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Background Atypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class. Methods In 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein. Results We detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving CFHR3-CFHR1. A significantly higher proportion of patients with bone marrow transplant-related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b. Conclusions Detectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H's active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.

BACKGROUND AND AIMS We evaluated retrospectively in a cohort of kidney-transplanted patients (KTxp), the variations of mineral metabolism (MM) parameters, femoral and vertebral bone density during the first year of kidney transplantation (KTx). METHOD 383 KTxp (M = 232), up to the 650 transplanted in our Department (2004–2017) were studied. At 1st(T1) and 12th(T2) mth of KTx biochemical, femoral and vertebral dual-energy X-ray absorption (DEXA) data were recorded. T-score (Ts) -1 >Ts > -2.5 was considered Osteopenia (F-OPN/V-OPN) and Ts < -2.5 osteoporosis (F-OPS/V-OPS). RESULTS The KTxp age and dialysis vintage (DV) were 48 ± 12 years and 53 ± 25 months; 67% of KTxp had a history of hemodialysis. In 82.5% of cases, a donor deceased KTx (DD) was performed and in 40% of KTxp had a previous history of steroid therapy. During the first year of KTx 91% and 93% of KTxp received respectively calcineurin inhibitors and mycophenolate, and the steroids cumulative dose (SCD) was 2683 ± 926 mg. At T1, cholecalciferol and calcifediol were supplemented in 5% and 8% of KTxp, and AT T12 in 12% and 15% of KTxp. An increase in BMI (23 ± 3 versus 24 ± 3 kg/m2 P Femoral bone mineral density (F-BMD) at T1 and F-Ts-T1 were 0.749 ± 0.17 g/cm2 and -1.55 ± 1.06. F-OPS-T1 was present in 17.5% and F-OPN-T1 in 53% of KTxp. F-BMD-T1 correlated directly with BMI-T1 (P At T1, V-BMD-T1 and V-Ts-T1 were 0.92 ± 0.19 g/cm2 and −1.5 ± 1.58. V-OPS-T1 was present in 30% of KTxp and V-OPN-T1 in 34.5%. V-BMD-T1 correlated directly with BMI-T1 (P At T12, V-BMD-T12 and V-Ts-T12 were 0.90 ± 0.22 g/cm2 and −1.5 ± 1 .33 (both NS versus T1). V-OPS-T12 was present in 27.7% of KTxp and V-OPN-T12 in 37.2%. V-BMD-T12 correlated directly with BMI-T1 and T12 (P CONCLUSION In the first year of KTx several modifications of MM are present. Both femoral and vertebral DEXA seem to be strongly related to the pre-KTx status, in particular, nutritional status and dialysis vintage are related to bone status at T1. Strong importance on T12 evaluation is taken by the SCD.

BACKGROUND AND AIMS Immunomodulatory and anti-inflammatory properties have been hypothesized for native vitamin D (nVD). Very little is reported about nVD and risk of Sars-CoV-2 infection (COV) in renal transplant (RTx). In a cohort of renal transplanted patients (RTxp) we retrospectively evaluated: (i) nVD status in patients with (COV+) and without (COV-) COV infection; (ii) the impact of nVD status on severity of COV. METHOD The study includes 61 COV + in whom nVD status was available in the year before the infection, and 122 COV- matched 1:2 for age (53[45–64]years), gender (M = 60.7%), RTx vintage (7[2–15] years), presence of diabetes (18%), arterial hypertension (85%) and cardiac symptomatic disease (3%). Renal function, 24-h proteinuria and mineral metabolism (MM) parameters were evaluated at 1, 6 and 12 months before COV whereas nVD status was considered as the mean 25-OH-VD levels at the same timepoints. Severity of COV was based on the need for hospitalization (HOSP+: 27/61, 44.3%) and death (D+: 6/61, 9.8%). RESULTS (i) nVD levels were significantly lower in COV + than in COV- (19[12–26] ng/mL and 23[16–30] ng/mL, respectively, P = 0.01). No differences in the other biochemical parameters were found. The COV discriminative power of nVD status was evaluated by ROC curve (AUC 0.61, 95% CI: 0.54–0.68, P = 0.01), with a value of 25-OHVD 23.9 ng/mL showing the best discriminative power (sensibility 72%, specificity 47%). (ii) nVD levels showed a trend towards lower values in HOSP + COV + than HOSP-COV+ (17[8–25] ng/mL versus 20[14–26] ng/mL) and in D + COV + than D-COV+ (13[6–23] ng/mL versus 20[13–26] ng/mL), although these differences did not reach the statistical significance (P = 0.1 and P = 0.2, respectively). CONCLUSION With the limitations of the retrospective nature of the study and the small sample size, our data report that: No association was found between nVD levels in the year preceding the infection and COV severity.

