Creatinine Clearance Levels Research Articles

Abstract C228: Renal insufficiency secondary to Erlotinib: Is it real?

Abstract Objective: We conducted a retrospective chart review to assess the extent of renal insufficiency noted in patients receiving Erlotinib for refractory/relapsed non small cell lung cancer at our Institute. Methods: We reviewed the charts of 285 patients at Roswell Park Cancer Institute, who received Erlotinib for varying durations of time during 2004 and 2009. Baseline and post-erlotinib serum creatinine (SCr) and serum creatinine clearance (SCrCl) levels were noted. Cases with worsening of serum creatinine levels during treatment with erlotinib were isolated. Extent of worsening, associated co-morbidities and medications and other factors possibly contributing to renal dysfunction were noted along with improvement in renal status after discontinuation of erlotinib. Results: Of the 175 patients with data available for evaluation, 21(12%) had worsening of their baseline SCr level while on erlotinib. 13(62%) of the patients with renal insufficiency had documented hypertension as co morbidity and were on anti-hypertensives including diuretics and ACE inhibitors. 8(38%) were diagnosed with diabetes mellitus and 6(28%) had coronary artery disease. 6(28%) patients had established chronic renal insufficiency (CRI) at baseline and had worsening after initiation of erlotinib. 1 patient had CRI secondary to prior history of renal cell cancer and was post nephrectomy. 1 patient had evidence of autoimmune disorder with Reynaud's phenomenon and polycystic kidneys. Another patient had history of lupus without evidence of CRI at baseline. 6(28%) concomitantly had diarrhea as a side-effect with erlotinib and in at least 3(14%) patients was the reason for discontinuation of further drug administration. In the remainder of the patients, the cause of discontinuation of erlotinib was progression in 13(52%), severe rash in 2(9%) and 3(14%) were still on the drug at the time of this analysis. Overall 5(21%) of patients with renal insufficiency after initiation of erlotinib did not have any other confounding factors identified. The onset of worsening renal status ranged from 14 days up to 333 days with a mean of 60 days. Baseline SCrCl of patients ranged from 26.2 to 100.5 ml/min with a mean of 49.8 and baseline SCr levels ranged from 0.9 to 2.4 mg/dl. Post therapy SCrCl in patients with worsening ranged from 18.5 to 59.8 with a mean of 35.9 and SCr levels from 1.3 to 3.4. Hence mean decline in SCrCl in these patients was by approximately 14 ml/min and serum creatinine of 0.5mg/dl. Of the 19 patients not currently on erlotinib any more, 12(63%) were noted to have improvement in SCrCl in mean of 33 days. Conclusion: The incidence of isolated renal insufficiency due to erlotinib is rare but does exist. Most often it is confounded with preexisting hypertension and diabetes mellitus leading to baseline chronic renal dysfunction and multiple other medications or concomitant diarrhea as a side effect of erlotinib leading to pre-renal worsening of kidney function. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C228.

Medical Treatment for Tumoral Calcinosis with Eight Years of Follow-up: A Report of Four Cases

Three females and one male aged 13 to 25 years and born to non-consanguineous parents presented with tumoral calcinosis. They presented with swellings on the extensor surfaces of their hips, shoulders, and/or elbows, with or without skin ulcers exuding milk-like fluid and scars from previous excisions. Their joint movements were generally free apart from mild limitation caused by skin ulceration or large masses. The masses were made up of calcified material surrounded by a dense fibrovascular reaction and occasional giant cells. Their serum uric acid, blood urea and creatinine, and creatinine clearance levels were all normal, but they had higher serum phosphorus and lower serum calcium levels. Phosphate-binding antacid was prescribed to lower the intestinal absorption of phosphorus, and their diets were adjusted to lower their phosphorus and calcium intake. After 2 years of treatment, their serum phosphorus levels dropped to, or near, normal levels. The lesions resolved completely in 2 of the patients but less so in the other 2 owing to interruption of their treatment. No recurrence, complications, or side effects were noted.

