) who were under close and regular outpatient follow-up for up to 15 years and who did not receive conservative prophylactic therapy due to different reasons. The group consisted of 33 patients with uric acid lithiasis, 52 patients with calcium oxalate lithiasis, 42 patients with magnesium-ammonium- phosphate lithiasis. By the start of follow-up not a single patient had had urinary stones detected by ultrasound and X-ray. For the period of observation there were up to 7 recurrences diagnosed in each patient and we studied the chemical composition not only of the primary stones but also of 352 recurrent stones by means of infrared spectrophotometry and X-ray diffraction. In our investigation we also performed biochemical and microbiological analysis and urinalysis. We established the chance and we found prognostic factors of changes in the type of stone formation in patients with different chemical forms of the disease. In patients with uric acid lithiasis recurrent stones can be composed of calcium-oxalate or phosphate, in patients with calciumoxalate lithiasis recurrent stones could be composed of phosphate, and patients with magnesiumammonium- phosphate stones may develop stones of uric acid or calcium-oxalate.

The role of long-term loading of cholesterol in renal crystal formation

Yasunori Itoh, Mugi Yoshimura, Kazuhiro Niimi, Masayuki Usami, Shuzo Hamamoto, Takahiro Kobayashi, Masahito Hirose, Atsushi Okada, Takahiro Yasui, Keiichi Tozawa, Kenjiro Kohri


We studied the effects of cholesterol load on urinary stone in rats receiving a standard diet or a high fat diet. Sixty male rats were randomized to two groups and were fed either a standard diet (SD group) or a high fat diet (HFD group) for 8 weeks. Then the two groups were further divided into four groups. SD group, HFD group, SD + EG group (with standard diet + ethylene glycol administration for two weeks), and HFD + EG group (with high fat diet + ethylene glycol administration). The starting date of EG administration was considered to be week 0. Twenty-four-hour urine samples were collected in week 0, week 1, and week 2, and oxalate excretion and citrate excretion were measured by capillary electrophoresis analyzer. The excretion of phosphorus, magnesium, and creatinine for 24 hours was measured using an automated analyzer. Serum sodium, potassium, chloride, calcium, phosphate, magnesium, creatinine, total cholesterol, triglyceride, HDL-cholesterol and glucose were determined using an automated analyzer. The kidney tissues were obtained to perform hematoxyline-eosine staining and Pizzolato’s staining to detect oxalate-containing crystals. The average body weight in HFD groups and HFD + EG group in week 0 was significantly higher than that of SD group and SD + EG group. The calcium oxalate crystal deposition was not observed in all groups in week 0. HFD + EG group in week 1 had sporadically calcium oxalate crystal deposition in renal distal tubular cells and tubular lumens. In week 2, the number of crystal deposition in HFD + EG group was increased remarkably. The crystals were slightly observed in SD + EG group in week 2. The excretion of urinary calcium and phosphate in HFD group and HFD + EG group was significantly higher than that of the SD group and SD + EG group in week 0. The amount of urinary citrate excretion in the SD group and SD + EG group showed a significantly higher value compared with that of the HFD group and HFD + EG group in week 0. The level of serum total cholesterol in the HFD group and HFD + EG group was higher compared to that in the SD group and SD + EG group. The serum triglyceride level was not significantly different in the four groups in week 0. Interestingly, the level of triglyceride of EG administration groups (SD + EG and HFD + EG group) was significantly higher than that in EG no-administration groups (SD group and HFD group) in week 1 and week 2. The serum glucose level in the HFD group and HFD + EG group was significantly higher than that in the SD group and SD + EG group in week 0. In week 2, the glucose level of EG administration groups (HDF + EG group and SD + EG group) was significantly lower than that of EG no-administration groups (HFD group and SD group). In conclusion, this result suggested that long-term loading of cholesterol could increase renal calcium stone formation.

