Metabolism of complement factor D in renal failure

Pascual, Manuel; Steiger, G; Estreicher, J; Macon, Kevin; Volanakis, John E.; Schifferli, Jürg A.

doi:10.1038/ki.1988.214

Cited by 119 publications

(84 citation statements)

References 26 publications

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“…Correlations between levels of C3 and C4 and fat distribution have been previously reported, 6 but the disassociation between levels of factor D, which is produced predominantly by fat tissue, and several measures of body composition is notable. Factor D is not an acute phase protein, 20 and its level was not significantly raised in the relatives group, a result consistent with previous data in all but the morbidly obese. 21,22 We found no significant change in C3 and B in either group following a fat meal.…”

Section: Discussionsupporting

confidence: 81%

Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes

et al. 2004

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OBJECTIVE:To investigate levels of components of the alternative pathway of complement, and of two activation products, ASP and Bb, in persons ranging in insulin resistance both fasting and following the consumption of a high-fat, low-carbohydrate meal. SUBJECTS: Healthy controls (n ¼ 17) and normoglycaemic first-degree relatives of patients with type II diabetes (n ¼ 15). MEASUREMENTS: All subjects had normal glucose tolerance. Blood was collected for the measurement of plasma glucose, insulin, triglycerides and free fatty acids. Body composition was assessed with dual energy X-ray absorptiometry (DEXA) and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Basal and postprandial values over 6 h were determined for plasma C3, B, D, Bb and ASP. Basal levels of C1q, C4 and CRP were also determined. RESULTS: Controls did not differ significantly from the relatives of patients with type II diabetes for any metabolic parameter except in their degree of insulin resistance and central fat (kg). Across all subjects, basal levels of C3, but no other complement protein, were correlated with insulin resistance. Native complement proteins, but not ASP or Bb, were correlated with body mass index and the amount (kg) of central fat. Basal levels of C3 and factor B were significantly higher in the relatives group, whereas factor D and the classical pathway proteins C1q and C4 did not differ between the two groups. Postprandially, levels of factor D were significantly reduced in both groups. ASP levels also fell postprandially, the decline achieving significance in the relatives group. CONCLUSIONS: Elevated levels of C3 and factor B in the diabetic relatives group may have resulted from increased synthesis by adipose tissue. There was no evidence of alternative pathway activation in response to a fat meal in terms of ASP or Bb production, or significant consumption of C3 and factor B. These data do not support an essential requirement of the hypothesis that ASP is produced in response to the intake of fat.

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Section: Discussionsupporting

confidence: 81%

Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes

et al. 2004

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“…However, an increase in the total (free and bound) concentration of target following drug administration is often seen for therapeutic antibodies that bind soluble endogenous targets, especially when the antibody affinity is high and the target turnover is fast (Hayashi et al, 2007;Davda and Hansen, 2010 ). The high rate of fD synthesis, estimated to be 1.33 mg/kg per day in humans (Pascual et al, 1988), was substantiated by the persistently elevated total fD concentrations, even while total AFD decreased, as seen in the 2 and 20 mg i.v. groups.…”

Section: Discussionmentioning

confidence: 99%

Complement Inhibition in Cynomolgus Monkeys by Anti–Factor D Antigen-Binding Fragment for the Treatment of an Advanced Form of Dry Age-Related Macular Degeneration

Loyet¹,

Good²,

Davancaze³

et al. 2014

J Pharmacol Exp Ther

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Anti-factor D (AFD; FCFD4514S, lampalizumab) is a humanized IgG Fab fragment directed against factor D (fD), a rate-limiting serine protease in the alternative complement pathway (AP). Evaluation of AFD as a potential intravitreal (IVT) therapeutic for dry age-related macular degeneration patients with geographic atrophy (GA) is ongoing. However, it is unclear whether IVT administration of AFD can affect systemic AP activation and potentially compromise host-immune responses. We characterized the pharmacologic properties of AFD and assessed the effects of AFD administered IVT (2 or 20 mg) or intravenous (0.2, 2, or 20 mg) on systemic complement activity in cynomolgus monkeys. For the IVT groups, serum AP activity was reduced for the 20 mg dose group between 2 and 6 hours postinjection. For the intravenous groups, AFD inhibited systemic AP activity for periods of time ranging from 5 minutes (0.2 mg group) to 3 hours (20 mg group). Interestingly, the concentrations of total serum fD increased up to 10-fold relative to predose levels following administration of AFD. Furthermore, AFD was found to inhibit systemic AP activity only when the molar concentration of AFD exceeded that of fD. This occurred in cynomolgus monkeys at serum AFD levels $2 mg/ml, a concentration 8-fold greater than the maximum serum concentration observed following a single 10 mg IVT dose in a clinical investigation in patients with GA. Based on these findings, the low levels of serum AFD resulting from IVT administration of a clinically relevant dose are not expected to appreciably affect systemic AP activity.

