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BACKGROUND AND AIMS The development and massive use of mRNA COVID-19 vaccine BNT162b2 has raised new concerns on triggering de novo immune-mediated diseases, in particular rare diseases as glomerulonephritis (GN), even if the security profile is excellent and severe reactions have been rare. In literature few similar cases were recently described [1, 2]. We report six cases of newly diagnosed GN after a two-dose regimen of SARS-CoV-2 vaccine, from a single tertiary care institution in Northern Italy. METHOD We described six cases of de novo GN occurring after massive use of Pfizer-BioNTech BNT162b2 COVID-19 vaccine from March 2021 to December 2021. All cases were biopsy proven. Baseline characteristics and laboratory findings, treatments and outcomes were based on review of medical records. RESULTS From April 2021, we observed two IgA nephropathies (IgA-N), one membranous nephropathy (MN), one membranoprolipherative GN (MPGN), one acute interstitial nephritis (aTIN) and one minimal change disease (MCD). Of note, one IgA-N presented with diffuse purpura as in IgA-vasculitis. The median age at vaccination was 52.8 years (min–max 18–67) and three (50%) were female; arterial hypertension was the most common comorbidity (50%). Only one subject contracted COVID-19 before vaccine (16.6%). None of the points showed any sign of renal disease before vaccine; at the time of disease onset, the median creatinine was 1.49 mg/dL (min–max 0.6–10.5 mg/dL) and proteinuria 3.0 g/24 h (min–max 0.9–13.8 g/24 h). All cases presented after the second dose (1 day to 6 months thereafter) and three (50%) were within 3 weeks from the vaccine. Of note, the aTIN developed after the vaccine during a long-time therapy with statins and relapsed after a rechallenge with a statin few months later. All the nephropathies were treated as per center practice, with an overall good response (four partial remissions and one complete remission). Given a target population of about 100 000–200 000 residents in our area, we could estimate an incidence rate of 4–8 cases/100 000 patient-years. CONCLUSION This small series has a lot of limitations including the small number of patients and we probably missed some cases in our area. Furthermore, we could not investigate a causal association, even if the timing of disease onset might be suspicious in three cases and the incidence seemed to be almost twice as the expected in Europe (about 2–4/100.000 patient-years). As for SARS-CoV-2 vaccines, it is likely that the mRNA vaccine will result in a more potent inflammatory stimulus than the one observed after inactivated virus-vaccine: maybe some patients had already a subclinical GN and the vaccine constituted a flare leading to the full-blown disease [3].

BACKGROUND AND AIMS The mass vaccination for COVID-19 has raised new concerns for patients with immune-mediated nephropathies: there is a small but growing literature of case-reports linking SARS-CoV-2 vaccines with heightened off-target immune responses leading to de novo or relapsing glomerular diseases [1, 2]. Aim of this study was to evaluate how many and how severe were the relapses of immune-mediated nephropathies after the SARS-CoV-2 vaccine in a single center. METHOD This is a retrospective study held in Italy from the start of the vaccination campaign (late December 2020) to December 31st 2021. We included all patients with an immune-mediated nephropathy (either on or off immunosuppressive therapy—IS), excluding patients with an end-stage renal disease or kidney transplant. In Italy we used mRNA (Comirnaty by Pfizer-BioNTech or Spikevax by Moderna) or adenoviral vector vaccines (Vaxzevria by AstraZeneca or Janssen), without any preference for patients with kidney disease, but those on active IS were given preferentially an mRNA vaccine. There was no active surveillance of lab tests after vaccination and post-vaccine tests were either concomitant to programmed visits or suggested on a patient by patient basis. Recurrence was defined as relapse of nephrotic or nephritic syndrome, doubling of urinary proteins with a max value > 1 g/24h, acute kidney injury with an active urinary sediment, or positivization or 5-fold increase of serological markers of disease activity (i.e.: ANCA in AAV). RESULTS A total of 38 patients (M: F 28:10, age at vaccine 45.9 ± 19.1 years) completed the vaccination protocol: among them, the most common nephropathy was membranous nephropathy (n = 12, 31.6%), followed by IgA nephropathy (n = 7, 18.4%), minimal change disease (n = 6, 15.8%) and ANCA-associated vasculitis (n = 6, 15.8%); 26 patients (68.4%) had at least one other comorbidity. We observed six relapses (4 MN, 1 IgA, 1 AAV), of which only one (MN) developed a mild oedema. The mean time from the first vaccine dose to the relapse was 101 ± 71 days (5–199 days) and only two episodes occurred within 4 weeks from a vaccine dose. We could not find an association between recurrences and maintenance IS at the time of vaccine or any other variable. The overall post-vaccine incidence rate of relapses was 35.8/100 patient-years, as compared with 14.0/100 patient-years historically observed in the same cohort [IRR 2.55, 95% confidence interval (CI) 0.89–5.97]. CONCLUSION Relapses of immune-mediated nephropathies are not common after SARS-CoV-2 vaccine and we did not observe any clinically relevant relapse. However the overall rate of relapse seems to be a little higher than prior vaccination [3], but only 2/6 patients recurred soon after a vaccine dose. As these relapses seem to be self-limiting, a post-vaccine monitoring could be useful in patients at high risk of severe disease.

Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

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 ...

TCF7L2 rs7903146 CT polymorphism is associated with diabetes in the general population but its independent impact on cardiovascular disease is debated. On this basis, we investigated its association with major adverse cardiac events (MACE) in a single-center cohort of non-diabetic kidney transplant recipients (KTRs).Patients with pretransplant diabetes were excluded and patients who developed post-transplant diabetes were censored at time of diagnosis.rs7903146 CT polymorphism appeared to modulate the risk of MACE: 5-year prevalence was 0.8% in CC patients, 7.2% in CT patients and 9.7% in TT patients (P.001). TCF7L2 rs7903146 was an independent predictor of MACE in a multivariate Cox regression model (for each T allele, HR: 2.99, 95%CI: 1.62-5.52, P.001), together with history of cardiac ischemic events (HR: 8.69, 95%CI: 3.57-21.16, P.001), DGF (HR: 2.42, 95%CI: 0.98-5.95, P=.056) and HLA-mismatches (for each mismatch: HR: 1.55, 95%CI: 1.00-2.43, P=.053). Introduction of rs7903146 CT polymorphism into a model based on these clinical variables significantly increased predictive power for MACE (P=.003).TCF7L2 rs7903146 T allele may be strongly and independently associated with MACE in non-diabetic KTRs. These findings suggest the possibility of employing this SNP to more accurately stratify cardiological risk in KTRs.

Background Patients with a rare genetic disease may receive renal transplantation (KTx) without a correct diagnosis of causal nephropathy and therefore develop unexpected and even severe complications. The aim of the study was to describe the cases of rare genetic disorders diagnosed after KTx, in order to draw clinical lessons for the transplant physician. Methods We retrospectively assessed all patients who had received a diagnosis of a rare genetic disorder after KTx. Results In our center, more than 30% (278/911) of kidney transplant (KTx) recipients were diagnosed with a causal nephropathy: Prevalence of rare genetic disorders in this group was 4.32% (12/278), including 2,8-dihydroxyadeninuria (2,8-DHA) disease (n = 2), HNF-1B-associated nephropathy (n = 2), UMOD-related nephropathy (n = 5), Fabry disease (n = 1), INF2 focal segmental glomerulosclerosis (n = 1), and Senior-Loken syndrome (n = 1). 2,8-DHA nephropathy relapsed in both patients causing an acute renal failure and jeopardizing the graft. Conclusions Kidney transplant recipients without a diagnosis of causal nephropathy appear to be a selected population in which rare genetic diseases might be more common than expected. As even a belated diagnosis after KTx can have a significant impact on graft and patient survival and on other family members, this possibility should be evaluated in KTx recipients without a known causal nephropathy.

