PCSK9 in diabetic kidney disease.

BACKGROUND: Chronic Kidney Disease (CKD) and, specifically, diabetic kidney disease (DKD)+, is among the fastest increasing causes of death worldwide. A better understanding of the factors contributing to the high mortality may help design novel monitoring and therapeutic approaches, since protection offered by statins in CKD patients is not satisfactory. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes hypercholesterolemia and may be targeted therapeutically. Adding anti-PCSK9 agents to standard lipid lowering therapy further reduces the incidence of cardiovascular events. DESIGN: We studied plasma PCSK9 in a cross-sectional study of 134 diabetic kidney disease patients with estimated glomerular filtration rate (eGFR) categories G1-G4 and albuminuria categories A1-A3, in order to identify factors influencing plasma PCSK9 in this population. RESULTS: Mean±SD plasma PCSK9 levels were 309.8±113.9 ng/ml. Plasma PCSK9 was not influenced by eGFR or albuminuria, but was higher in patients on lipid lowering therapy. In univariate analysis, plasma PCSK9 showed a significant positive correlation with serum total iron binding capacity, vitamin E, plasma renin and phosphaturia, and there was a trend towards a positive correlation with total serum cholesterol. In multivariate models, only therapy with fibrate and statin, and renin remained independently correlated with plasma PCSK9. However, multivariate models explained very little of the PCSK9 variability. CONCLUSIONS: In DKD, therapy with lipid lowering drugs and specially the fibrate/statin combination were independently associated with higher PCSK9 levels. The biomarker potential of PCSK9 levels to identify DKD patients that may benefit from anti-PCSK9 strategies should be studied.

Circulating CXCL16 in Diabetic Kidney Disease.

BACKGROUND/AIMS: Chronic kidney disease and, specifically, diabetic kidney disease, is among the fastest increasing causes of death worldwide. A better understanding of the factors contributing to the high mortality may help design novel monitoring and therapeutic approaches. CXCL16 is both a cholesterol receptor and a chemokine with a potential role in vascular injury and inflammation. We aimed at identifying predictors of circulating CXCL16 levels in diabetic patients with chronic kidney disease. METHODS: We have now studied plasma CXCL16 in 134 European patients with diabetic kidney disease with estimated glomerular filtration rate (eGFR) categories G1-G4 and albuminuria categories A1-A3, in order to identify factors influencing plasma CXCL16 in this population. RESULTS: Plasma CXCL16 levels were 4.0±0.9 ng/ml. Plasma CXCL16 increased with increasing eGFR category from G1 to G4 (that is, with decreasing eGFR values) and with increasing albuminuria category. Plasma CXCL16 was higher in patients with prior cardiovascular disease (4.33±1.03 vs 3.88±0.86 ng/ml; p=0.013). In multivariate analysis, eGFR and serum albumin had an independent and significant negative correlation with plasma CXCL16. CONCLUSION: In diabetic kidney disease patients, GFR and serum albumin independently predicted plasma CXCL16 levels.

COVID-19 among Hospitalized Patients with Kidney Disease: Experience at a U.S. Midwestern Academic Medical Center.

We sought to characterize the clinical profiles and outcomes of patients with coronavirus disease 2019 and comorbid kidney disease hospitalized at urban, Midwestern tertiary care hospital. Material and Methods: In this single-center observational study, we describe 205 patients with acute kidney injury (n=98), dialysis-dependent chronic kidney disease stage 5 (n=54), or kidney transplant (n=53), admitted during the first surge of the local pandemic from March 19 2020, to July 31 2021. Results: Most patients in the cohort were African American (acute kidney injury, 51%; dialysis-dependent chronic kidney disease stage 5, 82%; kidney transplant, 62%), and obesity was common (acute kidney injury, 53%; dialysis-dependent chronic kidney disease stage 5, 44%; kidney transplant 56%). Mechanical ventilation was required in 50% of the acute kidney injury, 22% of the dialysis-dependent chronic kidney disease stage 5, and 13% of the kidney transplant recipients. Nearly half of the acute kidney injury patients (46%) died and 49% required replacement therapy, while in-hospital mortality was 24% in the dialysis-dependent chronic kidney disease stage 5 patients and 9% in the kidney transplant recipients. Logistic regression analysis identified older age and patient group as leading correlates of mortality, with lower death risk in the kidney transplant (24%; odds ratio (OR), 0.17; 95% CI 0.06-0.47) and dialysis dependent chronic kidney disease stage 5 (9%; OR, 0.36; 95% CI 0.16-0.78) patients compared to acute kidney injury patients (46%). Obesity was associated with 5-fold increased mortality risk in the coronavirus disease 2019 patients with acute kidney injury (OR, 5.32; 95% CI 1.41-20.03) but not in dependent dialysis chronic kidney disease stage 5 and kidney transplant patients. Conclusion: During the first surge of the pandemic, kidney patients hospitalized COVID-19 experienced high mortality, especially those with acute kidney injury, older age and obesity. Identifying those at highest risk for adverse outcomes may direct preventative strategies including counseling on vaccination.

