Pathogenesis, histopathologic findings and treatment modalities of lipoprotein glomerulopathy: A review / Patogênese, achados histopatológicos e modalidades de tratamento da glomerulopatia por lipoproteínas: Uma revisão

Abstract Lipoprotein glomerulopathy (LPG) is an uncommon cause of nephrotic syndrome and/or kidney failure. At microscopy, LPG is characterized by the presence of lipoprotein thrombi in dilated glomerular capillaries due to different ApoE mutations. ApoE gene is located on chromosome 19q13.2, and can be identified in almost all serum lipoproteins. ApoE works as a protective factor in atherosclerosis due its interaction with receptor-mediated lipoprotein clearance and cholesterol receptor. Most common polymorphisms include ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3, and ApoE4/4. All age-groups can be affected by LPG, with a discrete male predominance. Compromised patients typically reveal dyslipidemia, type III hyperlipoproteinemia, and proteinuria. LPG treatment includes fenofibrate, antilipidemic drugs, steroids, LDL aphaeresis, plasma exchange, antiplatelet drugs, anticoagulants, urokinase, and renal transplantation. Recurrence in kidney graft suggests a pathogenic component(s) of extraglomerular humoral complex resulting from abnormal lipoprotein metabolism and presumably associated to ApoE.

Resumo A glomerulopatia por lipoproteínas (GLP) é uma patologia rara que causa síndrome nefrótica e/ou insuficiência renal. Na microscopia, a GLP é caracterizada pela presença de trombos de lipoproteínas em capilares glomerulares dilatados devido a diferentes mutações no gene da ApoE. O gene da ApoE está localizado no cromossomo 19q13.2 e pode ser identificado em quase todas as lipoproteínas séricas. A ApoE age como fator de proteção na arterioesclerose por conta de sua interação com a depuração de lipoproteínas mediada por receptores e com o receptor de colesterol. Dentre os polimorfismos mais comuns destacam-se ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3 e ApoE4/4. A GLP pode acometer indivíduos de todas as faixas etárias, com discreta predominância do sexo masculino. Pacientes afetados tipicamente apresentam dislipidemia, hiperlipoproteinemia tipo III e proteinúria. O tratamento da GLP é conduzido com fenofibrato, antilipêmicos, corticosteroides, LDL-aferese, troca de plasma, antiplaquetários, anticoagulantes, uroquinase e transplante renal. Recidiva no enxerto renal indica a existência de componentes patogênicos do complexo humoral extraglomerular resultante de metabolismo lipoproteico anômalo, possivelmente associado a ApoE.

CODAP: A multidisciplinary consensus among Portuguese experts on the definition, detection and management of atherogenic dyslipidemia. / CODAP: um consenso multidisciplinar sobre a definição, diagnóstico e tratamento da dislipidemia aterogénica em Portugal.

INTRODUCTION AND AIMS: Atherogenic dyslipidemia is an important contributor to residual cardiovascular (CV) risk, but it is underdiagnosed and undertreated. This study aimed to assess the opinion of Portuguese experts to generate a consensus concerning the diagnosis and treatment of atherogenic dyslipidemia, as well as to contribute toward standardization of clinical practice in this disorder. METHODS: The study consisted in the application of a questionnaire to an expert panel, following a modified Delphi methodology. RESULTS: The majority (88.4%) of the proposed items were found to be consensual. The expert panel recognized the importance of the atherogenic dyslipidemia phenotype, the role played by low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol as risk markers and therapeutic targets, the choice of statins as first-line lipid-lowering drugs, and the value of associating statins with fenofibrate as a means to reduce residual CV risk. However, the role played by triglycerides in CV risk and the therapeutic value of fibrates lacked consensus. Taking into consideration the state of the art and the opinions expressed in this study, the scientific committee developed a treatment algorithm aimed to improve the perception and treatment of atherogenic dyslipidemia. CONCLUSIONS: The experts involved in this study were shown to be familiar with the concept and the importance of atherogenic dyslipidemia. The few situations in which a consensus could not be found were mainly related to the interpretation and/or relevance of the available evidence.

Residual cardiovascular risk of lipid origin. Components and pathophysiological aspects. / Riesgo cardiovascular residual de origen lipídico. Componentes y aspectos fisiopatológicos.

