Plasmapheresis in lupus nephritis with nephrotic syndrome: A long-term followup

Lupus nephritis with nephrotic syndrome is one of the most serious complications of systemic lupus erythematosus. Six female patients with systemic lupus and nephrotic syndrome, refractory to immunosuppressive drug therapy, received 15–20 exchange plasmaphereses. One patient, treated concurrently with high-dose steroids, showed temporary improvement, and five patients, treated concurrently with steroids and either cyclophosphamide or azathioprine, had long-term remissions. Plasmapheresis is a promising therapeutic modality in cases of refractory lupus nephritis with nephrotic syndrome.     

Efficacy of different low-density lipoprotein apheresis methods.

Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary heart disease and drug resistant hypercholesterolemia. Various apheresis systems based on different elimination concepts are currently in use. We compared the efficacy of 4 different apheresis systems concerning the elimination of lipoproteins. The study included 7 patients treated by heparin extracorporeal LDL precipitation (HELP), 10 patients treated by immunoadsorption, 8 patients treated by dextran-sulfate adsorption, and 4 patients treated by cascade filtration. Ten subsequent aphereses were evaluated in patients undergoing regular apheresis for more than 6 months. Total cholesterol decreased by approximately 50% with all 4 systems. LDL cholesterol (LDL-C) (64-67%) and lipoprotein a [Lp(a)] (61-64%) were decreased more effectively by HELP, immunoadsorption, and dextran-sulfate apheresis than by the less specific cascade filtration system [LDL-C reduction 56%, Lp(a) reduction 53%]. Triglyceride concentrations were reduced by 40% (dextran-sulfate) to 49% (cascade filtration) and high-density lipoproteins (HDL) by 9% (dextran-sulfate) to 25% (cascade filtration). On the basis of plasma volume treated, HELP was the most efficient system (LDL-C reduction 25.0%/L plasma), followed by dextran-sulfate (21.0%/L plasma), cascade (19.4%/L plasma), and immunoadsorption (17.0%/L plasma). However, a maximal amount of 3 L plasma can be processed with HELP due to concomitant fibrinogen reduction while there is no such limitation with immunoadsorption. Therefore, the decision of which system should be used in a given patient must be individualized taking the pre-apheresis LDL concentration, concomitant pharmacotherapy, and fibrinogen concentration into account.     

Effects of losartan on low-density lipoprotein apheresis.

The negative charges of dextran sulfate cellulose (DSC) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by bradykinin production. This study was undertaken to see whether an antagonist of angiotensin receptor (AT1), losartan, could be safely used in a patient treated by DSC-LDL apheresis. Losartan (50 mg/day) was given to a patient with coronary heart disease who had been treated by DSC-LDL apheresis and had experienced an anaphylactoid reaction by administration of an angiotensin converting enzyme inhibitor. The effects of losartan on blood pressures and humoral factors were examined by comparing these parameters between apheresis with and without losartan. Blood pressures and plasma levels of bradykinin, renin, and aldosterone were measured before and at 1,000, 2,000, and 3,000 ml of plasma treatment. Bradykinin levels during LDL apheresis tended to be higher with losartan than without losartan (without versus with, 529 +/- 121 [n = 4, mean +/- SE] pg/ml vs. 1,058 +/- 49 at the 2,000 ml stage, p < 0.01). The rise of plasma renin activity with losartan (221 +/- 26% at the 3,000 ml stage) was significantly greater than that without losartan (144 +/- 2.4%). Mean blood pressure decreased by 7% during apheresis with losartan, but blood pressure reduction was not accompanied by any complaints. These results suggest that AT1 receptor antagonists are safely used in patients treated by DSC-LDL apheresis.     

Effect of simvastatin on plasma lipid and lipoprotein concentrations and low-density lipoprotein metabolism in the nephrotic syndrome.

1. The effect of inhibiting the rate-limiting enzyme (3-hydroxy-3-methylglutaryl-CoA reductase, EC 1.1.1.88) in cholesterol synthesis on plasma lipid and lipoprotein concentrations was investigated in 16 patients with primary glomerular disease, heavy proteinuria, well-preserved renal function and hypercholesterolaemia. 2. Detailed studies of low-density lipoprotein metabolism were performed on eight patients before and after 12 weeks of simvastatin therapy. Radioiodinated tracers were used to quantify the fractional catabolic rate of low-density lipoprotein by apolipoprotein B/E receptors and alternative pathways. 3. Simvastatin produced consistent reductions in total plasma cholesterol concentration (median 36.9%), plasma low-density lipoprotein-cholesterol concentration (43.6%) and apolipoprotein B pool size (29.9%). 4. In contrast, the changes in kinetic parameters of low-density lipoprotein metabolism showed no clear pattern. Although an increase in the receptor-mediated catabolism of low-density lipoprotein was demonstrated in five patients, no change or a slight decrease was seen in three patients. Production rates were not significantly altered, although there was a slight decrease in the median value (from 12.4 to 9.7 mg day-1 kg-1). Plasma lathosterol concentration was reduced in all eight patients (range 34-71%), indirectly confirming significant inhibition of cholesterol synthesis. 5. These results suggest that, as in patients with primary moderate hyperlipidaemia, the significant cholesterol-lowering effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in the nephrotic syndrome is accompanied by variable changes in lipoprotein metabolism. The reasons for this heterogeneous response are unclear. This reflects our limited understanding of the metabolic basis of nephrotic hyperlipidaemia and the relationship between hepatic sterol synthesis and plasma lipoprotein kinetics.     

