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Based on the current projection of the general population and the combined increase in end-stage kidney disease with age, the number of elderly donors and recipients is increasing, raising crucial questions about how to minimize the discard rate of organs from elderly donors and improve graft and patient outcomes. In 2002, extended criteria donors were the focus of a meeting in Crystal City (VA, USA), with a goal of maximizing the use of organs from deceased donors. Since then, extended criteria donors have progressively contributed to a large number of transplanted grafts worldwide, posing specific issues for allocation systems, recipient management, and therapeutic approaches. This review analyzes what we have learned in the last 20 years about extended criteria donor utilization, the promising innovations in immunosuppressive management, and the molecular pathways involved in the aging process, which constitute potential targets for novel therapies., (© 2024. The Author(s).)

The quality of follow-up has clearly emerged as a key factor for long-term kidney graft survival. Currently, many clinics are facing difficulties in delivering optimal surveillance because of the increased number and complexity of kidney transplant recipients, and because of the COVID-19 pandemic. Additional ways of performing follow-up visits are needed and telemedicine has emerged as a tool to strengthen patient care intensity. Six Italian transplant surgeons and nephrologists convened via teleconference to develop a consensual model of video visits for the follow-up of kidney transplant recipients. Issues discussed were: profile of eligible patients; assessments that can be carried out; video visit organization and medical professionals involved; supporting tools and implementation. The video visit was consensually recognized as the most relevant for the follow-up of kidney transplant recipients. Eligible patients should have basic electronic devices and the skills to correctly use them and be in clinically stable condition. With the exception of physical and instrumental examination, and kidney biopsy, all other assessments are feasible during a video visit and can be implemented by specific training and use of supporting tools. The video visit model is simple and adaptable to most transplant patients. It is not intended to replace face-to-face examinations, but is an additional tool for improving the intensity of follow-up of kidney transplant recipients, which can be integrated into current monitoring protocols., (© 2022. The Author(s).)

Small bowel capsule endoscopy (SBCE) visualizes the small bowel (SB) mucosa. Gastrointestinal (GI) bleeding from SB accounts for the majority of SBCE indications. We aimed to assess, in a "real-world" prospective study, the diagnostic yield of SBCE in a cohort of consecutive patients with obscure gastrointestinal bleeding (OGIB). Secondary end point was to assess the frequency of adverse events and the role of SBCE in determining the diagnostic work-up and clinical outcome. From 2016 to 2018, all patients referred for SBCE examination were enrolled. Indication for SBCE was re-assessed by 2 dedicated gastroenterologists. Inclusion criteria: (1) age ≥ 18 and ≤ 85 years; (2) diagnosis of OGIB; 3) non-diagnostic standard bidirectional endoscopy; (4) informed consent. Exclusion criteria: (1) deglutition impairment; (2) SBCE contraindications; (3) pregnancy. The cohort included 50 patients [males 18 (36%), age 68 (27-83)]. SBCE indication: patients with ongoing overt OGIB (Group A) (n = 11; 22%), previous overt OGIB (Group B) (n = 14; 28%), occult bleeding (with Iron Deficiency Anaemia) (Group C) (n = 25; 50%). SBCE detected clinically relevant lesions in 46 (92%) cases. Clinically relevant lesions were more frequent in Group C (24/25; 96%), followed by Group A (10/11; 91%) and Group B (12/14; 85.5%). After SBCE, treatment was medical (60%); endoscopic (14%), surgical (36%) or conservative (18%). Clinical follow-up showed complete resolution in 63.2%, partial/absent resolution in 18.4% of cases. In a prospective study, the high diagnostic yield of SBCE supports its role as first-line investigation in patients with OGIB. However, this achievement requires an accurate and timely assessment by dedicated gastroenterologists., (© 2021. The Author(s).)

