Management of urinary stones: state of the art and future perspectives by experts in stone disease.

AIM: To present state of the art on the management of urinary stones from a panel of globally recognized urolithiasis experts who met during the Experts in Stone Disease Congress in Valencia in January 2024. Options of treatment: The surgical treatment modalities of renal and ureteral stones are well defined by the guidelines of international societies, although for some index cases more alternative options are possible. For 1.5 cm renal stones, both m-PCNL and RIRS have proven to be valid treatment alternatives with comparable stone-free rates. The m-PCNL has proven to be more cost effective and requires a shorter operative time, while the RIRS has demonstrated lower morbidity in terms of blood loss and shorter recovery times. SWL has proven to be less effective at least for lower calyceal stones but has the highest safety profile. For a 6mm obstructing stone of the pelviureteric junction (PUJ) stone, SWL should be the first choice for a stone less than 1 cm, due to less invasiveness and lower risk of complications although it has a lower stone free-rate. RIRS has advantages in certain conditions such as anticoagulant treatment, obesity, or body deformity. Technical issues of the surgical procedures for stone removal: In patients receiving antithrombotic therapy, SWL, PCN and open surgery are at elevated risk of hemorrhage or perinephric hematoma. URS, is associated with less morbidity in these cases. An individualized combined evaluation of risks of bleeding and thromboembolism should determine the perioperative thromboprophylactic strategy. Pre-interventional urine culture and antibiotic therapy are mandatory although UTI treatment is becoming more challenging due to increasing resistance to routinely applied antibiotics. The use of an intrarenal urine culture and stone culture is recommended to adapt antibiotic therapy in case of postoperative infectious complications. Measurements of temperature and pressure during RIRS are vital for ensuring patient safety and optimizing surgical outcomes although techniques of measurements and methods for data analysis are still to be refined. Ureteral stents were improved by the development of new biomaterials, new coatings, and new stent designs. Topics of current research are the development of drug eluting and bioresorbable stents. Complications of endoscopic treatment: PCNL is considered the most invasive surgical option. Fever and sepsis were observed in 11 and 0.5% and need for transfusion and embolization for bleeding in 7 and 0.4%. Major complications, as colonic, splenic, liver, gall bladder and bowel injuries are quite rare but are associated with significant morbidity. Ureteroscopy causes less complications, although some of them can be severe. They depend on high pressure in the urinary tract (sepsis or renal bleeding) or application of excessive force to the urinary tract (ureteral avulsion or stricture). Diagnostic work up:  Genetic testing consents the diagnosis of monogenetic conditions causing stones. It should be carried out in children and in selected adults. In adults, monogenetic diseases can be diagnosed by systematic genetic testing in no more than 4%, when cystinuria, APRT deficiency, and xanthinuria are excluded. A reliable stone analysis by infrared spectroscopy or X-ray diffraction is mandatory and should be associated to examination of the stone under a stereomicroscope. The analysis of digital images of stones by deep convolutional neural networks in dry laboratory or during endoscopic examination could allow the classification of stones based on their color and texture. Scanning electron microscopy (SEM) in association with energy dispersive spectrometry (EDS) is another fundamental research tool for the study of kidney stones. The combination of metagenomic analysis using Next Generation Sequencing (NGS) techniques and the enhanced quantitative urine culture (EQUC) protocol can be used to evaluate the urobiome of renal stone formers. Twenty-four hour urine analysis has a place during patient evaluation together with repeated measurements of urinary pH with a digital pH meter. Urinary supersaturation is the most comprehensive physicochemical risk factor employed in urolithiasis research. Urinary macromolecules can act as both promoters or inhibitors of stone formation depending on the chemical composition of urine in which they are operating. At the moment, there are no clinical applications of macromolecules in stone management or prophylaxis. Patients should be evaluated for the association with systemic pathologies. PROPHYLAXIS: Personalized medicine and public health interventions are complementary to prevent stone recurrence. Personalized medicine addresses a small part of stone patients with a high risk of recurrence and systemic complications requiring specific dietary and pharmacological treatment to prevent stone recurrence and complications of associated systemic diseases. The more numerous subjects who form one or a few stones during their entire lifespan should be treated by modifications of diet and lifestyle. Primary prevention by public health interventions is advisable to reduce prevalence of stones in the general population. Renal stone formers at "high-risk" for recurrence need early diagnosis to start specific treatment. Stone analysis allows the identification of most "high-risk" patients forming non-calcium stones: infection stones (struvite), uric acid and urates, cystine and other rare stones (dihydroxyadenine, xanthine). Patients at "high-risk" forming calcium stones require a more difficult diagnosis by clinical and laboratory evaluation. Particularly, patients with cystinuria and primary hyperoxaluria should be actively searched. FUTURE RESEARCH: Application of Artificial Intelligence are promising for automated identification of ureteral stones on CT imaging, prediction of stone composition and 24-hour urinary risk factors by demographics and clinical parameters, assessment of stone composition by evaluation of endoscopic images and prediction of outcomes of stone treatments. The synergy between urologists, nephrologists, and scientists in basic kidney stone research will enhance the depth and breadth of investigations, leading to a more comprehensive understanding of kidney stone formation.