Changes in plasma levels of cyclic nucleotides during low-density lipoprotein apheresis.

The negative charges of dextran sulfate (DS) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by the production of bradykinin. This study was undertaken to see whether cyclic nucleotide plasma levels are affected by DS LDL apheresis. Previously, we showed the rise in plasma levels of prostaglandins and nitric oxide derivatives accompanied by the rise in bradykinin levels. The physiologic effects of prostaglandins and nitric oxide become manifest through the intracellular signal of cyclic nucleotides. The plasma levels of the cyclic nucleotides (cyclic adenosine monophosphate [cAMP] and cyclic guanosine monophosphate [cGMP]) were examined when either of 2 anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. The plasma levels of cAMP during LDL apheresis using heparin were 9.2 +/- 0.3 (mean +/- SE) 12.4 +/- 0.6, 12.0 +/- 0.5, and 12.1 +/- 0.3 pmol/ml, respectively, at the 0, 1,000, 2,000, and 3,000 ml stages. The rise in cAMP levels was suppressed during apheresis using NM. There were no significant increases in cGMP during apheresis with heparin or with NM. There were significant negative correlations between changes in cAMP and those in the blood pressure. These findings suggest that bradykinin generated during apheresis exerts some physiologic effects via activation of the adenylate cyclase dependent pathway.     

儿童肾病综合征患者血浆氧化低密度脂蛋白及其免疫复合物水平

目的分析儿童肾病综合征(NS)患儿血浆氧化低密度脂蛋白(ox-LDL)及其免疫复合物(LDL-IC)水平的变化。方法采用酶联免疫吸附试验(ELISA)分别测定106例活动期儿童NS患儿、42例恢复期儿童NS患儿和155名健康对照者ox-LDL和LDL-IC水平,同时对受检者血脂水平进行检测。结果恢复期及活动期NS患儿的ox-LDL水平均高于对照组(P<0.05、P<0.01),且活动期高于恢复期(P<0.01);活动期NS患儿LDL-IC水平高于恢复期NS患儿和对照组(P<0.01)。NS患儿ox-LDL、LDL-IC分别与总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)和尿素(Urea)呈正相关,与白蛋白(A lb)呈负相关。活动期NS患儿经类固醇治疗后,A lb水平升高,ox-LDL、LDL-IC、TC、TG和LDL-C水平下降。结论 NS患儿ox-LDL及LDL-IC水平明显升高,可能参与动脉粥样硬化的发生、发展过程。     

儿童肾病综合征患者血浆氧化低密度脂蛋白及其免疫复合物水平

目的分析儿童肾病综合征（NS）患儿血浆氧化低密度脂蛋白（ox-LDL）及其免疫复合物（LDL-IC）水平的变化。方法采用酶联免疫吸附试验（ELISA）分别测定106例活动期儿童NS患儿、42例恢复期儿童NS患儿和155名健康对照者ox-LDL和LDL-IC水平,同时对受检者血脂水平进行检测。结果恢复期及活动期NS患儿的ox-LDL水平均高于对照组（P〈0.05、P〈0.01）,且活动期高于恢复期（P〈0.01）;活动期NS患儿LDL-IC水平高于恢复期NS患儿和对照组（P〈0.01）。NS患儿ox-LDL、LDL-IC分别与总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）和尿素（Urea）呈正相关,与白蛋白（A lb）呈负相关。活动期NS患儿经类固醇治疗后,A lb水平升高,ox-LDL、LDL-IC、TC、TG和LDL-C水平下降。结论 NS患儿ox-LDL及LDL-IC水平明显升高,可能参与动脉粥样硬化的发生、发展过程。     

