Geriatric Assessment and the Relation with Mortality and Hospitalizations in Older Patients Starting Dialysis.

BACKGROUND AND OBJECTIVES: A geriatric assessment (GA) is a structural method for identifying frail patients. The relation of GA findings and risk of death in end-stage kidney disease (ESKD) is not known. The objective of the GA in OLder patients starting Dialysis Study was to assess the association of GA at dialysis initiation with early mortality and hospitalization. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients ≥65 years old were included just prior to dialysis initiation. All participants underwent a GA, including assessment of (instrumental) activities of daily living (ADL), mobility, cognition, mood, nutrition, and comorbidity. In addition, a frailty screening (Fried Frailty Index, [FFI]) was applied. Outcome measures were 6- and 12-month mortality, and 6-month hospitalization. Associations with mortality were assessed with cox-regression adjusting for age, sex, comorbidity burden, smoking, residual kidney function and dialysis modality. Associations with hospitalization were assessed with logistic regression, adjusting for relevant confounders. RESULTS: In all, 192 patients were included, mean age 75 ± 7 years, of whom 48% had ≥3 geriatric impairments and were considered frail. The FFI screening resulted in 46% frail patients. Mortality rate was 8 and 15% at 6- and 12-months after enrolment, and transplantation rate was 2 and 4% respectively. Twelve-month mortality risk was higher in patients with ≥3 impairments (hazard ratio [HR] 2.97 [95% CI 1.19-7.45]) compared to less impaired patients. FFI frail patients had a higher risk of 12-month mortality (HR 7.22 [95% CI 2.47-21.13]) and hospitalization (OR 1.93 [95% CI 1.00-3.72]) compared to fit patients. Malnutrition was associated with 12-month mortality, while impaired ADL and depressive symptoms were associated with 12-month mortality and hospitalization. CONCLUSIONS: Frailty as assessed by a GA is related to mortality in elderly patients with ESKD. Individual components of the GA are related to both mortality and hospitalization. As the GA allows for distinguishing between frail and fit patients initiating dialysis, it is potentially of added value in the decision-making process concerning dialysis initiation.

Association of Initiation of Maintenance Dialysis with Functional Status and Caregiver Burden.

BACKGROUND AND OBJECTIVES: Little is known about the functional course after initiating dialysis in elderly patients with ESKD. The aim of this study was to assess the association of the initiation of dialysis in an elderly population with functional status and caregiver burden. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: This study included participants aged ≥65 years with ESKD who were enrolled in the Geriatric Assessment in Older Patients Starting Dialysis study. All underwent a geriatric assessment and a frailty screening (Fried Frailty Index and Groningen Frailty Indicator) at dialysis initiation. Functional status (activities of daily life and instrumental activities of daily life) and caregiver burden were assessed at baseline and after 6 months. Decline was defined as loss of one or more domains in functional status, stable as no difference between baseline and follow-up, and improvement as gain of one or more domains in functional status. Logistic regression was performed to assess the association between the combined outcome functional decline/death and potential risk factors. RESULTS: Of the 196 included participants functional data were available for 187 participants. Mean age was 75±7 years and 33% were women. At the start of dialysis, 79% were care dependent in functional status. After 6 months, 40% experienced a decline in functional status, 34% remained stable, 18% improved, and 8% died. The prevalence of high caregiver burden increased from 23%-38% (P=0.004). In the multivariable analysis age (odds ratio, 1.05; 95% confidence interval, 1.00 to 1.10 per year older at baseline) and a high Groningen Frailty Indicator compared with low score (odds ratio, 1.97; 95% confidence interval, 1.05 to 3.68) were associated with functional decline/death. CONCLUSIONS: In patients aged ≥65 years, functional decline within the first 6 months after initiating dialysis is highly prevalent. The risk is higher in older and frail patients. Loss in functional status was mainly driven by decline in instrumental activities of daily life. Moreover, initiation of dialysis is accompanied by an increase in caregiver burden.

