[Current aspects in pediatric urolithiasis treatment]. / Aktuelle Aspekte zur Steintherapie im Kindesalter.

Compared with adults, urolithiasis is quite rare in children (1-2% of all urinary stones occur during childhood). In principle, all therapy modalities for adults can also be used in children. However, due to some anatomic and functional peculiarities in children, the differential indication for the various treatment modalities differ. As a rule, asymptomatic renal stones are not treated but observed. More urinary stones pass spontaneously in children compared with adults. If spontaneous passage is not possible or does not occur, noninvasive and minimally invasive techniques are indicated. Extracorporeal shock wave lithotripsy is the therapy of choice in most instances. Today, endoscopic techniques, however, can be safely used even in very small infants. For larger renal stones and those consisting of cysteine or whewellite, percutaneous nephrolithotomy (PCNL) is the therapy of choice, and for distal ureteral stones ureteroscopy is the method of choice. Laparoscopic and open surgery are reserved for very rare cases, especially with concomitant pathologies. Bladder calculi are treated by transurethral or suprapubic lithotripsy.

[Update of the 2Sk guidelines on the diagnostics, treatment and metaphylaxis of urolithiasis (AWMF register number 043-025) : What is new?] / Aktualisierung der S2k-Leitlinie zur Diagnostik, Therapie und Metaphylaxe der Urolithiasis (AWMF Registernummer 043-025) : Was ist neu?

The increase of medical knowledge and technical innovations together with the demographic change represent a challenge for the new conception of guidelines and clinical studies. The present S2k guidelines, which are exclusively concerned with kidney and ureteral stones, should support the treatment of urolithiasis in hospitals and private practices and provide information on urolithiasis for patients. Increasing interdisciplinary collaboration in stone treatment is also demonstrated in the number of professional and working groups participating in the update of the new guidelines. The present S2k guidelines emerged from a consensus process and demonstrate the current recommendations in step with actual practice. They provide decision-making guidance for diagnostics, treatment and metaphylactic measures based on expert opinions and available published fundamental evidence from the literature.

[Secondary malignancies in urinary diversions]. / Sekundärmalignome in Harnableitungen.

In contrast to ureterosigmoidostomy no reliable clinical data exist for tumor risk in different forms of urinary diversion using isolated intestinal segments.In 44 German urological departments, operation frequencies, indications, patient age, and operation dates of the different forms of urinary diversion, operated between 1970 and 2007, could be registered. The secondary tumors up to 2009 were registered as well and related to the numbers of the different forms of urinary diversions resulting in tumor prevalences.In 17,758 urinary diversions 32 secondary tumors occurred. The tumor risk in ureterosigmoidostomy (22-fold) and cystoplasty (13-fold) is significantly higher than in other continent forms of urinary diversion such as neobladders or pouches (p<0.0001). The difference between ureterosigmoidostomy and cystoplasty is not significant, nor is the difference between ileocecal pouches (0.14%) and ileal neobladders (0.05%) (p=0.46). The tumor risk in ileocecal (1.26%) and colonic neobladders (1.43%) is significantly higher (p=0.0001) than in ileal neobladders (0.5%). Of the 16 tumors that occurred following ureterosigmoidostomy, 16 (94%) developed directly at the ureterocolonic borderline in contrast to only 50% following urinary diversions via isolated intestinal segments.From postoperative year 5 regular endoscopic controls of ureterosigmoidostomies, cystoplasties, and orthotopic (ileo-)colonic neobladders are necessary. In ileocecal pouches, regular endoscopy is necessary at least in the presence of symptoms or should be performed routinely at greater intervals. Following neobladders or conduits, only urethroscopies for urethral recurrence are necessary.

[Recurrence prevention of urolithiasis with respect to economic aspects]. / Rezidivprävention der Urolithiasis unter Berücksichtigung ökonomischer Aspekte.