Coronary artery calcifications(CACs), are related to the increased cardiovascular mortality during kidney transplantation(KTx). Using coronary-CT performed at 1 month(T0) and 5 years(T5) after KTx we evaluated: (1) the prevalence of CACs; (2) the clinical and biochemical factors related to CACs; 3) the factors implicated with CACs progression. We evaluated 67-pts selected from the 103-pts transplanted in our unit between 2007 and 2008. Clinical and biochemical parameters were recorded at the time of pre-KTx evaluation and for five years after KTx. Coronary-CT for the Agatson score (AS) evaluation was performed at T0 and at T5, and CACs progression was determined. At baseline AS was 45 [0–233]. At T5 AS was 119 [1–413]. At T0, 69% of patients had CACs. Age and dialytic vintage were the main independent variables related to CACs. At T5, CACs were present in 76% of patients. Age was the only independent factor in determining CACs. A progression of CACs was observed in 74% of patients. They were older, had higher CACs-T0 and higher SBP throughout the 5-years. The presence of CACs at T0 and age were the only independent factors in determining the CACs-progression. CACs-T0 had the best discriminative power for CACs progression. CACs prevalence is quite high in KTx patients; Age is strictly related to CACs; Age and the presence of CACs at baseline were the two major factors associated with the progression of CACs during the five years of follow up. CACs-T0 had the best discriminative power for progression of CACs.

Renal biopsy (RBx) informs about kidney transplantation (KTx) prognosis. In our observational study the prevalence of histological anomalies and the prognostic role of CD45, vimentin (VIM) and periostin (POSTN) in KTx-RBx have been evaluated. One hundred forty-six KTx-RBx (2009-2012) were analysed for general histology and in immunohistochemistry for CD45, VIM and POSTN. Clinical data of the 146-KTx patients were collected at the RBx time (T0), 6 and 12 months before and after RBx. Follow-up time was 21 ± 14 months. Glomerulosclerosis was 20% glomeruli/biopsy. Tubular atrophy (TA), Interstitial infiltrate (I-Inf) and interstitial fibrosis (IF) were slight in 21–18% and 25%, moderate in 22–30% and 26% and severe in 30–18% and 28% of patients. Fifty-eight percent of patients had lesions compatible with IF-TA. CD45, VIM and POSTN correlated to each-other and to TA, I-Inf and IF. VIM and POSTN correlated to GS. CD45 and VIM correlated directly to renal function (RF) and 25(OH)VitD, while POSTN inversely to 25(OH)VitD. Thirty patients restarted dialysis (HD+). HD+ had lower T0-eGFR, and higher CD45, VIM and POSTN than HD−. POSTN resulted the strongest in discriminate for HD+ . CD45, VIM and POSTN correlate to each-other and predict graft outcome. POSTN was the strongest in discriminate for HD+. 25(OH)VitD might influence inflammation and fibrosis in KTx.

In 32-kidney transplanted patients (KTxps), the safety and the effects on BMD and mineral metabolism (MM) of one-year treatment with denosumab (DB) were studied. Femoral and vertebral BMD and T-score, FRAX score and vertebral fractures (sVF) before (T0) and after 12 months (T12) of treatment were measured. MM, renal parameters, hypocalcemic episodes (HpCa), urinary tract infections (UTI), major graft and KTxps outcomes were monitored. The cohort was composed mainly of females, n = 21. We had 29 KTxps on steroid therapy and 22 KTxps on vitamin D supplementation. At T0, 25 and 7 KTxps had femoral osteoporosis (F-OPS) and osteopenia (F-OPS), respectively. Twenty-three and six KTxps had vertebral osteoporosis (V-OPS) and osteopenia (V-OPS), respectively. Seventeen KTxps had sVF. At T12, T-score increased at femoral and vertebral sites (p = 0.05, p = 0.008). The prevalence of F-OPS and V-OPS reduced from 78% to 69% and from 72% to 50%, respectively. Twenty-five KTxps ameliorated FRAX score and two KTxps had novel sVF. At T12, a slight reduction of Ca was present, without HpCa. Four KTxps had UTI. No graft rejections, loss of graft or deaths were reported. Our preliminary results show a good efficacy and safety of DB in KTxps. Longer and randomized studies involving more KTxps might elucidate the possible primary role of DB in the treatment of bone disorders in KTxps.

