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The aim of this study was to construct the fourth in a series of guidelines on the treatment of urolithiasis by the International Alliance of Urolithiasis (IAU) that by providing a clinical framework for the metabolic evaluation, prevention, and follow-up of patients with urolithiasis based on the best available published literature. All recommendations were summarized following a systematic review and assessment of the literature in the PubMed database from January 1976 to June 2022. Each generated recommendation was graded using a modified GRADE methodology. Guideline recommendations were developed that addressed the following topics: initial evaluation, metabolic testing, dietary measures, medical management, and follow-up of recurrent stone formers. It was emphasized by the Panel that prevention of new stone formation is as important as the surgical removal of the stones. Although general preventive measures may be effective in reducing stone recurrence rates in some patients, specific medical and dietary management should be well considered and eventually applied in an individualized manner based on the outcomes of metabolic work-up, stone analysis and some certain patient related factors. A detailed follow-up of each case is essential depending on the metabolic activity of each individual patient., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Estimation of state of saturation with stone-forming salt represents a reliable tool to assess the overall risk. The available methods are based on computer-assisted ab initio calculations. Our earlier method URSUS was subsequently substituted by Lithorisk®, a software including visualization of risk profiles. Unfortunately, Lithorisk does not adapt to new versions of Windows® and Macintosh® Apple, neither runs on smartphones or tablets. We propose a novel version of the software which can be directly used online on any device equipped by different operating systems. Upon online connection and after registration, the software is ready for unlimited accesses, in either Italian, English or French. After digiting input variables (urea and creatinine also included) in a fixed dashboard, state of saturation is promptly given. In addition to state of saturation (ß) with calcium oxalate, brushite and uric acid, ß struvite and cystine are available. Both input variables and ß results are graphically depicted as green or red horizontal bars to indicate recommended values. The software was implemented with equations allowing to omit sulphate and ammonium excretion for users with difficult access to these measurements. This simplified version, tested for ßCaOx and ßBsh on 100 urine samples showed close correlation with the full version. The software gives a list of total and free concentrations and soluble complex species distribution. Results can be printed or saved as PDF. So, we propose an easily accessible software to estimate state of saturation usable on any operating system and personal device.

The Consensus Group deliberated on a number of questions concerning urine and stone analysis over a period of months, and then met to develop consensus. The Group concluded that analyses of urine and stones should be routine in the diagnosis and treatment of urinary stone diseases. At present, the 24-h urine is the most useful type of urine collection, and accepted methods for analysis are described. Patient education is also important for obtaining a proper urine sample. Graphical methods for reporting urine analysis results can be helpful both for the physician and for educating the patient as to proper dietary changes that could be beneficial. Proper analysis of stones is also essential for diagnosis and management of patients. The Consensus Group also agreed that research has shown that evaluation of urinary crystals could be very valuable, but the Group also recognizes that existing methods for assessment of crystalluria do not allow this to be part of stone treatment in many places.

Background: Primary hyperoxaluria (PH) is a rare autosomal recessive disease commonly arising in childhood and presenting with nephrolithiasis, nephrocalcinosis and/or chronic renal failure. Three genes are currently known as responsible: alanine-glyoxylate aminotransferase (AGXT, PH type 1), glyoxylate reductase/hydroxypyruvate reductase (GRHPR, PH type 2), and 4-hydroxy-2-oxoglutarate aldolase (HOGA1, PH type 3). In our Centre, at the end of 2014 molecular diagnosis of PH1 had been performed in 80 patients, while one patient received a PH2 diagnosis., Materials and Methods: Fifteen patients referred to our Centre and suspected to have PH on clinical grounds were negative for pathogenic variants in the entire coding sequence and exon-intron boundaries of the AGXT gene. Therefore, we extended the analysis to the AGXT promoter region and the GRHPR and HOGA1 genes., Results: Two patients were heterozygous for two novel AGXT-promoter variants (c.-647C > T, c.-424C > T) that were probably non pathogenic. One patient was homozygous for a novel HOGA1 variant of intron 2 (c.341-81delT), whose pathogenicity predicted by in silico splicing tools was not confirmed by a minigene splicing assay in COS-7 and HEK293T cells., Conclusion: New genetic subtypes of PH can be hypothesized in our patients, that may be caused by mutations in other gene encoding proteins of glyoxylate metabolism. Alternatively, some kind of mutations (e.g., deletions/duplications, deep intronic splicing regulatory variants) could be missed in a few cases, similarly to other genetic diseases.