Recurrence prevention in urinary stone disease not only makes good medical but also economic sense. Up to 40% of recurrences can be prevented by a rational urinary stone metaphylaxis whereby not only treatment costs but also the cost of lost productive work time can be saved. Detailed knowledge of stone composition and medical history of the patient is a prerequisite for a rational metaphylaxis which according to the S2 guidelines results in assignment to the high or low risk group. The required diagnostic and therapeutic measures are also decided by this classification. In addition to general metaphylaxis (reduction of overweight, physical activity, appropriate fluid intake, balanced diet) further specific measures may be necessary depending on the risk group and stone type.

[Diagnostic imaging--the end of intravenous urography?]. / Bildgebende Diagnostik--das Ende des AUG?

For diagnosing patients with acute flank pain, unenhanced helical computed tomography (CT) is the most accurate method. However, conventional diagnosis using sonography and intravenous urography yields comparable results. For proper assessment, the availability, radiation dose, and cost have to be considered as well. Although the availability of CT has increased, radiation dose and cost are in favour of conventional diagnosis. At this time, we recommend sonography as the primary method. Depending on availability, intravenous urography or CT is a possible alternative.

[Economic aspects of evidence-based metaphylaxis]. / Okonomische Aspekte der evidenzbasierten Harnsteinmetaphylaxe.

The calculation model which we developed for the cost of stone therapy and metaphylaxis in Germany some years ago with a social health insurance company is based on estimates of stone incidence, types and recurrence rates, actual costs for stone removal, and metaphylaxis (based on data from a district of the social health care system). There are 200,000 stone recurrences per year in Germany. Costs for treatment of these stones amount to $687,000,000. Stone metaphylaxis reduces the recurrence rate by some 40%. The annual cost for stone removal could be lowered by $275,300,000. Metabolic evaluation/metaphylaxis amount to $70,100,000 per year, resulting in a net saving of $205,200,000. In 1997, there were 96 days off work per stone patient resulting in 5,800,000 days off work in Germany per year. Metaphylaxis is not only medically effective in stone formers but also can lower health care cost significantly. Although health care conditions may vary from country to country, in principle this calculation model is applicable also to other countries.

Diagnosis and metaphylaxis of stone disease. Consensus concept of the National Working Committee on Stone Disease for the upcoming German Urolithiasis Guideline.

This review draws the recent state of the art in metabolic diagnosis and metaphylaxis of stone disease. It is the basis for the consensus approval with the other medical societies and institutions in Germany involved in the guideline process of the new "Urolithiasis Guideline". The German Working Committee on Stone Disease reviewed critically the current literature in the field of urolithiasis-including the existing German and EAU-Guidelines as well as the Conference Book of the First International Consultation on Stone Disease. As far as possible the references were rated according to the EBM criteria. On this basis the expert group discussed all pathways and statements regarding the management of stone disease. The present review coincides with the consented guideline draft of the German Working Committee on Stone Disease. Occurrence of stone disease in the western world increases seriously. Modern lifestyle, dietary habits and overweight-problems of the affluent societies-emerge to be the important promoters of the "stone-boom" in the new millennium. This even affects children, whose stone prevalence is otherwise significantly less than that of adults. Criteria for the high risk group of stone formers were clearly defined. A diagnostic standard is formulated for the basic and the elaborate metabolic evaluation of a stone patient. Approximately 75% of all stone patients could anticipate stone recurrence with elementary reorientation of their lifestyle and dietary habits, summarized as general metaphylaxis. About 25% of the stone formers require additional pharmacological intervention to normalize their individual biochemical risk, precisely compiled for each stone type as specific metaphylaxis.

Renal tubular alteration by crystalluria in stone disease-an experimental study by means of MDCK cells.