Prospective long-term evaluation of incomplete distal renal tubular acidosis in idiopathic calcium nephrolithiasis diagnosed by low-dose NH4CL loading - gender prevalences and impact of alkali treatment.

PURPOSE: Prospective evaluation of the prevalence of incomplete distal renal tubular acidosis (idRTA) in idiopathic calcium stone formers (ICSF) diagnosed by half-dose ammonium chloride loading (NH4Cl, 0.05 g/kg body weight/day) and impact of alkali treatment of idRTA. METHODS: Evaluation of 386 consecutive idiopathic calcium stone formers (ICSF) (280 males, 106 females) for idRTA. If screening fasting urine pH was > 5.80, 1-day NH4Cl loading was performed without severe adverse effects. Normally, urine pH falls below 5.45. RESULTS: Sixty-four idiopathic calcium stone formers exhibited idRTA, one complete dRTA. Prevalence was higher in women (25.4%) than in men (13.6%). Thus, for more equilibrated comparisons, we formed pairs of 62 idiopathic calcium stone formers (ICSF) with and 62 without idRTA, matched for gender, age, BMI and serum creatinine. Idiopathic calcium stone formers with idRTA more often had hypercalciuria (p < 0.025) and urine citrate < 2 mmol/d (p < 0.05), formed calcium phosphate stones more frequently, exhibited higher numbers of stones/year (1.4 ± 1.5 vs. 0.9 ± 0.8, p = 0.034) and 2.5 times more intrarenal calcifications (4.6 ± 5.9 vs. 1.8 ± 3.6, p = 0.002). All idiopathic calcium stone formers with idRTA were recommended chronic alkali therapy. After 4-15 years of follow-up, stone events /years follow-up (stone passage or urologic intervention) were higher in patients non-adherent to alkali therapy (0.61 ± 0.92) than in patients adherent to treatment (0.11 ± 0.21, p = 0.006). CONCLUSION: Incomplete distal renal tubular acidosis is 1.8-fold more prevalent among female idiopathic calcium stone formers, predicts more stone recurrences, predisposes to calcium phosphate stones and is associated with 2.5 times more intrarenal calcifications vs. non-idRTA patients. Chronic alkali treatment reduces clinical stone recurrences by 5.5 times.

Results of a Gene Panel Approach in a Cohort of Patients with Incomplete Distal Renal Tubular Acidosis and Nephrolithiasis.

BACKGROUND: Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis, impaired renal function, and bone demineralization. dRTA is a well-defined entity that can be diagnosed by genetic testing of 5 genes known to be disease-causative. Incomplete dRTA (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH4Cl) challenge or furosemide and fludrocortisone test. It is still uncertain whether idRTA represents a distinct entity or is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. METHODS: In this cross-sectional study, we investigated a group of 22 stone formers whose clinical features were suspicious of idRTA. They underwent an NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 5 genes: SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72. RESULTS: Two unrelated individuals were found to have two different variants in SLC4A1 that had never been described before. CONCLUSIONS: Our results suggest the involvement of other genes or nongenetic tubular dysfunction in the pathogenesis of idRTA in stone formers. However, genetic testing may represent a cost-effective tool to recognize, treat, and prevent complications in these patients.