Effect of sex hormones on crystal formation in a stone-forming rat model

Iwao Yoshioka, Masao Tsujihata, Akihiko Okuyama


Sex hormones have substantial effects on crystal formation in the rat kidney through oxalate metabolism and oxidative cell damage. Testosterone is a promoter and estradiol an inhibitor of such crystal formation. The development of new medications related to sex hormones or GO are anticipated for sufferers of recurrent urolithiasis.

The role of functional urodynamic disorders in the pathogenesis of urolithiasis

Irina S. Mudraya, Lubov A. Khodyreva


Objective: The aim of this study was to analyze the functional urodynamic parameters, which affect renal function and can promote stone formation.

Materials and Methods: We examined sixty consecutive patients with renal and ureteral stones and indication to urinary diversion by nephrostomy tube or indwelling catheter. In upper urinary tract, urodynamics was assessed with the help of electromanometry and multichannel impedance ureterography. To measure ureteral peristalsis, a probe equipped with 9 successively incorporated electrodes was indwelled retrogradely into distal ureter through a urethroscope. The documented data included renal pelvic pressure (RPP) and the number of ureteric contractility parameters such as peristalsis amplitude, peristalsis rate, the ureteral wall tone, the characteristics of contractile waveform and its direction (antegrade or retrograde). Urinary biochemistry and enzymuria were studied in order to characterize the lithogenic activity and renal function. The patients were divided into three groups: group 1 included patients with acute pyelonephritis caused by unilateral stone obstruction (n = 24), group 2 patients with stones and non-acute latent chronic pyelonephritis (n = 31) and group 3 unobstructed patients without signs of inflammation (n = 5).

Results: In the three groups of patients, the mean baseline RPP values were, respectively 28.7 ± 2.6 (range 20.0-32.4); 15.6 ± 1.9 (range 3.5-29.0); and 3.6 ± 1.4 (range 0-8) cm H2O. The ratio of GGT to urinary creatinine changed similarly: it was elevated during acute inflammation, moderately enhanced during the chronic process, but significantly decreased after stone removal and resolution of inflammation (11.5 ± 3.2; 8.1 ± 2.0, and 1.6 ± 0.5 unit/L). Biochemical evaluation revealed 54% patients with enhanced lithogenic activity assessed by elevated calcium and oxalates in the urine (4.95 ± 0.25 mM and 504 ± 35 μM, correspondingly) and low level of citrates (2.5 ± 0.1 mM). In a subgroup of 11 patients with urolithiasis the baseline RPP values were assessed in relation to ureteral contractile activity in the distal region of ureter. Low RPP was found in a patient (9%) with strong ureteral contractions and a low tone while RPP was moderately higher in another patient (9%) with moderate mean peristaltic amplitude value but with elevated tone of ureteral wall. In the majority of examined patients with significantly elevated mean RPP value (45%), peristalsis of distal ureter was characterized by weak long-term and frequent contractions as well as increased tone with respect to the patients with normal RPP. The patients (36%) with moderately increased RPP demonstrated strong frequent contractions in the distal ureter and low ureteral wall tone. Changes in urodynamic parameters in patients examined before and immediately after ureteroscopy and lithotripsy procedures were observed. Factors affecting the ureteral wall tone were duration of stone disease, location and disposition of stones.

Conclusions: Our clinical observations obtained with the help of physiological methods revealed various factors modulating the urodynamic disorders in renal pelvis: temporary or persistent elevation of pelvic pressure; peculiarities of contractile function in distal ureter manifested by the tonic changes and variations in contractile amplitude, and certain abnormalities in propagation of contractile wave in the upper urinary tract. The reported urodynamic changes in patients with stone disease can be supplementary pathogenic factors causing deterioration of renal function probably followed by stone formation.