Background and Aims Urinary tract infections (UTIs) are the most common infectious disease in kidney transplanted patients (KTxps), especially during the first year of kidney transplantation (KTx). This study aims to examine the etiology of UTIs in a large cohort of KTxps, trying to identify their potential predisposing factors both during the first year and in the global follow-up (FU) of KTx. The impact of UTIs on KTx and patient’s survival in the long term will also be analyzed. Method In our study 585 KTxps (M 343; median age 49 years), out of the 616 KTxps transplanted in our Department between 2004 and 2016, were studied and followed up for a median time of 8 years. Clinical and biochemical data about the 1st (T1) and the 12th month (T12) of KTx were collected. Parameters related to UTIs, defined by a positive urine culture associated with urinary sediment suggestive of UTI, regardless of clinical symptoms, were considered in the global FU. A number of UTIs ≥3 was considered significant during the 1st year of KTx and in the overall FU. The reduction of the eGFR/year of FU, the loss of graft and the death of KTxps with a functioning graft were evaluated as outcome. Results The cohort had a slight prevalence of males (59%) and a median age of 49 years. At the time of KTx, JJ ureteral stent (JJ) was placed in 38% of KTxps, with a median stay time of 47 days. During the FU, 1700 UTIs were found in 458 KTxp, 550 UTIs during the first year of KTx. The pathogens most responsible for UTIs in the global FU were Escherichia coli (61%), Enterococcus (12%) and Klebsiella (8%). According to the number of UTIs found during the 1st year of KTx, KTxp were categorized in: UTI1≥3 (N=139) and UTI1 The studied cohort was also categorized according to the number of UTIs during the global FU in UTItot ≥3 (N=168) and UTItot During the FU, the median absolute reduction in eGFR was found to be -0.6[-2.0; +0.9](mL/min)/years. Despite a greater reduction in glomerular filtrate rate in UTI tot≥3 group, the graft loss and the death with functioning graft had no correlation with either UTI1≥3 (7 and 5 patients, respectively) or UTItot≥3 (12 and 8 patients, respectively). Graft loss was observed in 51 KTxps. The number of infections/follow-up time of these KTxps was comparable to that found in those who had a still functioning transplant at the end of observation, and no statistical differences were found in survival analysis according to IVU tot≥3 category. During the global FU, 40 KTxp died with functioning graft. Also with regard to this outcome, no significant correlations were observed with the number of UTIs/follow-up time and in the survival analysis. Conclusion Our data confirm that UTIs are frequent in KTxps. Some factors, such as induction therapy and JJ use, certainly have a favoring effect in UTIs development. Despite the relation observed between UTIs and eGFR reduction, UTIs had no significant impact on graft loss. Beyond prevention through the improvement of lifestyles and various behavioral aspects, the implementation of personalized immunosuppressive protocols associated with a careful management of JJ are desirable interventions in order to prevent the development of UTIs in KTxps.

The prevalence and the factors related to cytomegalovirus (CMV) disease (CMVd) during the 1st year of renal transplantation (RTx) and the relationship between CMVd and early and long-term graft and RTx-patient (RTx-p) survival were evaluated. In 505 RTx-p, followed up for 8(5–11) years, data were recorded after 1-(T1) and 12-(T12) months of RTx. CMVd was defined either by CMV replication without clinical signs of disease (CMVr, 43%), or CMV replication with signs of disease (CMVs, 57%). During the 1st year of RTx, 45% of RTx-p had CMVd (CMVd+). CMVd+ patients were older than CMVd− patients. Female gender and Donor CMV-IgG+ (CMV IgG−D+)/recipient IgG- (CMV IgG−R-) status were more prevalent in CMVd+. At T1, CMVd+ had lower albumin, haemoglobin, and higher uric-acid and reactive C-protein than CMVd− and, at T1 and T12, received more steroids. Albumin-T1 was the unique factor in determining CMVd+, maintaining its significance also after the inclusion of IgG−D+/IgG−R− status to the model. CMVs had higher prevalence of CMV IgG-D+/IgG-R- than CMVr. CMVd, CMVr, and CMVs had no impact on graft loss (11% of RTx-p) and RTx-p death (8% of RTx-p). CMVd is highly prevalent during the 1st year of RTx. Albumin-T1 influences CMVd insurgence. CMVd did not impact on RTx and RTx-p loss.

Introduction Atypical hemolytic uremic syndrome (aHUS) is mainly due to complement regulatory gene abnormalities with a dominant pattern but incomplete penetrance. Thus, healthy carriers can be identified in any family of aHUS patients, but it is unpredictable if they will eventually develop aHUS. Methods Patients are screened for 10 complement regulatory gene abnormalities and once a genetic alteration is identified, the search is extended to at-risk family members. The present cohort study includes 257 subjects from 71 families: 99 aHUS patients (71 index cases + 28 affected family members) and 158 healthy relatives with a documented complement gene abnormality. Results Fourteen families (19.7%) experienced multiple cases. Over a cumulative observation period of 7595 person-years, only 28 family members carrying gene mutations experienced aHUS (overall penetrance of 20%), leading to a disease rate of 3.69 events for 1000 person-years. The disease rate was 7.47 per 1000 person-years among siblings, 6.29 among offspring, 2.01 among parents, 1.84 among carriers of variants of uncertain significance, and 4.43 among carriers of causative variants. Conclusions The penetrance of aHUS seems a lot lower than previously reported. Moreover, the disease risk is higher in carriers of causative variants and is not equally distributed among generations: siblings and the offspring of patients have a much greater disease risk than parents. However, risk calculation may depend on variant classification that could change over time., Graphical abstract

Patients with atypical hemolytic uremic syndrome (aHUS) have long been considered ineligible for kidney transplantation (KTx) in several centers due to the high risk of disease recurrence, graft loss and life-threatening complications. The availability of Eculizumab (ECU) has now overcome this problem. However, the best approach towards timing, maintenance schedule, the possibility of discontinuation and patient monitoring has not yet been clearly established. This is a single center case series presenting our experience with KTx in aHUS. This study included 26 patients (16 females) with a diagnosis of aHUS, who spent a median of 5.5 years on kidney replacement therapy before undergoing KTx. We compared the aHUS relapse rate in three groups of patients who underwent KTx: patients who received no prophylaxis, patients who underwent plasma exchange, those who received Eculizumab prophylaxis. Complement factor H-related disease was by far the most frequent etiology (n = 19 patients). Untreated patients and patients undergoing pre-KTx plasma exchange prophylaxis had a relapse rate of 0.81 (CI 0.30–1.76) and 3.1 (CI 0.64–9.16) events per 10 years cumulative observation, respectively, as opposed to 0 events among patients receiving Eculizumab prophylaxis. The time between Eculizumab doses was tailored based on classic complement pathway activity (target to

