Cristina Consani

REAPPRAISAL OF SERUM β2-MICROGLOBULIN AS MARKER OF GFR

Introduction. Beta 2 microglobulin(β2M) is filtered by the glomeruli and reabsorbed by the proximal tubularcells where it is metabolized. Its plasma concentration increases with decreasingrenal function. Aim. To compare serum creatinine(Cr) and serum β2M as markers of GFR. Patientsand Methods. In 160 adult patients, with various kidney diseasesand different GFR, serum Cr (autoanalyzer), serum β2M (RIA) and GFR (bladdercumulative method using 99mTc-DTPA as glomerulartracer) were measured in the same day. Results.A linear relationship was observed between ln GFR and both ln serum Cr (lnCr= 3.112–0.716lnGFR; r = 0.92) and ln serum β2M (lnβ2M = 4.274–0.814lnGFR; r = 0.90). With decreasing GFR the increase in serum β2M was higherthan that of serum Cr (see regression coefficients that are significantlydifferent). The normal upper limit of serum Cr corresponds to a GFR 48.1 mL/minwhile that of serum β2M to a GFR 65.0. With decreasing GFR the increaseof serum β2M occurs before than that of serum Cr. Conclusions.With declining renal function, serum β2M increases more and before thanserum Cr. Serum β2M is a good endogenous marker of GFR, better than serumCr.

Interleukin-8 is a powerful prognostic predictor of all-cause and cardiovascular mortality in dialytic patients.

Background: Cohort studies have demonstrated an association between C-reactive protein (CRP) and interleukin-6 (IL-6) and all-cause and cardiovascular mortality in end-stage renal disease (ESRD) patients. Interleukin-8 (IL-8) appears to be not only the plasma expression of the acute-phase response but also a direct pathogenetic mediator of the atherosclerotic process. Methods: To evaluate the role of IL-8 in predicting outcome, 76 chronic dialytic patients were prospectively followed for 18 months. At baseline, blood samples were taken for analysis of high-sensitivity CRP, IL-6, IL-8 and other standard laboratory analyses. Results: Median IL-8 was 5.2 mg/l, therefore near half of the patients had IL-8 values within the range of ‘normal limits’. IL-6 and CRP were significantly correlated (r = 0.45, p < 0.001) and a positive correlation was also found between IL-6 and IL-8 (r = 0.39, p < 0.001). The correlation coefficient between IL-6 and CRP was 0.43 (p < 0.001) and 0.50 (p < 0.001) in patients without and with history and/or clinical signs of cardiovascular disease, respectively. After a follow-up of 1.5 years, 8 patients had died from cardiovascular causes and another 7 patients for other reasons; furthermore 9 major nonfatal cardiovascular events were recorded. Stepwise regression analysis showed IL-8 as the strongest independent predictor of all-cause and cardiovascular events (p = 0.0025) even after adjustment for age and dialytic age, followed by IL-6 and CRP (p < 0.01). Conclusion: Despite a small population and a relatively short follow-up period, this study firstly demonstrated that IL-8 is a powerful independent predictive factor for cardiovascular and overall mortality cause in ESRD patients.

Prediction of Glomerular Filtration Rate From Body Cell Mass and Plasma Creatinine

The gold standards for the measurement of glomerular filtration rate (GFR) are inulin clearance and radioisotopic methods. However, creatinine clearance is the most used test to evaluate GFR in clinical practice. Its adequacy is questionable, since its repeatability is quite poor, mainly due to errors in the collection of urine. The aim of this study was to evaluate a new method to predict GFR from the body cell mass (BCM) and plasma creatinine (Pcr), avoiding urine collection. The values of BCM were obtained in 275 adult renal patients with different renal function, ranging from normality to advanced renal failure. The relationship of GFR (clearance of (99m)Tc-DTPA) with BCM and Pcr was calculated in the first 85 patients. A highly significant linear correlation was found between GFR and the ratio BCM/Pcr. Thereafter, GFR was predicted from BCM and Pcr (BCM GFR) with formulas derived from the relationships found between GFR and the ratio BCM/Pcr. For comparison, GFR was predicted also according to other prediction formulas: Cockcroft and Gault (CG GFR), and the simplified MDRD formula (MDRD GFR). BCM GFR gave a more precise estimate of GFR than CG GFR and MDRD GFR. In fact, BCM GFR had the best correlation and agreement with true GFR ((99m)Tc-DTPA). Furthermore, CG GFR and MDRD GFR markedly overestimated true GFR. Finally, the error of prediction of BCM GFR was definitely lower than that of the two other estimates of GFR. GFR can be predicted from BCM and plasma creatinine. This method, which is very simple and accurate, seems suitable to establish the adequate dosage of drugs cleared by the kidneys.