Anti-glycative effects of oleanolic acid and ursolic acid in kidney of diabetic mice

Inhibitory effects of oleanolic acid (OA) and ursolic acid (UA) on aldose reductase (AR) and glycative products in kidney of diabetic mice were examined. OA or UA at 0.05, 0.1 or 0.2% was supplied for 10 weeks. Diabetic mice with 0.1 or 0.2% OA or UA treatments had significantly higher body weight and lower kidney weight at weeks 5 and 10 ( P < 0.05). OA or UA intake at 0.1 or 0.2% increased their content in the kidney, dose-dependently decreased plasma glucose, HbA1c, renal N ε-(carboxymethyl)lysine, urinary glycated albumin and urinary albumin levels; elevated plasma insulin and renal creatinine clearance levels; as well as decreased renal sorbitol and fructose concentrations ( P < 0.05). OA or UA treatments at 0.1 and 0.2% also significantly diminished renal AR activity and dose-dependently down-regulated renal AR mRNA expression ( P < 0.05). These two compounds at 0.2% significantly reduced renal sorbitol dehydrogenase activity ( P < 0.05). OA, not UA, treatments at 0.1 or 0.2% dose-dependently enhanced renal glyoxalase I (GLI) activity, up-regulated renal GLI mRNA expression and lowered renal methylglyoxal level ( P < 0.05). Based on these marked anti-glycative effects, the supplement of OA or UA might be helpful for the prevention or alleviation of glycation associated renal diseases.

Usefulness of Sirolimus as Rescue Therapy in Heart Transplant Recipients With Renal Failure: Analysis of the Spanish Multicenter Observational Study (RAPACOR)

Background Chronic renal failure is a common complication of heart transplantation. Sirolimus (SRL) is an immunosuppressive drug that, unlike calcineurin inhibitors (CNIs), is not associated with nephrotoxicity. Methods We collected efficacy and safety data from a Spanish registry of heart transplant recipients who were switched from a CNI to SRL due to renal failure. Patients were included if the serum creatinine level before switching was >1.5 mg/dL and/or the estimated creatinine clearance level was below 50 mL/min. Results Ninety-seven patients started SRL due to renal impairment. When SRL was started, CNIs were progressively tapered and in some cases withdrawn. Mean baseline creatinine level was 2.5 mg/dL and mean creatinine clearance level was 39 mL/min. Only 1 episode of acute rejection was observed in a patient receiving SRL plus cyclosporine (CsA) but the eventual allograft function remained stable. Compared with baseline, a significant improvement in renal function was observed at 6 months among patients who stopped CNIs before the third month after SRL was started, although not among those who continued taking CNIs. Upon multivariate analysis, no predictors of response were observed. SRL was withdrawn in 18% of patients due to adverse events. Conclusions Switching to SRL was safe in heart allograft recipients, improving renal function among those previously receiving a CNI. Renal function improves if CNIs are withdrawn soon after starting SRL.

Antiretroviral Therapy Dose Adjustments Based On Calculated Creatinine Clearance

Whereas therapy for HIV is dependent on level of creatinine clearance, most laboratories locally only report an absolute creatinine value. There is likelihood that the patients already on antiretroviral therapy (ART) may have required dosage adjustment at the time of initiation of therapy or sometime during ongoing therapy. This paper explores a group of patients who are already on ART to determine their creatinine clearance and assess the need for ART dose adjustment. To determine the proportion of stable HIV outpatients who have a documented creatinine clearance (CrCI) and the proportion requiring antiretroviral drug dose adjustments depending on their creatinine clearance. Retrospective observational study. One stop HIV medical clinic, Aga Khan University Hospital, Nairobi between January and February 2007. Ninety three patients seen. None of the study subjects had a calculated creatinine clearance in their medical records. Fifteen of the 93 patients (16.1%) had no serum creatinine performed in the twelve months preceding the last clinic visit. Nine of the remaining 78 patients (11.5%) had evidence of renal insufficiency (CrCI <60mls/min) as estimated by the Cockroft Gault method, with six patients (7.7%) requiring dose adjustments to the one or more drugs in their antiretroviral therapy (ART) regime (CrCI <50mls/min). It is imperative to have a CrCI prior to and during follow up of patients with HIV disease on ART to reduce potential drug toxicities and interactions, especially with the increased utilisation of newer and potentially more nephrotoxic antiretrovirals.

Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis

To determine the cytokine balance in patients with lupus nephritis (LN), we analysed kidney-infiltrating T cells. Renal biopsy samples from 15 systemic lupus erythematosus (SLE) patients were used. In accordance with the classification of International Society of Nephrology/Renal Pathology Society, they were categorized into Class III, Class III+V (Class III-predominant group, n = 4), Class IV, Class IV+V (Class IV-predominant group, n = 7) and Class V (n = 4) groups. The single-cell samples of both the glomelular and interstitial infiltrating cells were captured by laser-microdissection. The glomerular and interstitial infiltrating T cells produced interleukin (IL)-2, IL-4, IL-10, IL-13 and IL-17 cytokines in the Class III-predominant, Class IV-predominant and Class V groups. Interferon-gamma was detected only in the glomeruli of the Class III-predominant and Class V group samples. The expression level of IL-17 was correlated closely with clinical parameters such as haematuria, blood urea nitrogen level, SLE Disease Activity Index scores in both glomeruli and interstitium, urine protein level in glomeruli and serum creatinine and creatinine clearance levels in interstitium. This suggests that the glomerular infiltrating T cells might act as T helper type 1 (Th1), Th2 and Th17 cells while the interstitial infiltrating T cells, act as Th2 and Th17 cells in the Class III-predominant and Class V groups. In contrast, both the glomerular and interstitial infiltrating T cells might act as Th2 and Th17 cells in the Class IV-predominant group. The cytokine balances may be dependent upon the classification of renal pathology, and IL-17 might play a critical role in SLE development.

A Retrospective, Multicenter Study of the Tolerance of Induction Chemotherapy With Docetaxel, Cisplatin, and 5-Fluorouracil Followed by Radiotherapy With Concomitant Cetuximab in 46 Cases of Squamous Cell Carcinoma of the Head and Neck

To investigate, in a multicenter study, the tolerance of induction chemotherapy (ICT) and external radiotherapy (ERT) with concomitant cetuximab in the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN). Clinical data from 46 patients with Stage III or IV nonmetastatic SCCHN who received docetaxel, cisplatin, and 5-fluorouracil as ICT, followed by ERT with concomitant cetuximab, were retrospectively analyzed. Clinical safety (weight, allergy, mucositis, and dermatitis) and paraclinical safety (levels of hemoglobin, polynuclear neutrophils, and creatinine clearance) were studied. The primary objective was the proportion of patients who completed the protocol. The percentage of patients completing ICT was 73.9%, ERT 93.5%, and cetuximab 69.6%. Induction chemotherapy was better tolerated than that previously reported. The rates of temporary suspensions of radiation (39.1%, mean duration of 13 days) and hospitalization (26.1%) during ERT with concomitant cetuximab were high. Weight loss during treatment (21.4% of patients lost >10% of their body weight), radiodermatitis, and radiomucositis were the main causes of temporary suspension of treatment, although Grade 4 dermatitis was not experienced. There were no allergic reactions to cetuximab. The completed protocol rate for SCCHN patients receiving ICT and ERT with concomitant cetuximab is high and the toxicity acceptable. Future improvements to protocol will be possible through early action and systematic implementation of nutritional support coupled with antibiotic treatment upon the first signs of radiodermatitis. These data could be useful for prospective studies on the safety and efficacy of this protocol.

Preemptive Living Donor Renal Transplantation: A Single-Center Experience

Renal transplantation is considered preemptive if it occurs before initiation of dialysis. In our experience and in the literature, preemptive transplantation has been shown not only to reduce the costs of renal replacement therapy but also to avoid the long-term adverse effects of dialysis. Preemptive renal transplantation therefore is associated with better survival of both the allograft and the recipient. Our aim was to evaluate the outcomes of preemptive renal transplantation experience at our center. Since 1985, 1385 renal transplantations have been performed at our center. We retrospectively analyzed the 16/1385 recipients (11 male, 5 female) of overall mean age of 28.5 +/- 15 years who underwent preemptive procedures. The causes of end-stage renal failure were focal segmental glomerulosclerosis (n = 5), vesicular ureteral reflux (n = 4), Berger disease (n = 2), polycystic renal disease (n = 2), and others (n = 3). Ten patients were adults, the remaining six, children. The mean creatinine clearance and plasma creatinine levels of the recipients before renal transplantation were 13.5 +/- 8.5 mL/min and 6.7 +/- 2.4 mg/dL, respectively. All renal transplantations were performed from living related donors. The mean preoperative serum creatinine levels, mean glomerular filtration rate, and creatinine clearance rates of the donors were 0.8 +/- 0.1 mg/dL, 61.6 +/- 6.5 mL/min, and 112.5 12 mL/min, respectively. Two episodes of acute cellular rejection and one of humoral rejection occurred during a mean follow-up of 48.7 +/- 14 months (range = 25-76 months). The two patients who experienced graft losses due to humoral rejection or chronic rejection were retransplanted 2 and 48 months thereafter, respectively. At this time all patients are alive with good renal function. In conclusion, our single-center results are promising for preemptive renal transplantation as the optimal, least-expensive mode of treatment for end-stage renal disease.