Background: Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research., Design: A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved., Results: Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during stone treatment in the management of these patients; on the identification of patients warranting preventive measures; on the role of fluid and nutritional measures and of drugs to prevent recurrent episodes of stones; and finally, on the cooperation between the urologist and nephrologist in the renal stone patients., Conclusions: This document has addressed idiopathic calcium nephrolithiasis from the perspective of a disease that can associate with systemic disorders, emphasizing the interplay needed between urologists and nephrologists. It is complementary to the American Urological Association and European Association of Urology guidelines. Future areas for research are identified., Competing Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical approval No research involving patients or animals have been carried on specifically for this study. Informed consent For this type of study formal consent is not required.

An internet survey was set up to assess the geriatric competence and perceived needs of 337 members of the Italian society of nephrology (SIN). The survey assessed how well aware nephrologists are of the typical geriatric conditions and needs of their elderly chronic kidney disease (CKD) patients. SIN associates were also questioned about their current use of comprehensive geriatric assessment, prescription of potentially nephrotoxic drugs, and screening for osteoporosis. The main finding is that CKD and dialysis are almost unanimously perceived as typically geriatric conditions, but knowledge and use of geriatric tools are scanty. While use of potentially inappropriate drugs is rare, almost half of the patients are not screened for osteoporosis. The significant clinical gaps observed could greatly impair the management of older CKD patients, and call for an urgent educational intervention.

Background: Unfractionated heparin (UFH) is the standard anticoagulant in regular dialysis treatments (RDTs), despite the fact that it may induce thrombocytopenia, dyslipidemia, allergy and osteoporosis. Dermatan sulfate (DS) selectively inhibits thrombin, does not inhibit F-Xa and does not interfere with platelets (PLTS). Here we described an original protocol for the use of DS as anticoagulant in RDT and compared its effects with those of UFH., Methods: In 102 patients, 7,254 RDTs were performed using DS for anticoagulation (DS-phase) and 5,707 with UFH (UFH-phase). DS was supplied as initial bolus (80 ± 12 mg) and continuous infusion (14 ± 7 mg/hour). With UFH, the initial bolus was 1,475 ± 141 IU and continuous infusion 576 ± 349 IU/hour. Activated partial thromboplastin time and its ratio were measured at least monthly, both before (pre-RDT APTT ratio) and after (post-RDT APTT ratio) RDT sessions. With 41 of 102 patients, both DS and UFH doses were not changed during study phases (stable patients). In this subset, the coefficient of variation (CV) of all pre-RDT APTT ratio and post-RDT APTT ratio values was calculated., Results: In DS and UFH phases, post-RDT APTT ratio increased by 61% and 50%, respectively, by comparison with pre-RDT APTT ratio (p<0.001). PLTS count was lower in the UFH than in the DS phase (p<0.01). In stable patients, post-RDT APTT ratio CV was lower in the DS than in the UFH phase (p<0.001), which indicates a more predictable anticoagulant effect of DS compared with UFH., Conclusions: DS appeared as effective as UFH for anticoagulation in RDT. It can reliably be considered as an alternative approach especially in cases of thrombocytopenia or other adverse effects of UFH.

Background: Dermatan sulfate (DS) is a natural glycosaminoglycan with a unique mechanism of action on the coagulation system. Unlike unfractionated heparin (UFH), DS selectively inhibits thrombin, does not inhibit factor Xa, is effective on both free and fibrin-bound thrombin and does not interfere with platelets. This study represents the first experience using DS as anticoagulant in patients on continuous renal replacement therapy (CRRT)., Methods: A total of 147 patients in our intensive care unit who developed acute renal failure after cardiovascular surgery were on CRRT according to the same protocol: machine, Gambro Prisma; filter, AN69, 0.9 m2; QB, 150 ml/min; QD, 2,000 ml/hour; and Q(Infusate), 500 ml/hour. In a retrospective cohort of 100 patients, anticoagulation was performed with UFH (UFH-CRRT): initial bolus of 530 +/- 363 IU, then i.v. infusion of 598 +/- 261 IU/hour. A prospective cohort of 47 patients received DS (DS-CRRT) as a 150-mg bolus followed by a 13.5 +/- 3 mg/hour infusion. Hematology tests were performed at baseline and during CRRT; filter lifetime was measured from the start to filter clotting., Results: Median filter lifetime was 58 hours in DS-CRRT vs. 47 hours in UFH-CRRT (p<0.001). No differences emerged in basal hematology and hemostasis tests between groups. During CRRT, DS produced a smaller activated partial thromboplastin time increase than UFH (p<0.01). Platelet count exhibited a comparable small decline in both DS-CRRT and UFH-CRRT (p<0.01). No significant bleeding episodes occurred during DS-CRRT. In-hospital mortality was similar in the 2 cohorts., Conclusions: DS can be suggested as an anticoagulant for CRRT in patients who develop acute renal failure following major cardiovascular surgery.

