Claudio Musetti

Malignancy after kidney transplantation : results of 400 patients from a single center

Abstract: 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.

Peritoneal Ultrafiltration in Refractory Heart Failure: A Cohort Study

♦ 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.

New trends of an old disease: the acute post infectious glomerulonephritis at the beginning of the new millenium

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.

Chronic renal failure of unknown origin is caused by HNF1B mutations in 9% of adult patients: A single centre cohort analysis

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.

Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy

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.

Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population

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.

Experience of 70-cm-long femoral tunnelled twin Tesio catheters for chronic haemodialysis

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.

The Role of TCF7L2 rs7903146 in Diabetes After Kidney Transplant: Results From a Single-Center Cohort and Meta-Analysis of the Literature.

Background 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. 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 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; P < 0.0001) and absence of heterogeneity among studies (I2 = 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.

Kidney transplant recipients receiving mTOR inhibitors experienced twice as many thrombotic events: A single cohort observational study

Thrombotic events are ominous complications in patients undergoing kidney transplant (Kidney Transplant Recipients – KTR) [1] and different immunosuppressive (IS) medications have been involved [2]. Recently, Baas et al have shown that KTRs receiving everolimus have higher levels of circulating von Willebrand factor, prothrombin fragment 1 + 2, thrombin-activable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1, leading eventually to a pro-thrombotic state, which may be associated with more thrombotic events [3]. The mammalian target of rapamycin inhibitors (mTOR-I) sirolimus and everolimus are immunosuppressive agents used in renal transplantation for the prevention of acute rejection: their main mechanism of action is the inhibition of the mTOR, a regulatory protein kinase involved in lymphocyte proliferation [4]. Moreover they inhibit the crosstalk among mTORC1, mTORC2, and PI3K with a potential antineoplastic activity, so some mTOR-I (ie: temsirolimus) are being used at higher doses as chemotherapy in renal clear cell carcinoma. Even if a high dosemTOR-I therapy is associatedwith renal toxicity [5], in kidney transplantation mTOR-I based regimens have been shown to have similar or lower nephrotoxicity when compared to standard cyclosporineor tacrolimus-based regimens [6]. In lung transplant recipients, significantlymore venous thromboembolisms (VTE)were observed in patients treatedwith sirolimus and low dose tacrolimus, as comparedwith patients treatedwith tacrolimus and azathioprine (17,2% vs 3,2%) [7]. Moreover, some case reports described devastating thrombotic events in solid organ transplant recipients treated with mTOR-I [8,9], but randomized controlled trials on mTOR-I in KTR did not describe vascular complications as common adverse events [10,11]. This could reflect differences between different solid organ transplants and possibly drug dosing and associations, or it may be due to a different subtype of cardiovascular (CV) events: for instance in patients treatedwithmTOR-I the incidence of coronary artery disease was reported as significantly higher unlike overall CV adverse events [12]. Therefore we retrospectively studied the incidence of major thrombotic events (MTE) in a cohort of unselected KTRs to evaluate if patients experienced more MTE while on mTOR-I.

A nephrologist’s point of view on sodium-glucose linked transporter-2 inhibitors: not all that glitters is gold

To the Editor: A recent review forecasts unexpected long-term benefits for sodium-glucose linked transporter-2 (SGLT2) inhibitors, which are somewhat ‘reminiscent of those associated with blockade of renin–angiotensin system (RAS)’, owing to a reduced activity of the macula densa.1