Simple dietary advice targeting five urinary parameters reduces urinary supersaturation in idiopathic calcium oxalate stone formers.

Among 208 kidney stone patients referred within 2 years, 75 patients (66 men, nine women) with truly idiopathic calcium oxalate stones (ICSF) were recruited. Dietary advice (DA) aimed at (1) urine dilution, (2) reduced crystallization promotion (lowering oxalate), and (3) increased crystallization inhibition (increasing citrate). We recommended higher intakes of fluid and calcium with meals/snacks (reducing intestinal oxalate absorption) as well as increased alkali and reduced meat protein (acid) for increasing urinary citrate. The intended effects of DA were elevations in urine volume, calcium (U-Ca) and citrate (U-Cit) as well as reductions in oxalate (U-Ox) and uric acid (U-UA). We retrospectively calculated an adherence score (AS), awarding + 1 point for parameters altered in the intended direction and - 1 point for opposite changes. Calcium oxalate supersaturation (CaOx-SS) was calculated using Tiselius' AP(CaOx) index EQ. DA induced changes (all p < 0.0001) in urine volume (2057 ± 79 vs. 2573 ± 71 ml/day) and U-Ca (5.49 ± 0.24 vs. 7.98 ± 0.38 mmol/day) as well as in U-Ox (0.34 ± 0.01 vs. 0.26 ± 0.01 mmol/day) and U-UA (3.48 ± 0.12 vs. 3.13 ± 0.10 mmol/day). U-Cit only tendentially increased (3.07 ± 0.17 vs. 3.36 ± 0.23 mmol/day, p = 0.06). DA induced a 21.5% drop in AP(CaOx) index, from 0.93 ± 0.05 to 0.73 ± 0.05 (p = 0.0005). Decreases in CaOx-SS correlated with AS (R = 0.448, p < 0.0005), and highest AS (+ 5) always indicated lowering of CaOx-SS. Thus, simple DA can reduce CaOx-SS which may be monitored by AS.

Publisher Correction: On the role of ocular torsion in binocular visual matching.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

On the retinal correspondences across the binocular visual field.

We have recently reported that objects seen at near distances require adjustments of the relative torsion of the eyes to avoid blurred binocular images or double vision and ultimately to allow binocular fusion. The reason underlying these rotational adjustments is that converging eye movements undo the eyes' torsional alignment, generating disparate binocular images of objects outside the horizontal plane of regard. We show mathematically that it is the distance between the two eyes, their relative orientation in the frontal plane and the distances from each eye to the binocularly intended visual target, that determine the binocular alignment of the lines of sight. As an example, we analyze the binocular disparity field that is generated when a viewer examines objects on a planar surface whose viewing distances differ in each gaze direction. The underlying geometric computations are simple, and require no explicit knowledge of 3D eye movement kinematics.

On the role of ocular torsion in binocular visual matching.

When an observer scans the visual surround, the images cast on the two retinae are slightly different due to the different viewpoints of the two eyes. Objects in the horizontal plane of regard can be seen single by aligning the lines of sight without changing the torsional stance of the eyes. Due to the peculiar ocular kinematics this is not possible for objects above or below the horizontal plane of regard. We provide evidence that binocular fusion can be achieved independently of viewing direction by adjusting the mutual torsional orientation of the eyes in the frontal plane. We characterize the fusion positions of the eyes across the oculomotor range by deriving simple trigonometric equations for the required torsion as a function of gaze direction and compute the iso-torsion contours yielding binocular fusion. Finally, we provide experimental evidence that eye positions in far-to-near re-fixation saccades indeed converge towards the predicted positions by adjusting the torsion of the eyes. This is the first report that describes the three-dimensional orientation of the eyes at binocular fusion positions based on the three-dimensional ocular kinematics. It closes a gap between the sensory and the motor side of binocular vision and stereoscopy.