OBJECTIVES: Physicochemical properties of urine do not explain the formation of urinary stones. Clinical findings and results of animal experiments suggest that alteration to the renal tubular cell plays a key role in the initiation of urinary stone formation. It is not clear whether this is a primarily intracellular alteration of metabolic origin which, after lysis of the renal tubular cell in the lumen, presents a nucleus for the formation of concretions, or whether in the lumen it is tubular cell damage induced by crystalluria that triggers the formation of urinary stones. MATERIALS AND METHOD: Using Madin-Darby canine kidney cells, the influence of crystalluria on the renal tubular cell was tested in cell cultures. The influence of parathyroid hormone, vitamin D(3), oxalate and calcium concentrations and the extent to which these processes can be inhibited by allopurinol and selenium were investigated. RESULTS: Calcium oxalate monohydrate crystals produced reproducible damage to the renal tubular cell which was independent of parathyroid hormone and vitamin D(3). The crystalluria-induced effects were unrelated to the oxalate and calcium concentration or the pH. Allopurinol and selenium were able to inhibit the processes. CONCLUSION: The results indicate secondary involvement of the renal tubular cell in lithogenesis as a result of luminal alteration caused by calcium oxalate crystals. Mechanical damage and interaction between crystal and tubular cell lead to the apposition of crystals. The nephroprotective effect of allopurinol and selenium as antioxidants might explain the benefit of allopurinol found clinically in terms of stone metaphylaxis.

[Treatment of a subcapsular renal bleeding after extracorporeal shockwave lithotripsy with recombinant, activated factor VII]. / Behandlung einer subkapsulären Nierenblutung nach extrakorporaler Stosswellenlithotripsie mit rekombinantem Faktor VIIa.

We report on a patient who suffered a large subcapsular and perirenal haematoma after extracorporeal shockwave lithotripsy. Despite surgical intervention the bleeding did not stop for 6 days and 10 units of packed red blood cells were transfused. With the treatment of recombinant, activated factor VIII (NovoSeven((R))) an immediate haemostasis could be reached, so that impending nephrectomy could be avoided. This is the first case where FVIIa has been successfully used to stop a trauma-related bleeding in a patient without any obvious accompanying coagulation disorder.

GTP cyclohydrolase I mRNA: novel splice variants in the slime mould Physarum polycephalum and in human monocytes (THP-1) indicate conservation of mRNA processing.

GTP cyclohydrolase I (EC 3.5.4.16) is the first enzyme in the biosynthesis of tetrahydrobiopterin [(6R)-5,6,7,8-tetrahydro-L-biopterin, H(4)-biopterin] in mammals and of folic acid in bacteria. Here we have characterized the GTP cyclohydrolase I gene structure and two mRNA species from Physarum polycephalum, an acellular slime mould that synthesizes H(4)-biopterin and metabolites of the folic acid biosynthetic pathway. Its GTP cyclohydrolase I gene consists of seven exons, and the two GTP cyclohydrolase I cDNA species isolated from Physarum encode for proteins with 228 (25.7 kDa) and 195 (22.1 kDa) amino acids. Furthermore, we identified two previously undescribed mRNA species in interferon-gamma-treated human myelomonocytoma cells (THP-1) in addition to the cDNA coding for the fully functional 250-residue (27.9 kDa) protein, which is identical with that in human phaeochromocytoma cells. One of the new splice variants codes for a 233-residue (25.7 kDa) protein, whereas the other codes for the full-length protein but is alternatively spliced within the 3'-untranslated region. In heterologous expression, the shorter proteins of Physarum as well as of THP-1 cells identified here are degraded by proteolysis. Accordingly, only the 27.9 kDa protein was detectable in Western blots from THP-1 cell extracts. Quantification of GTP cyclohydrolase I mRNA species in different human cell types with and without cytokine treatment showed that in addition to the correct mRNA the two splice variants isolated here, as well as the two splice variants known from human liver, are strongly induced by cytokines in cell types with inducible GTP cyclohydrolase I (THP-1, dermal fibroblasts), but not in cell types with constitutive GTP cyclohydrolase I expression (SK-N-SH, Hep-G2). As in human liver, splicing of the new mRNA variant found in THP-1 cells occurs at the boundary of exons 5 and 6. Strikingly, the 195-residue protein from Physarum is alternatively spliced at a homologous position, i.e. at the boundary of exons 6 and 7. Thus alternative splicing of GTP cyclohydrolase I at this position occurs in two species highly distant from each other in terms of evolution. It remains to be seen whether variant proteins encoded by alternatively spliced GTP cyclohydrolase I mRNA transcripts do occur in vivo and whether they participate in regulation of enzyme activity.