EGFR and creatinine clearance in relation to metabolic changes in an unselected patient population

Background It is widely assumed that moderate to severe renal failure (creatinine clearance < 60 ml/min; or an MDRD-4 (Modification of Diet in Renal Disease equation) < 60 ml/min/1.73 m 2) is associated with metabolic changes, often needing further assessment and treatment. We investigated whether such abnormalities are already present at earlier stages of kidney disease, as assessed by 24-hour urine sampling and MDRD-4 calculation. Methods A select, retrospective cohort study was conducted. Creatinine clearance was measured by collecting 24-hour urines. The individual eGFRs were calculated with the MDRD-4 formula and patients were then divided by renal function category (< 15, 15–30, 30–45, 45–60, 60–90, > 90 ml/min(/1.73 m 2)). Per clearance category the number of people with anaemia, hypokalaemia, uraemia and hyperphosphataemia was evaluated. Results The median creatinine clearance rate was 67.3 ml/min (quartiles: 42.9–95.8) versus a median MDRD-4-eGFR of 51.6 ml/min/1.73 m 2 (35.8–67.7). Anaemia, hyperkalaemia, hypocalcaemia, and uraemia were found to be present at higher levels of creatinine clearance rate and eGFR than previously reported ( p < 0.0005). This increased prevalence was more pronounced in elderly subjects, particularly with respect to anaemia (OR 2.71 and 2.02 for MDRD-4 and creatinine clearance respectively, p < 0.0005). The same holds for the proportion with uraemia (OR 1.85, p < 0.0005) and hypocalcaemia (OR 1.97, p = 0.011) for MDRD-4. Conclusion Metabolic changes in an in- and outpatient hospital population are present at earlier stages than was stated in recent guidelines, especially when creatinine clearance levels are used as indicators. This might have implications for testing and treatment of patients with suspected kidney disease and/or loss of renal function.

Methyltetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia as a novel risk factor for diabetic nephropathy

Hyperhomocysteinemia is a well-defined risk factor for endothelial dysfunction and atherosclerosis. A point mutation (677 C-T) of MTHFR gene results in a significant increase at plasma homocysteine levels. In this study we aimed to evaluate the effects of MTHFR gene mutation and consequent hyperhomocysteinemia on the development of diabetic microvascular complications in comparison with the other defined risk factors. Diabetic patients without a history of macrovascular complication or overt nephropathy enrolled into the study. The presence of MTHFR 677 C-T point mutation was evaluated by Real-Time PCR technique by using a LightCycler. MTHFR heterozygous mutation was present in 24 patients over 52. Patients with diabetes were divided into two groups according to the presence of MTHFR gene mutation. Both groups were well matched regarding age and diabetes duration. Metabolic parameters, plasma homocysteine, microalbuminuria, folic acid, and vitamin B12 levels were also studied. Presence of neuropathy and retinopathy were evaluated by specific tests. Duration of diabetes, BMI, systolic and diastolic blood pressure, plasma CRP, HbA1c, and lipid levels were not different between the two groups. Plasma homocysteine (12.89 +/- 1.74 and 8.98 +/- 1.91 micromol/l; P < 0.0001) and microalbuminuria levels (73.40 +/- 98.15 and 29.53 +/- 5.08 mg/day; P = 0.021) were significantly higher in the group with MTHFR gene mutation while creatinine clearance levels (101.1 +/- 42.6 and 136.21 +/- 51.50 ml/min; P = 0.008) were significantly lower. Sixteen over 22 (73%) of the patients with diabetic nephropathy had MTHFR gene mutation, while this was only 27% (8 over 30) in normoalbuminuric patients (P = 0.017). There was a significant correlation of plasma homocysteine level with microalbuminuria (r = 0.54; P = 0.031) in the patients with diabetic nephropathy who had C677T polymorphism. We did not find any specific association of MTHFR gene mutation and hyperhomocysteinemia with retinopathy or neuropathy.

