This article, written by several authors, describes the birth and early development of the nephrology at Molinette Hospital in Torino, Italy. In particular, it supplies important information on Antonio Vercellone, very motivated and innovative clinician and one of the fathers of Italian nephrology, and on Giuseppe Piccoli, his right-hand man and then his successor. This article also shows the strong professional and human engagement that was requested to the young doctors who, in the early Sixties and Seventies of the past century, had chosen to devote their professional lives to the patients with kidney diseases: from endless workdays without schedules to the anguish caused by the shortage of artificial kidneys to the cure of very fragile and unfortunate patients, and much more.

We report the transmission of acute myeloid leukemia (AML) undetected at donation from a deceased organ donor to two kidneys and one liver recipients. We reviewed the medical records, and performed molecular analyses and whole exome sequencing (WES) to ascertain AML donor origin and its molecular evolution. The liver recipient was diagnosed 11 months after transplantation and died from complications 2 months later. The two kidney recipients (R1 and R2) were diagnosed 19 and 20 months after transplantation and both received treatment for leukemia. R1 died of complications 11 months after diagnosis, while R2 went into complete remission for 44months, before relapsing. R2 died 10 months later of complications from allogenic bone marrow transplantation. Microsatellite analysis demonstrated donor chimerism in circulating cells from both kidney recipients. Targeted molecular analyses and medical records revealed NPM1 mutation present in the donor and recipients, while FLT3 was mutated only in R1. These findings were confirmed by WES, which revealed additional founder and clonal mutations, and HLA genomic loss in R2. In conclusion, we report the first in--depth genomic analysis of AML transmission following solid organ transplantation, revealing distinct clonal evolution, and providing a potential molecular explanation for tumor escape.

In this viewpoint, we summarize the relevance of thromboinflammation in COVID-19 and discuss potential mechanisms of endothelial injury as a key point for the development of lung and distant organ dysfunction, with a focus on direct viral infection and cytokine-mediated injury. Entanglement between inflammation and coagulation and resistance to heparin provide a rationale to consider other therapeutic approaches in order to preserve endothelial function and limit microthrombosis, especially in severe forms. These strategies include nebulized heparin, N-acetylcysteine, plasma exchange and/or fresh frozen plasma, plasma derivatives to increase the level of endogenous anticoagulants (tissue factor pathway inhibitor, activated protein C, thrombomodulin, antithrombin), dipyridamole, complement blockers, different types of stem cells, and extracellular vesicles. An integrated therapy including these drugs has the potential to improve outcomes in COVID-19.

BACKGROUND Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.

BACKGROUND:Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies.METHODS:RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The results were validated in an independent set of kidney biopsies.RESULTS:We identified 616 and 243 differentially expressed genes with a fold change ≥1.5 and a false discovery rate <0.05 in chronic and acute TCMR, respectively. Pathway analysis revealed upregulation of OX40 signalling. This pathway is involved in the generation of CD8+ effector memory T cells and the upregulation of killer cell lectin-like receptor G1 (KLRG-1), B lymphocyte-induced maturation protein 1 (BLIMP-1) and CD25, which characterize CD8+ effector memory T cells. However, the enhanced OX40 signalling pathway was specific to chronic TCMR; a significant increase of KLRG-1+/CD8+ and BLIMP-1+/CD8+ was only detected in these specimens.CONCLUSIONS:These results suggest the involvement of memory-committed CD8+ effector T cells in chronic TCMR. The generation of effector memory T cells is mediated by the OX40 gene pathway, and could be considered a future target for the specific treatment of chronic TCMR.

Systemic lupus erythematosus is a multisystem inflammatory disease characterized by autoantibody production. Recent investigations are providing insights into the immunoregulatory disturbances underlying this disease, and are clarifying the approach to diagnosis and treatment.

Background. Several genetic polymorphisms modulate the risk of posttransplant diabetesmellitus (PTDM), a complication associated with an increased morbidity and mortality after kidney transplantation; however, their clinical utility is still undefined. Methods. Genetic analysis was performed in 464 kidney transplantation recipients to evaluate whether transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism is associated with the risk of PTDM and a meta-analysis of similar studies including our results was performed (total kidney transplantation recipients, n = 3105). A predictive model of PTDM was built on the basis of this polymorphism and clinical parameters. Results. In our cohort, 163 patients possessed the CC genotype of rs7903146 (35.1%), 237 were CT (51.1%), and 64 were TT (13.8%): their 2 years PTDM incidence was, respectively, 7.8%, 11.9%, and 22.7%. At multivariate analysis, age (per year; hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.005-1.054; P = 0.017), body mass index (25.0-29.9 vs <25.0; HR, 2.43; 95% CI, 1.40-4.23; P = 0.0018; >= 30 vs <25.0; HR, 5.70; 95% CI, 2.77-11.74; P < 0.0001), TCF7L2 rs7903146 (per each Tallele; HR, 1.81; 95% CI, 1.26-2.59; P = 0.001) and previous transplants (HR, 2.80; 95% CI, 1.39-5.64; P = 0.004) emerged as independent predictive factors for PTDM. Meta-analysis of present and 5 previous studies showed higher risk of PTDM in carriers of rs7903146 TT genotype (odds ratio, 1.95; 95% CI, 1.39-2.74; P < 0.0001) and absence of heterogeneity among studies (I-2 = 0%). Inclusion of this polymorphism in a predictive model appeared to improve its ability to stratify patients according to the risk of PTDM. Conclusions. In renal transplant patients, TCF7L2 rs7903146 is strongly and independently associated with PTDM and might hold the potential to identify patients at risk for this complication.