Abnormal distal renal tubular acidification in patients with low bone mass: prevalence and impact of alkali treatment.

Chronic acid retention is known to promote bone dissolution. In this study, 23 % of patients with osteopenia/osteoporosis were diagnosed with abnormal distal renal tubular acidification (dRTA), a kidney dysfunction leading to chronic acid retention. Treating those patients with alkali-therapy shows improvement in bone density. To evaluate the prevalence of abnormal distal renal tubular acidification in patients with low bone mass (LBM) and the impact of additional alkali treatment on bone density in patients with concomitant LBM and dRTA,183 patients referred for metabolic evaluation of densitometrically proven low bone mass were screened for abnormal distal renal tubular acidification between 2006 and 2013. In all LBM urine pH (U-pH) was measured in the 2nd morning urines after 12 h of fasting. If U-pH was ≥5.80, LBM underwent a 1-day ammonium chloride loading, and U-pH was remeasured the next morning. If U-pH after acid loading did not drop below 5.45, patients were diagnosed with abnormal distal renal tubular acidification. Normal values were obtained from 21 healthy controls. All LBM with dRTA were recommended alkali citrate in addition to conventional therapy of LBM, and follow-up DXAs were obtained until 2014. 85 LBM underwent NH4Cl loading. 42 LBM patients were diagnosed with incomplete dRTA (idRTA; prevalence 23.0 %). During follow-up (1.6-8 years) of idRTA-LBM patients, subjects adhering to alkali treatment tended to improve BMD at all sites measured, whereas BMD of non-adherent idRTA patients worsened/remained unchanged. (1) About one out of four patients with osteopenia/osteoporosis has idRTA. (2) Upon NH4Cl loading, idRTA patients do not lower urine pH normally, but show signs of increased acid-buffering by bone dissolution. (3) In idRTA patients with low bone mass on conventional therapy, additional long-term alkali treatment improves bone mass at lumbar spine and potentially at other bone sites. (4) All patients with low bone mass undergoing metabolic evaluation should be screened for idRTA.

Renal stone clinic survey: calcium stone formers' self-declared understanding of and adherence to physician's recommendations.

Nothing is known about how well stone formers understand physician's explanations of stone formation, and a few data are available on adherence to provided recommendations. In this study, two groups of recurrent calcium stone formers (RCSFs) were compared. Group 1: 153 consecutive RCSF (118 men, 35 women) referred 1/2011-6/2014. At least 3 months after a 60-75 min consultation explaining metabolic evaluation and therapeutic measures, RCSF received a questionnaire by mail, regarding understanding of stone formation and adherence to therapeutic recommendations (diet, lifestyle, drug treatment). Response rate was 62 %. Group 2 (control): 81 consecutive RCSFs referred 7/2014-3/2016 (60 men, 21 women) were asked to answer the same questionnaire in the stone center while waiting for their follow-up consultation 3 months after starting prevention; response rate was 100 %. Alkali citrate was prescribed in 45 %. Answer sheets were analyzed anonymously, and frequencies of answers were compared by Chi-square test. RESULTS: 67 % (group 1) and 62 % (group 2) indicated >80 % understanding of the given information (NS). Over 80 % adherence to recommendations occurred in 26 and 30 % (NS). Most frequent changes in dietary/lifestyle habits were increases in calcium (93 vs. 89 %) and fluid intakes (81 vs. 78 %); lowering psychosocial stress (23 vs. 24 %) was least popular. Adherence to 100 % on 6-7 days/week was significantly more frequent for medication than for dietary/lifestyle interventions, both in group 1 (84 vs. 24 %, p < 0.001) and group 2 (91 vs. 28 %, p < 0.001). CONCLUSIONS: (1) results do not differ whether RCSFs are voluntarily participating by mail or asked to answer questionnaires in the stone clinic; (2) pathophysiologic explanations of stone disease are understood to >80 % by 2/3 of RCSFs; (3) after 3 months, perfect adherence to recommended treatment is more frequent on alkali citrate than on dietary/lifestyle measures; and (4) increasing calcium and fluid intake are the most popular dietary measures.

