Marco Quaglia

The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: a systematic review and meta-analysis.

In the present study, we performed a systematic review and meta-analysis on published data to examine the impact of CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms on tacrolimus dose-adjusted trough levels (C0/D) and acute rejection rates in adult renal transplant patients. Despite the presence of significant heterogeneity in all comparisons, random-effects model showed significantly higher tacrolimus C0/D in CYP3A53/3 compared with CYP3A51 allele carriers, either in the overall analysis and when stratifying for ethnicity or time of post-transplantation (≤1, 3-6, 12-24 months). In contrast, no consistent evidence of an effect of the ABCB1 3435C>T variant was detected on tacrolimus C0/D, except for a modest effect limited to the first month after renal transplantation. In addition, from the current evidence available, CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms seem to have little or no effect on the acute rejection rates in renal transplant patients under immunosuppressive therapy with tacrolimus.

Correlation between Cytomegalovirus Infection and Raynaud’s Phenomenon in Lupus nephritis

Relationships between viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) are still elusive. Recent reports demonstrated the association of some viral infections with peculiar clinical events in the general population, such as cytomegalovirus (CMV) with arterial damage and Parvovirus B19 (PV-B19) with hematologic abnormalities. We planned to look for this kind of viral imprinting in SLE, hypothesizing that traces of specific features of some viral infections might be found in some subsets of seropositive SLE patients. In 60 SLE patients recruited at our nephrologic center, serology for CMV, PV-B19, Epstein-Barr virus viral capsid antigen (EBV-VCA), Epstein-Barr nuclear antigen (EBNA) and Epstein-Barr virus early antigen (EBV-EA) was performed. χ2 and ANOVA were employed to compare the frequency and titers of antiviral antibodies in SLE patients with groups of transplant, hemodialysis and blood donor subjects. χ2, Fisher’s test, Bonferroni and Scheffe’s test were employed to compare the different biochemical/clinical features between seropositive and seronegative SLE patients. Univariate and multivariate analysis (logistic regression models) were employed to evaluate the odds ratio (OR) of different risk factors for vascular events (including Raynaud’s phenomenon, deep venous thrombosis) and hematologic abnormalities (including severe anemia, leukopenia and thrombocytopenia). Anti-CMV (82%), anti-PV-B19 (60%), anti-EBV-VCA (92%) and EBV-EA (45%) IgG antibodies were frequent in SLE, with higher prevalence in comparison with the blood donor group and higher titers in comparison with transplant and hemodialysis groups. CMV seropositivity was a highly significant risk factor for Raynaud’s phenomenon (OR +α in univariate and multivariate analysis = 13.51 using a correction of 0.5 in case of a zero event), but not for venous vascular events (OR = 1.31). An increased though not significant risk factor was found for antiphospholipid antibodies (OR = 2.71, p = 0.19), while the presence of nephrotic syndrome during the follow-up was a significant protective factor (OR = 0.15, p = 0.035). There was no significantly increased OR for PV-B19 seropositivity in cases with severe anemia (OR = 2.09, p = 0.29). No significant associations were found with the status of EBV reactivation. In conclusion, our results support the hypothesis that viral infection may imprint the course of SLE leading to specific clinical subsets (i.e. CMV and ‘vascular’ SLE, with more frequent Raynaud’s phenomenon and a less frequent typical histological renal picture responsible for nephrotic syndrome). Further prospective studies are justified to validate these correlations, mainly dealing with associations between acute viral infections and vascular events, thus eventually leading to a better understanding of mutual relationships between viruses and SLE.