Background: A considerable minority of patients on waiting lists for kidney transplantation either have no diagnosis (and fall into the subset of undiagnosed cases) because kidney biopsy was not performed or histological findings were non-specific, or do not fall into any well-defined clinical category. Some of these patients might be affected by a previously unrecognised monogenic disease., Methods: Through a multidisciplinary cooperative effort, we built an analytical pipeline to identify patients with chronic kidney disease (CKD) with a clinical suspicion of a monogenic condition or without a well-defined diagnosis. Following the stringent phenotypical and clinical characterization required by the flowchart, candidates meeting these criteria were further investigated by clinical exome sequencing followed by in silico analysis of 225 kidney-disease-related genes., Results: By using an ad hoc web-based platform, we enrolled 160 patients from 13 different Nephrology and Genetics Units located across the Piedmont region over 15 months. A preliminary "remote" evaluation based on well-defined inclusion criteria allowed us to define eligibility for NGS analysis. Among the 138 recruited patients, 52 (37.7%) were children and 86 (62.3%) were adults. Up to 48% of them had a positive family history for kidney disease. Overall, applying this workflow led to the identification of genetic variants potentially explaining the phenotype in 78 (56.5%) cases., Conclusions: These results underline the importance of clinical exome sequencing as a versatile and highly useful, non-invasive tool for genetic diagnosis of kidney diseases. Identifying patients who can benefit from targeted therapies, and improving the management of organ transplantation are further expected applications., (© 2020. The Author(s).)

Metformin is currently considered a first-line therapy in type 2 diabetic patients. After issuing warnings for decades about the risks of lactic acidosis in patients with chronic nephropathy, metformin is now being re-evaluated. The most recent evidence from the literature has demonstrated both a low, acceptable risk of lactic acidosis and a series of favorable effects, which go beyond its hypoglycemic activity. Patients treated with metformin show a significant mortality reduction and lower progression towards end-stage renal disease in comparison with those treated with other hypoglycemic drugs. Concerning lactic acidosis, in the last few years it has been shown how lactic acidosis almost always developed when patients kept taking the drug in the face of a concomitant disease or situation such as sepsis, fever, diarrhea, vomiting, which reduced metformin renal clearance. Actually, clearance of metformin is mainly renal, both by glomerular filtration and tubular secretion (apparent clearance 933-1317 ml/min, half-life < 3 h). As regards treatment, in cases of lactic acidosis complicated by acute kidney injury, continuous renal replacement therapy (CRRT) plays a crucial role. Besides the elimination of metformin, CRRT  improves survival by correcting acidosis, electrolyte alterations, and maintaining fluid balance. Lactic acidosis almost always develops because of preventable drug accumulation. Therefore, prevention is a key factor. Patients should be aware that discontinuation for a limited time does not affect their health, even when it may be inappropriate, but it may avoid a serious, potentially fatal adverse event., (© 2020. The Author(s).)

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer., Patients and Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability., Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status., Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.

New pharmacokinetics insight suggests that the furosemide pharmacology occurring in ICU patients with AKI is similar, but not equal to that described in chronic stable renal patients. Even if the diuretic response to furosemide is expressed by a steep dose-response curve positively correlated with renal function, pharmacodynamic limitations occur when creatinine clearance is < 20 ml/min or urine output is < 500 ml/12 h. In such cases, other factors specifically due to acute tubular injury can interfere with the furosemide-induced diuretic output. As modality of administration recent reports and metanalysis, even if not conclusive, suggest that for the same given dose a continuous infusion of furosemide was superior in diuretic response. For septic shock patients on CVVHDF where treatment adds an additional clearance of furosemide the maximum diuretic response is achieved by a continuous infusion of 20 mg/h of furosemide. At this infusion rate the reached plasma level was < 20 mg/L, a range considered safe and not ototoxic. Therefore, the severity of AKI establishes whether a patient will respond to furosemide. In this review we summarized all these recent updates, also suggesting that the diuretic response under continuous infusion may allow assessing glomerular and tubular functions with increased reliability than a bolus dose. However, validation studies are still needed to support continuous infusion as a stress test.

Background: This study assessed the contribution of intracorporeal (IC) and extracorporeal clearance (EC) of furosemide in patients with septic acute kidney injury (AKI), and the relationship between plasma concentrations and urine volume., Methods: Prospective cohort observational study of 15 patients with septic AKI undergoing continuous veno-venous hemodiafiltration (CVVHDF) divided according to urine volume (< 500 ml/12 h, Oliguria group, n = 5; > 500 ml/12 h, Diuresis group, n = 10) during continuous infusion of furosemide (120 mg/12 h) at steady-state condition. Plasma and effluent furosemide concentrations were determined by high-performance liquid chromatography (HPLC)-mass spectrometry every 12 h for 48 h., Results: Furosemide plasma concentrations and total body clearance (TBC) were 6.14 mg/l and 22.1 ml/min for the Oliguria group, and 2.63 mg/l and 54.4 ml/min for the Diuresis group, respectively (p < 0.05). When urine volume was < 500 ml/24 h, the furosemide plasma concentrations peaked at the potentially toxic value of 13.0 mg/l. Furosemide EC was not relevant for the Diuresis group, but it represented 18% of TBC for the Oliguria group. Furosemide plasma concentrations correlated positively with dose infusion for both groups (r = 0.728 and 0.685, p < 0.05), and negatively with urine volume only for the Diuresis (r = - 0.578, p < 0.01) but not for the Oliguria group (r = - 0.089, p = 0.715)., Conclusions: For patients with urine volume > 500 ml/12 h continuous infusion of furosemide up to 480 mg/24 h leads to increasing urine volume, which can predict furosemide plasma levels within its safety range. When the urine volume is lower, the furosemide plasma levels are increased beyond any further diuretic efficacy.