Introduction Medullary cystic kidney disease type 1 (MCKD1; OMIM #174000) is a familial progressive tubule-interstitial nephropathy belonging to the recently defined group of autosomal dominant tubulointerstitial kidney diseases (ADTKD).Case reportA specific type of cytosine insertion in the extracellular variable number tandem repeat (VNTR) domain of the MUC1 gene causing the disease was tested in a group of 21 families with ADTKD. We identified this type of MUC1 mutation in two families, whose affected members are described in detail in this case report. Affected (ADTKD-MUC1) members developed end-stage renal disease (ESRD) with a higher incidence (p = 0.033) and at a younger age (p = 0.013) than probands with ADTKD but without this type of mutation. All patients with MUC1-associated kidney disease shared a rather unspecific tubule-interstitial laboratory pattern without medullary cysts, leading to ESRD between the age of 33 and 47 years. We were not able to identify any single common extra-renal feature among affected patients, even if they had various comorbidities, which are described in detail.ConclusionsWe identified this type of MUC1 mutation in 9.5 % of families from an ADTKD Italian cohort; larger studies are needed to better define the criteria for genetic testing for this type of mutation.

The aim of this study was to evaluate the association between cancer occurrence and risk of graft failure in kidney transplant recipients. From November 1998 to November 2013, 672 adult patients received their first kidney transplant from a deceased donor and had a minimum follow-up of 6 months. During a median follow-up of 4.7 years (3523 patient-years), 47 patients developed a nonmelanoma skin cancer (NMSC) and 40 a noncutaneous malignancy (NCM). A total of 59 graft failures were observed. The failure rate was 6 per 100 patient-year (pt-yr) after NCM versus 1.5 per 100 pt-yr in patients without NCM. In a time-dependent multivariable model, the occurrence of NCM appeared to be associated with failure (HR = 3.27; 95% CI = 1.44-7.44). The effect of NCM on the cause-specific graft failure was different (P = 0.002) when considering events due to chronic rejection (HR = 0.55) versus other causes (HR = 15.59). The reduction of the immunosuppression after NCM was not associated with a greater risk of graft failure. In conclusion, our data suggest that post-transplant NCM may be a strong risk factor for graft failure, particularly for causes other than chronic rejection.

The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal-IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p ≤ 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/β1, p = 0.039; LPM7/β5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin–proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT.

BACKGROUND:Often the reduced contrast enhancement on CT renal imaging is radiologically interpreted as acute pyelonephritis (PNA), but it is the task of the clinician to assess a possible differential diagnosis such as a renal infarct and look for a cause.METHODS:In our experience (2010-2013), we hospitalized 51 patients with radiological imaging consistent with acute pyelonephritis in native kidneys. However, three of these cases result, after a second look, to be ischemic lesions, only sometimes complicated by over-infections (Tabella 1).RESULTS:FIRST CASE:a woman hospitalized for fever and flank pain with blood culture positive for Klebsiella Pneumoniae. Antibiotic therapy allowed a clinical-laboratory improvement, but after 45 days persisted a focal wedge to the CT scan. The labs showed a anemia due to a sickle cell disease (SLC). The overview was finally interpreted as a renal infarct secondary to a sickle cell anemia, initially complicated by over-infection.SECOND CASE:a men hospitalized for a acute flank pain. The CT scan showed a left renal infarct and a partial renal artery thrombosis, resulting in abuse of cannabinoids and LAC positivity.Third case: a woman hospitalized for flank pain and slight movement of inflammatory markers. CT showed a cuneiform area in the right kidney not vascularized, that did not resolved after prolonged antibiotic therapy. The labs evidence a heterozygous mutation of prothrombin and MTHFR causing the renal infarction.CONCLUSIONS:6% of radiographic imaging consistent with acute pyelonephritis concealed an underlying infarct, due to a unknown state of thrombophilia. The presence of hypovascular imaging to the TC scan, therefore, requires a differential diagnosis between PNA and infarct, especially in the case of atypical development.

