Katja Venborg Pedersen

How should patients with cystine stone disease be evaluated and treated in the twenty-first century?

Cystinuria continues to be one of the most challenging stone diseases. During the latest decades our knowledge of the molecular basis of cystinuria has expanded. Today 160 different mutations in the SLC3A1 gene and 116 in the SLC7A9 gene are listed. The full implications of type A, B or AB status are not yet fully understood but may have implications for prognosis, management and treatment. Despite better understanding of the molecular basis of cystinuria the principles of recurrence prevention have remained essentially the same through decades. No curative treatment of cystinuria exists, and patients will have a life long risk of stone formation, repeated surgery, impaired renal function and quality of life. Therapy to reduce stone formation is directed towards lowering urine cystine concentration and increasing cystine solubility. Different molecules that could play a role in promoting nucleation and have a modulating effect on cystine solubility may represent new targets for cystinuria research. Investigation of newer thiol-containing drugs with fewer adverse effects is also warranted. Determining cystine capacity may be an effective tool to monitor the individual patient’s response. Compliance in cystinuric patients concerning both dietary and pharmacological intervention is poor. Frequent clinical follow-up visits in dedicated centres seem to improve compliance. Cystinuric patients should be managed in dedicated centres offering the complete range of minimal invasive treatment modalities, enabling a personalized treatment approach in order to reduce risk and morbidity of multiple procedures.

Pathophysiological aspects of ureterorenoscopic management of upper urinary tract calculi.

Purpose of review Indications for ureterorenoscopy are expanding without hard scientific evidence to support its efficacy. Therefore, it is extremely important to focus on potential harmful effects of the procedure itself. This review explores how physiology of the upper urinary tract reacts to ureterorenoscopy, potentially translating into harmful effects, and how such pathophysiological processes may be minimized. Recent findings Complications to ureterorenoscopy and postoperative pain seem to be related to intrarenal pressure and/or access. Mean intrarenal pressures in the range of 60–100 mmHg during ureterorenoscopy without access sheaths have been measured, thus by far exceeding the threshold for intrarenal backflow, potentially resulting in septic complications. Intrarenal pressure may be reduced by use of ureteral access sheaths, which, however, may cause ureteral damage due to the limited size of the ureter and strain-induced ureteral contractions (peristalsis). Different receptor types modulate this peristaltic activity. &bgr;-receptor agonists have been investigated in animal and human trials for the purpose of relaxing the ureter. In randomized, placebo-controlled trials in pigs and humans, usage of the &bgr;-receptor agonist isoproterenol in the irrigation fluid has shown a potential for reducing both intrarenal pressure and ureteral tone during ureterorenoscopy. Summary Upper urinary tract physiology has unique features that may be pushed into pathophysiological processes by the unique elements of ureterorenoscopy: access and irrigation. Pharmacological ureteral relaxation during ureterorenoscopy deserves further attention with regard to reducing complications and postoperative pain.

Visceral pain originating from the upper urinary tract

Pain originating from the upper urinary tract is a common problem and stone colic is one of the most intense pain conditions that can be experienced in the clinic. The pain is difficult to alleviate and often leads to medical attention. In humans, pain mechanisms of the upper urinary tract pain are still poorly understood, which often leads to a trial and error approach in clinical pain management. Pain from the upper urinary tract seems to have all the characteristics of pure visceral pain, including referred pain with or without hyperalgesia/trophic changes in somatic tissues and viscero-visceral hyperalgesia. However, further studies are needed to better understand these visceral pain mechanisms with regard to optimising pain management. This review gives an introduction to visceral pain in general and upper urinary tract pain in particular, with special reference to pain pathways and pharmacological and non-pharmacological pain modulation.