There is no doubt about the relationship between LDL-c and cardiovascular risk, as well as about the benefits of statin treatment. Once the objective of LDL-c has been achieved, the evidences that demonstrate the persistence of a high cardiovascular risk, a concept called residual risk, are notable. The residual risk of lipid origin is based on atherogenic dyslipidemia, characterized by an increase in triglycerides and triglyceride-rich lipoproteins, a decrease in HDL-c and qualitative alterations in LDL particles. The most commonly used measures to identify this dyslipidemia are based on the determination of total cholesterol, triglycerides, HDL, non-HDL cholesterol and remaining cholesterol, as well as apolipoprotein B100 and lipoprotein (a) in certain cases. The treatment of atherogenic dyslipidemia is based on weight loss and physical exercise. Regarding pharmacological treatment, we have no evidence of cardiovascular benefit with drugs aimed at lowering triglycerides and HDL-c, fenofibrate seems to be effective in situations of atherogenic dyslipidemia.

Practical recommendations for the management of cardiovascular risk associated with atherogenic dyslipidemia, with special attention to residual risk. Spanish adaptation of a European Consensus of Experts. / Recomendaciones prácticas para el manejo del riesgo cardiovascular asociado a la dislipemia aterogénica, con especial atención al riesgo residual. Adaptación española de un Consenso Europeo de Expertos.

This document has discussed clinical approaches to managing cardiovascular risk in clinical practice, with special focus on residual cardiovascular risk associated with lipid abnormalities, especially atherogenic dyslipidaemia (AD). A simplified definition of AD was proposed to enhance understanding of this condition, its prevalence and its impact on cardiovascular risk. AD can be defined by high fasting triglyceride levels (≥2.3mmol/L / ≥200mg/dL) and low high-density lipoprotein cholesterol (HDL-c) levels (≤1,0 / 40 and ≤1,3mmol/L / 50mg/dL in men and women, respectively) in statin-treated patients at high cardiovascular risk. The use of a single marker for the diagnosis and treatment of AD, such as non-HDL-c, was advocated. Interventions including lifestyle optimization and low density lipoprotein (LDL) lowering therapy with statins (±ezetimibe) are recommended by experts. Treatment of residual AD can be performed with the addition of fenofibrate, since it can improve the complete lipoprotein profile and reduce the risk of cardiovascular events in patients with AD. Others clinical condictions in which fenofibrate may be prescribed include patients with very high TGs (≥5.6mmol/L / 500mg/dL), patients who are intolerant or resistant to statins, and patients with AD and at high cardiovascular risk. The fenofibrate-statin combination was considered by the experts to benefit from a favorable benefit-risk profile. In conclusion, cardiovascular experts adopt a multifaceted approach to the prevention of atherosclerotic cardiovascular disease, with lifestyle optimization, LDL-lowering therapy and treatment of AD with fenofibrate routinely used to help reduce a patient's overall cardiovascular risk.

[Fibrates therapy: Rational use fenofibrate 2016. Executive summary]. / Terapia con fibratos: uso racional del fenofibrato 2016. Resumen ejecutivo.

To control lipid factors risk, beyond proper management of LDL cholesterol according to individual risk, detection and treatment of atherogenic dyslipidemia and abnormal levels of triglycerides or HDL cholesterol it should be considered for address a global cardiovascular protection, both in primary and secondary prevention. In this sense, these recommendations collect data on efficacy and safety about the combination statin with fibrates, often necessary for total control of dyslipidemia, particularly in patients with metabolic disorders such as diabetes mellitus, metabolic syndrome or visceral obesity. Reference to control and monitoring of treatment is also done, as well as benefits of fenofibrate not linked directly to their lipid-lowering effect.

[Consensus for pharmacologic treatment of atherogenic dyslipidemia with statin-fenofibrate combined therapy]. / Consenso sobre tratamiento farmacológico de la dislipidemia aterogénica con terapia combinada estatina-fenofibrato.

LDLc levels are associated with increase of cardiovascular risk, and statins are currently used for their control. Nevertheless, a despite of LDLc levels at goal, a residual risk is persistent, commonly associated with persistent lipids modifications (high triglycerides and low HDLc). So, it is necessary to evaluate triglycerides and HDL to assessment cardiovascular risk. Clinical data are consistent with efficacy and safety of combination therapy with statin and other lipid lowering drugs, for instance fenofibrate. Patients with hipertriglyceridemia and low HDLc are the group with most potential improve. In that patients with atherogenic dyslipidemia, the target for therapeutic objectives related with non-HDL-cholesterol is a priority, because non-HDL-cholesterol is considered as a more accuracy measure to assessment cardiovascular risk.

[The fixed combination of pravastatin and fenofibrate: what can it provide?]. / Combinación fija pravastatina/fenofibrato: ¿qué puede aportar?