Background HNF1B gene mutations might be an underdiagnosed cause of nephropathy in adult patients mainly because of their pleomorphic clinical presentations. As most studies are based on paediatric populations, it is difficult to assess the likelihood of finding HNF1B mutations in adult patients and consequently define clinical settings in which genetic analysis is indicated. The aim of this study was the search for mutations in the HNF1B gene in a cohort of unrelated adult patients with nephropathy of unknown aetiology. Methods Patients were tested for the HNF1B gene if they had chronic kidney disease of unknown origin and renal structure abnormalities (RSA) or a positive family history of nephropathy. The HNF1B coding sequence and intron–exon boundaries were analysed by direct sequencing. The search for gene deletions was performed by Multiple Ligation Probe Analysis (MLPA). Results Heterozygous mutations were identified in 6 out of 67 screened patients (9.0%) and included two whole gene deletions, one nonsense (p.Gln136Stop), two missense (p.Gly76Cys and p.Ala314Thr) mutations and a frameshift microdeletion (c.384_390 delCATGCAG), the latter two (c.384_390 del and p.Ala314Thr) not ever being reported to date. Mean age of the mutated patients at screening was 48.5 years with a M/F ratio of 2/4. The clinical manifestations of affected patients were extremely pleomorphic, including several urological and extra-renal manifestations. Conclusions Mutations of HNF1B could explain chronic kidney disease in up to 9% of adult patients with a nephropathy of unknown aetiology and RSA: therefore an HNF1B mutation analysis should be considered in this group of patients.

The association between acute renal disease and infection has been known since the mid '800s: acute post-infectious glomerulonephritis (PIGN) is a reactive immunological process against the kidney secondary to an infection, classically caused by a Streptococcus. The typical clinical presentation of PIGN is an acute nephritic syndrome with macro- or microscopic hematuria, proteinuria, hypertension, edema and renal function impairment of variable degree. The histology is characterized by an intracapillary glomerular proliferation, but may rarely be associated with an extracapillary proliferation. The classical childhood form is still present nowadays, even with severe cases, in developing countries, while in the last decades it almost disappeared in industrialized countries, where post-infectious GN are often found in elderly patients with multiple comorbidities. These clinical variants are usually related to other infective agents, like Staphylococcus aureus, both methicillin resistant (MRSA) and susceptible, and may be characterized by an IgA-dominant deposition. Kidney biopsy is rarely needed, especially in the child, while in the adult or old patient a biopsy is warranted if there is an atypical presentation or evolution, like rapidly progressive renal failure, absent or delayed function recovery, persisting low C3, nephrotic range proteinuria and persisting high proteinuria. Current therapy strategies rely on culture-guided systemic antibiotics, especially in the old patient, in which MRSA are relatively frequent, support therapy and only in very selected cases on steroids. These latter cases include the rare PIGN with crescents and those with a severe interstitial inflammation.

Introduction Acutely decompensated heart failure (HF) in patients with diuretic resistance is often treated with extracorporeal ultrafiltration. Peritoneal ultrafiltration (PUF) has been proposed for the long-term management of severe HF after resolution of the acute episode. The aim of the present study was to evaluate the use of PUF in the treatment of chronic refractory HF in patients without end-stage renal disease. Methods This multicenter (10 nephrology departments throughout Italy) retrospective observational study included patients with severe HF refractory to maximized drug treatment. The patients were proposed for PUF because they had experienced at least 3 hospital admissions in the preceding year for acutely decompensated HF requiring extracorporeal ultrafiltration. Results Of the 48 study patients (39 men, 9 women; mean age 74 ± 9 years), 30 received 1 nocturnal icodextrin exchange, 5 required 2 daily exchanges, and 13 received 2 – 4 sessions per week of automated peritoneal dialysis. During the first year, renal function remained stable (initial: 20.8 ± 10.0 mL/min/1.73 m2; end: 22.0 ± 13.6 mL/min/1.73 m2), while pulmonary artery systolic pressure declined to 40 ± 6.09 mmHg from 45.5 ± 9.18 mmHg ( p = 0.03), with a significant concomitant improvement in New York Heart Association functional status. Hospitalizations decreased to 11 ± 17 days/patient–year from 43 ± 33 days/ patient–year before the start of PUF ( p < 0.001). The incidence of peritonitis was 1 episode in 45 patient–months. Patient survival was 85% at 1 year and 56% at 2 years. Conclusions This study confirms the satisfactory results of using PUF for chronic HF in elderly patients.

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.