In 178-kidney transplanted patients (KTxp), the prevalence of hypovitaminosis-D, the presence and novel development of left ventricular hypertrophy(LVH) and the correlations between native Vitamin-D (25OHD) and LVH were evaluated during the 1st year of transplantation (KTx). Clinical and instrumental data were recorded at pre-KTx and at one (T1) and 12 (T12) months after KTx. 25OHD levels were considered sufficient (s25OHD, ≥ 30 ng/dL) or insufficient (i25OHD

Background CMV disease (CMVd) is a frequent complication in renal transplanted patients (RTxp), especially during the first year of transplantation (RTx). CMVd impacts on long term graft and patients outcomes is still debated. Our observational retrospective study aims to evaluate: 1) the prevalence of CMVd during the first year of RTx; 2) the factors related to CMVd; 3) the relationship between CMVd and early and long term graft and patients survival. Method In 505 RTxp (age: 50[41;58]yrs – 292 males), up to the 616 transplanted in our unit between 2004 and 2016, clinical, blood and urinary parameters were recorded after 1 (T1) and 12 (T12) months of RTx. eGFR was estimated by MDRD formula. Donor (D) and Recipient (R) CMV serology was tested at the moment of RTx. CMV IgG-D+/IgG-R- RTxp (12%) and high risk patients (second or more RTx, ATG induction therapy), received prophylaxis therapy until the 3rd month of RTx. CMVd, was defined by the presence either of CMVr (CMV replication without clinical signs of CMV disease) or CMVs (CMV replication with signs of disease and/or need of antiviral therapy/reduction of immunosuppressive therapy). Median follow up (FU) was 8[5-11]yrs. The following outcomes were investigated: 1) graft: reduction of eGFR >20% between T1 and T12; reduction of eGFR >50% between T1 and end of FU (eGFRr>50%); graft loss (GL); eGFRr>50% + GL.; 2) RTxp survival at the end of FU. Results Ninty percent of RTxp had a kidney from a deceased D; 73% and 21% received haemodialysis (HD+) and peritoneal dialysis before RTx. Dialysis vintage was 50[33-75] months. In 12% of RTxp, induction therapy included ATG. Cumulative steroids dose was 880[840-105]mg and 2272[2598-3223]mg at T1 and T12 respectively. During the first year of RTx, 45% of patients had CMVd (CMVd+). CMVd+ were older than CMV free RTxp (CMVd-). Female gender, HD+ and CMV IgG-D+/IgG-R- were more prevalent in CMVd+. In addition, at T1, CMVd+ had lower albumin, haemoglobin and higher PTH, uric acid and reactive C protein levels than CMVd- and, both at T1 and T12, received higher steroid dose. In multivariate analysis, albumin-T1 was the most significant modifiable factor in determining CMVd+ (p=0.009 OR 0.50 – IC 0.29-0.84). Albumin-T1 maintained its significance also after the addiction of CMV serology IgG-D+/IgG-R- to the model (albumin T1: p=0.008 OR 0.48 – IC 0.29-0.84; CMV serology IgG-D+/IgG-R-: p=0.01 OR 2.16 – IC 1,18 -3,95). Among CMVd, 19% and 25% had respectively CMVr and CMVs. CMVs were characterized by lower dialysis vintage and higher prevalence of CMV IgG-D+/IgG-R- than CMVr. GL and death were observed in 11% and 8% of RTxp respectively. In univariate and survival analyses, CMVd, CMVr and CMVs didn’t show any impact on the graft and patients outcomes examined. Conclusion Our retrospective study confirms the high prevalence of CMVd during the first year of RTx, and identifies albumin at T1 as the most impacting parameter in influence CMVd insurgence. This might reflect the importance of the pre-RTx status in CMVd development after RTx. Nevertheless, CMVd seems not impact significantly on early and long term outcomes, experienced however in a small part of the cohort studied. Future studies, possibly prospective and including higher number of patients might better elucidate this issue.