We describe the theoretical features and in vivo assay of an original computer-based program, which describes Na and HCO3 kinetics with acetate-free biofiltration performed as a continuous veno-venous renal replacement therapy (CVVAFB). In 14 patients, CVVAFB sessions were performed as follows. Machine Hospal Prisma, membrane AN69 0.9 m2, blood circuit Hospal M100 pre Set, dialysate bags of electrolyte solution with basic composition of: Na 139 mEq/L, K 2 mEq/L, Ca 3.0 mEq/L, Mg 2 mEq/L, Cl 146 mEq/L, and glucose 5.5 mmol/L. Predilutional infusion bags of 167 mEq/L of NaHCO3 solution (Hospal Biosol). To guide the prescription of the dialysate (QD) and the infusate (QInf ) flow rates we designed a suitable computer program, which calculated Na and HCO3 kinetics and predicted their plasma profiles at equilibrium. Prescribed flow rates were QB 150 ml/min, QD 1636 +/- 42 ml/hr, Q Inf 639 +/- 74 ml/hr and ultrafiltration (UF) rate 110 +/- 41 ml/hr. During CVVAFB, plasma profiles of HCO3 and Na became stable after 24 hr. With HCO3 , the average predicted and observed plasma levels at equilibrium were 27.1 +/- 1.5 and 27.3 +/- 1.5 mEq/L, respectively (p=ns); with Na, the predicted and observed levels at equilibrium were 140.2 +/- 1.8 and 141.3 +/- 1.7 mEq/L, respectively (p=ns). There was a good correlation between predicted and observed values for both Na (p<0.01, r=0.78) and HCO3 (p<0.01, r=0.87). These results confirmed the reliability of our mathematical model for CVVAFB. A Long-term trial is needed to obtain more information on its clinical effects and compare CVVAFB with other continuous renal replacement therapy techniques.

Background: We implemented a program for continuous renal replacement therapies (CRRT) in intensive care units (ICU) based on the cooperative work of dialysis and ICU personnel. Our aim was to report the main details of this program and compare its cost with that of intermittent hemodiafiltration (IHDF)., Methods: The study referred to 181 ICU patients with renal failure. We considered the costs of both technical devices and assisting personnel. CRRT was performed as continuous veno-venous hemodiafiltration (CVVHDF) (24 hr daily); dialysis and ICU nurses shared surveillance. Only dialysis nurses performed IHDF (as acetate-free biofiltration, 4 hr daily) in the ICU., Results: The daily cost of CRRT was Euro 276.70; of which 79% was for devices and 21% was for human resources. Nurse surveillance required 141 min per day, ICU nurses supplied 55% (77 min) and dialysis nurses 45% (64 min). On average, CRRT surveillance required less than 1 min/nurse/hr for both dialysis and ICU nurses. The daily cost of 4-hr IHDF sessions of was Euro 247.83, of which 44% was for technical devices and 56% was for human resources., Conclusions: The cooperation between dialysis and ICUs improved the use of human resources and allowed us to supply CRRT to all critically ill patients with acute renal failure. The expenditure for CRRT was 12% higher than that for IHDF, due to the cost of technical devices.

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by a deficiency of alanine-glyoxylate aminotransferase (AGT), which is encoded by a single copy gene (AGXT). Molecular diagnosis was used in conjunction with clinical, biochemical and enzymological data to evaluate genotype-phenotype correlation. Patients can present a severe form of PH1, an adult form and a mild to moderate decrease in renal function. Biochemical diagnosis is made by plasma, urine and dialyzate oxalate and glycolate assays, and by liver AGT activity and pyridoxine responsitivity. Molecular genetic diagnosis can be made using different techniques, for example, the single strand conformation polymorphism technique (SSCP), followed by the sequencing of the 11 AGXT exons. The disease is clinically and genetically classified as highly heterogeneous. Mutant alleles can be recognised in 80- 90% of chromosomes, depending on the techniques used. Mutations in exons 1, 2, 4 and 10 are more frequent in Italian patients. Normalized AGT activity seems to be lower in the severe form than in the adult form. Double heterozygous patients present a lower age at disease onset and they were more frequent in the more severe than in mild severe disease. The 444T>C mutation was more frequent in the severe form, while the opposite was observed for 630G>A. 630G>A mutation homozygotes had a higher AGT residual activity. The presence of allelic heterogeneity of the AGXT could be responsible, to some extent, for the phenotypic heterogeneity in PH1. Homozygous genotypes were more frequent than expected and were associated with a less severe form of the disease.