BACKGROUND Tunnelled femoral catheters with their tip in the lower inferior vena cava (IVC) are proposed only in few cases, but they often provide less than optimal blood flows and frequently have complications. The aim of this prospective observational study is to evaluate the use of 70-cm-long tunnelled cuffed femoral twin Tesio catheters with their tip in the upper IVC for haemodialysis. METHODS Between May 2007 and May 2009, 25 tunnelled femoral catheters (fCVC) have been placed in 25 patients (77.7 +/- 10.8 years) with exhausted thoracic venous accesses or old patients with several comorbidities. Two 10 Fr carbothane 70-cm-long Tesio catheters with a Dacron cuff at 45 cm from the tip were placed in the femoral vein of each patient and then tunnelled; tips were in the upper third of the IVC. fCVCs were removed for either malfunction (Qb < 200 ml/min) or infection that did not resolve with antibiotics. RESULTS Technical success of placement was 100%. The 6- and 12-month assisted primary patency rate were respectively 67 +/- 13% and 54 +/- 17%. The mean session Kt/V was 1.45 +/- 0.19, and the blood flow was 270 +/- 17 ml/min. Six fCVCs have been removed: three for infection, one for accidental damaging and two for the making of a different vascular access. The main complications were 2 catheter tip thrombi, 3 tunnel infections and 11 fCVC-related bacteraemia (1.77 episodes per 1000 CVC-days). CONCLUSION The placement of twin fCVCs with their tip in the high IVC can provide an adequate dialysis and can be considered for patients with no remaining thoracic accesses.

Background: Post-transplant malignancies (PTM) occur in a percentage as high as 50% in patients followed 20 yr and have become a main cause of mortality and are expected to be the first cause of death within the next 20 yr in kidney transplant recipients. Patients and methods: We analyzed the PTM incidence in our kidney transplant recipients, and its main risk factors. The records of 400 patients (min follow up = one yr) have been retrospectively reviewed and categorized into three groups: patients without any tumor, with a non-melanoma skin cancer and with a solid or hematologic cancer. A cancer-free multivariate survival study was performed stratified by age, sex, immunosuppressive therapy, time on dialysis, body mass index (BMI), smoke, diabetes and nephropathy. Results: Thirty patients developed PTM: 12 non-melanoma skin cancer, three lymphomas and 15 solid malignancies (seven genitourinary, three lung, two breast, two gastrointestinal and one sarcoma). The mean age at diagnosis was 55 yr, with a mean time from transplant of 27 months. We observed six deaths and two graft losses. Non-melanoma skin cancer-free survival and the solid/hematologic cancer-free survival was 99.5% and 98.5% at one yr, and 95.2% and 94.6% at five yr, respectively. At univariate analysis, age and induction therapy were significant risk factors for both types of PTM, while only recipient age significantly increased the risk of all PTM, and anti CD25 significantly reduced the risk of non-melanoma skin cancer at the multivariate study. Conclusions: These data confirm the role of age and induction strategies in modulating the risk of neoplasia. To look for which strategies might reduce the PTM risk, including a personalized therapy to minimize the effects of chronic immunosuppressant, will be a crucial goal.

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). A 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. We 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.

Several genetic polymorphisms modulate the risk of posttransplant diabetes mellitus (PTDM), a complication associated with an increased morbidity and mortality after kidney transplantation; however, their clinical utility is still undefined.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.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 vs25.0; HR, 2.43; 95% CI, 1.40-4.23; P = 0.0018; ≥30 vs25.0; HR, 5.70; 95% CI, 2.77-11.74; P0.0001), TCF7L2 rs7903146 (per each T allele; 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; P0.0001) and absence of heterogeneity among studies (I = 0%).Inclusion of this polymorphism in a predictive model appeared to improve its ability to stratify patients according to the risk of PTDM.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.

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.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.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], p0.0001), while neither VKA nor AAT had any impact.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.