The treatment of patients with high cardiovascular risk and mixed hyperlipidemia is difficult due to multiple quantitative and qualitative lipid abnormalities. The priority is to reduce LDL-c levels, for which statins are the drug of choice. Despite the benefits of statins, the residual cardiovascular risk is very high in patients with atherogenic dyslipidemia. To reduce this risk, we also need to control non-HDL cholesterol levels, decreasing triglyceride levels and increasing HDL-c levels. To achieve these objectives and lifestyle changes, the use of combined therapy is often required. Fibrates are drugs that can be used in combination with statins to reduce this residual risk. Fenofibrate is well tolerated in combination with statins. The fixed combination of pravastatin/ fenofibrate has been shown to have complementary benefits in the atherogenic lipid profile in general. The combination is well tolerated and is indicated in patients with high risk and mixed hyperlipidemia who have controlled or are close to their objectives for LDL-c levels, using 40-mg pravastatin in monotherapy. The beneficial eff ect of the combination on LDL-c levels is minimal and is primarily observed in non-HDL cholesterol, triglycerides and HDL-c. The combination of pravastatin 40 and fenofibrate 160 can provide a considerable clinical benefit to patients with high risk and mixed atherogenic dyslipidemia, to patients with LDL-c levels that are controlled or near the objectives for decreasing their residual risk of lipid origin and is especially useful for patients with type 2 diabetes, obesity and combined metabolic syndrome and familial hyperlipidemia.

[Combination of pravastatin and fenofibrate (Pravafenix ®). Safety studies]. / Asociación de pravastatina y fenofibrato (Pravafenix ®). Estudios de seguridad.

Although LDL cholesterol is the primary treatment objective for reducing cardiovascular risk, the increase in triglyceride levels and the reduction of HDL cholesterol levels constitute the so-called residual cardiovascular risk. Treatment with statins combined with fibrates is an actual possibility for the treatment of overall cardiovascular risk. However, this combination is often associated with adverse eff ects, especially muscular and hepatic. Due to its pharmacological characteristics, the combination of pravastatin and fenofibrate can be effective and safe, with few adverse eff ects. In this review, we analyze the available safety studies and conclude that Pravafenix(®) (the combination of 40-mg pravastatin and 160-mg fenofibrate) achieves complementary benefits on the overall atherogenic lipid profile, is well tolerated and has few adverse eff ects, which is similar to the monotherapy of each of its components. It remains to be seen whether this combination confers additional long-term benefits for patients treated with statins.

[Indications for the combination of pravastatin and fenofibrate according to the type of dyslipidemia]. / Indicaciones de la combinación de pravastatina más fenofibrato según el tipo de dislipemia.

The combination with fixed doses of pravastatin (40 mg) and fenofibrate (160 mg) offers a therapeutic alternative, especially in the comprehensive approach to mixed hyperlipidemia in patients with high cardiovascular risk of metabolic origin. It also ensures the efficacy and safety as a result of the evidence that supports the clinical benefit of both pravastatin in primary and secondary prevention and fenofibrate in patients with atherogenic dyslipidemia. This combination also has few adverse effects, which are similar in all cases to those produced by the isolated monotherapy of each of the drugs. Consequently, the possible indications for this combination include patients with mixed hyperlipidemia, patients with atherogenic dyslipidemia (increased triglyceride levels, reduced HDL-c levels and moderately increased LDL-c levels), patients with hypertriglyceridemia who need to reduce their LDL-c levels, patients with low HDL syndrome who also require a reduction in LDL-c levels, patients with moderate hypercholesterolemia who require an additional reduction of triglyceride levels and especially patients with high atherogenic metabolic risk who require an overall intervention for each of the lipid fractions.

[Rhabdomyolysis secondary to simvastatin and phenofibrate]. / Rabdomiolisis secundaria a simvastatina y fenofibrato.

Statins, which are used as first-line drugs in the prevention of cardiovascular disease, are usually safe, but in some cases there may be muscular toxicity. Statin-associated myopathy, can present as myalgia, myositis or rhabdomyolysis. Only 0.44 per 10,000 treated and per year, develop rhabdomyolysis. There are many risk factors associated with the patient and with the pharmacological treatment. A risk of muscle injury of 1-5% has been reported with some statins combined with fibrates. The fibrate with the highest risk of myopathy in combination with statins is gemfibrozil, while phenofibrate seems to be the safest. The case is presented of a 60 year-old woman with clinical symptoms and laboratory findings that suggested rhabdomyolysis secondary to a combination of simvastatin and phenofibrate. This case reminds physicians of the need to closely monitor these patients, in addition to alert them to the onset of muscle pain or weakness.