Porcine urinary tract as a training model for ureteroscopy.

OBJECTIVES: Endourological procedures as ureteroscopy require an advanced level of skills. To facilitate the training of the proper technique, simulators are helpful. Nonbiological models, useful to learn the basic steps, do not represent the clinical situation in an ideal way. We therefore looked for a biological but nevertheless easily available model. METHODS: The complete urinary tract is dissected off the retroperitoneal organ package of freshly slaughtered pigs. RESULTS: The porcine urinary tract model allows for training all aspects of diagnostic and therapeutic ureteroscopy including lithotripsy and stenting in a way which is almost identical to the clinical situation in humans. CONCLUSIONS: The porcine urinary tract model is an ideal ex vivo model. Concerning 'tissue feeling' and anatomic relations, it is superior to nonbiological simulators. Nevertheless, it is quite easily available and inexpensive. In training courses, we have used it with great success.

Minimally invasive PCNL in patients with renal pelvic and calyceal stones.

Stones of the renal pelvis can be treated either by extracorporeal shock wave lithotripsy (SWL) or percutaneous nephrolithotomy (PCNL). As a low-risk procedure with a longer treatment period, SWL often leads to persistent residual stone fragments, whereas conventional PCNL achieves a higher stone-free rate and allows a shorter treatment period albeit with a somewhat higher surgical risk. To reduce the invasiveness of conventional PCNL, the application of a miniaturised instrument for PCNL (MPCNL) was evaluated. For MPCNL a rigid nephroscope with a calibre of 12 F was developed and used in 19 patients. After puncture of the kidney under ultrasound control and single-step dilatation, a 15 F Amplatz sheath was placed. Data on the stone size and location, stone-free rate, blood transfusions, operating time and complications were recorded. In all patients, the part of the kidney afflicted by the stone was successfully punctured. On average, retreatment rate was 0.7. The mean stone size was 2.4 cm(2). The average operating time was 99.2 min. In every case, the absence of residual stones was confirmed radiologically and nephroscopically. Hemorrhages requiring a blood transfusion did not occur. A febrile pyelonephritis occurred as a postoperative complication in one patient (= 5.3%). MPCNL represents an alternative to SWL for renal calculi with a size from 1 to 2 cm located in the renal pelvis and calices, especially the lower calix. The advantages are the short treatment time, the high stone-free rate and the accessibility of lower pole stones which are less amenable to SWL. MPCNL is not suitable for large concrements since the limited sheath diameter would increase the operating time. Due to this limitation, MPCNL represents an extension of the indication for conventional PCNL that it can in no way replace.

Arterial blood pressure following different types of urinary stone therapy. Presented at the 8th European Symposium on Urolithiasis, Parma, Italy, 1999.

OBJECTIVE: Several studies reported increased blood pressure (BP) values following extracorporeal shock wave lithotripsy (ESWL) treatment of renal stones. It is unclear, however, whether this is due to ESWL, since nephrolithiasis itself increases the relative risk of developing hypertension. Therefore we prospectively studied the BPs of stone patients undergoing different types of treatment. METHODS: 252 stone patients (63% males, 37% females, median age 44.3, range 11.7-86.4 years) participated. 168 suffered from uretral stones: 50 underwent ESWL; 40 ureteroscopy, and 78 patients passed stones spontaneously (SP). 84 had renal stones: 60 underwent ESWL; 8 percutaneous nephrolithotomy/open surgery, and 16 no treatment. Systolic (SBP) and diastolic (DBP) BP were measured according to Riva-Rocci prior to, immediately after, and 3, 6, 12, 18 and 24 months after stone therapy. RESULTS: Immediately after SP, SBP decreases, whereas after active stone treatment increases (highest after ESWL) in SBP were seen. DBP was unchanged. During the further follow-up, a gradual increase in BP was observed in all groups. At 24 months in all groups, regardless of the stone location and type of treatment, SBP and DBP were significantly higher than the pretreatment levels (p = 0.000). There was no a difference between renal and ureteral stones, or between the ESWL treatment and the other groups. CONCLUSION: Renal stone disease itself rather than the type of treatment significantly increases SBP and DBP during a follow-up period of 24 months. The underlying mechanisms remain to be elucidated.