BACKGROUND: Inactivating mutations of the calcium-sensing receptor (CaSR), of the G-protein subunit α11 (GNA11) and of the adaptor-related protein complex 2, sigma 1 subunit (AP2S1) genes are responsible for familial hypocalciuric hypercalcaemia (FHH). The aim of this study was to analyse prevalence and pathogenicity of CaSR, GNA11 and AP2S1 mutations in patients with an FHH phenotype and to compare them with a sample of patients with primary hyperparathyroidism (PHPT) in order to identify the most useful laboratory parameter for a differential diagnosis. METHODS: Patients with an FHH phenotype were studied with polymerase chain reaction amplification and direct sequencing of the entire CaSR, GNA11 and AP2S1 coding sequences. Novel mutations were introduced in a Myc-tagged human wild-type (WT) CaSR cDNA-expressing vector, and functional assay was performed on human embryonic kidney cells evaluating expression and function of mutated proteins. RESULTS: Among 16 FHH patients, none had an inactivating GNA11 or AP2S1 mutation while 3 (18.8%) carried a CaSR mutation and 10 (62.5%) at least one CaSR polymorphism. Within the latter group, 7 of 10 patients had more than one polymorphism (4.1 ± 2.1 per patient). Two novel CaSR mutations [c.2120A>T (E707V) and c.2320G>A (G774S)] were identified: the E707V mutation prevented CaSR expression (western blot), whereas the G774S mutation determined a reduced receptor sensitivity to calcium (IP3 assay). PHPT patients showed significantly (P < 0.001) higher serum calcium, parathyroid hormone, urinary calcium and calcium-creatinine clearance ratio (CCCR) and significantly lower serum phosphate than FHH ones. CONCLUSIONS: FHH should be clearly differentiated by PHPT to avoid unnecessary surgery: CCCR could be a useful screening tool while genetic analysis should include the two novel CaSR mutations herein described. The role of multiple polymorphisms deserves further investigation in patients with an FHH phenotype.

Circulating levels of soluble urokinase-like plasminogen activator receptor (suPAR) have been associated with proteinuria and renal function in focal segmental glomerulosclerosis (FSGS). This study aimed to evaluate if circulating suPAR levels are independently associated with proteinuria in patients with non-FSGS glomerulonephritis.This is a cross-sectional analysis of suPAR levels on 42 patients with primary non-FSGS glomerulonephritis (group GN) and 140 patients with secondary glomerulonephritis within an autoimmune disease (group AID).suPAR serum levels were significantly higher in AID patients (4,733 ± 3,073 pg/ml) than in healthy controls (1,908 ± 1,685 pg/ml; p0.001), whereas GN patients displayed intermediate levels (3,670 ± 2,435 pg/ml; p = 0.021). Multivariate analysis for elevated serum suPAR (3,000 pg/ml) showed an independent association with estimated glomerular filtration rate (eGFR)60 ml/min/1.73 m(2) [odds ratio (OR) = 4.19, 95% confidence interval (CI): 1.67-10.54, p = 0.002], proteinuria0.5 g/day (OR = 2.97; 95% CI: 1.32-6.70; p = 0.009) and presence of secondary vs. primary GN (OR = 2.87, 95% CI: 1.25-6.23; p = 0.013). A general linear model confirmed that suPAR levels were significantly affected by proteinuria0.50 g/day (coefficient +1,477 pg/ml), eGFR (-38 pg/ml per 1 ml/min/1.73 m(2) increase) and presence of secondary vs. primary GN (+1,368 pg/ml).This study shows that elevated serum suPAR levels are associated with reduced eGFR and presence of proteinuria in both primary and secondary GN, suggesting that circulating suPAR may represent a common biomarker of renal involvement in a wide spectrum of GN.

HNF1B gene mutations might be an underdiagnosed cause of nephropathy in adult patients mainly because of their pleomorphic clinical presentations. As most studies are based on paediatric populations, it is difficult to assess the likelihood of finding HNF1B mutations in adult patients and consequently define clinical settings in which genetic analysis is indicated. The aim of this study was the search for mutations in the HNF1B gene in a cohort of unrelated adult patients with nephropathy of unknown aetiology.Patients were tested for the HNF1B gene if they had chronic kidney disease of unknown origin and renal structure abnormalities (RSA) or a positive family history of nephropathy. The HNF1B coding sequence and intron-exon boundaries were analysed by direct sequencing. The search for gene deletions was performed by Multiple Ligation Probe Analysis (MLPA).Heterozygous mutations were identified in 6 out of 67 screened patients (9.0%) and included two whole gene deletions, one nonsense (p.Gln136Stop), two missense (p.Gly76Cys and p.Ala314Thr) mutations and a frameshift microdeletion (c.384_390 delCATGCAG), the latter two (c.384_390 del and p.Ala314Thr) not ever being reported to date. Mean age of the mutated patients at screening was 48.5 years with a M/F ratio of 2/4. The clinical manifestations of affected patients were extremely pleomorphic, including several urological and extra-renal manifestations.Mutations of HNF1B could explain chronic kidney disease in up to 9% of adult patients with a nephropathy of unknown aetiology and RSA: therefore an HNF1B mutation analysis should be considered in this group of patients.

