Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases.

OBJECTIVES: Complement deficiencies are difficult to diagnose because of the variability of symptoms and the complexity of the diagnostic process. Here, we applied a novel 'complementomics' approach to study the impact of various complement deficiencies on circulating complement levels. METHODS: Using a quantitative multiplex mass spectrometry assay, we analysed 44 peptides to profile 34 complement proteins simultaneously in 40 healthy controls and 83 individuals with a diagnosed deficiency or a potential pathogenic variant in 14 different complement proteins. RESULTS: Apart from confirming near or total absence of the respective protein in plasma of complement-deficient patients, this mass spectrometry-based profiling method led to the identification of additional deficiencies. In many cases, partial depletion of the pathway up- and/or downstream of the absent protein was measured. This was especially found in patients deficient for complement inhibitors, such as angioedema patients with a C1-inhibitor deficiency. The added value of complementomics was shown in three patients with poorly defined complement deficiencies. CONCLUSION: Our study shows the potential clinical utility of profiling circulating complement proteins as a comprehensive read-out of various complement deficiencies. Particularly, our approach provides insight into the intricate interplay between complement proteins due to functional coupling, which contributes to the better understanding of the various disease phenotypes and improvement of care for patients with complement-mediated diseases.

Adult renal size is not a suitable marker for nephron numbers: an individual patient data meta-analysis.

BACKGROUND: Renal size is often used as a marker for nephron numbers as estimation of glomerular numbers is not yet possible in vivo. However, the validity of an association between the two is questionable. As a proper marker for nephron number in an individual is needed in clinical practice, this study was designed to assess the association between renal size and nephron numbers. METHODS: An individual patient data meta-analysis was performed on data retrieved with a PubMed and Embase search. Only studies were included that described individual human data on kidney size and nephron numbers determined by stereology, the gold standard methodology to estimate nephron numbers. As renal size increases until the end of puberty, and nephron numbers decline after the age of 60 years, only data from individuals aged 18-60 years without renal disease were included. RESULTS: Six papers were identified that provided data on renal weight and nephron numbers from 114 individuals. Backward linear regression identified kidney weight and race as the only 2 significant factors explaining nephron numbers (R square 0.085, p=0.007). Controlling for race, there was a significant correlation between nephron number and kidney weight (r=0.231, r square=0.053, p=0.01). CONCLUSION: These data indicate that only ∼5% of the variation in nephron numbers is explained by differences in renal size. Renal size in adulthood should not be used as a marker for nephron numbers in an individual.

Increased arterial stiffness in young adults with end-stage renal disease since childhood.

Increased arterial stiffness is a risk factor for mortality in adults over 40 yr of age with end-stage renal disease (ESRD). As no data exist on vascular changes in young adults with ESRD since childhood, a long-term outcome study was performed. All living Dutch adult patients with onset of ESRD between 1972 and 1992 at age 0 to 14 yr were invited for carotid artery and cardiac ultrasound and BP measurements. Data on clinical characteristics were collected by review of all medical charts. Carotid ultrasound data were compared with those of 48 age-matched and gender-matched healthy controls. Carotid artery and cardiac ultrasound was performed in 130 out of 187 eligible patients. Mean age was 29.0 (20.7 to 40.6) yr. Compared with controls, patients had a similar intima media thickness but a reduced mean arterial wall distensibility DC (40.0 versus 45.0 kPa(-1). 10(-3); 95% CI, -9.1 to -0.8; P < 0.001), an increased stiffness parameter beta (4.2 versus 3.8; 95% CI, 0.05 to 0.68; P = 0.02), an increased elastic incremental modulus E(inc) (0.35 versus 0.27 kPa. 10(3); 95% CI, 0.02 to 0.12; P < 0.001). Multiple regression analyses in all subjects revealed that ESRD was associated with an increase in beta and E(inc). Arterial wall properties of patients currently on dialysis and transplanted patients were comparable. In all patients, current systolic hypertension was associated with increased E(inc) and decreased DC. In conclusion, carotid arterial wall stiffness is increased in young adult patients with pediatric ESRD. Hypertension is a main determinant and might be a target for treatment of these potentially lethal arterial wall changes.