Sacubitril/Valsartan in Dialysis Patients: Update on Current Perspectives.

Sacubitril/Valsartan is a combination of neprilysin inhibitor and angiotensin II receptor blocker that proved its own efficacy and safety in heart failure patients to ameliorate cardiovascular morbidity and mortality compared to angiotensin II-converting enzyme inhibitors alone. However, end-stage renal disease patients have not been included in the randomized controlled trials, so the beneficial effects as well as the risk profile of this association remain still undefined in these patients. Only observational studies on this drug association have been carried out in end-stage renal disease patients investigating mostly biohumoral or echocardiographic markers. Therefore, its application is still controversial and not free of complications due to the potential risk of hypotension and hyperkaliemia. The efficacy to improve biohumoral markers and cardiac function in dialysis patients and the potential application especially in those patients with severe and resistant hypertension and/or left ventricular dysfunction could be crucial in end-stage renal disease patients. Ongoing long-term randomized controlled trials should thoroughly define the effective benefits and/or adverse effects in patients on substitutive treatment.

Lithium poisoning and renal replacement therapy: pathophysiology and current clinical recommendations.

Lithium intoxication is still an undefined and underestimated disease, especially those cases requiring extracorporeal treatment. Lithium is a monovalent cation with small molecular mass of 7 Da that has been regularly and successfully used since 1950 in the treatment of mania and bipolar disorders. However, its careless assumption can lead to a wide spectrum of cardiovascular, central nervous system and kidney diseases in case of acute, acute on chronic and chronic intoxications. In fact, lithium serum range is strict between 0.6 and 1.3 mmol/L, with a mild lithium toxicity observed at the steady-state of 1.5-2.5 mEq/L, moderate toxicity when lithium reaches 2.5-3.5 mEq/L, and severe intoxication with observed serum levels > 3.5 mEq/L. Its favorable biochemical profile allows the complete filtration and partial reabsorption in the kidney due to the similarity to sodium and also the complete removal by renal replacement therapy, that should be considered in specific poisoning conditions. In this narrative and updated review we discussed a clinical case of lithium intoxication, the different pattern of diseases attributable to excessive lithium load and the current indications for extracorporeal treatment.

The risks associated with percutaneous native kidney biopsies: a prospective study.

BACKGROUND: The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy. METHODS: The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression. RESULTS: Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08-1.17], liver disease (OR 2.27, 95% CI 1.21-4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07-1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92-0.99) were protective. CONCLUSIONS: This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.

A Wide-Proteome Analysis to Identify Molecular Pathways Involved in Kidney Response to High-Fat Diet in Mice.

The etiopathogenesis of obesity-related chronic kidney disease (CKD) is still scarcely understood. To this aim, we assessed the effect of high-fat diet (HF) on molecular pathways leading to organ damage, steatosis, and fibrosis. Six-week-old male C57BL/6N mice were fed HF diet or normal chow for 20 weeks. Kidneys were collected for genomic, proteomic, histological studies, and lipid quantification. The main findings were as follows: (1) HF diet activated specific pathways leading to fibrosis and increased fatty acid metabolism; (2) HF diet promoted a metabolic shift of lipid metabolism from peroxisomes to mitochondria; (3) no signs of lipid accumulation and/or fibrosis were observed, histologically; (4) the early signs of kidney damage seemed to be related to changes in membrane protein expression; (5) the proto-oncogene MYC was one of the upstream transcriptional regulators of changes occurring in protein expression. These results demonstrated the potential usefulness of specific selected molecules as early markers of renal injury in HF, while histomorphological changes become visible later in obesity-related CDK. The integration of these information with data from biological fluids could help the identification of biomarkers useful for the early detection and prevention of tissue damage in clinical practice.

Cardiovascular implantable electronic devices in hemodialysis patients: an updated review.