Elevated serum levels of osteopontin have been associated with cardiovascular disease, diabetic nephropathy, and autoimmune disease activity. Aim of the study was to investigate the relationship between osteopontin serum levels and renal damage in a population of patients with systemic lupus erythematosus (SLE). Osteopontin serum levels were analyzed in 101 SLE patients and compared to those of 115 healthy controls. Associations between osteopontin levels and renal involvement, disease activity and damage index, biochemical parameters, and therapy were assessed. Overall osteopontin serum levels were higher in SLE patients (median, 17.93 ng/mL; interquartile range, 8.13–35.07 ng/mL) than in healthy controls (median, 5.62 ng/mL; interquartile range, 2.61–13.83 ng/mL). Univariate logistic analysis among cases showed that high osteopontin levels (higher vs medium–lower tertile) were associated with renal involvement (p = 0.012), renal function (p = 0.007), proteinuria (p = 0.011), anemia (p < 0.001), and SLICC/ACR Damage Index (p < 0.001). Multivariate analysis showed an independent association between high osteopontin serum levels (higher vs medium–lower tertile) and chronic kidney disease (OR = 4.89; 95 % CI, 1.24–19.24; p = 0.008), proteinuria (OR = 4.56; 95 % CI, 1.15–18.04; p = 0.027), anemia (OR = 4.66; 95 % CI, 1.25–17.43; p = 0.008), and use of renin–angiontensin system antagonists (OR = 0.234; 95 % CI, 0.06–0.98; p = 0.047). This study shows that elevated osteopontin serum levels significantly correlate with renal involvement and anemia in SLE. Moreover, it suggests that renin–angiontensin system antagonists decrease osteopontin levels—this effect is consistent with the inhibitory effect of these drugs on osteopontin renal expression, detected in animal models by other authors, and may provide a new rationale for their employment.

Immunoglobulin-G4 (IgG4)-related disease (IgG4RD) is a fibro-inflammatory disorder characterized by tissue-infiltrating IgG4 plasma cells, and, often, high serum IgG4. Several autoimmune, infectious, or proliferative conditions mimic IgG4RD. Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by foamy histiocytic infiltration, fibrosis, and chronic inflammation. ECD and IgG4RD manifestations may overlap.A patient presented with huge fibrous retroperitoneal masses causing compression on neighboring structures; the case posed the challenge of the differential diagnosis between IgG4RD and ECD mainly because of a prominent serum and tissue IgG4 response.Retroperitoneal biopsy led to the diagnosis of ECD; the V600E BRAF mutation was found. Treatment with the BRAF inhibitor vemurafenib was started.Treatment failed to induce mass regression and the patient died after 3 months of therapy. Prompted by this case, we examined serum and tissue IgG4 in a series of 15 ECD patients evaluated at our center, and found that approximately one-fourth of the cases have increased IgG4 in the serum and often in the tissue.The differential diagnosis between IgG4RD and ECD can be challenging, as some ECD patients have prominent IgG4 responses. This suggests the possibility of common pathogenic mechanisms between ECD and IgG4RD.

Epidemiological and observational data indicate that there is a close relationship between progressive renal dysfunction in chronic kidney disease (CKD), cardiovascular disease, and mortality. In addition, deficits in vitamin D (25-hydroxyvitamin D) and vitamin D receptor (VDR) activation play a crucial role in adversely affecting cardiovascular health in CKD patients. Even in patients with mild CKD, renal dysfunction is associated with cardiovascular events. Modulation of vitamin D levels results in correlative regulatory effects on mineral homeostasis, hypertension, and vascular calcification. The use of VDR activators such as paricalcitol to treat these and other parameters outside of cardiovascular and renal disease not only results in enhanced patient health but significantly reduces the mortality risk in CKD patients.