Background and aims Bone and mineral metabolism (MM) disorders are relevant problems in renal transplanted patients (RTxp). In our observational monocentric study, we evaluated the effects on femoral and lumbar bone mineral density (BMD) and on MM parameters, and the safety of one year-treatment with Denosumab (DB) in a cohort of RTxp. Method We recorded data about 32 RTxp treated with DB in our Center in the last year. RTxp were evaluated for BMD and T-score (Ts) before the start (T0) and after 12 months (T12) of treatment. Osteopenia was defined, at femoral (F-OPN) and lumbar (L-OPN) sites as Ts:-1>Ts>-2.5 whereas osteoporosis, in the same sites (F-OPS and L-OPS) as Ts9.0 mg/dL were the finding at T0 of: 1) F-OPS and/or V-OPS; 2) sVF. During the year of treatment, hypocalcemic (HpCa=Ca Results The cohort was composed mainly by females (n=21). The time of RTx was 144[59-232]mths. Steroid therapy was prescribed in 30 RTxp (93%), 22(68%) and in 2 (6%) RTxp were taking 25OHD and 1-25OH. Three RTxp (9%) were receiving Ca supplements. Bisphosphonate therapy was reported in 15 RTxp (46%) in the year before DB start. At T0, 25(78%) and 7 (22%) RTxp had F-OPS and F-OPN. Twenty-three (71%) and 6 (20%) RTxp had L-OPS and L-OPN. In 3 RTxp normal lumbar T-score was found. sVF were present in 17 RTxp (53%). Ca and P were 9.6±0.6 mg/dL and 3.1±0.6 mg/dL whereas PTH, ALP and 25OHD were 64±32 pg/mL, 80±37 U/L and 28±16 mg/dL. SCr and Prot-U were 1,32±0,4 mg/dL and 0,23±0,16 g/24h. At T12, F-Ts increased significantly (T0: -3.0[-3.5/-2.5] vs T12:-2.8[-3.5/-2.4) as like as V-Ts (T0: -3.0[-3.7/-1.9] vs T12:-2.8[-3.0/-1.6) both p Conclusions The preliminary results presented in our study, limited by the monocentric, not randomized design and by the smallness of the cohort, reported a good bone efficacy of DB in RTxp, especially at lumbar level. The therapy was characterized by a good general safety. Future longer and randomized studies, involving more RTxp might elucidate the possible primary role of DB in the treatment of bone disorders in RTxp.

The management of hepatitis C virus (HCV)-induced glomerular disease remains unsatisfactory despite novel advances in antiviral and immunosuppressive therapy. Recent evidence highlighted the role of ribavirin, a drug provided with immunomodulatory properties, in the treatment of glomerular diseases associated with chronic HCV. We administered low-dose ribavirin (200 mg/day or 200 mg twice a week or 200 mg thrice weekly) in a prospective fashion to a group of patients with HCV-associated glomerular disease (n = 7). Ribavirin monotherapy was given in most (n = 6) patients and was accompanied by erythropoietin therapy in all. The primary endpoint was reduction of 24-h proteinuria after treatment ended; the secondary end-points were decrease in serum creatinine and amelioration of urinary abnormalities. We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. Many patients (n = 6) had inactive HCV infection as they had shown HCV RNA clearance from serum after antiviral therapy with direct-acting antivirals. Some patients (n = 4) had membranoproliferative glomerulo- nephritis, the diagnosis being confirmed by kidney histology in three cases; others (n = 2) received diagnosis of diabetic glomerulosclerosis, confirmed in one by kidney biopsy. We observed consistent reduction of 24-h proteinuria in two individuals after ribavirin therapy; another patient reported disappearance of microscopic hematuria. We found severe AE (hemolytic anemia) in three patients which required discontinuation of ribavirin treatment in two patients, one required hospitalization. Other AEs were cutaneous rash (n = 1), dyspepsia (n = 1), and fatigue (n = 1). Low-dose ribavirin was able to give consistent reduction of 24-h proteinuria in two patients; tolerance to ribavirin was unsatisfactory. We need further studies aimed to expand our knowledge on ribavirin therapy of HCV-associated glomerular disease. The low incidence of the disease hampers the conduction of clinical trials on this aim.

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41-0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%-38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS.

The research of novel markers in urinary samples, for the description of renal damage, is of high interest, and several works demonstrated the value of urinary mRNA quantification for the search of events related to renal disease or affecting the outcome of transplant kidneys. In the present pilot study, a comparison of the urine mRNA expression of specific podocyte markers among patients who had undergone clinical indication to renal transplanted (RTx, n = 20) and native (N, n = 18) renal biopsy was performed. The aim of this work was to identify genes involved in podocytes signaling and cytoskeletal regulation (NPHS1, NPHS2, SYNPO, WT1, TRPC6, GRM1, and NEUROD) in respect to glomerular pathology. We considered some genes relevant for podocytes signaling and for the function of the glomerular filter applying an alternative normalization approach. Our results demonstrate the WT1 urinary mRNA increases in both groups and it is helpful for podocyte normalization. Furthermore, an increase in the expression of TRPC6 after all kinds of normalizations was observed. According to our data, WT1 normalization might be considered an alternative approach to correct the expression of urinary mRNA. In addition, our study underlines the importance of slit diaphragm proteins involved in calcium disequilibrium, such as TRPC6.

COVID-19 is a life-threatening infection among elderly patients, comorbid patients, or transplanted patients. Lombardy (region of Italy), accounts for 786,324 cases as of 21 April 2021. We retrospectively describe our single Centre experience in 82 adult kidney-transplant patients with COVID-19 infection during two pandemic outbreaks: 27 (first outbreak) and 65 (second outbreak). Thirty-seven patients were hospitalized (HP) and sixty-five were home managed (HM). Infection presented with fever (80%), cough (51%), and dyspnea (33%). HP were older (60 ± 11 vs. 50 ± 14 years, p = 0.001), had more severe respiratory symptoms (dyspnea 62.1%, p &lt, 0.0001–cough 67% p = 0.008), and a longer length of disease (30 ± 28 vs. 21 ± 10, p = 0.04). The incidence of acute kidney injury (AKI) was 29.7% (p &lt, 0.0001). Steroid dosage was increased in 66% of patients (p = 0.0003), while calcineurin inhibitors were reduced by up to one third in 45% of cases, p &lt, 0.0001. Eleven patients died (13%). HM patients recovered completely without sequelae. In the overall cohort, AKI development (p = 0.006 OR 50.4 CI 95% 3.0–836) and age (p = 0.04 OR 1.1 CI 95% 1.0–1.2) were the most important factors influencing the probability of death during the infection. Although we report a relatively low incidence of infection (5.1%) the incidence of death is almost four times higher than it is in the general population.