Somatosensory and trophic findings in the referred pain area in patients with kidney stone disease

Abstract Background and purpose Visceral and somatic afferents activate the same neuronal structures in the central nervous system. Assessing somatosensory function and trophic changes in the referred pain area may therefore indirectly increase information on mechanisms involved in painful visceral diseases. The aim of this study was to evaluate the sensory and trophic changes in the flank corresponding to the referred pain area in patients with kidney stone disease. Methods A total of 24 patients with unilateral pain-causing kidney stone disease were studied before and after endoscopic percutaneous kidney stone surgery. Trophic changes and sensitivity on the affected and on the contra-lateral side in the pain free period were investigated. For this purpose we used standardized experimental sensory testing including pressure stimulation and electrical (single and repeated) skin stimulation. Five repeated stimuli were used to investigate temporal summation (increased responses to repeated stimuli). To investigate trophic changes ultrasound as well as CT-scan was used, since the latter is considered more precise for exact tissue layer measurements. Results The pain tolerance thresholds to pressure and pain thresholds to electrical stimulation were not significantly different on the two sides (all P>0.1). After surgery no significant alterations in sensitivity were detected, but there was a tendency to higher pain thresholds to electrical stimuli on the affected side (single stimuli P=0.06; repeated stimuli P=0.09). No trophic changes were observed (all P>0.3), and there were no relations between the pain thresholds or trophic findings and the number of colics (all P >0.08). Conclusion In patients with unilateral pain-causing kidney stone disease the pain to experimental pressure and electrical stimuli were comparable on the affected and contra-lateral side. For the first time a CT-scan was used to evaluate tissue thickness in the referred pain area. No trophic changes were seen in the muscle or subcutaneous tissue at the affected side, and there were no correlations between the pain thresholds or trophic findings and the patients history of number of colics. After the operation no significant alterations in sensitivity were detected. Implications This study could not confirm previous studies showing referred hyperalgesia in the skin and trophic changes in the referred pain area to painful visceral disease. Differences in the pain intensity/duration between different diseases and hence the corresponding central neuronal changes may explain the negative findings in the present study.

A Model-Based Approach for Joint Analysis of Pain Intensity and Opioid Consumption in Postoperative Pain

Joint analysis of pain intensity and opioid consumption is encouraged in trials of postoperative pain. However, previous approaches have not appropriately addressed the complexity of their interrelation in time. In this study, we applied a non-linear mixed effects model to simultaneously study pain intensity and opioid consumption in a 4-h postoperative period for 44 patients undergoing percutaneous kidney stone surgery. Analysis was based on 748 Numerical Rating Scale (NRS) scores of pain intensity and 51 observed morphine and oxycodone dosing events. A joint model was developed to describe the recurrent pattern of four key phases determining the development of pain intensity and opioid consumption in time; (A) Distribution of pain intensity scores which followed a truncated Poisson distribution with time-dependent mean score ranging from 0.93 to 2.45; (B) Probability of transition to threshold pain levels (NRS ≥ 3) which was strongly dependent on previous pain levels ranging from 2.8–15.2% after NRS of 0–2; (C) Probability of requesting opioid when allowed (NRS ≥ 3) which was strongly correlated with the number of previous doses, ranging from 89.8% for requesting the first dose to 26.1% after three previous doses; (D) Reduction in pain scores after opioid dosing which was significantly related to the pain intensity at time of opioid request (P < 0.001). This study highlights the importance of analyzing pain intensity and opioid consumption in an integrated manner. Non-linear mixed effects modeling proved a valuable tool for analysis of interventions that affect pain intensity, probability of rescue dosing or the effect of opioids in the postoperative pain period.

The challenges of cystinuria in the twenty-first century: a mini review

The challenges of cystinuria in the twenty-first century – a mini review Louise F. Øbro1, Katja V. Pedersen2, Søren K. Lildal1, Susanne S. Osther1, Helene U. Jung1, Kim H. Andreassen1 and Palle J. S. Osther1 1Department of Urology, Urological Research Center, Lillebaelt Hospital, University of Southern Denmark, Fredericia, Denmark 2Department of Clinical Genetics, Lillebaelt Hospital, University of Southern Denmark, Vejle, Denmark