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“…The proportion of adipsin elimination in the urine was increased in patients with tubular dysfunction, indicating that under normal circumstances adipsin is filtered through the glomeruli and reabsorbed by tubular cells. 21 Based on this observation and the pathological changes of glomeruli in preeclampsia, the adipsin concentration changes in the urine of patients with preeclampsia can be explained. At the time of full preeclampsia activity, the damaged glomeruli filter an excessive amount of adipsin into the preurine, surpassing the reabsorption capacity of the tubules, and that leads to Table 2.…”

Section: Discussionmentioning

confidence: 99%

Elevation of Urinary Adipsin in Preeclampsia

et al. 2014

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846P reeclampsia, a devastating pregnancy-specific syndrome complicating 2% to 8% of pregnancies, is responsible for ≈60 000 maternal deaths worldwide every year. It is characterized by new-onset hypertension, proteinuria, and edema and usually develops after 20 weeks of gestation.1,2 Early diagnosis and treatment of preeclampsia is essential for prevention of seizure development and maintaining the fetus in the uterus to mature. Many attempts have been made to meet these purposes. It has been found that altered concentration of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PIGF) can predict the occurrence of preeclampsia weeks before the appearance of the clinical symptoms. [3][4][5][6] Uterine artery Doppler studies that assess the pulsability index reveal increased uterine vascular resistance well before the preeclampsia clinical signs arise.7 These predictive tests are valuable for identifying highrisk pregnant women but are incapable of conveniently monitoring the exact occurrence of the disease. In this study, we assumed that in preeclampsia a urinary protein that closely correlated with the 24-hour urine protein could be identified with advanced proteomics technologies and could be developed as a simple rapid assay for point-of-care use and for home monitoring as well.In 1843, John Lever of Guy's Hospital in London discovered the presence of albumin by boiling the urine from pregnant women with puerperal convulsions. 8 Proteinuria in preeclampsia since then has been studied extensively. The glomerular injury that results in proteinuria is characterized as endotheliosis, manifested as glomerular endothelial swelling with loss of endothelia fenestrae and occlusion of the capillary lumens.9,10 Proteinuria is measured currently by a 24-hour urine protein determination or a dipstick examination on a random urine sample. The 24-hour urine protein quantification is no doubt the most accurate and reliable approach but is time consuming and inconvenient. Dipstick is semiquantitative, easy to use, quick, and inexpensive. However, many studies have reported a poor correlation between the dipstick examination and the 24-hour urine assay with high false-positive or false-negative rates. 11,12 We aimed to find a urine protein in preeclampsia that closely correlated with the 24-hour urine protein and was at a Abstract-Early diagnosis and treatment of preeclampsia are essential for prevention of seizure development and fetus maturation. Although various methods have been developed for predicting or monitoring the onset of preeclampsia, a simple assay that can be used as a home or point of care test remains unavailable. We attempted to find a urinary protein that could be used as a biomarker for developing such a test. Urinary samples were collected from 124 preeclampsia and 135 healthy pregnant women for screening using a protein array technology and quantification by ELISA. A urinary protein, adipsin, was found significantly increased, and the adipsin creatinine ratio was closely correlated wi...

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Metabolism of complement factor D in renal failure

Cited by 119 publications

References 26 publications

Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes

Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes

Complement Inhibition in Cynomolgus Monkeys by Anti–Factor D Antigen-Binding Fragment for the Treatment of an Advanced Form of Dry Age-Related Macular Degeneration

Elevation of Urinary Adipsin in Preeclampsia

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