Renal outcome and monoclonal immunoglobulin deposition disease in 289 old patients with blood cell dyscrasias: A single center experience

Monoclonal components (MC) formed by chains/fragments of intact/truncated globulin components produced in different lymphoproliferative diseases are responsible for monoclonal immunoglobulin deposition disease (MIDD) and consequent tissue damage by organized (amyloid fibrils) or non-organized (amorphous) deposits. The kidneys are the most commonly affected organs in MIDD, and renal failure represents an important adverse factor for prognosis. The renal outcome and the role of renal pathology in diagnosing MIDD was evaluated in 289 elderly patients with multiple myeloma (MM, n=115) and monoclonal gammopathy (MGUS, n=174). Renal impairment was the only significant risk factor for patient death, while significant risk factors for renal impairment were diabetes (HR 3.65, 95% CI: 2.08-6.41), light chain (LC) proteinuria (HR 2.18; 95% CI: 1.10-4.32) and type of MC (p=0.0019). Renal pathology documented MIDD in 12/30 cases (40%): six cases of AL-amyloidosis, two of LC disease, one of heavy chain disease and three of cast nephropathy, as well as four cases of glomerulonephritis, eight of arteriolosclerosis and six of normal picture. Main conclusions are that diabetes, sharing common glomerular damage with LC disease, is the strongest risk factor for progression of renal disease, and glomerular proteinuria or heavy LC proteinuria should raise a strong suspicion index of MIDD and prompt pathology assessment to reach the correct diagnosis.

Synergistic effect of renin-angiotensin system and nitric oxide synthase genes polymorphisms in pre-eclampsia

Background. Components of the renin‐angiotensin system and endothelial nitric oxide synthase may co‐operate in spiral artery remodelling during placentation, and thus reduce the uteroplacental resistance typical of normal pregnancy. Since lack of such remodelling and abnormal placentation are specific features of pre‐eclampsia, it has been suggested that abnormal function of both components of the renin‐angiotensin system and endothelial nitric oxide synthase may be involved in its pathogenesis. However, previous studies of the association between pre‐eclampsia and polymorphisms of single genes encoding renin‐angiotensin system components and endothelial nitric oxide synthase have yielded conflicting results. The aim of this study was to assess if interactions among different polymorphisms of the renin‐angiotensin system and nitric oxide synthase are involved in the pathogenesis of pre‐eclampsia. Methods. Some 359 pregnant women were enrolled: 103 normotensive, 50 with chronic hypertension, 86 with gestational hypertension, and 120 with pre‐eclampsia. DNA analysis was performed to evaluate angiotensin‐converting enzyme I/D, angiotensin‐II receptor 1 1166A/C, angiotensinogen M235T and endothelial constitutive nitric oxide synthase 4b/a polymorphisms. Odds ratios (OR) with 95% confidence interval (CI) and χ2 tests were calculated. Results. The frequency of single gene polymorphisms was similar in each group. The frequency of pairs including the DD genotype of the angiotensin‐converting enzyme I/D polymorphism plus other homozygous genotypes was significantly higher in pre‐eclamptic patients than in controls (OR = 3.04, 95% CI = 1.16–7.93). Conclusions. Synergism of angiotensin‐converting enzyme I/D and other polymorphisms of renin‐angiotensin system components and nitric oxide synthase may be a risk factor for pre‐eclampsia.

Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy

Background: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. Methods: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. Results: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. Conclusion: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.

Pitfall in nephrology: contrast nephropathy has to be differentiated from renal damage due to atheroembolic disease.

INTRODUCTION The topic of contrast-induced nephropathy (CIN) has been receiving an enormous amount of interest in recent times; however, this review is not a review of what CIN is, but what it is not. METHODS We will review the main topics demonstrating that the post hoc ergo propter hoc assumption that renal impairment occurring after contrast medium (CM) infusion is necessarily because of it, is wrong, as we are dealing with different diseases, depending on the way the CM is administered and on the type of patient. RESULTS After >1,000 often repetitive papers, we must deal with an unacceptably wide range of incidences of CIN, with completely different prognoses and astonishingly conflicting results regarding the efficacy of preventive measures with the exception of hydration. So what went wrong? How to separate tares from wheat? When years ago we challenged the diagnosis of CIN, the words cholesterol embolism had never appeared in this setting. Now, we can split the possible renal dysfunctions following CM administration into CM-related hemodynamic and/or tubular damage, cholesterol embolism, ischemia from acute blood loss or hypotension/hypoperfusion and nephrotoxicity from concomitant drugs. CONCLUSIONS In a setting regarding millions of patients and millions of dollars/year, in order to clarify the true renal damage directly related to CM, we ask for prospective studies differentiating cohorts receiving intravenous and intra-arterial, transradial and transfemoral injections, and clinically relevant renal outcomes, thus avoiding the dangers that can come from the idolatry of a surrogate end point such an asymptomatic 25% transient increase of serum creatinine. To avoid that, patients may lose the possibility of a more useful radiological diagnosis, because of an exaggerated suspicion of risk.