Evaluation of methods for urine inhibitory potential for precipitation of calcium oxalate

Teuta Opačak-Bernardi, Vesna Babić-Ivančić, Vatroslav Šerić, Milenko Marković, Helga Füredi-Milhofer, Ivana Marić, Robert Smolić, Martina Smolić, Antun Tucak


Renal lithiasis is a significant medical and social problem. Worldwide recurrence is anywhere from 3% to 5%. Objective of this paper is to evaluate two methods for distinguishing between stone formers and non-stone formers. Urine samples were titrated with calcium and seed crystals were added to facilitate precipitation. Ionic calcium levels were monitored and compared between the two groups. Stone formers showed impaired tolerance to the calcium added and increased precipitation on seed crystals. Both methods discriminated between stone formers and non-stone formers. Further evaluations are needed to establish the better of the two for wider clinical use.

Nephrolithiasis in medullary sponge kidney

Elisa Cicerello, Franco Merlo, Luigi Maccatrozzo


Seventy-one patients with documented Medullary Sponge Kidney (MSK) and nephrolithiasis underwent complete metabolic evaluation. These patients constituted 7.3% of our calcium stone-forming population Metabolic anomalies (hypercalciuria, hyperoxaluria, hypocitraturia and hyperuricosuria) were observed in 82% of patients. No patient was hypercalcemic and none had hyperparathyroidism. Thus the patients with medullary sponge kidney and renal stones had the same spectrum of metabolic anomalies as the overall population of idiopathic stone formers. Although these patients may have anatomic anomalies which determine stasis of urine and infection causing stone formation, they should be evaluated and treated appropiately for any metabolic defect.

Increasing water intake by 2 liters reduces crystallization risk indexes in healthy subjects

Viviane de La Guéronnière, Laurent Le Bellego, Inmaculada Buendia Jimenez, Oriane Dohein, Ivan Tack, Michel Daudon


Objective: The objective of the present study was to evaluate the effects of drinking 2 additional litres of water/day on several urinary risk factors for lithiasis in healthy subjects, through measurement of crystallization risk indices (Tiselius CRI).

Materials and methods: 48 healthy subjects, aged 25 to 50 were studied for urinary parameters including CRI in the laboratory ward, for 24 hours. After this first period, they were randomized either to a 2L/d additional water intake (treated group) or usual fluid consumption (control group) for a 6 days period, which ended by a second measurement period in the laboratory ward for 24 hours.

Results: Total additional water intake was actually 1.3L/d on average in treated subjects, because subjects decreased other usual sources of fluid intake. In 24 hour urine, Tiselius CRI varied differently among treated subjects and controls between the 2 periods; male controls subjects experienced much higher values (above 2 in average in first morning urine sample) in the second period (p = 0.05). Of interest, in a transversal analysis, we observed a positive relation between BMI or waist circumference on the one hand, and with 24 hour urea excretion or osmotic load on the other hand.

Conclusion: These results show a beneficial effect of a final 1.3L additional water intake on Tiselius CRI in healthy subjects.

Ureterolithiasis in children

Beata Jurkiewicz, Joanna Samotyjek


The aim of our work is to present our own experience in the field of urolithiasis treatment in children using ureteroscopic lithotripsy.

Diagnostic difficulties with estimation of the cause of nephrolithiasis. Case presentation

Katarzyna Gadomska-Prokop, Katarzyna Jobs


In some patients with recurrent urolithiasis we cannot identify the cause of stone formation. A 18 years old girl was evaluated for recurrent urolithiasis. Analysis of her stones demonstrated: calcium oxalate and 10% cystine; calcium phosphate and traces of magnesium and chloride, calcium phosphate and traces of potassium and calcium oxalate and ammonium-magnesium phosphate. We failed to make a correct etiological diagnosis despite of a very broad spectrum of laboratory investigations.

Stenting after ureteroscopy for ureteral lithiasis: Results of a retrospective study

Franco Merlo, Elisa Cicerello, Mario Mangano, Giandavide Cova, Luigi Maccatrozzo


Objectives: Routine ureteral stenting after ureteroscopy for stone removal is common. However ureteral stent negatively impact quality of life and can cause significant morbidity. This study was carried out to report our experience.