Pegylated liposomal doxorubicin in ovarian cancer patients with renal compromise

e16569 Background: Ovarian cancer patients with renal compromise poses problem in choosing chemotherapy for them. Pegylated liposomal doxorubicin (PLD) can be used in such cases. However there is not much data regarding the efficacy and toxicity of PLD. We used PLD in a few renal compromised ovarian and peritoneal cancer patients. Methods: The clinical records of patients with recurrent ovarian and peritoneal cancer patients with high creatinine or low creatinine clearance level who were given PLD at the Netaji Subhas Chandra Bose Cancer Research institute) (NCRI) from July 2005 to July 2008 was reviewed retrospectively to study efficacy and toxicity. Results: Twenty-one patients were identified, which included 16 with epithelial ovarian cancer, 5 with peritoneal cancer. Renal compromise was diagnosed and graded according to creatinine clearance test (CCT) as severe when less than 28 mL/min/1.5 m2, moderate when CCT is 28–55 mL/min/1.5 m2, and mild when CCT is 55–84 mL/min/1.5 m2. Normal value was taken as 85 mL/min/1.5 m2. Patients had distribution as mild: 4 patients, moderate:7 patients, and severe:10 patients. The initial doses of PLD were classified into regular initial dose (40 mg/m2/4 weeks) and lower initial dose (20–30 mg/m2/4 weeks). The median cycle was 5 (range 1–12). We used lower dose for moderate and severe renal disease. The incidence of palmar-plantar erythrodysesthesia 5/21 (23.8%), stomatitis 6/21(28.5%), and hematologic toxicity 3/21(14.2 %). Dose reduction due to toxicities occurred in 19.04 % (4/21) patients. Amongst 21 cases no patient had deterioration of renal function while and after the treatment with PLD. However we had primary treatment with PLD in four cases (2 moderate and 2 severe) while others had platinum based initial treatment. We did not have any complete responder though we had 6 (28.5%) partial responders, 8 (38.1%) stable diseases and 7(33.3%) progressive diseases. Conclusions: Patients with renal compromise who received PLD therapy at an initial dose lower than 40 mg/m2/4 weeks tolerated their treatment well. They required subsequent dose reduction due to mucocutaneous and cardiological toxicities in 19% cases. Treatment response in this population with ovarian and peritoneal cancer was similar to that of patients with normal renal function. No significant financial relationships to disclose.

Chronic treatment with recombinant human erythropoietin exerts renoprotective effects beyond hematopoiesis in streptozotocin-induced diabetic rat

Recombinant human erythropoietin (rHuEPO), which has been used clinically for the management of renal anemia, is reported to exert pleiotropic beneficial properties against acute ischemic/reperfusion injury in various tissues. To investigate the hypothesis that chronic treatment with rHuEPO might ameliorate diabetic nephropathy beyond hematopoiesis, rHuEPO (150 U/kg, subcutaneously) was administered three times per week to the streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, intravenously) significantly increased urinary protein excretion and collagen deposition in glomerular and tubulointerstitial areas in the kidney, which were attenuated by rHuEPO. rHuEPO normalized the levels of creatinine clearance, serum creatinine, and blood urea nitrogen of diabetic rats. RT-PCR analysis revealed that the expressions of mRNA for transforming growth factor-β, osteopontin and adhesion molecules were enhanced in the diabetic rat kidney and that the overexpression of these molecules was suppressed by rHuEPO. rHuEPO exerted antioxidant properties by inhibiting renal activation and overexpression of NADPH oxidase. We found the activation of the Akt signaling pathway by the increased expression of phosphorylated Akt and GSK-3β and a reduction of TUNEL-positive apoptotic cell death in renal tissue from rHuEPO-treated diabetic group. We also demonstrated that rHuEPO restored the endothelial nitric oxide synthase (eNOS) content in the diabetic rat kidney. On the other hand, treatment with rHuEPO did not affect blood glucose level, blood pressure, or hematocrit in diabetic rats. These results suggest that chronic treatment with rHuEPO attenuated renal injury beyond hematopoiesis and regulated apoptosis and eNOS expression, which might be due to the activation of Akt pathway.