Alport syndrome combined with lupus nephritis in a Chinese family: A case report

BACKGROUNDAlport syndrome (ATS) is a rare hereditary disease caused by mutations in genes such as COL4A3, COL4A4, and COL4A5. ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities. Although ATS can be combined with other diseases or syndromes, ATS combined with lupus nephritis has not been reported before.CASE SUMMARYA Chinese family with ATS was recruited for the current study. Clinical characteristics (including findings from renal biopsy) of ATS patients were collected from medical records, and potential causative genes were explored by whole-exome sequencing. A heterozygous substitution in intron 22 of COL4A3 ({"type":"entrez-nucleotide","attrs":{"text":"NM_000091","term_id":"1732746140","term_text":"NM_000091"}}NM_000091 c.2657-1G>A) was found in the patients, which was further confirmed by quantitative polymerase chain reaction.CONCLUSIONHeterozygous substitution of a COL4A3 gene splice site was identified by whole-exome sequencing, revealing the molecular pathogenic basis of this disorder. In general, identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.     

Changes in plasma levels of nitric oxide derivative during low-density lipoprotein apheresis.

The negative charges of dextran-sulfate (DS) used for low-density lipoprotein (LDL) apheresis activates the intrinsic coagulation pathway, in which plasma kallikrein acts on high-molecular-weight kininogen (HMWK) to produce large amounts of bradykinin. This study was undertaken to see whether bradykinin generated during DS LDL apheresis has some physiologic effects in vivo. The plasma levels of bradykinin and nitric oxide derivatives (NOx) were examined when either of 2 anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. Although anticoagulative action by NM depends on the inhibition of thrombin activity, this substance also inhibits the activity of plasma kallikrein. During apheresis using heparin, the marked increase in bradykinin levels (before apheresis, 18 +/- 3 (mean +/- SE, n = 5) pg/ml; after apheresis 470 +/- 140, p < 0.01) was associated with the increase in NOx (before apheresis 50 +/- 11 pg/ml; after apheresis 66 +/- 15). Interestingly, these changes in bradykinin and NOx levels were suppressed during apheresis using NM. The changes in plasma NOx levels were negatively correlated with those in blood pressures. These findings suggest that bradykinin generated during apheresis exerts some physiologic effects by means of activation of endothelium-derived relaxant factor (EDRF). Our results support the view that bradykinin produced during DS LDL apheresis has physiologic significance.     

State of percutaneous transluminal coronary artery angioplasty and effectiveness of low-density lipoprotein apheresis.

We have recognized percutaneous transluminal coronary artery angioplasty (PTCA) as an important procedure for achieving myocardial revascularization. PTCA has been performed for stable and unstable angina, acute myocardial infarction, and silent myocardial ischemia. Among many new devices, the coronary stent is the most important advancement in PTCA. Frequent stent use is due to the introduction of antiplatelet therapy to prevent stent thrombosis. One serious problem is that PTCA, even with stent use, often causes chronic restenosis. This problem has not been solved, however, despite various strategies. Aggressive lipid-lowering therapy is one of the most important therapies for coronary heart disease. The findings in aggressive lipid-lowering therapy show us its importance. We report that low-density lipoprotein (LDL) apheresis, when performed immediately before and after PTCA, can prevent restenosis of coronary artery lesions. Lipid-lowering therapy should be applied more aggressively with medicine and/or with LDL apheresis for patients who have undergone PTCA.     

Acute changes in plasma levels of hepatocyte growth factor during low-density lipoprotein apheresis.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor, and angiogenesis is included in a variety of its functional effects. HGF levels were measured in 5 sessions of low-density lipoprotein (LDL) apheresis in 3 patients with severe hypercholesterolemia. Blood was collected at the start (T0) and at 1,000 ml (T1), 2,000 ml (T2), and 3,000 ml (T3) plasma treatments. During LDL apheresis, HGF levels increased from 1.59 +/- 0.78 (mean +/- SE, n = 5) ng/ml at T0 to 6.64 +/- 0.97 at T1, 6.28 +/- 0.97 at T2, and 5.20 +/- 0.94 at T3. In one apheresis session, HGF increased immediately at the 100 ml plasma treatment stage. HGF was adsorbed completely by a dextran-sulfate (DS) column. Despite the adsorption by the DS column, HGF in the patient blood increased to the levels with functional effects. The improvement of ischemic symptoms due to LDL apheresis may be related to the angiogenic activities of HGF.     

Improvements in artery occlusion by low-density lipoprotein apheresis in a patient with peripheral arterial disease.

Peripheral arterial disease (PAD; arteriosclerosis obliterans) shows ischemic symptoms along the peripheral arteries due to reduced blood flow, and the number of patients with PAD is increasing. Several papers have reported on the clinical effect of low-density lipoprotein apheresis (LDL-A) on PAD, but there has been no report so far on the improvement of total peripheral artery stenosis by LDL-A. We report on the clinical course of a female PAD patient with intractable decubitus in her heel due to the complete occlusion of anterior tibial artery who was treated by a series of LDL-A sessions. The complete occlusion of the anterior tibial artery improved as seen on angiography, and the decubitus in her heel also markedly improved after LDL-A therapy. This report supports the clinical benefit of LDL-A for the treatment of PAD.     