Introduction Recurrence of atypical hemolytic uremic syndrome (aHUS) in renal allografts is common, leading to dialysis and graft failure. Pretransplant versus posttransplant initiation of eculizumab treatment in patients with aHUS has not been rigorously investigated. We hypothesized eculizumab pretransplant would reduce dialysis incidence posttransplant. Methods Of patients enrolled in the Global aHUS Registry (n = 1549), 344 had ≥1 kidney transplant. Of these, 188 had received eculizumab. Eighty-eight patients (47%) were diagnosed with aHUS and received eculizumab before, and during, their most recent transplant (group 1). A total of 100 patients (53%; group 2) initiated eculizumab posttransplantation. This second group was subdivided into those diagnosed with aHUS before (n = 52; group 2a) or after (n = 48; group 2b) their most recent transplant. Results Within 5 years of transplantation, 47 patients required dialysis; the risk of dialysis after transplantation was significantly increased in group 2b (hazard ratio [HR] 4.6; confidence interval [CI] 1.7–12.4) but not 2a (HR 2.3; CI 0.9–6.2). Graft function within 6 months of transplantation was significantly better in group 1 (median estimated glomerular filtration rate of 60.6 ml/min per 1.73 m2) compared with 31.5 and 9.6 ml/min per 1.73 m2 in groups 2a (P = 0.004) and 2b (P = 0.0001), respectively. One meningococcal infection (resolved with treatment) and 3 deaths (deemed unrelated to eculizumab) were reported. Conclusions Outcomes for transplant patients with aHUS treated with eculizumab were improved compared with previous reports of patients with aHUS not treated with eculizumab. Our findings suggest delayed aHUS diagnosis and therefore treatment is associated with an increased risk of dialysis posttransplantation and reduced allograft function., Graphical abstract

Background Atypical hemolytic uremic syndrome (aHUS) is life-threatening condition particularly when complicating allograft hematopoietic stem cell transplant (HSCT). In the past, the outcome was very poor with the majority of patients reaching end-stage renal disease or dying with little or no chances of kidney transplant (KTx) due to the high risk of relapse. The availability of C5 inhibition has opened up significant therapeutic opportunities and has improved the outcome particularly if complement dysregulation (CD) is the underlying pathogenetic mechanism. Methods We describe a peculiar case of a girl with aHUS complicating HSCT and her subsequent successful KTx received from the same donor thus performed without immunosuppression but anti-C5 inhibition. Results Soon after HSCT performed for acute lymphoblastic leukemia, the patient developed a TMA due to CD and reached end-stage renal disease. After 2 years on dialysis, the patient received a KTx from her father who was already the HSCT donor. Given the full chimerism, no immunosuppressive agent was prescribed except a short (2 days) course of steroids and eculizumab to prevent aHUS relapse. Nine months after the KTx, the patient is well with normal renal function, no immunosuppression and continues eculizumab prevention of aHUS (1 infusion every 21 days). Conclusions All patients with transplant-associated thrombotic microangiopathy should be screened for the causes of CD. C5 inhibition with eculizumab is an important therapeutic resource to manage this complication. When KTx is necessary, immunosuppression can be safely withhold in case of same donor for both grafts and documented full chimerism.

Background: The evidence in the medical literature on the treatment of hepatitis C virus–associated glomerular disease is extremely limited. The advent of nonconventional immunosuppressive agents and direct-acting antivirals promises high efficacy and safety. Aims: We conducted an open-label, single-arm clinical study to examine the efficacy and safety of a combined approach for hepatitis C virus–associated glomerular disease. Methods: In the first phase of the study, patients with hepatitis C virus–associated glomerular disease received interferon-based antiviral therapy and immunosuppressive agents; since 2013, interferon-free antiviral therapy was adopted and novel immunosuppressants (including B-cell depleting agents and mycophenolate mofetil) or immunomodulators (ribavirin) were choiced. Virological and clinical responses were evaluated over a long observation period (median follow-up of 60 weeks and 46.5 months after the end of treatment with interferon and direct-acting antiviral agents, respectively). Results: We enrolled 25 consecutive patients with hepatitis C virus–associated glomerular disease, 8 being liver transplant recipients for hepatitis C. A total of 13 patients received therapy with direct-acting antivirals and experienced sustained viral response (serum hepatitis C virus RNA Conclusion: Treatment with direct-acting antivirals provides excellent rates of viral response and safety in patients with hepatitis C virus–related glomerular disease; viral response was frequently accompanied by clinical improvement. The absence of hepatitis C virus RNA from serum allowed immunosuppressive and immunomodulatory therapies with benefits for glomerular abnormalities and no concern on hepatitis C virus replication.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by platelet consumption, hemolysis, and organ damage. Eculizumab (ECU), a humanized antibody that blocks complement activity, has been successfully used in aHUS, but the best treatment schedule is not yet clear. Here, we report our experience with ECU maintenance treatment and the interval between subsequent doses being extended based on global classical complement pathway (CCP) activity aimed at

