Acute Kidney Injury in Monoclonal Gammopathies.

Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees of injury, including acute kidney injury (AKI). AKI is generally a consequence of tubular obstruction by luminal aggregates of LC, a pattern known as "cast nephropathy". Monoclonal Ig LC can also be found as intracellular crystals in glomerular podocytes or proximal tubular cells. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent form of kidney injury with a sizable impact on renal function. Hypercalcemia (in turn related to bone reabsorption triggered by proliferating plasmacytoid B cells) may lead to AKI via functional mechanisms. Pharmacologic treatment of MG may also result in additional renal injury due to local toxicity or the tumor lysis syndrome. The present review focuses on AKI complicating MG, evaluating predictors, risk factors, mechanisms of damage, prognosis, and options for treatment.

Monoclonal Gammopathies of Renal Significance: Renal Biopsy and Beyond.

Monoclonal Gammopathies of Renal Significance (MGRS) are a rather heterogeneous group of renal disorders caused by a circulating monoclonal (MC) immunoglobulin (Ig) component, often in the absence of multiple myeloma (MM) or another clinically relevant lymphoproliferative disorder. Nevertheless, substantial kidney damage could occur, despite the "benign" features of the bone-marrow biopsy. One example is renal amyloidosis, often linked to a small clone of plasma cells, without the invasive features of MM. However, patients with amyloidosis may present with a nephrotic syndrome and renal failure, eventually leading to end-stage kidney disease. At the same time, other organs, such as the heart and the liver, may be severely damaged by Ig light chains or amyloid deposits, occasionally resulting in fatal arrhythmias and/or organ failure. Acute kidney injury (AKI) may as well result from massive excretion of MC proteins, with deposition disease in glomeruli or renal tubules, not rarely obstructed by luminal aggregates, or "casts". Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent clinical presentation of an MGRS. The present review deals with the implications of MGRS for renal function and prognosis, and the potential of tools, such as the renal biopsy, for assessing clinical risk and guiding therapy of the underlying condition.

Prognostic value of high-sensitive cardiac troponin I in asymptomatic chronic hemodialysis patients.

INTRODUCTION: Increased levels of cardiac troponins (cTn) are a hallmark of acute myocardial infarction (AMI), along with symptoms and electrocardiographic (ECG) changes. Stably elevated cTn concentrations are frequently observed in asymptomatic patients with chronic kidney disease (CKD) and/or on hemodialysis (HD); the meaning of this elevation, as assessed by conventional techniques, remains unclear. Aim of our study was to evaluate the clinical significance of cTnI levels in asymptomatic HD patients by employing a newer high-sensitive cTnI (hs-cTnI) assay. METHODS: We enrolled 49 patients undergoing regular HD treatment for more than 3 months; all patients were asymptomatic for chest pain and had no history of acute coronary syndrome in the past 2 months. For every patient we measured hs-cTnI, cTnI and brain natriuretic peptide (BNP) before initiation of one HD session at baseline (T0), after 3 (T1) and 9 months (T2). Demographic, anamnestic, dialytic and echocardiographic characteristics of the examined population were evaluated. We also recorded the number of cardiovascular events from T0 to 12 months after T2. RESULTS: Fifteen patients were lost to follow-up: 6 died, 2 underwent kidney transplantation, 7 did not match the inclusion criteria later during observation. At T0 (49 patients) we observed 14 hs-cTnI positive patients vs. 4 standard c-TnI positive patients (28,5% vs 8,1%); at T1 (40 patients) 16 vs 3 (26.4% vs 7.5%); at T2 (34 pz) 9 vs 0 (26.4% vs 0%). During the study we recorded 10 cardiovascular events, 8 of which in patients that were hs-cTNI positive, leading to death in 3. Hs-cTnI levels were predictive of cardiovascular events at all times and predictive of cardiovascular mortality at T0 and T1 (p < 0.001). In a multivariate analysis, a history of coronary artery disease (CAD) was an independent variable of high hs-cTnI levels at T0 (p < 0.04) and T1 (p < 0.03). CONCLUSIONS: Our study shows that a novel sensitive assay detects more asymptomatic HD patients compared to previously used methods, being at the same time predictive of cardiovascular mortality and morbidity. The only independent variable of high hs-cTnI concentrations was a positive history of cardiovascular disease, suggesting a possible role of hs-cTnI in identifying a high-risk subset of patients.