Cardiovascular diseases are the leading life-threatening complications in hemodialysis patients. In this scenario, both tachy-arrhythmias and brady-arrhythmias are involved with related hemodialysis and nonhemodialysis-dependent mechanisms; moreover, those arrhythmias usually occur in different time intervals before sudden cardiac death (SCD). Furthermore, current evidence shows that the presence of advanced chronic kidney disease (CKD) reduces the benefits of implantable cardioverter--defibrillators (ICDs), which increases the risk of both arrhythmic and nonarrhythmic death, especially in patients with advanced stages of heart failure. Notably, patients with advanced CKD show a more severe degree of heart failure compared with mild CKD patients. However, the benefits of the ICD implantation in the primary prevention of hemodialysis patients is still controversial, and by now, no significant benefits have emerged compared with nonhemodialysis-dependent CKD patients. In secondary prevention, hemodialysis patients with ICD implantation have higher mortality rates compared with nonhemodialysis-dependent CKD patients with ICD. On the other hand, most articles include hemodialysis patients with reduced left ventricular ejection fraction, neglecting those with preserved systolic function. This review focuses on the epidemiology of SCD in the setting of hemodialysis and the current evidence on ICD implantation in patients on hemodialysis therapy analyzing novel strategies, which might reduce the risk of ICD placing.

An enigmatic case of IgG4-related nephropathy and an updated review of the literature.

IgG4-related disease (IgG4-RD) is still an underestimated disorder which affects multiple organs, and its recognition as a distinct clinical disease has been only proved in the recent decades. The renal involvement has been documented in approximately 15% of patients with IgG4-RD, and the typical manifestation is a tubulo-interstitial nephritis. The main histological findings in IgG4-RD are typically a dense tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, and frequently elevated IgG4 serum levels. Herein we report our atypical and peculiar clinical presentation of an IgG4-related nephropathy (IgG4-RN) and the remarkable response to rituximab (RTX) treatment at the renal imaging with computerized tomography assessment. The current nephrological evidences support the renal function recovery after steroids or steroids plus RTX therapy, even if the renal imaging data are not always shown. In a complex and enigmatic clinical scenario such as the IgG4-RN, both the renal biopsy and the renal imaging before and after the immunosuppressive therapy become mandatory tools to thoroughly define the diagnosis, the management and the response to the immunological therapy.

Cardiovascular implantable electronic devices and native arteriovenous fistula in hemodialysis patients: novel perspectives.

The benefits from cardiovascular implantable electronic devices (CIED) implantation in hemodialysis (HD) patients are still far to be thoroughly defined, especially on primary prevention. In addition, CIED placement is not a risk-free procedure, because it could be followed by a not negligible burden of complications that could compromise the health and the vascular access of HD patients. In fact, the arteriovenous fistula (AVF) dysfunction following CIED implantation is usually due to a hemodynamically significant alteration of blood flow. This condition could lead to a potential decrease of dialysis efficacy and a raised risk of thrombosis of both the central vein and the efferent vein of the AVF.The pathological pathway that leads to AVF dysfunction after CIED implantation may involve the irritating actions of the CIED and their leads to the vascular wall in HD patients that are more prone to show previous vascular diseases.The aim of this review is to focus the physiopathology of the CIED-induced AVF dysfunction, the current treatment strategies and the novel perspectives that could be taken into consideration and offered to the HD population to preserve both their AVF and their quality of life.

Geriatric Nutritional Risk Index Is Predictive of Subjective Global Assessment and Dialysis Malnutrition Scores in Elderly Patients on Hemodialysis.

