Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study.

It has not been firmly established whether disturbed calcium-phosphate metabolism affects progression of chronic kidney disease (CKD) in humans. In this cohort study of 227 nondiabetic patients with CKD, we assessed fibroblast growth factor 23 (FGF23) plasma concentrations in addition to other variables involved in calcium-phosphate metabolism, and we followed 177 of the patients prospectively for a median of 53 months to assess progression of renal disease. In the baseline cohort, we found a significant inverse correlation between glomerular filtration rate and both c-terminal and intact FGF23 levels (both P < 0.001). The 65 patients who experienced a doubling of serum creatinine and/or terminal renal failure were significantly older, had a significantly lower glomerular filtration rate at baseline, and significantly higher levels of intact parathormone, c-terminal and intact FGF23, and serum phosphate (all P < 0.001). Cox regression analysis revealed that both c-terminal and intact FGF23 independently predict progression of CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone. The mean follow-up time to a progression end point was 46.9 (95% CI 40.2 to 53.6) months versus 72.5 (95% CI 67.7 to 77.3) months for patients with c-terminal FGF23 levels above or below the optimal cut-off level of 104 rU/mL (derived by receiver operator curve analysis), respectively. In conclusion, FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD. Its pathophysiological significance remains to be elucidated.

Intracellular calcium and sodium-lithium countertransport in type 2 diabetic patients with and without albuminuria.

Increased intracellular calcium concentrations ([Ca(2+)](i)) and enhanced sodium-lithium countertransport (Na/Li CT) activities may play a role in the development of diabetic complications such as diabetic nephropathy. The present study was designed to test the hypothesis that albuminuria in patients with type 2 diabetes is associated with increased [Ca(2+)](i) in response to stimulation with platelet-activating factor (PAF) or with enhanced Na/Li CT activities. The study population comprised 203 type 2 diabetic patients. Albuminuria was defined as an albumin excretion rate exceeding 30 mg/d (117 cases). PAF-evoked rises in [Ca(2+)](i) and Na/Li CT activities were determined in Epstein-Barr-virus-immortalized lymphoblasts. Albuminuria was related to high stimulated [Ca(2+)](i) but not to high basal [Ca(2+)](i). The association was independent of age, sex and several non-diabetes related confounders, but depended on diabetes-related factors, such as the duration of diabetes. The risk of albuminuria was highest in subjects with high [Ca(2+)](i) who reported a diabetes duration of < or =10 years. There was no association between Na/Li CT activities and albuminuria. The present results support the hypothesis that albuminuria in type 2 diabetic patients is associated with a primary defect in intracellular calcium homeostasis. The association between stimulated [Ca(2+)](i) and albuminuria is most prominent in early diabetes.

Sodium/lithium countertransport and intracellular calcium concentration in patients with essential hypertension and coronary heart disease.

The present study was designed to test the hypothesis that enhanced intracellular calcium signalling and increased sodium/lithium countertransport (Na(+)/Li(+) CT) activity may be associated with coronary heart disease (CHD) in non-diabetic patients with essential hypertension. Platelet-activating factor (PAF)-evoked rises in the intracellular calcium concentration ([Ca(2+)](i)) were measured in Epstein-Barr-virus-immortalized lymphoblasts from 62 hypertensive patients with CHD and 34 patients without CHD. Na(+)/Li(+) CT activity was assessed in erythrocytes from 80 hypertensive patients with CHD and 46 patients without CHD. Baseline values of unstimulated and PAF-stimulated [Ca(2+)](i) were not significantly different between hypertensive subjects with (baseline, 126+/-5 nmol/l; stimulated, 550+/-43 nmol/l) and without (baseline, 125+/-5 nmol/l; stimulated, 654+/-105 nmol/l) CHD. Similarly, Na(+)/Li(+) CT activity was not significantly different between the two groups (patients with CHD, 219+/-8 micromol x l(-1) x h(-1); patients without CHD, 234+/-10 micromol x l(-1) x h(-1)). We conclude that intracellular signal transduction, as indicated by PAF-induced rises in [Ca(2+)](i) and Na(+)/Li(+) CT activity, is not associated with an increased risk of CHD in non-diabetic patients with essential hypertension.

Apolipoprotein A-IV serum concentrations are elevated in patients with mild and moderate renal failure.

Cell culture studies and investigations in mice that overexpress either human or mouse apolipoprotein A-IV (apoA-IV) revealed anti-atherogenic properties of apoA-IV. An association between low apoA-IV concentrations and coronary artery disease in humans was demonstrated; therefore, apoA-IV may also play an antiatherogenic role in humans. Because apoA-IV is markedly elevated in dialysis patients, patients with the earliest and modest stages of renal impairment were studied to assess the association of apoA-IV with GFR and atherosclerotic complications. GFR was measured by the use of iohexol in 227 non-nephrotic patients with different degrees of renal impairment. ApoA-IV increased significantly with decreasing GFR and was already elevated in earliest stages of renal disease (GFR > 90 ml/min per 1.73 m2). Multiple linear regression analysis identified renal function parameters (GFR, creatinine, and urea) as the most important determinants of apoA-IV levels in serum of these patients. Twenty-six patients had already experienced 36 atherosclerotic events. Logistic regression analysis identified three variables associated with atherosclerotic complications: age, apoA-IV, and gender. Each 1 mg/dl increase of apoA-IV decreased the odds ratio for an atherosclerotic complication by 8% (P = 0.011). The data clearly show that the anti-atherogenic apoA-IV starts to increase during the earliest phases of renal insufficiency, which makes apoA-IV an early marker of renal impairment.

Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.

High lipoprotein(a) (Lp(a)) serum concentrations and the underlying apolipoprotein(a) (apo(a)) phenotypes are risk factors for cardiovascular disease in the general population as well as in patients with renal disease. Lp(a) concentrations are markedly elevated in patients with end-stage renal disease. However, nothing is known about the changes of Lp(a) depending on apo(a) size polymorphism in the earliest stages of renal impairment. In this study, GFR was measured by iohexol technique in 227 non-nephrotic patients with different degrees of renal impairment and was then correlated with Lp(a) serum concentrations stratified according to low (LMW) and high (HMW) molecular weight apo(a) phenotypes. Lp(a) increased significantly with decreasing GFR. Such an increase was dependent on apo(a) phenotype. Only renal patients with HMW apo(a) phenotypes expressed higher median Lp(a) concentrations, i.e., 6.2 mg/dl at GFR >90 ml/min per 1.73 m2, 14.2 at GFR 45 to 90 ml/min per 1.73 m2, and 18.0 mg/dl at GFR <45 ml/min per 1.73 m2. These values were markedly different when compared with apo(a) phenotype-matched control subjects who had a median level of 4.4 mg/dl (ANOVA, linear relationship, P < 0.001). In contrast, no significant differences were observed at different stages of renal function in patients with LMW apo(a) phenotypes when compared with phenotype-matched control subjects. The elevation of Lp(a) was independent of the type of primary renal disease and was not related to the concentration of C-reactive protein. Multiple linear regression analysis found that the apo(a) phenotype and GFR were significantly associated with Lp(a) levels. Non-nephrotic-range proteinuria modified the association between GFR and Lp(a) levels. In summary, an increase of Lp(a) concentrations, compared with apo(a) phenotype-matched control subjects, is seen in non-nephrotic patients with primary renal disease even in the earliest stage when GFR is not yet subnormal. This change is found only in subjects with HMW apo(a) phenotypes, however.