Inflammatory Pattern in Hemodiafiltration

Chronic inflammation may play an important role in early morbidity and mortality in hemodialysis (HD) patients. Interleukin-6 (IL-6) production is enhanced in long-term HD patients and this activated phase response has been shown to be a predictor of cardiovascular disease in the uremic syndrome as well as in the general population. Furthermore, IL-6 and C-reactive protein (CRP) have been negatively related to low serum albumin levels (MIA syndrome). Several studies have attempted to address the question as to whether the type of the dialysis membrane, the quality of the dialysate, and the dialysis technique may be responsible for the induction of a chronic inflammatory state. Recently, the Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown that high-efficiency hemodiafiltration (HDF)- treated patients had a better survival than HD-treated patients accounting for sex, dialysis dose, co-morbid condition and country specificities. Here we report data from the RISCAVID study, an observational and prospective trial including the whole chronic HD population in the north-west part of Tuscany (1,235 million people). The aim of the study was to elucidate the relevance of traditional and non-traditional risk factors on mortality and morbidity in HD patients as well as the impact of different HD modalities. Data at 30 months from this study showed the synergic effect of CRP and pro-inflammatory cytokines as the strong predictors of overall and cardiovascular mortality. HDF was associated to an improved cumulative survival independently of dialysis dose.

Study of skin vasomotion in type 1 diabetic patients and of its possible relationship with clinical and laboratory variables

Vascular oscillation (vasomotion) occurs in the microcirculation and is thought to be a significant contributor to tissue perfusion. Our aim was to assess skin vasomotion (SV) of type 1 diabetic patients (T1D-pts) and its relationship with clinical or laboratory variables of the studied T1D-pts. Forearm endothelial-, sympathetic- and myogenic-dependent SV were assessed basally and after 3 min of forearm ischemia in 40 T1D-pts and 50 healthy controls, by spectral analysis of laser-Doppler (LD) signal at the frequency ranges of 0.009-0.02 Hz, 0.021-0.06 Hz and 0.061-0.2 Hz, respectively. Post-ischemic per cent increase (PI%-increase) in power spectral density (PSD) of skin endothelial- and sympathetic-dependent VS was significantly reduced in T1D-pts compared to controls (p < 0.0005, p < 0.0001, respectively). Linear regression analysis showed a significant positive relationship between PI%-increase of endothelial-dependent SV and heart rate variation during laying-standing test (R = 0.65, p = 0.00001), and a negative relationship between PI%-increase in PSD of skin LD signal 0.009-1.6 Hz spectrum and glycated haemoglobin serum levels (R = 0.44, p = 0.0036) in T1D-pts. These results are consistent with reduced skin endothelial- and sympathetic-dependent stimulated SV and with relationships between some clinical or laboratory variables and SV parameters in the T1D-pts studied.

Circadian blood pressure variability in type 1 diabetes subjects and their nondiabetic siblings - influence of erythrocyte electron transfer

BackgroundNormotensive non-diabetic relatives of type 1 diabetes (T1D) patients have an abnormal blood pressure response to exercise testing that is associated with indices of metabolic syndrome and increased oxidative stress. The primary aim of this study was to investigate the circadian variability of blood pressure and the ambulatory arterial stiffness index (AASI) in healthy siblings of T1D patients vs healthy control subjects who had no first-degree relative with T1D. Secondary aims of the study were to explore the influence of both cardiovascular autonomic function and erythrocyte electron transfer activity as oxidative marker on the ambulatory blood pressure profile.MethodsTwenty-four hour ambulatory blood pressure monitoring (ABPM) was undertaken in 25 controls, 20 T1D patients and 20 siblings. In addition to laboratory examination (including homeostasis model assessment of insulin sensitivity) and clinical testing of autonomic function, we measured the rate of oxidant-induced erythrocyte electron transfer to extracellular ferricyanide (RBC vfcy).ResultsSystolic blood pressure (SBP) midline-estimating statistic of rhythm and pulse pressure were higher in T1D patients and correlated positively with diabetes duration and RBC vfcy; autonomic dysfunction was associated with diastolic BP ecphasia and increased AASI. Siblings had higher BMI, lower insulin sensitivity, larger SBP amplitude, and higher AASI than controls. Daytime SBP was positively, independently associated with BMI and RBC vfcy. Among non-diabetic people, there was a significant correlation between AASI and fasting plasma glucose.ConclusionsSiblings of T1D patients exhibited a cluster of sub-clinical metabolic abnormalities associated with consensual perturbations in BP variability. Moreover, our findings support, in a clinical setting, the proposed role of transplasma membrane electron transport systems in vascular pathobiology.