Influence of Renal Function and Diet on Acid-Base Status in Chronic Kidney Disease Patients

We investigated the influence of potential renal acid load (PRAL) and renal function on the degree of metabolic acidosis in patients with chronic kidney disease (CKD). This was a cross-sectional study. This study was conducted at the Nephrology Outpatient Division of the Hospital Universitário Clementino Fraga Filho (Rio de Janeiro, Brazil). Thirty CKD patients undergoing conservative treatment were divided according to plasma HCO(3)(-) values into acidotic (HCO(3)(-) <or=22 mM, n = 15) and nonacidotic (HCO(3)(-) >22 mM, n = 15). Biochemical, nutritional, and anthropometric parameters and PRAL were measured. The mean of plasma HCO(3)(-) values was 17.7 +/- 2.8 mM in the acidotic group, and 25.1 +/- 2.2 mM in the nonacidotic group. There was no significant difference in mean PRAL values between the acidotic (9.8 +/- 6.4 mEq/day) and nonacidotic (12.7 +/- 10.0 mEq/day) groups, but there was a significant correlation between plasma HCO(3)(-) and creatinine clearance (r = 0.78, P < .0001). Based on the receiver operating characteristic curve, the level of creatinine clearance to begin detection of acidosis was 31.8 mL/min, with a sensitivity and specificity of 86.7%. The acid-base status of this group of CKD patients undergoing conservative treatment was mainly determined by degree of renal insufficiency rather than diet.

Alterations in l-arginine and inflammatory markers in type 2 diabetic patients with and without microalbuminuria

Low-grade inflammation is closely involved in the pathogenesis of type 2 diabetes and associated micro- and macrovascular complications. The nitric oxide (NO) precursor L-arginine, is relevant to diverse pathological conditions including type 2 diabetes and its complications. High sensitive-CRP (hs-CRP), neopterin and arginine levels were measured in 46 normoalbuminuric, 45 microalbuminuric type 2 diabetics and in 32 healthy controls in order to assess the relationship between markers of inflammation and L: -arginine. Hs-CRP concentrations were higher in microalbuminuric diabetic patients compared to normoalbuminuric patients and controls. Diabetics had higher serum and urine neopterin levels than controls. Urine neopterin and L-arginine levels differed significantly among diabetic patients with and without microalbuminuria. There were significant positive correlations between hs-CRP and BMI in healthy controls and diabetics with and without microalbuminuria. In microalbuminuric diabetics, hs-CRP correlated with microalbuminuria (MAU). Significant predictors for the development of microalbuminuria were higher postprandial glucose levels, lower creatinine clearance and lower serum L-arginine levels. Assessment of early markers of inflammation and endothelial function, such as neopterin and NO precursor L-arginine, may help to predict incipient nephropathy more accurately in type 2 diabetic patients.

Pharmacokinetics of Mycophenolic Acid in Patients with Lupus Nephritis

To evaluate and describe the pharmacokinetics of mycophenolic acid and its metabolite, mycophenolic acid glucuronide (MPAG), in patients with lupus nephritis, and to determine the effects of clinical parameters (urinary protein excretion as measured by the urinary protein:creatinine ratio, serum albumin level, and creatinine clearance) and demographic variables (age, race, sex) on the pharmacokinetics of total and unbound mycophenolic acid and MPAG. Pharmacokinetic analysis. University-affiliated general clinical research center. Eighteen patients with biopsy-confirmed lupus nephritis who were receiving maintenance therapy with mycophenolic acid for at least 2 weeks. Plasma and urine samples were collected for 24 hours and were assayed by high-performance liquid chromatography with ultraviolet detection. Time to maximum concentration was variable (0.5-8 hrs). Mean +/- SD fraction of unbound mycophenolic acid was 2.6 +/- 1.9%, and oral clearance (Cl/F) was about 2-fold higher (343 +/- 200 ml/min) than previously reported. Multiple regression analysis showed that Cl/F of mycophenolic acid was predicted by creatinine clearance and serum albumin level: ln Cl/F = 5.358 + 0.0092 (creatinine clearance) - 0.078 (ranked albumin), R(2)=51.1%, p=0.0195. Patients with urinary protein excretion of 1 g/day or higher had lower minimum (trough) concentrations and area under the concentration-time curve (AUC(0-12)) profiles and higher Cl/F values compared with patients with urinary protein excretion of less than 1 g/day. Patients with serum albumin levels less than 4 g/dl had higher mycophenolic acid unbound clearance and MPAG renal clearance from 0-12 hours versus those with serum albumin levels of 4 g/dl or greater. Recycling AUC (AUC(6-12)), as well as sex and age (both equally), predicted renal clearance of MPAG. Both creatinine clearance and serum albumin level were identified as primary contributors to mycophenolic acid exposure and should be considered when evaluating dosages. The results of future studies should clarify the interactions of other variables on drug exposure and treatment responses. Clinicians need to be mindful of clinical changes that occur throughout the course of lupus nephritis in order to maintain efficacy and reduce toxicity from mycophenolic acid therapy.