Comparison of symptoms, morphological, microbiological and urodynamic findings in patients with chronic prostatitis/pelvic pain syndrome. Is it possible to differentiate separate categories?

164 patients with prostatitic symptoms were evaluated by segmented urinalysis and culture and classified according to the National Institutes of Health classification system: 64 patients (38%) suffered from chronic bacterial prostatitis; 12 (7%) from inflammatory chronic pelvic pain syndrome, and 92 (55%) from non-inflammatory chronic pelvic pain syndrome. Transrectal ultrasound of the prostate, uroflowmetry and measurement of residual urine were also performed. Complaints were recorded using a questionnaire. Our studies revealed that leukocytes in expressed prostatic secretions could be detected in only 24 and 36% of patients with positive bacterial or chlamydial culture. Complaints, ultrasound and urodynamic findings were similar in the 3 groups. Therefore the differential diagnosis and therapy, based on the results of the 4-glass test and cultures as well as on transrectal ultrasound of the prostate, seem to be difficult.

Protection against endotoxemia in rats by a novel tetrahydrobiopterin analogue.

We studied the effects of a novel pterin antagonist of NO synthase, the 4-amino analogue of tetrahydrobiopterin (4-ABH4), in a rat model of endotoxic shock and compared its properties with those of N(G)-monomethyl L-arginine (L-NMMA). Treatment with a bolus dose of 4-ABH4 at 2 h after LPS challenge significantly improved the 6-day survival rate, compared with the controls treated with saline. L-NMMA treatment did not significantly influence the survival rate. This bolus treatment, using either compound, had no effect on the plasma nitrite + nitrate or plasma IL-6 levels. The continuous infusion of 4-ABH4 efficiently suppressed the enhanced calcium-dependent/independent NO synthase activities induced by endotoxin in lung homogenates and completely suppressed the increase in plasma nitrite + nitrate caused by endotoxin at 5 h, with no significant difference compared with the L- NMMA treatment. Treatment of RAW264.7 murine macrophages with 4-ABH4 but not with L-NMMA suppressed endotoxin-induced tumor necrosis factor-alpha release by the cells, whereas nitrite in the supernatant decreased in a dose-dependent fashion in both assay systems. Our data show that 4-ABH4, an inhibitor of inducible NO synthase, significantly improves survival in a rat model of endotoxic shock when administered in a bolus dose that does not reduce plasma total nitrite + nitrate levels. Because we observed no overt signs of toxicity and no influence on organ-specific tetrahydrobiopterin levels, we conclude that the novel compound 4-ABH4 is a promising drug candidate for protection against endotoxin-related mortality.

[Socioeconomic aspects of urinary calculi and metaphylaxis of urinary calculi]. / Volkswirtschaftliche Aspekte des Harnsteinleidens und der Harnsteinmetaphylaxe.

A calculation model was developed for the cost of stone therapy and metaphylaxis in Germany based on estimates of stone incidence, types and recurrence rates, actual costs for stone removal and metaphylaxis (based on data from a district of the social health care system). There are 200,000 stone recurrences per year in Germany. Cost for treatment of these stones amount to $687,000,000. Stone metaphylaxis reduces the recurrence rate by some 40%. The annual cost for stone removal could be lowered by $275,300,000. Metabolic evaluation/metaphylaxis amount to $70,100,000 per year, resulting in an net saving of $205,200,000. In 1997, there were 96 days off-work per stone patient resulting in 5,800,000 days off-work in Germany per year. Metaphylaxis in stone formers can lower health care cost significantly. Although health care conditions may vary from country to country, in principle this calculation model is applicable also to other countries.

Course of calcium stone disease without treatment. What can we expect?