Care of pregnant woman, including fertility and procreation counseling, has become a significant part of the nephrological practice in the last years. In this context, the management of immunosuppression assumes a primary role both for autoimmune diseases and for post-transplant follow up. The present review analyzes the latest evidence on immunosuppressive drugs of current use in nephrology and kidney transplantation. Although the placenta inactivates prednisone and prednisolone, it is advisable to limit the dose to the minimal effective one, to prevent side effects. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancies in autoimmune diseases because of the safety profile and its steroid-sparing property. In lupus nephropathy, hydroxychloroquine is a current indication in the prevention of flares. Cyclosporine and tacrolimus can also be used as steroid-sparing agents as well as in post-transplant maintenance therapy. Experience on mammalian target of rapamycin inhibitors is limited and its use during pregnancy is still controversial even if initial positive data are emerging. Intravenous immunoglobulins are safe and represent an important option for relapses of lupus and vasculitis. Mycophenolate mofetil and cyclophosphamide are to avoid. An important part is reserved to biologic agents, which are having a huge impact on therapy protocols for several pathologies. Data on the utilization of these molecules during pregnancy, however, are still scant and therefore they do not yet allow a definitive evaluation of their safety profile.

Background: No specific treatment for IgA nephropathy (IgAN) after kidney transplantation is currently available., Methods: We conducted a retrospective single-center study on 29 patients with biopsy-proven de novo and recurrent IgAN after kidney transplantation, divided into two groups. Group 1 (n = 16) received intravenous methylprednisolone 500 mg per day for three consecutive days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for 6 months. The control group (n = 13, Group 2) received supportive therapies., Results: The two groups were comparable for serum creatinine (sCr) and proteinuria at the time of renal biopsy, but differed significantly at the end of follow-up. sCr was 1.8 ± 0.4 mg/dl in Group 1 vs. 2.7 ± 0.9 in Group 2 (p = 0.002), and proteinuria was 0.9 g/day in Group 1 vs. 1.9 in Group 2 (p = 0.04). The composite outcome of death-censored graft loss or doubling of sCr displayed 2 events in Group 1 (12.5 % of the entire group) and 5 events in Group 2 (38.5 % of the entire group), p = 0.19, odds ratio (OR) 4.4 [95 % confidence interval (CI) 0.7-27.8]., Conclusions: In the absence of therapeutic guidelines for de novo or recurrent IgAN after kidney transplantation, our study reports that therapy with pulse and oral steroids for 6 months is associated with an improved renal function. Nevertheless, further randomized controlled studies in larger patient cohorts are necessary to establish the gold standard treatment.

Background: Colistin pharmacokinetics data are scarce regarding patients undergoing renal replacement therapy (RRT), or even absent as in patients treated with sorbent technologies potentially capable of removing colistin by extensive absorption on many polymeric materials., Methods: Twelve septic shock patients with acute kidney injury (AKI) undergoing RRT [continuous venovenous hemodiafiltration (CVVHDF) n = 7, coupled-plasma filtration adsorption-HF (CPFA-HF) n = 4, hemoperfusion n = 1] treated with colistin methanesulfonate at a dose of 4.5 × 10(6) U bid were studied. Colistin A (Col-A) and colistin B (Col-B) concentrations on plasma and effluent at time 0, 0.2, 1, 3, 6, 12, 24 and 48 h were determined by the liquid chromatography-tandem mass spectrometry method., Results: With CVVHDF the sieving coefficient was lower for Col-A, peaked early (0.40 for Col-A at 10 min, and 0.59 for Col-B at 3 h) and declined after 48 h (0.22 and 0.30 for Col-A and Col-B, respectively). Colistin's filter clearance showed a similar pattern, with the highest clearance value of 18.7 ml/min for Col-B at 1 h. With CPFA-HF after the cartridge the Col-A and Col-B levels were negligible (<0.2 mg/l) or not detectable. The sum of the effluent and cartridge clearances reached values of 30 and 40 ml/min for Col-A and Col-B, respectively. With hemoperfusion the postcartridge concentrations for Col-A and Col-B were about 30 % lower than those determined precartridge., Conclusions: During CPFA-HF and CVVHDF, the extent of colistin removal is high, and patients should receive an unreduced dosage. However, due to risk of accumulation in long-term administration colistin plasma levels determination is recommended.