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.

Idiopathic Membranous Nephropathy: Management Strategies

Treatment of idiopathic membranous nephropathy is based on a ‘symptomatic’ therapy that includes ACE inhibitors or angiotensin II receptor antagonists, and on an ‘aetiological’ therapy aimed at modulating underlying immunological mechanisms. The role of the latter is still debated given the usually indolent course of disease; furthermore, traditional immunosuppressants would not have an impact on patient and renal survival according to a systematic review of literature. However, up to 40% of untreated patients eventually develop end-stage renal disease and remission of nephrotic syndrome protects patients from related life-threatening complications and is the strongest positive prognostic factor for long-term kidney function. Therefore, immunosuppressive therapy seems to be rational in high-risk patients with nephrotic syndrome or deteriorating renal function. This article outlines a possible role for each ‘aetiological’ therapy on the basis of available evidence in order to provide some practical recommendations. The first-line therapy is based on a 6-month regimen of alternating corticosteroids and an alkylating agent (‘Ponticelli’ regimen), whereas oral ciclosporin and intramuscular corticotrophin (adrenocorticotrophic hormone) are alternatives that provide comparable results in terms of remission of proteinuria, with a different adverse effect profile. New drugs are emerging as potential treatments, such as mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Specific settings, such as chronic renal failure or elderly age, require a careful balance between benefits and toxicity of immunosuppression. The tailor-made use of this repertoire of drugs can provide a tool to achieve remission of proteinuria and modify the natural course of idiopathic membranous nephropathy.

The concept of 'glomerulonephritis'. the fascinating history of evolution and emergence of a specialist's nosology focus on Italy and Torino.

Though the term ‘nephritis’ first appeared in the 19th century, this word did not bear the same meaning as it does today; indeed, for many years it was used to indicate ‘renal diseases’ (in the sense of Bright’s disease) in a larger sense. This review summarizes the long gestation of the concept of ‘glomerulonephritis’ from the prehistory of medicine up to the beginning of the second half of the 20th century with emphasis on Italy and, in particular, on Torino, which was the capital of the Kingdom of Italy from 1861 to 1865. To the best of our kowledge, this is the first study reporting an epidemiology survey of Bright’s disease in Italy from 1880 up to 1960. Towards the end of the 19th century, Bright’s disease accounted for 26 deaths/year/105 population (in comparison with more than 200 from tuberculosis) in Italy, roughly paralleling that reported in the USA. At the beginning of the 20th century, Bright’s disease was the seventh cause of death (almost 1% of total deaths) in Italy. Furthermore, in Italy, as elsewhere, autopsy studies showed a higher percentage of deaths attributed to Bright’s disease (5–7%) in comparison with those obtained from vital statistics. In 1960, just before the beginning of renal replacement therapy, Bright’s disease accounted for 15.7 deaths/year/105 population (= 1.46% of all deaths), roughly paralleling that reported in the United Kingdom (13.8/105 population = 1.25% of deaths). Probably, it was difficult to recognize the real incidence of chronic renal diseases leading to death in the 1960s, and vital statistics were able to furnish only approximate estimates. However, noteworthy is the fact that these values were very close to those estimated as being the annual need for renal replacement therapy (10–20 cases/year/105 population).

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.