Effects of calcitriol on the immune system: new possibilities in the treatment of glomerulonephritis

1. 1,25‐Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, is widely appreciated to play a central role in calcium and phosphate homeostasis. However, it is becoming increasingly clear that the sterol also play an important role in the regulation of cellular growth, haematopoietic tissues and the immune system, as well as in the modulation of hormone secretion by several endocrine glands.

Exploring Leukocyte Mitochondrial Membrane Potential in Type 1 Diabetes Families

Proper cellular function requires the maintenance of mitochondrial membrane potential (MMP) sustained by the electron transport chain. Mitochondrial dysfunction is believed to play a role in the development of diabetes and diabetic complications possibly because of the active generation of free radicals. Since MMP can be investigated in clinical settings using fluorescent probes and living whole blood cells, mitochondrial membrane alterations have been observed in some chronic disorders. We have used the mitochondrial indicator 5,5′,6,6′-tetra chloro-1,1′,3,3′-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) in conjunction with flow cytometry to measure the MMP in peripheral blood granulocytes from type 1 diabetes (T1D) families. The intracellular ROS levels and the respiratory burst activity were also measured. Leukocyte MMP was elevated in 20 T1D patients and their 20 non-diabetic siblings compared with 25 healthy subjects without family history of T1D. Fasting plasma glucose was the only correlate of MMP. If confirmed by further observations, the functional implications of mitochondrial hyperpolarisation (probably different among different cells) will require extensive investigation.

Severe Hypotension During Hemofiltration in an Uremic Patient with Metabolic Alkalosis

We describe a case of medication induced metabolic alkalosis in a maintenance dialysis patient who developed severe hypotension while undergoing a lactate hemofiltration procedure. A 73‐year‐old man with ESRD due to renovascular disease was used to ingesting up to 30 grams per day of a non‐prescription medication (Effervescent granulare 250 grams, CRASTAN™, Pisa Italy) consisting of sodium bicarbonate, citric acid, glucose and lemon flavor. For technical problem lactate hemofiltration was performed and thirty minutes after dialysis was started a severe symptomatic hypotension occurred (blood pressure 65/35 mmHg). Lactate hemofiltration was suspended and one‐hour later standard bicarbonate dialysis was performed without any clinical problem. The different mechanisms in acidosis buffering occurring in lactate and bicarbonate hemofiltration were discussed.

UNINEPHRECTOMY INCREASES KIDNEY β2-MICROGLOBULIN: CAN IT PLAY A ROLE IN THE PROGRESSION OF KIDNEY DAMAGE?

β2-microglobulin (β2M) is highly accumulated by the kidneys of normal rats. The aim of this study was to verify if uninephrectomy can modify the renal uptake of labeled β2M. For this purpose the radioactivity of plasma and those of the remaining kidney, liver and urine have been measured in uninephrectomized rats (NX) and in controls (C) at different times after the injection as i.v. bolus of 131I-β2M. The experiments were performed in 114 Sprague-Dawley male rats. Fifty seven animals underwent right nephrectomy, the other animals being the C. NX and their C were divided in 3 groups, studied 2, 4 and 6 weeks after nephrectomy, respectively. Part of the animals were sacrificed 12 min after the injection of labeled β2M (peak-time, i.e. time of highest kidney accumulation of 131I-β2M in the normal rat) and part 10 min later. The results demonstrate that: uninephrectomy increases plasma retention of 131I-β2M kidney uptake (total and per gram) is always higher in NX liver uptake (much lower than that of kidney) is not influenced by uninephrectomy urine excretion of radioactivity is minimal in both NX and C.The behavior of β2M is similar to that we previously observed with α1-microglobulin and lysozyme. The higher kidney content of some low mw proteins after uninephrectomy could play a role in the progressive reduction of renal function determined by the reduction of renal mass.