Three-dimensional ocular kinematics underlying binocular single vision.

We have analyzed the binocular coordination of the eyes during far-to-near refixation saccades based on the evaluation of distance ratios and angular directions of the projected target images relative to the eyes' rotation centers. By defining the geometric point of binocular single vision, called Helmholtz point, we found that disparities during fixations of targets at near distances were limited in the subject's three-dimensional visual field to the vertical and forward directions. These disparities collapsed to simple vertical disparities in the projective binocular image plane. Subjects were able to perfectly fuse the vertically disparate target images with respect to the projected Helmholtz point of single binocular vision, independent of the particular location relative to the horizontal plane of regard. Target image fusion was achieved by binocular torsion combined with corrective modulations of the differential half-vergence angles of the eyes in the horizontal plane. Our findings support the notion that oculomotor control combines vergence in the horizontal plane of regard with active torsion in the frontal plane to achieve fusion of the dichoptic binocular target images.

Quality Assessment of Urinary Stone Analysis: Results of a Multicenter Study of Laboratories in Europe.

After stone removal, accurate analysis of urinary stone composition is the most crucial laboratory diagnostic procedure for the treatment and recurrence prevention in the stone-forming patient. The most common techniques for routine analysis of stones are infrared spectroscopy, X-ray diffraction and chemical analysis. The aim of the present study was to assess the quality of urinary stone analysis of laboratories in Europe. Nine laboratories from eight European countries participated in six quality control surveys for urinary calculi analyses of the Reference Institute for Bioanalytics, Bonn, Germany, between 2010 and 2014. Each participant received the same blinded test samples for stone analysis. A total of 24 samples, comprising pure substances and mixtures of two or three components, were analysed. The evaluation of the quality of the laboratory in the present study was based on the attainment of 75% of the maximum total points, i.e. 99 points. The methods of stone analysis used were infrared spectroscopy (n = 7), chemical analysis (n = 1) and X-ray diffraction (n = 1). In the present study only 56% of the laboratories, four using infrared spectroscopy and one using X-ray diffraction, fulfilled the quality requirements. According to the current standard, chemical analysis is considered to be insufficient for stone analysis, whereas infrared spectroscopy or X-ray diffraction is mandatory. However, the poor results of infrared spectroscopy highlight the importance of equipment, reference spectra and qualification of the staff for an accurate analysis of stone composition. Regular quality control is essential in carrying out routine stone analysis.

Transmitter inputs to different motoneuron subgroups in the oculomotor and trochlear nucleus in monkey.

In all vertebrates the eyes are moved by six pairs of extraocular muscles enabling horizontal, vertical and rotatory movements. Recent work showed that each extraocular muscle is controlled by two motoneuronal groups: (1) Motoneurons of singly-innervated muscle fibers (SIF) that lie within the boundaries of motonuclei mediating a fast muscle contraction; and (2) motoneurons of multiply-innervated muscle fibers (MIF) in the periphery of motonuclei mediating a tonic muscle contraction. Currently only limited data about the transmitter inputs to the SIF and MIF motoneurons are available. Here we performed a quantitative study on the transmitter inputs to SIF and MIF motoneurons of individual muscles in the oculomotor and trochlear nucleus in monkey. Pre-labeled motoneurons were immunostained for GABA, glutamate decarboxylase, GABA-A receptor, glycine transporter 2, glycine receptor 1, and vesicular glutamate transporters 1 and 2. The main findings were: (1) the inhibitory control of SIF motoneurons for horizontal and vertical eye movements differs. Unlike in previous primate studies a considerable GABAergic input was found to all SIF motoneuronal groups, whereas a glycinergic input was confined to motoneurons of the medial rectus (MR) muscle mediating horizontal eye movements and to those of the levator palpebrae (LP) muscle elevating the upper eyelid. Whereas SIF and MIF motoneurons of individual eye muscles do not differ numerically in their GABAergic, glycinergic and vGlut2 input, vGlut1 containing terminals densely covered the supraoculomotor area (SOA) targeting MR MIF motoneurons. It is reasonable to assume that the vGlut1 input affects the near response system in the SOA, which houses the preganglionic neurons mediating pupillary constriction and accommodation and the MR MIF motoneurones involved in vergence.