Chronic systemic inflammation accompanies impaired ventricular diastolic function, detected by Doppler imaging, in patients with newly diagnosed systolic heart failure (Hellenic Heart Failure Study)

We sought to evaluate the relationship between plasma cytokine levels (sCD14, tumor necrosis factor [TNF]-alpha, and interleukin [IL]-6) and tissue Doppler derived indices of left ventricular systolic and diastolic function in patients with newly diagnosed heart failure. We enrolled 101 consecutive patients (mean age 65+/-13 years) with newly diagnosed heart failure who were hospitalized in our institute. Echocardiographic assessment was performed in all patients during the third day of their initial hospitalization. The pulsed tissue Doppler imaging (TDI) of the systolic and diastolic function of mitral annulus was characterized by the systolic wave Smv, and the diastolic waves: Emv and Amv. Left atrial kinetic energy (LAKE), an index of left atrial function, was calculated using the equation 1/2 x LASV x 1.06 x Amv(2); where LASV is left atrial systolic volume. Furthermore the ratio E/Emv and the flow propagation velocity were also calculated; where E is the rapid mitral filling wave, detected by pulse Doppler. Soluble plasma levels of CD14, TNF-alpha, and IL-6 were measured in all patients during their third day of hospitalization. Linear regression analysis, after adjustment for sex, age, left ventricular ejection function, body mass index, arterial hypertension, smoking, physical activity, creatinine clearance, diabetes mellitus, and blood lipid levels, revealed that IL-6 levels were inversely associated with LAKE (b= - 5422.4+/-2031.5, P=0.03), Sm (b= -0.375+/-0.1, P=0.03), and flow propagation (b= -5.404+/-0.621, P=0.001). CD14 levels were inversely associated with flow propagation (b = -17.655+/-2.6, P=0.001), and positively associated with E/Emv ratio (b=2.58+/-3.6, P=0.002) and A/Amv ratio (b=0.629+/-0.6, P=0.04). TNF-alpha was inversely associated with Smv (b-1.189+/-0.3, P=0.005). This study reveals that increased plasma levels of CD14, IL-6 and TNF-alpha are associated with impaired left atrial function and more advanced left ventricular diastolic and systolic dysfunction, in patients with newly diagnosed heart failure.

Elastase, myeloperoxidase, nitric oxide metabolites and oxidative status in subjects with clinical stable chronic renal failure on conservative treatment

We evaluated, in a group of 41 CRF undialyzed subjects (29 men and 12 women, mean age 64.1 +/- 11.3 years), some parameters that reflect leukocyte activation (elastase, myeloperoxidase - MPO), plasma NO metabolites (NO(x)) and the oxidative status (lipid peroxidation expressed as thiobarbituric acid-reactive substances (TBARS) and total antioxidant status (TAS). Elastase was determined, on plasma separated from fasting venous blood, as elastase/alpha1-proteinase inhibitor complex. MPO was evaluated employing the Myeloperoxidase ELISA kit. The NO production was evaluated by a micromethod. The oxidation of polyunsaturated fatty acids was evaluated in plasma by detection of the thiobarbituric acid-reactive substances (TBARS). Total antioxidant status was measured by spectrophotometry. We found a significant increase of elastase, TBARS and NO(x), without any significant variation of MPO and TAS. In this group of CRF subjects, no statistical correlation was found between these examined parameters, creatinine level, creatinine clearance, leukocyte count and hemoglobin level. These findings need to be underlined if we consider that chronic renal failure is an inflammatory condition and this research furtherly supports literature data regarding the role of activated leukocytes in the development of the vascular complications. These observations explain why the examination of leukocyte count and function could become a tool to verify the clinical outcome in these patients.