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal.

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFß1, TGFßRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities.

Safety and efficacy of denosumab in osteoporotic hemodialysed patients.

BACKGROUND AND AIMS: In elderly subjects, renal insufficiency and osteoporosis often coexist with high risk of fracture and elevated socio-economic burden. Today a large number of effective anti-osteoporotic drugs are available but generally they are contraindicated in patients with chronic kidney disease (CKD) because of their progressive accumulation. Denosumab, instead, does not require dose adjustments for different degrees of renal impairment so it can be a valid treatment in osteoporotic patients with CKD. Limited data are available in the literature concerning the use of denosumab in hemodialysis (HD). The aim of our study was, therefore, to study the efficacy and tolerability of this drug in this particular subset of patients. METHODS: We retrospectively reviewed the charts of 12 osteoporotic HD patients who received a single 60-mg subcutaneous dose of denosumab every 6 months for an observation period of 24 months. Serum electrolyte, markers of bone turnover and quantitative ultrasound (QUS) were evaluated. RESULTS: Over 24 months, we observed a gradual improvement of bone metabolism: ß-CrossLaps from 2567.08 ± 1264 to 1492.5 ± 1182.5 pg/ml; bone alkaline phosphatase (BALP) from 33.5 ± 28.8 to 11.8 ± 3.7 mcg/l, and of QUS index (T-score from -5.33 ± 1.58 to -4.84 ± 1.2; risk of fracture from 13.9 ± 4.7 to 11.07 ± 5.3 %). Few cases of hypocalcemia were detected, more significant after the first and second injection, but with careful monitoring of serum calcium and rapid therapy adjustment we could easily manage serum Ca levels. CONCLUSIONS: Our pilot experience highlights the safety and efficacy of denosumab in the treatment of osteoporosis in HD patients, potentially supporting its use to reduce the burden of fractures in this patient population.

Metformin associated lactic acidosis (MALA): clinical profiling and management.

Metformin (MF) accumulation during acute kidney injury is associated with high anion gap lactic acidosis type B (MF-associated lactic acidosis, MALA), a serious medical condition leading to high mortality. Despite dose adjustment for renal failure, diabetic patients with chronic kidney disease (CKD) stage III-IV are at risk for rapid decline in renal function by whatever reason, so that MF toxicity might arise if the drug is not timely withdrawn. Sixteen consecutive patients were admitted to our Hospital's Emergency Department with clinical findings consistent with MALA. Fifteen had prior history of CKD, 60 % of them with GFR between 30 and 60 ml/min. Of these, 5 required mechanical ventilation and cardiovascular support; 3 promptly recovered renal function after rehydration, whereas 10 (62 %) required continuous veno-venous renal replacement treatment. SOFA and SAPS II scores were significantly related to the degree of lactic acidosis. In addition, lactate levels were relevant to therapeutic choices, since they were higher in dialyzed patients than in those on conservative treatment (11.92 mmol/l vs 5.7 mmol/l, p = 0.03). The overall death rate has been 31 %, with poorer prognosis for worse acidemia, as serum pH was significantly lower in non-survivors (pH 6.96 vs 7.16, p > 0.04). Our own data and a review of the literature suggest that aged, hemodynamically frail patients, with several comorbidities and CKD, are at greater risk of MALA, despite MF dosage adjustment. Moreover, renal replacement therapy rather than simple acidosis correction by administration of alkali seems the treatment of choice, based on eventual renal recovery and overall outcome.