Despite intensive studies in the last decades many aspects of nephrolithiasis still remain to be elucidated. Supersaturation with respect to lithogenic substances explains stones composed of cystine, uric acid, struvite, and calcium stones secondary to systemic diseases. In this subset there is a clear separation between patients and controls, and stone activity is well related to alterations in the physicochemistry of the urine environment. The understanding of the mechanisms of idiopathic calcium nephrolithiasis, on the other hand, is controversial, because we are still unable to establish clear-cut cause-effect relations between metabolic and physicochemical abnormalities and stone formation. Recent studies have been centered on the kidney, not only as the end organ of biochemical derangements due to systemic or environmental factors, but also as a complex laboratory where some events conduct to and others defend from lithogenesis. Many of these phenomena occur in the proximal tubule. Molecular biology has explained some types of hypercalciuria, which are due to genetic mutations altering tubular function, and similar results are expected for hypocitraturia and hyperoxaluria. The latter is conducive to stone formation through several mechanisms including supersaturation, oxidative stress on tubular cells, and interference with some natural inhibitors. The long list of inhibitors includes ionic and macromolecular moieties, some being produced within the nephron in response to lithogenic insults, and some affecting not only crystallization but also crystal cell adherence. Crystal trapping is believed to anticipate a renal stone. However, much has still to be clarified on their actual role in calcium nephrolithiasis, by what mechanisms they act, if patients and controls differ in the excretion and structure of some inhibitors, and whether differences are genetically determined.

The overall probability of forming stones differs in various parts of the world: 1-5% in Asia, 5-9% in Europe, 13% in North America, 20% in Saudi Arabia. The composition of stones and their location in the urinary tract, bladder or kidneys may also significantly differ in different countries. Moreover, in the same region, the clinical and metabolic patterns of stone disease can change over time. We examined some epidemiological evidence about the main risk factors for stone formation, both individual and environmental. A slightly higher rate of renal stone disease emerged in males than in females, and in white Caucasians than in Blacks. Stones in the upper urinary tract appear to be related to the life-style, being more frequent among affluent people, living in developed countries, with high animal protein consumption. Bladder stones are nowadays mainly seen in the Third World, on account of very poor socio-economic conditions. A high frequency of stone formation among hypertensive patients has been reported, and among those with high body mass as well. There is no evidence of any rise in the risk of stone formation in relation to dietary calcium intake or tap water hardness.

Specimens were collected from 22 Italian patients with primary hyperoxaluria type 1 (PH1). Ten of them had already been analyzed by molecular biology. To clarify the molecular characteristics of the AGXT gene disease responsible for PH1, DNA samples were examined for known mutations by hybridisation of PCR products with Sequence Specific Oligonucleotides (PCR-SSO). We planned to identify new mutations of the AGXT gene by heteroduplex analysis followed by direct sequencing. We had already standardized a) the conditions for the amplification of the 11 exons of AGXT, b) the PCR-SSO technique and c) the heteroduplex analysis of amplified products. Preliminary results demonstrated that the AGXT mutations described in previous studies were found only in 40% of the examined Italian patients with PH1. The remaining 60% of mutations should be characterised in future studies.

The hyperoxaluria syndromes can be differentiated by the assessment of associated abnormalities in generation and urine excretion of metabolically related molecules. Based on the experience gained in our laboratory during the last decade, we have developed a comprehensive diagnostic work-up, which includes measurements of oxalate, glycolate and L-glycerate in plasma, urine and dialysis fluids, and an assay for AGT activity on liver biopsy. The availability of reliable assays for each of these parameters is indispensable for the recognition and differentiation of hyperoxalurias. Patients suspected to have abnormalities in oxalate metabolism are first screened by analysing spot urines and serum, and subsequently are subjected to more extensive studies using properly pre-treated blood samples and 24-hour urine collection. AGT activity, in the case of PH1, is assayed on few milligrams liver specimen by using a sensitive chromatographic procedure. Pertinent biochemistries will also assist in the long-term medical follow-up of these patients and in view of the choice of renal replacement or transplantation strategies.