[Relevance and Application of Opioids in the Treatment of Chronic Pain in Switzerland­a National Survey]. / Stellenwert und Einsatz von Opioiden in der Therapie chronischer Schmerzen in Schweizer Arztpraxen--eine nationale Umfrage.

METHOD: National survey on treatment with opioids among 1206 Swiss general internists and rheumatologists, using a questionnaire. TYPES OF PAIN: More self-declared pain specialists than non-specialists treat neuropathic pain (49,3 vs. 35,8%; p=0,002), whereas other types of pain are similarly often treated by specialists and non-specialists. OPIOID PRESCRIPTION: Pain specialists more often than non-specialists use opioids in visceral (12,8 vs. 5,9%, p=0,004) and postoperative pain (29,3 vs. 20,1%, p=0,013). TUMOR PAIN: Non-specialists rather than specialists prescribe opioids (80,4 vs. 72,8%, p=0,039); younger physicians (<50 years) rather than older ones often prescribe opioids (82,5 vs. 76,9%; p=0,026), and rheumatologists use opioids less often than general internists (43,3 vs. 83,0%, p<0,0001). WHO ANALGESIC LADDER: Specialists more often change directly from level 1 to level 3 analgesics (66,4 vs. 53,8%; p=0,001).

The kinematics of far-near re-fixation saccades.

We have analyzed the three-dimensional spatiotemporal characteristics of saccadic refixations between far and near targets in three behaviorally trained rhesus monkeys. The kinematics underlying these rapid eye movements can be accurately described by rotations of the eyes in four different planes, namely, first disconjugate rotations in the horizontal plane of regard converging the eyes toward the near target, followed by rotations in each eye's vertical direction plane, and finally, disconjugate rotations in a common frontoparallel plane. This compounded rotation of the eye was underlying an initially fast-rising variable torsion that typically overshot the final torsion, which the eyes attained at the time of target acquisition. The torsion consisted of a coarse, widely varying component of opposite polarity in the two eyes, which contained a more robust, much smaller modulation that sharply increased toward the end of saccades. The reorientation of the eyes in torsion depended on each eye's azimuth, elevation, and target distance. We conclude that refixation saccades are generated by motor commands that control ocular torsion in concert with the saccade generator, which operates in Donders-Listing kinematics underlying Listing's law.

Kinematics of visually-guided eye movements.

One of the hallmarks of an eye movement that follows Listing's law is the half-angle rule that says that the angular velocity of the eye tilts by half the angle of eccentricity of the line of sight relative to primary eye position. Since all visually-guided eye movements in the regime of far viewing follow Listing's law (with the head still and upright), the question about its origin is of considerable importance. Here, we provide theoretical and experimental evidence that Listing's law results from a unique motor strategy that allows minimizing ocular torsion while smoothly tracking objects of interest along any path in visual space. The strategy consists in compounding conventional ocular rotations in meridian planes, that is in horizontal, vertical and oblique directions (which are all torsion-free) with small linear displacements of the eye in the frontal plane. Such compound rotation-displacements of the eye can explain the kinematic paradox that the fixation point may rotate in one plane while the eye rotates in other planes. Its unique signature is the half-angle law in the position domain, which means that the rotation plane of the eye tilts by half-the angle of gaze eccentricity. We show that this law does not readily generalize to the velocity domain of visually-guided eye movements because the angular eye velocity is the sum of two terms, one associated with rotations in meridian planes and one associated with displacements of the eye in the frontal plane. While the first term does not depend on eye position the second term does depend on eye position. We show that compounded rotation - displacements perfectly predict the average smooth kinematics of the eye during steady- state pursuit in both the position and velocity domain.