Treatment of hepatitis C-mediated glomerular disease.

Chronic kidney disease (CKD) is becoming a major public health issue worldwide, mainly due to the increasing prevalence of hypertension, diabetes and aging population. Chronic hepatitis C virus (HCV) infection commonly involves the kidneys, can be a cause of CKD, and significantly impacts morbidity and mortality in these patients. Prompt recognition and knowledge of how to best manage these patients are essential in order to have a successful renal outcome. Patients with HCV and kidney involvement can often be managed with a specific combination of antiviral drugs, immunosuppressants, plasmapheresis, and newer monoclonal antibodies. However, no large randomized controlled trials have been conducted in this patient population, optimal management of HCV-mediated kidney diseases is not well defined, and treatment itself can be associated with significant toxicity in patients with CKD. This article reviews the recent literature, discusses the limitations of current therapies, as well as toxicity associated with treatment, and suggests future areas for research.

Treatment of hepatitis B virus-associated nephropathy.

Epidemiological studies have shown a relationship between hepatitis B virus (HBV) infection and development of proteinuria in some patients (most commonly children), with a predominance for male gender and histological findings of membranous nephropathy on renal biopsy. The presence of immune complexes in the kidney suggests an immune complex basis for the disease, but a direct relation between HBV and membranous nephropathy (or other types of glomerular diseases) remains to be proven. Clearance of HBV antigens, either spontaneous or following antiviral treatments results in improvement in proteinuria. Thus, prompt recognition and specific antiviral treatment are critical in managing patients with HBV and renal involvement. The present review focuses on treatment of HBV with special emphasis given to antiviral therapies, its complications, and dosing in patients with HBV-associated kidney disease.

Treatment of HIV-associated nephropathies.

In patients with HIV, the use of highly active antiretroviral therapy has improved life expectancy. At the same time, this increase in life expectancy has been associated with a higher frequency of chronic kidney disease due to factors other than HIV infection. Besides HIV-associated nephropathy, a number of different types of immune complex and non-immune complex-mediated processes have been identified on kidney biopsies, including vascular disease (nephrosclerosis), diabetes, and drug-related renal injury. In this setting, renal biopsy needs to be considered in order to obtain the correct diagnosis in individual patients with HIV and kidney impairment. Many issues regarding the optimal treatment of the different pathological processes affecting the kidneys of these patients have remained unresolved. Further research is needed in order to optimize treatment and renal outcomes in patients with HIV and kidney disease.

Modifiable risk factors for increased arterial stiffness in outpatient nephrology.

Arterial stiffness, as measured by pulse wave velocity (PWV), is an independent predictor of cardiovascular events and mortality. Arterial stiffness increases with age. However, modifiable risk factors such as smoking, BP and salt intake also impact on PWV. The finding of modifiable risk factors may lead to the identification of treatable factors, and, thus, is of interest to practicing nephrologist. We have now studied the prevalence and correlates of arterial stiffness, assessed by PWV, in 191 patients from nephrology outpatient clinics in order to identify modifiable risk factors for arterial stiffness that may in the future guide therapeutic decision-making. PWV was above normal levels for age in 85/191 (44.5%) patients. Multivariate analysis showed that advanced age, systolic BP, diabetes mellitus, serum uric acid and calcium polystyrene sulfonate therapy or calcium-containing medication were independent predictors of PWV. A new parameter, Delta above upper limit of normal PWV (Delta PWV) was defined to decrease the weight of age on PWV values. Delta PWV was calculated as (measured PWV) - (upper limit of the age-adjusted PWV values for the general population). Mean±SD Delta PWV was 0.76±1.60 m/sec. In multivariate analysis, systolic blood pressure, active smoking and calcium polystyrene sulfonate therapy remained independent predictors of higher delta PWV, while age, urinary potassium and beta blocker therapy were independent predictors of lower delta PWV. In conclusion, arterial stiffness was frequent in nephrology outpatients. Systolic blood pressure, smoking, serum uric acid, calcium-containing medications, potassium metabolism and non-use of beta blockers are modifiable factors associated with increased arterial stiffness in Nephrology outpatients.