Background: Encapsulating peritoneal sclerosis (EPS) is a serious complication in patients on peritoneal dialysis (PD) causing intestinal obstruction. Two different forms of EPS are reported: the classical one observed in patients on PD, and post-transplantation EPS (PostTx-EPS). The first-line therapy of classical and PostTx-EPS remains surgical treatment, but for both the complication rate and mortality are high. Recently, a few cases of EPS were successfully treated with inhibitors of mammalian target of rapamycin (mTORi). The aim of this study was to evaluate PostTx-EPS outcome in our patients, focusing on the potential benefit of mTORi treatment., Methods: We performed a retrospective analysis on 1,048 kidney transplanted patients at our center between 11/2001 and 12/2011., Results: In the 226 patients treated with PD at any time before grafting, we found 10 cases of PostTx-EPS (prevalence 4.4%). The mean age was 54.9 years (26-69), with a mean time on PD of 83.1 months (33-156). The interval between kidney transplant and EPS diagnosis was 10.5 months (4-18.9). Five of the ten patients were treated after the diagnosis with mTORi, with a favorable outcome in 4/5 cases. This result was substantially independent of surgical and steroid therapy, performed in 9/10 and 10/10 patients respectively., Conclusion: EPS is a serious complication but susceptible to improvement if early diagnosed. mTORi represent a useful option for EPS treatment. We too suggest adopting an immunosuppressive protocol based on mTORi, mycophenolate mofetil and steroids in order to prevent PostTx-EPS in transplanted patients at high risk.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disease caused by thymidine phosphorylase deficiency which leads to toxic accumulations of thymidine (dThd) and deoxyuridine (dUrd). It lacks an established treatment and the prognosis is traditionally poor. We report a case of a young female patient with normal renal function and MNGIE treated by peritoneal dialysis (PD) and allogeneic bone marrow transplantation (BMT). PD was effective in reducing dThd and dUrd plasma levels and in improving clinical symptoms. To our knowledge, this is the first report on the beneficial effects of PD regarding MNGIE neurological symptoms. PD, therefore, should be considered especially in medically compromised patients as a supportive treatment to improve clinical conditions before BMT.

Background: Urinalysis is a fundamental test in internal medicine and nephrology. Figures for costs are available in the general laboratory, where biochemical and microscopic urinalysis are commonly performed as semiautomated screening tests. Information on costs is lacking in the nephrology laboratory, where a time-consuming morphological analysis is usually preferred. This study analyses the costs of urinalysis in a nephrology laboratory., Methods: In the nephrology laboratory at the University of Turin - Italy, biochemical urinalysis consists of multi-property strip and proteinuria/creatininuria, done by laboratory technicians. Phase-contrast microscopy is done by a nephrologist or biologist. Time dedicated to the tests was recorded by the same operator over 20 working days, during which 350 urine samples were processed (median 19/day, range 842). The production costs were calculated with the logic bottom-up technique., Results: Overall time needed was 11.9 minutes/sample. Biochemical urinalysis required 6.6 minutes/sample; time required and samples processed were inversely related (< or =19 samples: 7.95 minutes/sample; >19 samples: 5.6 minutes/sample, p=0.01). Microscopic urinalysis took 5.3 minutes/slide; the best time-to-samples ratio was at 18-22 samples per day (with peak efficiency at 21 samples: 4.6 minutes). Cost of reagents and disposables was Euro1.06/sample. Time accounted for euro 5.32/sample (technicians, nephrologist-biologist), with total direct cost of euro 6.38/sample., Conclusion: In a nephrology laboratory, microscopic urinalysis is a time-consuming, expensive test. Analysis of cost and modalities may be useful, in a time of budget constrains, to maintain a role for this precious semeiotic art.