Hepatitis C virus (HCV) infection may be associated with extra-hepatic illness including mixed cryoglobulinemia (MC). Consistent evidence exists on HCV-MC in the non-transplantation setting but information on HCV-related cryoglobulinemia after solid organ transplantation is limited, particularly after liver transplantation (LT). We report on a 48-year-old man who developed HCV-associated cryoglobulinemic vasculitis with recurrent hepatitis after liver transplant. One year after transplant for HCV-positive cirrhosis, he presented severe cutaneous manifestations, and biopsy-proven cryoglobulinemic membrano-proliferative glomerulonephritis (MPGN). HCV RNA clearance occurred within a few weeks of antiviral therapy; sustained viral response (SVR) was obtained by one year of anti-HCV combination therapy (eight months of pegylated IFN/ribavirin and four months of standard IFN/ribavirin). SVR was linked to complete remission of skin, liver, and kidney abnormalities. Tolerance to the pegylated IFN/ribavirin regimen was not excellent due to the occurrence of lobar pneumonia with anemia; thus, peg-IFN was replaced by recombinant IFN, with a favorable outcome. Clinical and viral remission persisted over a 48-month follow-up. HCV-associated mixed cryoglobulinemia flareups following LT were successfully managed with combined antiviral therapy. HCV-related MC is uncommon in developed countries and this clearly hampers randomized controlled clinical trials aimed at evaluating the efficacy and safety of anti-HCV therapy after solid organ transplantation or in the non-transplantation setting.

Background Hepatitis C virus infection is associated with a variety of extrahepatic disorders such as membrano-proliferative glomerulonephritis, which is generally due to cryoglobulinemia. Setting We describe the case of one liver transplant recipient who received antiviral therapy (subcutaneous administration of peg-IFN-alpha-2a 180 mcg weekly and oral ribavirin 200 mg thrice a day) for HCV-related membrano-proliferative glomerulonephritis. He presented normal kidney function, non-nephrotic proteinuria (2 g/24 h) and mild hematuria. Results Urinary abnormalities disappeared within a few weeks after the initiation of antiviral therapy; however, combination antiviral therapy was not able to obtain viral clearance. After 11 months, IFN-therapy was interrupted and the patient continued low-dose ribavirin monotherapy (200 mg once per day) for one additional year- remission of proteinuria (Conclusions Antiviral therapy may be effective in patients with HCV-induced glomerulonephritis. Further evidence is needed to evaluate efficacy and safety of ribavirin monotherapy for HCV-related glomerulonephritis.

We describe the case of a 51-year-old woman with HCV-associated cryoglobulinemic glomerulonephritis (GN). She presented mild deterioration of kidney function, non-nephrotic proteinuria, and active urinary sediment. Kidney biopsy showed features of membranoproliferative changes with some sclerosis. Sustained viral response (SVR) was obtained by 6 months of antiviral therapy (peg-IFN-α2a plus ribavirin). SVR was linked with improvement of kidney function and remission of proteinuria. Clinical and virological remission persists over a 25-month follow-up. This case report emphasizes efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis – preliminary but encouraging results exist. We identified by systematic review of the literature 9 studies (156 unique patients); the pooled estimate of frequency of sustained virological response after IFN-based therapy was 0.49 (95% confidence interval, CI: 0.21, 0.77; p < 0.0005; random effects model). Heterogeneity was found (I2 = 98.9%, p < 0.0001). Two possible regimens should be considered for the treatment of HCV-associated cryoglobulinemic GN according to the clinical presentation. Immunosuppressive therapy is recommended for HCV-related kidney disease having aggressive course, and recent evidence supports rituximab (RTX) use with a reduced exposure to corticosteroids. We identified six studies (66 unique patients) on RTX therapy for HCV-associated kidney disease; at the end of RTX therapy, the pooled estimate of the mean decrease in proteinuria was 1.4 g/24 h (95% CI: 0.75, 2.05, p < 0.001); The p test for heterogeneity gave a value of 0.94 (I2 = 0). Several questions related to RTX use remain. HCV-induced GN is uncommon among CKD patients of developed countries, and this clearly hampers prospective controlled clinical trials aimed to evaluate efficacy and safety of antiviral or immunosuppressive therapy in this population.

Plasma levels of the platelet markers beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) are among the most sophisticated indexes of biocompatibility available to evaluate new members for hemodialysis. This investigation was designed to determine the extent of platelet activation by measuring the alpha-granule release products, beta-TG and PF4; anticoagulation and thrombogenesis by monitoring plasma heparin; and fibrinopeptide A (FPA) and thromboxane B2 (TX B2) levels during treatment with a combined hemodialysis-hemoperfusion system. Both in vivo and in vitro results showed that the platelet markers had a pattern different from that generally observed during treatment with hemodialysis alone. This is due to the avidity of charcoal for the markers studied, which therefore cannot be used to evaluate the biocompatibility of the system.