[Pitfalls in the interpretation of laboratory parameters-electrolytes, urea, creatinine]. / Pitfalls bei Laborwerten - Elektrolyte, Harnstoff und Kreatinin.

When it comes to interpret parameters of electrolyte balance and kidney function, it is important to keep pathophysiology and the theory on reference intervals in mind. Hyponatremia is most often caused by excess water. A low sodium concentration in urine should prompt a clinical evaluation of volume status. In case of suspected acute kidney failure, fractionated sodium excretion and fractionated urea excretion are able to provide insights on prerenal or renal origin of the disorder. Disruption in potassium homoeostasis can occur due to changes in supply or renal elimination as well as due to changes in the potassium balance between the extra- and intracellular compartments. The transtubular potassium gradient can help in the differential diagnosis of hyperkalemia. Evaluation of kidney function should begin with determination of serum creatinine, accompanied by an estimate of the glomerular filtration rate, as calculated by the CKD-EPI equation. As a consequence of non-renal determinants of serum creatinine, this equation has been shown to overestimate true GFR in elderly and hospitalized patients. This can result in overdosing of renally-cleared drugs. Clearance determinations can be of use in this context.

Calretinin inputs are confined to motoneurons for upward eye movements in monkey.

Motoneurons of extraocular muscles are controlled by different premotor pathways, whose selective damage may cause directionally selective eye movement disorders. The fact that clinical disorders can affect only one direction, e.g., isolated up-/downgaze palsy or up-/downbeat nystagmus, indicates that up- and downgaze pathways are organized separately. Recent work in monkey revealed that a subpopulation of premotor neurons of the vertical eye movement system contains the calcium-binding protein calretinin (CR). With combined tract-tracing and immunofluorescence, the motoneurons of vertically pulling eye muscles in monkey were investigated for the presence of CR-positive afferent terminals. In the oculomotor nucleus, CR was specifically found in punctate profiles contacting superior rectus and inferior oblique motoneurons, as well as levator palpebrae motoneurons, all of which participate in upward eye movements. Double-immunofluorescence labeling revealed that CR-positive terminals lacked the γ-aminobutyric acid (GABA)-synthesizing enzyme glutamate decarboxylase, which is present in inhibitory afferents to all motoneurons mediating vertical eye movements. Therefore, CR-containing afferents are considered to be excitatory. In conclusion, a strong CR input is confined to motoneurons mediating upgaze, which derive from premotor pathways mediating saccades and smooth pursuit, but not from secondary vestibulo-ocular neurons in the magnocellular part of the medial vestibular nucleus. The functional significance of CR in these connections is unclear, but it may serve as a useful marker to locate upgaze pathways in the human brain.

Three-dimensional visuo-motor control of saccades.

Although the motion of the line of sight is a straightforward consequence of a particular rotation of the eye, it is much trickier to predict the rotation underlying a particular motion of the line of sight in accordance with Listing's law. Helmholtz's notion of the direction-circle together with the notion of primary and secondary reference directions in visual space provide an elegant solution to this reverse engineering problem, which the brain is faced with whenever generating a saccade. To test whether these notions indeed apply for saccades, we analyzed three-dimensional eye movements recorded in four rhesus monkeys. We found that on average saccade trajectories closely matched with the associated direction-circles. Torsional, vertical, and horizontal eye position of saccades scattered around the position predicted by the associated direction-circles with standard deviations of 0.5°, 0.3°, and 0.4°, respectively. Comparison of saccade trajectories with the likewise predicted fixed-axis rotations yielded mean coefficients of determinations (±SD) of 0.72 (±0.26) for torsion, 0.97 (±0.10) for vertical, and 0.96 (±0.11) for horizontal eye position. Reverse engineering of three-dimensional saccadic rotations based on visual information suggests that motor control of saccades, compatible with Listing's law, not only uses information on the fixation directions at saccade onset and offset but also relies on the computation of secondary reference positions that vary from saccade to saccade.

Prevalence and densitometric characteristics of incomplete distal renal tubular acidosis in men with recurrent calcium nephrolithiasis.