BACKGROUND:Oral anticoagulation with vitamin K antagonists (VKA) and antiaggregant therapy (AAT) are common among dialysis patients, but it is not known if they increase the risk of hemorrhagic (HE) or cardiovascular events (CVE) in the early post-transplant weeks.METHODS:We conducted a retrospective analysis on 911 consecutive kidney transplants (KTxs) in order to analyze the impact of AAT and VKA on early HE and CVE-which might be related to their withdrawal-and to identify the main risk factors for these complications.RESULTS:We observed 21/911 HE (2.3%; 1 death, 4 allograft loss); risk factors for HE at multivariate analysis were: KTx before 2004 (when anti-factor Xa activity measurement was not available; odds ratio, OR 5.835, [95% confidence interval, 1.241-27.436], p = 0.026), and VKA (OR 7.090 [2.030-24.772], p = 0.002), while AAT was not a risk factor. CVE were 32/911 (3.5%; 3 deaths, 11 allograft loss): risk factors for CVE at multivariate analysis were: previous cardiovascular events (OR 4.180 [1.615-10.948], p = 0.0032) and cinacalcet use (OR 7.930 [3.002-20.945], p < 0.0001), while neither VKA nor AAT had any impact.CONCLUSIONS:In conclusion, HE and CVE are relatively rare but can be severe, but there are no pre-KTx modifiable risk factors. If an anticoagulant therapy with low molecular weight heparins has to be started soon after surgery, monitoring of anti-Xa activity is highly recommended.

The Piedmont Group of Clinical Nephrology compared the activity of 15 nephrology centers in Piedmont and Aosta Valley as regards bone protection in patients on corticosteroids therapy. Fracture prevalence shows great variability: in 4/15 centers (27%) no fractures were found, in 6/15 centers (40%) fractures were present in 1-4% of cases, in 1 center in 18% of patients. Clinical risk of fracture was based on sex, age and postmenopausal status in 11/14 of the centers (79%), history of fractures and bone disease in 4/14 centers (27%), smoking and alcohol consumption in 3 and 2 centers respectively, glucocorticoid dose and duration in 4, in children bone age and calcium phosphorus status. Dual energy X-ray absorptiometry was performed in 12 centers based on risk factors, in 8 (57%) DXA was performed during the follow-up, in 4 it was performed after 12 months and in 2 after 2-3 years. DXA is not prescribed in children. Only in one center, risk assessment is based on FRAX. Most of the patients are treated with vitamin D supplementation at a dose of steroids of 5 mg/d (80%). Calcium carbonate is used in 9 centers (60%), in two it is used only in the presence of low ionized calcium or bone mineral density. Bisphosphonates are used following AIFA prescription, in particular alendronate in all centers, risedronate in seven and denosumab in one. The analysis shows the great variability of the clinical and therapeutic approach regarding bone protection in patients on corticosteroids therapy, in Piedmont and Aosta Valley.

Rituximab (RTX), a B-lymphocytes depleting monoclonal antibody, deeply changed the therapeutic landscape of secondary glomerulonephritis in the past decade. RTX has proved to be as effective as cyclophosphamide in inducing remission in ANCA-associated vasculitis and better than azathioprine as maintenance therapy in three different RCT. Treatment's duration and modality, however, remain debated. RTX has been widely used in resistant or relapsing proliferative lupus nephritis (LN), with positive results reported by retrospective studies; however, when employed as an “add-on” induction therapy in a RCT, it did not show a definite additive effect to standard therapy with mycophenolate mofetil and steroid in moderate forms of LN. In prospect, it remains a promising tool both as second-line therapy for resistant forms and as a “steroid-sparing” agent to strengthen induction and to allow reduced or minimal maintenance therapy. RTX is effective in the treatment of HCV-related cryoglobulinemic vasculitis, including glomerulonephritis. Monotherapy appears more effective than traditional cytostatic drugs in anti-viral drugs resistant forms. Association of RTX with antiviral therapy (pegINFα and ribavirin) produces a more rapid and effective immunological response with a similar virological one. Direct antiviral agents are beginning to be employed in association with traditional ones and RTX with promising results. RTX has been also anecdotally employed in fibrillary glomerulonephritis and in “monoclonal immunoglobulin deposits-related glomerulopathy” (mIgGN) secondary to non-Hodgkin lymphomas, either alone or within the setting of a hematological chemotherapy. Although many aspects need to be clarified, the role of RTX in the treatment of secondary glomerulonephritis has become increasingly important due to a favorable risk/benefit profile.