Low Mannose-Binding Lectin (MBL) genotype is associated with future cardiovascular events in type 2 diabetic South Asians. A prospective cohort study.

BACKGROUND: South Asians have a high burden of type 2 diabetes and vascular complications. Vascular inflammation is considered central in the pathophysiology of atherosclerosis, and the complement system is thought to play an important role. Mannose-Binding Lectin (MBL), which activates the lectin pathway of complement activation, has been introduced as a risk marker of vascular damage. The present study explores the association of MBL levels, genotype and cardiovascular events in type 2 diabetic South Asians. METHODS: We conducted a prospective observational study. A cohort consisting of 168 type 2 diabetic South Asians was followed for a median duration of 7.66 years. At baseline, MBL levels and genotype were determined. The association with future cardiovascular events was assessed by Cox proportional hazard regression. RESULTS: During follow-up, 31 cardiovascular events occurred in 22 subjects (11 men, 11 women). The O/O genotype was significantly associated with the occurrence of cardiovascular events (hazard ratio 3.42, 95%CI 1.24-9.49, P = 0.018). However, log MBL levels were not associated with the occurrence of cardiovascular events (hazard ratio 0.93, 95% CI 0.50-1.73). CONCLUSIONS: In type 2 diabetic South Asians, the O/O MBL genotype is associated with cardiovascular events, although single serum MBL levels are not.

Urinary properdin excretion is associated with intrarenal complement activation and poor renal function.

BACKGROUND: Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric states, activation of filtered or locally produced complement is toxic for renal tubular cells and likely contributes to the progression of renal failure. Recent experimental evidence suggests an important role for properdin in promoting intrarenal complement activation. We measured properdin in proteinuric urine and assessed its relation with urinary SC5b-9 levels, the soluble form of the effector phase of complement activation. METHODS: Seventy patients with renal disease of different origin but all with a protein excretion of at least 1 g/day were studied. Urinary properdin and SC5b-9 levels were measured using an ELISA technique. RESULTS: Properdin was detectable in the urine of 37 patients (53%). These subjects had higher urinary SC5b-9 levels {median 0.50 U/ml [interquartile range (IQR) 0.13-1.81] versus 0.049 U/ml (IQR 0.024-0.089), P < 0.001}. When adjusted for proteinuria and renal function, properdin excretion was strongly associated with increased urinary SC5b-9 levels (odds ratio 16.2, 95% confidence interval 3.6-74.4). Properdin excretion was associated with worse renal function. CONCLUSION: Our results suggest that urinary properdin excretion enhances intrarenal complement activation and thus may contribute to the progression of renal damage in proteinuric states.

Complement activation by tubular cells is mediated by properdin binding.

Activation of filtered complement products on the brush border of the tubular epithelium is thought to be a key factor underlying proteinuria-induced tubulointerstitial injury. However, the mechanism of tubular complement activation is still unclear. Recent studies on mechanisms of complement activation indicate a key role for properdin in the initiation of an alternative pathway. We hypothesized that properdin serves as a focal point for complement activation on the tubulus. We observed a strong staining for properdin on the luminal surface of the tubules in kidney biopsies from patients with proteinuric renal disease. In vitro experiments revealed dose-dependent binding of properdin to proximal tubular epithelial cells (PTEC), whereas no significant binding to endothelial cells was detected. Exposure of PTEC with normal human serum as a source of complement resulted in complement activation with deposition of C3 and generation of C5b-9. These effects were virtually absent with properdin-deficient serum. Preincubation of PTEC with properdin before addition of properdin-depleted serum fully restored complement activation on the cells, strongly suggesting a key role for properdin in the activation of complement at the tubular surface. In proteinuric renal disease, filtered properdin may bind to PTEC and act as a focal point for alternative pathway activation. We propose that this contribution of properdin is pivotal in tubular complement activation and subsequent damage. Interference with properdin binding to tubular cells may provide an option for the treatment of proteinuric renal disease.