OBJECTIVE: Malnutrition is a frequent complication in patients on hemodialysis (HD), even if its adequate appraisal remains one of the most complicated challenges in the HD scenario because of the limits of current malnutrition biomarkers. The aim of our study was to assess the relation of subjective nutritional tools Subjective Global Assessment (SGA) and Dialysis Malnutrition Score (DMS) with the objective malnutrition tool Geriatric Nutritional Risk Index (GNRI) in elderly patients on HD. METHODS: This is a cross-sectional study involving 71 patients on maintenance HD. Mann-Whitney U and chi-square tests were used to compare data of male and female patients on HD. Linear and logistic regression models were used to assess the variables tested in all patients. RESULTS: GNRI was not different between male and female patients on HD, and it was negatively related to SGA and DMS: B, -0.05 (95% confidence interval, -0.08 to -0.02) P = 0.00 and B, -0.30 (95% confidence interval, -0.47 to -0.14) P = .00, respectively. Both continuous and categorical GNRI data were predictive of SGA = 3: Odds Ratio (OR), 0.74 (0.63 to 0.87) P = 0.00 and OR, 6.74 (1.54 to 29.45) P = 0.01, respectively. Similarly, GNRI data were related to DMS > 13: OR, 0.85 (0.76 to 0.85) P = 0.00 and 3.29 (1.08 to 10.05) P = 0.03, respectively. Continuous GNRI data remained significant in both male and female patients separately, whereas categorical GNRI data, only in male patients. CONCLUSIONS: GNRI is a reliable nutritional tool predictive of subjective malnutrition scores SGA and DMS, pointing out a relation between objective and subjective malnutrition indexes in both genders.

Subjective Global Assessment-Dialysis Malnutrition Score and arteriovenous fistula outcome: A comparison with Charlson Comorbidity Index.

INTRODUCTION:: Malnutrition is a well-recognized risk factor for all-cause mortality in hemodialysis patients. However, its role for arteriovenous fistulas outcome has not been exhaustively investigated. Our aim was to point out the impact of Subjective Global Assessment-Dialysis Malnutrition Score as independent predictor of arteriovenous fistulas thrombosis (vascular access thrombosis) and/or significant stenosis (vascular access stenosis). In addition, we compared it with the widespread Charlson Comorbidity Index. METHODS:: We assessed 57 hemodialysis patients for a 2-year interval and evaluated the incidence of vascular access thrombosis and/or stenosis. Linear regression analysis was used to test the relation of variables with Subjective Global Assessment-Dialysis Malnutrition Score at baseline. Logistic and Cox regression analysis evaluated markers as predictors of both vascular access thrombosis and stenosis. Receiver operating characteristic curve analysis was used to compare area under the curve values of Subjective Global Assessment-Dialysis Malnutrition Score, Charlson Comorbidity Index, and modified Charlson Comorbidity Index. RESULTS:: Age and Charlson Comorbidity Index were positively related to Subjective Global Assessment-Dialysis Malnutrition Score: B = 0.06 (95% CI = 0.01; 0.11) and B = 0.31 (95% CI = 0.01; 0.63). Higher albumin and normalized protein catabolic rate levels had a protective role against vascular access failure: OR = 0.67 (95% CI = 0.56; 0.81) and OR = 0.46 (95% CI = 0.32; 0.67), respectively. Higher Subjective Global Assessment-Dialysis Malnutrition Score and Charlson Comorbidity Index values were significant risk factors: HR = 1.42 (95% CI = 1.04; 1.92) and HR = 1.48 (95% CI = 1.01; 2.17), respectively. Area under the curve of Subjective Global Assessment-Dialysis Malnutrition Score was significantly higher than those of both Charlson Comorbidity Index and modified Charlson Comorbidity Index: 0.70 (95% CI = 0.50; 0.88) versus 0.61 (95% CI = 0.41; 0.80) and 0.55 (95CI% = 0.41; 0.70). CONCLUSION:: Subjective Global Assessment-Dialysis Malnutrition Score, as well as Charlson Comorbidity Index, are useful tools to predict vascular access failure and should be carefully and periodically evaluated in order to check significant variations that may compromise vascular access survival.

HCV-negative mixed cryoglobulinemia and kidney involvement: in-depth review on physiopathological and histological bases.