Encapsulating peritoneal sclerosis (EPS) is a rare but severe disease with a mortality rate of 24%-54%, whose main risk factor is peritoneal dialysis (PD) (cumulative incidence 0.5%-7.3%). Although the role of the time spent on peritoneal dialysis is not completely clear, the available evidence suggests that peritoneal dialysis should not be discontinued early for the sake of reducing the EPS risk. We proposed a ''pro-con'' debate which confirmed that PD is not a time-limited technique. Nevertheless, in patients on long-term PD, surveillance of the peritoneal membrane is crucial. The development of EPS requires two ''hits'': first a chronic, inflammatory stimulus, which is typical of peritoneal dialysis, then a second event like PD interruption or kidney transplant. The main pharmacological and dialysis strategies that have been used as primary prevention did not show any significant results, and benefits are more likely to be achieved by reducing the peritoneal inflammation and better preservation of the membrane integrity, for example by means of more biocompatible PD solutions. Among the main surveillance and early diagnosis procedures other than the peritoneal equilibration test, the Ca-125 appearance rate and new tests that evaluate the peritoneal water transport seem to be promising.

It is still a matter of debate whether peritoneal dialysis should be initiated with a full dose regimen or with incremental doses. The use of low-dose dialysis is not always feasible, but it may have the advantages of improved quality of life and lower infective and metabolic complication rates. However, incremental peritoneal dialysis has to meet the minimal suggested adequacy targets in terms of depuration (Kt/V, creatinine clearance), ultrafiltration, and electrolyte balance. Incremental peritoneal dialysis has been proved feasible and safe in asymptomatic patients with a glomerular filtration rate (GFR)6 mL/min, but the residual renal function has to be monitored strictly. A second population is composed of asymptomatic, mostly older patients with GFR between 6 and 10 mL/min, in whom a low-dose start may preserve the residual renal function and favor a more gradual training. Lastly, patients with severe, terminal, chronic cardiomyopathy who are not candidates for a heart transplant may experience beneficial effects on cardiac function and hospitalization with low-dose peritoneal dialysis treatment even when they have GFR10 mL/min. In conclusion, incremental peritoneal dialysis is a feasible therapeutic option that the nephrologist should know and be able to perform in those patients who may benefit from it.

Energy and protein metabolism are both altered in chronic kidney disease (CKD) from its early stages. Patients undergoing peritoneal dialysis (PD) use peritoneal solutions with glucose as osmotic agent, which exposes them to an increased glucose load (40-80 g/day) and during PD there is a net loss of proteins through the peritoneum (4-8 g/day). Insulin resistance may lead to a reduction of the anabolic effects of insulin, while its proliferative effects on adipose tissue are potentially enhanced. Insulin resistance is also an important factor in the development of hypertriglyceridemia in PD patients: it increases free fatty acid availability, which then stimulates the release of large triglyceride-rich VLDL. Moreover, inhibitors of lipolytic enzymes (apoC-III, inflammation, oxidative modification and carbamoylation of apolipoproteins) may reduce lipid clearance, contributing to the development of dyslipidemia. Inflammatory molecules also play an important role in regulating glucose metabolism, and the excessive activation of inflammatory pathways may represent a fundamental step in the development of insulin resistance, including an over-expression of cytokines. Frequently, protein intake is reduced in PD because of under-dialysis, glucose load, abdominal discomfort and abnormal hormones levels, leading to a complex "protein-energy malnutrition". Optimization of dialysis dose, correction of acidosis and anemia and nutritional counseling, together with "non-traditional" management strategies, such as the use of PD solutions without glucose, like icodextrin and amino acid based solutions, represent the best strategies to prevent and correct malnutrition in PD patients. The mainstay of therapy is a reduction of glucose-based PD solutions and a correct dietary prescription.