OBJECTIVES: The knowledge of the natural history (i.e. the course of the disease without metaphylaxis is the base for establishing rational guidelines for metaphylaxis in urolithiasis. METHODS: This review is based on a Medlinetrade mark Search (1966-1999) and the proceedings of the Bonn-Vienna and European symposia on urolithiasis. Only 31 references were sufficient for the purpose of this review. RESULTS: In idiopathic calcium stone disease, stone frequency without metaphylaxis is 0.10-0.15 stones per patient per year. The average recurrence rate is 30-40%. Recurrence rate increases with age and observation time. Risk for recurrence is highest during the first 4 years after the first stone episode. More than 50% of all recurrent stone formers have only one recurrence during their lives. 10% of recurrent stone formers have more than 3 recurrences. Risk factors for recurrence are: male sex, multiple and lower calyx stones, early onset, familial history, complications after stone removal. Metabolic evaluation is a poor predictor of the risk for recurrence. CONCLUSIONS: Renunciation of metaphylaxis is justified in first stone formers with idiopathic calcium oxalate and apatite stones. All patients, however, should be advised to increase their fluid intake.

Reduction of high-energy shock-wave-induced renal tubular injury by selenium.

In shock-wave-induced renal injury cavitation-generated free radicals play an important role. Using an in vitro model with Madin-Darby canine kidney (MDCK) cells, we investigated the influence of selenium, a free radical scavenger, in shock-wave-induced tubular cell injury. Suspensions of MDCK cells (33 x 10(6) cells/ml) were placed in small containers (volume 1.1 ml) for shock wave exposure. Two groups of 12 containers each were examined: (1) control (no medication), (2) selenium (0.4 microg/ml nutrient medium). Six containers in each group were exposed to shock waves (impulse rate 256, frequency 60 Hz, generator voltage 18 kV), while the other six containers in each group served as a control. After shock wave exposure, the concentration of cellular enzymes such as lactate dehydrogenase (LDH), N-acetyl-beta-glucosaminidase (NAG), glutamate oxaloacetate transaminase (GOT) and glutamate lactate dehydrogenase (GLDH) in the nutrient medium was examined. Following shock wave exposure there was a significant rise in LDH, NAG, GOT and GLDH concentrations. Selenium reduced this enzyme leakage significantly. Thus we conclude that selenium protects renal tubular cells against shock-wave-induced injury. Since selenium is an essential part of glutathione peroxidase, this effect seems to be mediated by a reduction in reactive oxygen species.

Comparison of extracorporeal shock wave lithotripsy and ureteroscopy in the treatment of ureteral calculi: a prospective study.

146 patients whose ureteral stones did not pass spontaneously participated in a prospective study on optimal management. Patients were offered two treatment options: extracorporeal shock wave lithotripsy (ESWL) and ureteroscopy (URS). The stone was treated with the technique preferred by the patient. In case of treatment failure after first-line therapy, patients again could decide on how to proceed. Stone analysis could be obtained from 72.6% patients. ESWL was the primary treatment in 66.4% patients. In 2 patients, ESWL was the secondary treatment after failed URS. URS was the first-line therapy in 33.6% patients. In 29 patients URS was done after failed ESWL. For analgesia, sedoanalgesia or spinal anesthesia were used. Analgesia was required in 74.2% ESWL and 100% URS sessions. Following ESWL, 70.1% patients became stone free. In 29.9% ESWL failed. Distal stones had a higher failure rate than proximal or mid-ureteral calculi. Distal stones treated without success were significantly larger than those treated successfully. Failures were switched to URS. Stone analysis could be obtained in 26 patients with failed ESWL: 23/26 consisted of pure whewellite or mixed whewellite stones. Clinically relevant complications were not observed. After URS, 94.9% of the patients became stone free. In distal stones, the stone-free rate was 97.5%. There was only 1 relevant complication: a proximal ureteral lesion requiring surgical repair. Our study demonstrates that URS is a safe and highly effective treatment option for ureteral stones. In patients with distal ureteral stones, it should be offered as a first-line treatment. When whewellite is expected as the stone mineral, URS is the treatment of choice.