Type II mixed cryoglobulinemia without evidence of HCV infection but rather with renal involvement has been occasionally described. The pathogenesis of cryoglobulinemic kidney disease is most likely related to immune complex deposition including cryoglobulins, and cryoaggregation after cold exposure could play a pivotal role in clinical expression of cryoglobulinemia. In these cases, acute kidney injury and proteinuria remain the most frequent clinical expression of a cryoglobulinemic glomerulonephritis. Type II cryoglobulinemia with the laboratory finding of both monoclonal and polyclonal cryoglobulins is the most prevalent bio-humoral pattern among HCV-negative phenotypes with renal involvement, while type III cryoglobulinemia with polyclonal Ig is rare. Histological data in renal biopsies support the hypothesis that regardless of the HCV status cryoglobulinemia vasculitis share the same frequent pathological finding of membranoproliferative glomerulonephritides, but other histological patterns have also been observed in a minority of cases. In HCV-negative mixed cryoglobulinaemia, the paraneoplastic origin of the immune dysfunction should be ruled out and sporadic cases have been reported, while there is no cumulative evidence on the prevalence of these tumour-associated manifestations. Moving from the classification criteria and the etiopathogenesis of mixed cryoglobulinaemia, we provide a comprehensive review of the literature on the appearance of the disease with kidney injury in association with malignancies or autoimmune disorders without HCV coexistence.

Subjective Global Assessment-Dialysis Malnutrition Score and cardiovascular risk in hemodialysis patients: an observational cohort study.

BACKGROUND: Malnutrition is an important risk factor for cardiovascular mortality in hemodialysis (HD) patients. However, current malnutrition biomarkers seem unable to accurately estimate the role of malnutrition in predicting cardiovascular risk. Our aim was to investigate the role of the Subjective Global Assessment-Dialysis Malnutrition Score (SGA-DMS) compared to two well-recognized comorbidity scores-Charlson Comorbidity Index (CCI) and modified CCI (excluding age-factor) (mCCI)-in predicting cardiovascular events in HD patients. METHODS: In 86 maintenance HD patients followed from June 2015 to June 2017, we analyzed biohumoral data and clinical scores as risk factors for cardiovascular events (acute heart failure, acute coronary syndrome and stroke). Their impact on outcome was investigated by linear regression, Cox regression models and ROC analysis. RESULTS: Cardiovascular events occurred in 26/86 (30%) patients during the 2-year follow-up. Linear regression showed only age and dialysis vintage to be positively related to SGA-DMS: B 0.21 (95% CI 0.01; 0.30) p 0.05, and B 0.24 (0.09; 0.34) p 0.02, respectively, while serum albumin, normalized protein catabolic rate (nPCR) and dialysis dose (Kt/V) were negatively related to SGA-DMS: B - 1.29 (- 3.29; - 0.81) p 0.02; B - 0.08 (- 1.52; - 0.35) p 0.04 and B - 2.63 (- 5.25; - 0.22) p 0.03, respectively. At Cox regression analysis, SGA-DMS was not a risk predictor for cardiovascular events: HR 1.09 (0.9; 1.22), while both CCI and mCCI were significant predictors: HR 1.43 (1.13; 1.87) and HR 1.57 (1.20; 2.06) also in Cox adjusted models. ROC analysis reported similar AUCs for CCI and mCCI: 0.72 (0.60; 0.89) p 0.00 and 0.70 (0.58; 0.82) p 0.00, respectively, compared to SGA-DMS 0.56 (0.49; 0.72) p 0.14. CONCLUSIONS: SGA-DMS is not a superior and significant prognostic tool compared to CCI and mCCI in assessing cardiovascular risk in HD patients, even it allows to appraise both malnutrition and comorbidity status.

Metabolic syndrome and uric acid nephrolithiasis: insulin resistance in focus.

Uric acid nephrolithiasis (UAN) is an increasingly common disease in ethnically diverse populations and constitutes about 10% of all kidney stones. Metabolic syndrome and diabetes mellitus are accounted among the major risk factors for UAN, together with environmental exposure, individual lifestyle habits and genetic predisposition. The development and overt manifestation of UAN appears to stem on the background of insulin resistance, which acts at the kidney level by reducing urinary pH, thus hampering the ability of the kidney to generate renal ammonium in response to an acid load. Unduly acidic urinary pH and overt UAN are both considered renal manifestations of insulin resistance. The mechanisms underlying increased endogenous acid production and/or defective ammonium excretion are yet to be completely understood. Although the development of UAN and, more in general, of kidney stones largely recognizes modifiable individual determining factors, the rising prevalence of diabetes, obesity and accompanying metabolic disorders calls for the identification of novel therapeutic approaches and intervention targets. This review aims at providing an updated picture of existing evidence on the relationship between insulin resistance and UAN in the context of metabolic syndrome and in light of the most recent advancements in our understanding of its genetic signature.