Acquired cystic kidney disease (ACKD) is a complication of end-stage renal disease, the prevalence of which is related to dialysis duration; incidence of ACKD and associated conditions (neoplasia, hemorrhage) have decreased with improvements in renal transplantation and with the ageing of the dialysis population. This report regards spontaneous kidney rupture in a 57-year old patient, on home hemodialysis for 11 years, with ACKD for 5 years. At the end of a dialysis session, the patient reported sudden onset of colicky flank pain, followed by macrohematuria. Pain remitted with low doses of pain relievers, leaving dull flank discomfort. The patient self diagnosed a renal colic, and called the hospital two days later. At referral, two large hemorrhagic renal masses (7 and 2.8 cm) were found at ultrasound and CT scan. At surgery, kidney rupture was diagnosed. This case highlights the life threatening complications associated with ACKD, and underlines that massive renal hemorrhage may occur with relatively minor symptoms.

We report the case of a 48-year-old male, whose musculoskeletal manifestations, previously related to long-term renal replacement therapy (RRT), were diagnosed as ankylosing spondylitis when symptoms changed their pattern on daily hemodialysis (DHD). The patient started RRT in 1981; in 1985 he received a cadaver graft, which failed in 1987. Secondary hyperparathyroidism, amyloid geoids, bilateral carpal tunnel syndrome and high aluminium levels were present. Musculoskeletal pain, reported since 1986, involved feet, heels, hips, shoulders, hands, spine. Symptoms impairing daily life did not improve after parathyroidectomy. He developed chronic hypotension and recurrent atrial fibrillation. In 1994 and 1998, because of thoracic pain, coronarography was performed (normal on both occasions). In June 2000, DHD was started. Equivalent renal clearance increased from 9-12 to 15-17 mL/min. Well-being remarkably improved. In September 2000, musculoskeletal pain worsened and bilateral Achilles tendinitis occurred. The worsening of musculoskeletal symptoms despite the improvements in well-being and other dialysis related symptoms prompted a re-evaluation of the case. The diagnosis of ankylosing spondylitis was based on: history of plantar fasciitis, bilateral Achilles tendinitis, inflammatory spinal pain with limitation of lumbar spine mobility (positive Schober test), radiological evidence of grade 2 bilateral sacroiliitis, presence of HLA-B27. This diagnosis cast light on the episodes of chest pain, explained by enthesopathy at the costosternal and manubriosternal joints and atrial fibrillation, due to HLA-B27 associated impairment in heart conduction. This case exemplifies the difficulty of differential diagnosis of multisystem illness in patients with long RRT follow-up.

Cell-to-cell signal exchange during antigen presentation deeply influences the profile and extent of the immune response. Together with the TCR/MHC-mediated signal, accessory signals are provided to the T cell by the antigen-presenting cell (APC), through specific receptor-ligand interactions that represent indispensable costimulation for T-cell activation and survival. The main costimulatory pathways are the B7 family members and the CD40-CD154 receptor-ligand pair. B7-1 and B7-2 costimulate T-cells by binding to CD28. Their binding is prevented by the neoexpression of CTLA4, a CD28 homologue that can deliver a negative signal. Another CD28-like molecule, called ICOS (inducible costimulator), has been described and binds B7RP-1, a third member of the B7 family, but not B7-1 and B7-2. The CD40-CD154 interaction works as a two way costimulatory system by triggering activation signals to both T-cell and APCs. Its importance is highlighted by the discovery that mutations of the CD154 gene are responsible for a severe human immunodeficiency. Disruption of the natural costimulatory interaction was highly effective for prevention and treatment in several experimental models of autoimmune disease and transplant rejection. This review focuses on the most significant advances in understanding the physiopathological events involving costimulatory molecules, and their impact on renal diseases and transplantation.

While the clinical impact of the impaired immune response, commonly described in chronic dialysis patients, is still a matter of discussion, it is usually considered that immunological diseases tend to become progressively less active after the start of regular renal replacement therapy (RRT). We reported a case of Henoch-Schonlein Purpura in a 51-year-old male, on RRT for 20 years, 8 on dialysis and 12 with renal graft, because of ESRD of unknown origin (chronic glomerulonephritis?). The acute onset of the syndrome, presenting purpuric rash, abdominal discomfort and asymmetric joint pain with edema and local signs of acute inflammation, was followed by several relapses over a 2 years period. This biopsy proven diagnosis offered an explanation for his chronic renal failure; furthermore, we conclude that, possibly because of the usually good correction of uremic immunodepression by efficient dialysis (this patient's Kt/V ranged from 1.1 to 1.3 according to Lowrie's formula), the possibility of immune diseases should be carefully considered even in long long-term RRT patients.