Renal replacement therapies (RRTs) produce a partial loss of antioxidants and formation of reactive oxygen species (ROS), which are a major factor involved in alterations of plasma membrane fluidity and endothelial activation, but their role on plasma membrane fluidity in vivo is still unclear. We compared erythrocyte plasma membrane fluidity, ROS and total plasma antioxidant defenses (Lagtime) in aged patients with chronic renal failure (CRF) on conservative treatment, peritoneal dialysis (PD) and hemodialysis (HD) before (HD-pre) and after (HD-post) a treatment, to evaluate the role of different RRTs on oxidative stress and plasma membrane fluidity in aged patients.We assessed erythrocyte plasma membrane fluidity, plasma lipid hydroperoxide levels and Lag-Time in 11 CRF patients on conservative treatment, 15 on PD, 12 on HD and 30 healthy controls.Hydroperoxides were higher in CRF, PD and HD-post, whereas Lag-time was significantly lower in PD, CRF and in HD-post. CRF, PD and HD-pre also had higher membrane fluidity (rsDPH), compared with HD-post and controls.These findings are in keeping with the hypothesis that the Lag-time decrease is due not only to the effect of the RRT but also to the uremic state, and that PD patients undergo a chronic, greater oxidative stress. Contrary to expectations, all patients showed greater erythrocyte membrane fluidity, which can be attributed to uremic toxicity. These observations reinforce the hypothesis that oxidative stress is an intrinsic component of this disease state and indeed is already present also in CRF not yet requiring RRT.

The aging population starting hemodialysis treatment raises the question as to which is the best vascular access in an older patient with multiple complications. The center effect is an important element in the choice of a vascular access, as shown by the DOPPS data and by a recent audit held in Lombardy. However, other data show an increase in the use of permanent CVCs in the last years and other factors must be taken into account in this clinical choice. Also the timing of proposing a vascular access to a patient has changed over the years (see K-DOQI 2006 vs 2000). Most of the literature agrees on the strategy of a global clinical evaluation of the patient to decide when to place a vascular access and which type of access to use. Native and prosthetic fistulas are considered superior to CVCs although the latter have certain advantages in selected patients, such as those with severe cardiac problems. The nephrologist has a major role in vascular access management as part of a team made up also by a vascular surgeon and an interventional radiologist. Only in a center where both native and prosthetic fistulas can be constructed and permanent CVCs be placed can a nephrologist choose the most appropriate vascular access for individual patients after evaluation not only of their renal function but their cardiovascular risk as well.

Post-transplant malignancies (PTM) occur in a percentage as high as 50% in patients followed 20 yr and have become a main cause of mortality and are expected to be the first cause of death within the next 20 yr in kidney transplant recipients.We analyzed the PTM incidence in our kidney transplant recipients, and its main risk factors. The records of 400 patients (min follow up = one yr) have been retrospectively reviewed and categorized into three groups: patients without any tumor, with a non-melanoma skin cancer and with a solid or hematologic cancer. A cancer-free multivariate survival study was performed stratified by age, sex, immunosuppressive therapy, time on dialysis, body mass index (BMI), smoke, diabetes and nephropathy.Thirty patients developed PTM: 12 non-melanoma skin cancer, three lymphomas and 15 solid malignancies (seven genitourinary, three lung, two breast, two gastrointestinal and one sarcoma). The mean age at diagnosis was 55 yr, with a mean time from transplant of 27 months. We observed six deaths and two graft losses. Non-melanoma skin cancer-free survival and the solid/hematologic cancer-free survival was 99.5% and 98.5% at one yr, and 95.2% and 94.6% at five yr, respectively. At univariate analysis, age and induction therapy were significant risk factors for both types of PTM, while only recipient age significantly increased the risk of all PTM, and anti CD25 significantly reduced the risk of non-melanoma skin cancer at the multivariate study.These data confirm the role of age and induction strategies in modulating the risk of neoplasia. To look for which strategies might reduce the PTM risk, including a personalized therapy to minimize the effects of chronic immunosuppressant, will be a crucial goal.

To the Editor: Tin et al.1 have prospectively associated hypomagnesemia with chronic kidney disease (CKD) and end-stage renal disease (ESRD): they identified different potential causes of this association, such as endothelial dysfunction, chronic inflammation, and increased platelet aggregation. However, ‘tubular’ nephropathies might also be the cause of both hypomagnesemia and CKD.