Materials and Methods: A total of 529 patients underwent ureteroscopy for the treatment of ureteral stones. In 436 pts (82%) a stent was placed, in 281 double J (removed within 2-4 weeks) and in 155 mono J (removed within 24 h). Ninethy-three did not received stenting. At 24 hour the mesaured outcomes were post operative pain, fever and hematuria, at 4 weeks need for hospital care (readmission or visit in the clinic) for lower urinary tract symptoms (LUTS), hematuria, fever or pain.

Results: No significant difference was observed between two groups regarding the complications at 24 hour after the treatment ( pain p = 0.6, fever = 0.7, hematuria p = 0.8). At 4 weeks after the ureteroscopy the incidence of LUTS, hematuria, pain and fever requiring the need for hospital care (readmission or visit in the clinic) was higher in the group with double J stent respect to the group with mono J stent (p < 0.05). At 3 months follow-up no difference was oberved between the two groups regarding stone-free rate and incidence of ureteral stricture formation.

Conclusions: Routine stenting is necessary after ureteroscopy for ureteral lithiasis to prevent pain and fever without difference in stone free rate and incidence of stricture formation rate between the two groups. LUTS, hematuria and /or pain needing for hospital care were more frequent in the group with double J stent in spite of high stone free rate and low incidence of stricture formation. Further prospective randomized studies are needed to assess the role of using “short” and “long-term” stenting after ureteroscopy lithotripsy, considering that the choice actually depends on the surgeon's intraoperative judgment.

The management of erectile dysfunction: Innovations and future perspectives

Rosario Leonardi, Matteo Alemanni


Phosphodiesterase 5 (PDE5) inhibitors are recommended as first line therapy for the treatment of erectile dysfunction (ED). To date, three PDE5 inhibitors are on the market: sildenafil, vardenafil and tadalafil. These compounds are available as oral tablets; they are rapidly absorbed in the gastrointestinal tract and are excreted mainly in the feces and, to a lesser extent, in the urine. Recently, an orodispersible formulation of vardenafil (vardenafil ODT) has been developed, which is able to dissolve in the mouth within seconds, releasing a minty flavor, without the need of being swallowed with water. The clinical studies so far performed showed that vardenafil ODT has a bioavailability superior to the traditional film-coated tablet. Among the other PDE5 inhibitors under development we report mirodenafil, lodenafil carbonate, avalafil and SLx-2101 It is likely that in the future molecules that act on pathways other than the one of NO/cGMP will be available. Such as Rho-kinase inhibitors, which inhibit the mechanism that leads to smooth muscle contraction thus allowing erection and hydrogen sulphide (H2S), an endogenous molecule synthesized from cysteine that can be both a vasodilator and a vasoconstrictor according to its concentration.

Prostate cancer and androgen deprivation: Optimal castration? Prospects and developments

Carmelo Boccafoschi


Prostate cancer (PCa) therapy has always been connected with the problem of what optimal male castration is and how to achieve and control it. Optimal medical castration should follow quite the same characteristics as surgical castration, then it should allow testosterone levels to be quickly and permanently reduced to levels ranging between 12 and 20 ng/dl. It should also be pointed out that using luteinizing hormone-releasing hormone (LHRH) agonists does not result in immediate castration; castration occurs 2-4 weeks after the first injection. Furthermore testosterone levels could also increase after subsequent injections if the depot formulation does not adequately cover the period between injections, as some LHRH receptors can remain free. This results in a new testosterone surge in conjunction with the following injections. Such episodes of increased testosterone levels in vicinity with injections are known as “miniflares”. Yet, also persistently increased testosterone levels (> 50 ng/dl) might be shown, even under continuous treatment with LHRH analogues. Such increases are known as “late breakthrough escapes”. A depot formulation of leuprolide acetate using a novel delivery system provides steady blood levels above the threshold of 0.1 mg/ml and completely suppresses pituitary gonadotropin secretion.