CXCL16 in kidney and cardiovascular injury.

CXC chemokine ligand 16 (CXCL16) is a CXC soluble chemokine, an adhesion molecule and a cell surface scavenger receptor. CXCL16 regulates inflammation, tissue injury and fibrosis. Parenchymal renal cells, vascular wall cells, leukocytes and platelets express and/or release CXCL16 under the regulation of inflammatory mediators. CXCL16 expression is increased in experimental and human nephropathies. Targeting CXCL16 protected from experimental glomerular injury or interstitial fibrosis. Conflicting results were reported for experimental cardiovascular injury. High circulating CXCL16 levels are associated to human kidney and cardiovascular disease and urinary CXCL16 may increase in kidney injury. In conclusion, mounting evidence suggests a role of CXCL16 in kidney and cardiovascular disease. However, a better understanding is still required before exploring CXCL16 targeting in the clinic.

Next-generation phosphate binders: focus on iron-based binders.

Phosphate excess is associated with increased mortality in patients with chronic kidney disease (CKD) and has recently been linked to accelerated aging. Oral phosphate binders are prescribed to patients with CKD to prevent absorption of dietary phosphate. Currently available binders have been associated with impaired outcomes (calcium-based binders) or are expensive (non-calcium-based binders). Iron-based phosphate binders represent a new class of phosphate binders. Four iron-based phosphate binders have undergone testing in clinical trials. The development of fermagate and SBR759 is currently on hold due to suboptimal and adverse effect profiles in at least some clinical trials. Ferric citrate and sucroferric oxyhydroxide (PA21) are at different stages of application for regulatory approval after being found safe and efficacious in decreasing serum phosphate. Iron from ferric citrate is more readily absorbed than that from sucroferric oxyhydroxide. Sucroferric oxyhydroxide was launched in the USA in 2014 for the treatment of hyperphosphatemia in adult dialysis patients. Ferric citrate may be more suited for chronic treatment of hyperphosphatemia in CKD patients requiring iron supplements but its use may have to be limited in time because of potential for iron overload in patients not needing iron or not receiving erythropoiesis-stimulating agents. In contrast, sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplements.

Bisphenol a in chronic kidney disease.

Phenols are uremic toxins of intestinal origin formed by bacteria during protein metabolism. Of these molecules, p-cresol is the most studied and has been associated with renal function impairment and vascular damage. Bisphenol A (BPA) is a molecule with structural similarity with phenols found in plastic food and beverage containers as well as in some dialyzers. BPA is considered an environmental toxicant based on animal and cell culture studies. Japanese authorities recently banned BPA use in baby bottles based on observational association studies in newborns. BPA is excreted in urine and uremic patients present higher serum levels, but there is insufficient evidence to set cut-off levels or to link BPA to any harmful effect in CKD. However, the renal elimination and potential exposure during dialysis warrant the monitoring of BPA exposure and the design of observational studies in which the potential health risks of BPA for end-stage renal disease patients are evaluated.

Cardiovascular risk biomarkers in CKD: the inflammation link and the road less traveled.

End-stage renal disease patients suffer a syndrome of accelerated aging characterized by a 10- to 100-fold increase in cardiovascular and all-cause mortality when compared to age-matched controls. No specific therapeutic interventions have been shown to improve this dismal outcome. Inflammation, chronic kidney disease-mineral and bone disorder (CKD-MBD) and other biomarkers predict outcome in observational studies. However, we lack clinical trials that address the role of these biomarkers in risk stratification and therapeutic decision making. Biomarkers may also provide insights into the pathophysiology of disease and identify novel therapeutic targets. Inflammation emerges as a prime potential target for intervention. Thus, CKD-MBD biomarkers, asymmetrical dimethyl arginine and tri-iodothyronine have a link to inflammation. Interleukin-6 (IL-6) is one of the inflammation biomarkers with highest predictive value for outcome in ESRD. Biologicals targeting IL-6 are approved for the treatment of chronic inflammatory conditions such as rheumatoid arthritis. Furthermore, trials are underway to test IL-6 targeting potential to decrease cardiovascular injury in non-CKD patients. In this regard, targeting IL-1 was recently shown to decrease systemic inflammation in hemodialysis patients. The success of these trials will likely influence future studies on biomarker targeting in CKD.