The evidence in the medical literature on the efficacy and safety of rituximab therapy for primary glomerulonephritis is limited and controversial. We describe two male Caucasian patients with rapidly progressive kidney failure due to primary proliferative glomerulonephritis. Both of them received high-dose intravenous corticosteroids and oral cyclophosphamide with limited benefit. The first patient (hepatitis C virus-negative mixed cryoglobulinemia) underwent plasma-exchange with intravenous immunoglobulins; he showed significant benefit on kidney function (he became dialysis independent with serum creatinine going back to 1.6 mg/dL) after one rituximab pulse even if urinary abnormalities were still present. No improvement in renal function or urinary changes occurred in the second patient. Both these individuals developed sepsis over the follow-up, the first patient died two months after rituximab therapy. This report is in keeping with the occurrence of severe infections after rituximab therapy in patients with renal impairment at baseline and concomitant high-dose steroids.

Summary Background Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS. Objectives To optimize eculizumab therapy in aHUS patients by monitoring complement functional tests and markers of disease activity. Patients/Methods We studied 18 patients with aHUS (10 males; eight females; age range, 2–40 years) treated with eculizumab to induce and/or maintain disease remission. Patients were followed up for a cumulative observation period of 160 months, during which blood samples were obtained at various time intervals to measure complement activity (Wieslab for the classical, alternative and mannose-binding lectin complement pathways) and the parameters of disease activity (haptoglobin and lactate dehydrogenase serum levels, and platelet count). The intravenous eculizumab doses of 12–33 mg kg−1 were initially administered every week, with the interval between doses being gradually extended to 2 weeks, 3 weeks and 4 weeks on the basis of strict laboratory and clinical control. Results Complement activity was normal before eculizumab treatment, regardless of the state of the disease (activity or remission). It was completely suppressed 1 week, 2 weeks and 3 weeks after the last eculizumab infusion (mean values ± standard deviation: 1% ± 1% to 3% ± 5% for both the classical and alternative pathways; P = 0.0001 vs. baseline), and partially suppressed after 4 weeks (22% ± 26% and 16% ± 27%; P = 0.0001 vs. baseline). The increase in the time interval between eculizumab infusions did not change disease activity markers. Conclusions Monitoring complement tests can allow a safe reduction in the frequency of eculizumab administration in aHUS while keeping the disease in remission.

Secondary hyperparathyroidism (SHP) is one of the most challenging complications in the most advanced stages of end-stage renal disease. In the last decade, newly available medical tools have greatly increased the possibilities for controlling SHP. However, one of these tools, cinacalcet, has not yet been approved for its use in transplanted patients and the evidence for its safety in this clinical setting is still incomplete. For these reasons, many questions still remain open for the clinical nephrologist: when to consider a parathyroidectomy (PTX) in a patient on a waiting list for kidney transplant (KTx); when to recommend PTX after KTx; when could a regression of parathyroid hyperplasia be expected at any time after KTx. In the present paper, we will briefly deal with these questions in the light of an unusual clinical case.

Recent studies have pointed out that the incidence of primary glomerular diseases is similar in the elderly and in younger populations. However the clinical characteristics of the different subtypes may be different in the advanced age. Minimal change nephropathy responds favorably to corticosteroids and/or cyclophosphamide, but many untreated or non-responder patients progress to end-stage renal disease or die from nephrotic complications. Focal and segmental glomerulosclerosis also has a severe prognosis in older patients but some 50% of patients may attain remission of the nephrotic syndrome with a prolonged corticosteroid treatment. The responders tend to maintain normal renal function over time. Membranoproliferative glomerulonephritis and IgA nephritis have a severe prognosis and do not respond to treatment. The clinical presentation and the outcome of membranous nephropathy are similar in the elderly and in younger adults. Corticosteroids are of little benefit while a 6-month treatment with chlorambucil and methylprednisolone may obtain remission of the nephrotic syndrome in about 2/3 of older patients. Crescentic glomerulonephritis has an ominous prognosis in older patients but some patients may improve if treatment with methylprednisolone pulses is started early. Acute postinfectious glomerulonephritis is often associated with renal failure in older patients. The prognosis may be severe.

Defibrotide, a polydesoxyribonucleotide derivative with antithrombotic and fibrinolytic activity, capable of inducing the release of PGI2 from vascular endothelia, was proposed as an alternative to standard heparin coverage during blood dialysis for patients at risk of bleeding. The original procedure featured the preliminary washing of the dialysis circuit with heparin, which was then recirculated and eliminated, and the two drugs, heparin and defibrotide, are known to interact with each other. The purpose of this present study was to explore the ex-vivo heparin activity (assessed as anti-Xa activity) in diverse hemodialysis models using defibrotide (800 mg intravenous, in 4 bolus injections) and various dosages of heparin. Anti-Xa activity is negligible in dialysis conducted with defibrotide alone. When the circuit was prewashed with heparin (5000 and 2500 IU), there was evident anti-Xa activity (0.3-0.5 U/ml) in the first 30-60 minutes of dialysis; continuous heparin infusion (500 U/hour) resulted in high anti-Xa activity levels at the end of dialysis. Thus the best hemodialysis procedure for patients at high risk of bleeding should be one utilizing only defibrotide, or defibrotide plus small amounts of calcium heparin infused at the rate of 500 U/hour for not more than two hours.