The aim of this study was to assess the prevalence of incomplete distal renal tubular acidosis (idRTA) in men with recurrent calcium nephrolithiasis and its potential impact on bone mineral density. We conducted a retrospective analysis of 150 consecutive, male idiopathic recurrent calcium stone formers (RCSFs), which had originally been referred to the tertiary care stone center of the University Hospital of Berne for further metabolic evaluation. All RCSFs had been maintained on a free-choice diet while collecting two 24-h urine samples and delivered second morning urine samples after 12 h fasting. Among 12 RCSFs with a fasting urine pH >5.8, a modified 3-day ammonium chloride loading test identified idRTA in 10 patients (urine pH >5.32, idRTA group). We matched to each idRTA subject 5 control subjects from the 150 RCSFs, primary by BMI and then by age, i.e., 50 patients, without any acidification defect (non-RTA group) for comparative biochemistry and dual energy X-ray absorptiometry (DEXA) analyses. The prevalence of primary idRTA among RCSFs was 6.7% (10/150). Patients with idRTA had significantly higher 2-h fasting and 24-h urine pH (2-h urine pH: 6.6 ± 0.4 vs. 5.2 ± 0.1, p = 0.001; 24-h urine pH: 6.1 ± 0.2 vs. 5.3 ± 0.3, p = 0.001), 24-h urinary calcium excretion (7.70 ± 1.75 vs. 5.69 ± 1.73 mmol/d, p = 0.02), but significantly lower 24-h urinary urea excretion (323 ± 53 vs. 399 ± 114 mmol/d, p = 0.01), urinary citrate levels (2.32 ± 0.82 vs. 3.01 ± 0.72 mmol/d, p = 0.04) and renal phosphate threshold normalized for the glomerular filtration rate (TmPO(4)/GFR: 0.66 ± 0.17 vs. 0.82 ± 0.21, p = 0.03) compared to non-RTA patients. No significant difference in bone mineral density (BMD) was found between idRTA and non-RTA patients for the lumbar spine (LS BMD (g/cm(2)): 1.046 ± 0.245 SD vs. 1.005 ± 0.119 SD, p = 0.42) or femoral neck (FN BMD (g/cm(2)): 0.830 ± 0.135 SD vs. 0.852 ± 0.127 SD). Thus, idRTA occurs in 1 in 15 male RCSFs and should be sought in all recurrent calcium nephrolithiasis patients. Bone mineral density, however, does not appear to be significantly affected by idRTA.

Metabolic syndrome, obesity and kidney stones.

OBJECTIVES: To give a comprehensive and focused overview on the current knowledge of the causal relations of metabolic syndrome and/or central obesity with kidney stone formation. METHODS: Previous reports were reviewed using PubMed, with a strict focus on the keywords (single or combinations thereof): urolithiasis, nephrolithiasis, kidney stones, obesity, metabolic syndrome, bariatric surgery, calcium oxalate stones, hyperoxaluria, insulin resistance, uric acid stones, acid-base metabolism. RESULTS: Obesity (a body mass index, BMI, of >30 kg/m(2)) affects 10-27% of men and up to 38% of women in European countries. Worldwide, >300 million people are estimated to be obese. Epidemiologically, a greater BMI, greater weight, larger waist circumference and major weight gain are independently associated with an increased risk of renal stone formation, both for calcium oxalate and uric acid stone disease. CONCLUSIONS: There are two distinct metabolic conditions accounting for kidney stone formation in patients with metabolic syndrome/central obesity. (i) Abdominal obesity predisposes to insulin resistance, which at the renal level causes reduced urinary ammonium excretion and thus a low urinary pH; the consequence is a greater risk of uric acid stone formation. (ii) Bariatric surgery, the only intervention that facilitates significant weight loss in morbidly obese people, carries a greater risk of calcium oxalate nephrolithiasis. The underlying pathophysiological mechanisms are profound enteric hyperoxaluria due to intestinal binding of calcium by malabsorbed fatty acids, and severe hypocitraturia due to soft or watery stools, which lead to chronic bicarbonate losses and intracellular metabolic acidosis.