Beneficial effect of aggressive low-density lipoprotein apheresis in a familial hypercholesterolemic patient with severe diabetic scleredema.

We present a 59-year-old woman with severe diabetic scleredema (DS) associated with heterozygous familial hypercholesterolemia (FH). She had been treated with drugs to lower blood glucose, with insulin for diabetes mellitus (DM), and with low-density lipoprotein (LDL) apheresis therapy monthly or every 2 weeks in addition to drugs to lower serum lipids for FH. However, her scleredema had not improved. After we had tried weekly LDL apheresis therapy for a period of 3 years to treat her hyperlipidemia, the levels of her serum lipids were reduced to normal ranges, and scleredema in her nape improved. We also demonstrated the histopathological improvement in dermis of her cervical skin. We conclude that weekly LDL apheresis therapy is effective for diabetic scleredema that is resistant to conventional treatments.     

Aorta and coronary angiographic follow-up of children with severe hypercholesterolemia treated with low-density lipoprotein apheresis

BACKGROUND: In this single‐center, nonrandomized, prospective study, 11 children with severe genetic hypercholesterolemia, without previous cardiovascular disease events, were treated with low‐density lipoprotein apheresis (LDLa). STUDY DESIGN AND METHODS: LDLa was given every 1 or 2 weeks for 2 to 17 years. Clinical cardiovascular events and coronary revascularization, as well as aortic and coronary angiographic findings and ejection fractions, were serially evaluated for 2 to 17 years. RESULTS: Total cholesterol (TC) and LDL cholesterol levels at baseline were 826.1 ± 183.3 and 767.8 ± 181.9 mg/dL, respectively. After LDLa, these levels decreased to 122.6 ± 24.4 and 79.1 ± 20.7 mg/dL, respectively (both differences, p ≤ 0.001). There were no cardiac deaths, and 6 children were free from any coronary lesions. Nonfatal myocardial infarction was not observed, and coronary revascularization was not required in any patient. Regression of coronary stenosis in children with existing angiographically established lesions after treatment with LDLa was prospectively demonstrated. The statistical analysis applicable to a scoring model (overall atherogenic index [OAI]) highlighted a significant relation between values of 0 to 4 years relevant to the score (p ≤ 0.018) and a weaker significant statistic for the value of OAI between 0 and 2 years (p ≤ 0.03). The OAI score at baseline was significantly related to the basal values of TC (p = 0.015), LDL cholesterol (p = 0.015), and triglycerides (p = 0.01), but not of high‐density lipoprotein cholesterol (p = 0.075) as demonstrated by the logistic regression analysis (Cox and Snell pseudo‐R² of 0.67). CONCLUSION: LDLa interrupted the development of new aortic and coronary lesions in the native arteries and prevented cardiac events and the need for coronary revascularization in children without previous cardiovascular disease events.     

A case report of neonatal congenital heart block due to undiagnosed maternal lupus syndrome

IntroductionCongenital Heart Block (CHB) is a relatively rare disease that can be considered a component of neonatal lupus syndrome caused by maternal lupus. In cases where neonatal lupus does occur, the incidence of recurrence is 2%–5% and the recurrence rate is 12–25% in subsequent pregnancies. While many mothers carry asymptomatic Lupus disease, less than 1/3 of mothers are already diagnosed with the disease (Manolis et al., 2019). A fetal heart rate of 50–60 beats per minute via fetal echocardiography leads to the diagnosis of Congenital Heart Block (CHB). In this article, a neonate with congenital heart block from undiagnosed maternal lupus is presented.Case presentationA fetus with a diagnosis of congenital heart block via fetal echocardiography with a heart rate of 50 beats per minute, weighing 3790 g was born via cesarean section after a 37-week uneventful gestation. After birth, the baby's heart rate remained less than 60beats per minute and electrocardiography showed a complete blockage of the ventricular atrium, therefore, the one-day old neonate was admitted to our hospital. There was no specific disease history in either parent nor other family members, but there was a suspicion of neonatal Lupus Syndrome; therefore, the mother was immediately assessed for lupus and a positive result was confirmed. The neonate received a pacemaker and was diagnosed with congenital heart block due to undiagnosed maternal lupus.ConclusionSince congenital heart block is a dangerous and lethal complication of maternal lupus, early diagnosis in mothers who have suspected symptoms of rheumatologic disease and/or lupus, and subsequent management and treatment of the mother could prevent premature birth and further progression of the baby's congenital cardiac block and possibly other complications.