Clinical aspects of acute intermittent porphyria in northern Sweden: A population-based study

The objective of this study was to update the clinical issues of acute intermittent porphyria (AIP), as they have not been in focus for years, and to be aware of potentially associated disorders and social consequences. A total of 356 gene carriers of AIP from northern Sweden participated in this retrospective population-based study. Eight mutations were found with a predominance of W198X (89%). Clinical manifestations of AIP (manifest AIP) were identified in 42%, 65% were women. Women were more severely stricken by AIP attacks concerning number and duration, hospital admission and early onset. Men reporting most attacks were > 40 years of age. In addition to traditional symptoms during attacks, fatigue was commonly described. Chronic AIP symptoms and disability pension due to AIP were reported in about 20% of subjects. Precipitating factors were reported with evident sex differences. Half of the gene carriers who were on medications used drugs considered not safe (in 1999), mainly antihypertensive drugs. Smoking was associated with high AIP attack frequency. Elevated levels of ALT, bile acids, creatinine, U-ALA and U-PBG and decreased levels of creatinine clearance were associated with manifest AIP. The same was true for hypertension and myalgia in the legs. Hepatoma was strikingly overrepresented. The high prevalence of manifest AIP in this study could be explained by a mutation-dependent penetrance. Our results emphasize the importance of early diagnosis, counselling and treatment of attacks, screening and treatment of associated disorders.

Lead exposure study among workers in lead acid battery repair units of transport service enterprises, Addis Ababa, Ethiopia: a cross-sectional study.

BackgroundLead exposure is common in automobile battery manufacture and repair, radiator repair, secondary smelters and welding units. Urinary Aminolevulinic acid has validity as a surrogate measure of blood lead level among workers occupationally exposed to lead. This study had therefore assessed the magnitude of lead exposure in battery repair workers of three transport service enterprises.MethodsTo this effect, a cross-sectional study was carried out on lead exposure among storage battery repair workers between November 2004 and May 2005 from Anbasa, Comet and Walia transport service enterprises, Addis Ababa, Ethiopia. Subjective information from the workers was obtained by making use of structured questionnaire. Other information was obtained from walkthrough evaluation of the repair units. Aminolevulinic acid levels in urine were used as an index of the exposure. This was coupled to measurements of other relevant parameters in blood and urine collected from adult subjects working in the repair units as well as age matched control subjects that were not occupationally exposed to lead. Aminolevulinic acid was determined by spectrophotometry, while creatinine clearance, serum creatinine, urea and uric acid levels were determined using AMS Autolab analyzer.ResultsUrinary aminolevulinic acid levels were found to be significantly higher in exposed group (16 μg/ml ± 2.0) compared to the non-exposed ones (7 μg/ml ± 1.0) (p < 0.001). Alcohol taking exposed subjects exhibited a significant increase in urinary aminolevulinic acid levels than non-alcohol taking ones (p < 0.05). Moreover, urinary aminolevulinic acid levels of exposed subjects increased with age (p < 0.001) as well as duration of employment (p < 0.001). Whereas serum uric acid levels of exposed subjects was significantly higher than non-exposed ones (p < 0.05), no statistically significant difference had been found in renal indices and other measured parameters between exposed and non-exposed subjects. From the questionnaire responses and walkthrough observations, it was also known that all the repair units did not implement effective preventive and control measures for workplace lead exposure.ConclusionTaken together, these findings indicated that workers in lead acid battery repair units of the transport service enterprises are not protected from possibly high lead exposure. Thus, strict enforcement of appropriate and cost effective preventive and control measures is required by all the enterprises.

Agreement between methods

Before new tests are implemented, it is important to compare their results with those of other measurement methods that are already in use. In the determination of this so-called agreement between methods, one may choose between several statistical approaches. The correlation coefficient is a popular approach to determine the agreement between measurement methods. It is easy to calculate, but has important limitations: it does not provide any information on the type of association and it is extremely sensitive to the range of values within the study. Finally, a correlation coefficient does not reveal whether any difference between two measurements is systematic or random. Therefore, it is highly preferable to use Bland-Altman plots instead, as these reveal both systematic and random errors. Bland-Altman plots are also preferable in case of repeated measurements and calibrations.