SGLT1 and SGLT1 Inhibitors: A Role to Be Assessed in the Current Clinical Practice.

Diabetes is a complex disease of increasingly common occurrence worldwide. Attaining optimal glycemic control is the main challenge to prevent the development of diabetes-related complications and/or to stop their progression. In recent years, the pharmacologic toolkit for the treatment of diabetes has considerably expanded, thus paving the way to more pathophysiology-oriented therapies. For instance, the sodium-glucose cotransporters SGLT2 and SGLT1 have been in the spotlight because of better knowledge of their physiology and therapeutic potential. At present, whereas the SGLT2 inhibitors are widely applied in current clinical practice as an effective and well-tolerated treatment that increases the urinary excretion of glucose, less is known about the use of SGLT1 inhibitors. SGLT1s are of primary importance in the small intestine, an organ that does not express SGLT2, while in the kidney they are expressed in the late renal proximal tubules, where it reabsorbs the glucose escaped from the upstream SGLT2. Hence, SGLT1-mediated glucose reabsorption in the kidney is increased when the tubular glucose load overwhelms the capacity of SGLT2 or when the latter is inhibited. The role of SGLT1 in intestinal and renal glucose transport makes the transporter a potential target for antidiabetic therapy. Here, we briefly report the evidence on LX2761, a new inhibitor against SGLT1 and SGLT2 in vitro, which acts in vivo as a selective inhibitor of SGLT1 in the gastrointestinal tract. LX2761 improves glycemic control without the glycosuria-related side effects of SGLT2 inhibitors, particularly genitourinary tract infections. However, whether it represents a valid therapeutic option for all patients with diabetes or is more appropriate for specific phenotypes, e.g., patients with concomitant diabetes and chronic kidney disease, who may benefit less from the renal mechanism of selective SGLT2 inhibitors, remains to be tested in large randomized controlled trials.

[Clinical practice for the diagnosis of cardiac arrhythmias in patients on renal replacement therapy: data from a Lombard survey]. / Pratica clinica per la diagnostica delle aritmie cardiache in pazienti in terapia renale sostitutiva: dati di una survey lombarda.

Among dialysis patients, 40% of deaths are due to cardiovascular causes, and 60% of cardiac deaths are due to an arrhythmia. The purpose of this survey, carried out with the organizational support of the Lombard Section of the Italian Society of Nephrology, is to evaluate the frequency and mode of use of non-invasive instruments for the diagnosis of cardiac arrhythmias in the dialysis centers of Lombardy. Information on the prevalence and type of cardiac devices at December 1, 2016 in this population was also required. Data from 18 centers were collected for a total of 3395 patients in replacement renal therapy, including 2907 (85.6%) in hemodialysis and 488 (14.4%) in peritoneal dialysis. All centers use the 12-lead ECG in case of evocative symptoms of an arrhythmic event and 2/3 perform the exam with programmed cadence (usually once a year). Twenty four-hour ECG Holter is not used as a routine diagnostic tool. The proportion of cardiac devices is relatively high, compared to literature data: n=259, equal to 7.6% of the population. Pace-Maker patients are 166 (4.9%), those with intracardiac defibrillator 52 (1.5%), those with resynchronization therapy 18 (0.5%) and those with resynchronization therapy and intracardiac defibrillator 23 (0.7%). The survey provides interesting information and can be an important starting point for trying to optimize clinical practice and collaboration between nephrologists and cardiologists in front of a major problem like that of arrhythmic disease in patients on renal replacement therapy.