Serum Uromodulin, a Potential Biomarker of Tubulointerstitial Damage, Correlates Well with Measured GFR and ERPF in Patients with Obstructive Nephropathy.

Background and Objectives: In chronic kidney obstruction, the severity of tubulointerstitial damage correlates best with the loss of kidney function and the risk for progression to end-stage kidney disease. The present study aimed to investigate the potential clinical significance of serum uromodulin (sUmod) as a marker of early kidney disfunction in patient with obstructive nephropathy (ON). Materials and Methods: Serum Umod level was measured by sensitive ELISA method in 57 adult patients with obstructive nephropathy and 25 healthy subjects in control group. Kidney function was precisely evaluated via measured glomerular filtration rate (mGFR) (renal clearance of 99 mTc-diethylenetriamine penta-acetic acid), effective renal plasma flow (ERPF) and Cystatin C level. Recruited patients were divided into subgroups based on the mGFR: group I­GFR ≤ 60 mL/min/1.73 m2 (N = 31), group II­GFR > 60 mL/min/1.73 m2 (N = 26). Results: A significantly lower level of serum uromodulin was measured in patients with ON (50.2 ± 26.3 ng/mL) compared to the control group (78.3 ± 24.5 ng/mL) (p < 0.001). The mean level of serum Umod was significantly different between group I (30.5 ng/mL ± 11.1) and group II (73.6 ng/mL ± 18.6) (p < 0.001), but not between group II (73.6 ng/mL ± 18.6) and control group (78.3 ± 24.5 ng/mL). There was a positive correlation between sUmod and mGFR (R = 0.757, p < 0.001) and ERPF (R = 0.572 p < 0.001), with lower sUmod levels in patients with impaired renal function. An inverse relationship was detected between sUmod and filtration markers­cystatin C (R = −0.625, p < 0.001), creatinine, urea and uric acid. ROC analysis of sUmod to differentiate between ON patients with GFR below 60 mL/min/1.73 m2 and above 60 mL/min/1.73 m2 resulted in AUC of 0.98 (p < 0.001, 95% CI 0.922 vs. 0.998) at a cut-off value of 46 ng/mL (specificity 96.8%, sensitivity 92.2%). Conclusions: The significant correlation of sUmod with kidney function parameters may imply potential clinical significance as a noninvasive biomarker of early kidney disfunction in obstructive nephropathy.

The Importance of Correlation between Aldosterone and Parathyroid Hormone in Patients with Primary Hyperparathyroidism.

In primary hyperparathyroidism, an increased risk of developing the cardiovascular disease may exist due to increased activity of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the relationship between parathyroid hormone and aldosterone in patients with primary hyperparathyroidism. The study included 48 patients with primary hyperparathyroidism and 30 healthy subjects who matched age and gender to the study group. This study was conducted at the Center for Laboratory medicine, Clinical center of Vojvodina, Novi Sad, Serbia. In addition to clinical data and laboratory determination of the concentration of total and ionized calcium, phosphorus, measurements of parathyroid hormone, vitamin D, direct renin, and aldosterone were performed by the method of chemiluminescent technology. Compared to the controls, the study group had statistically significantly higher values of aldosterone (p=0.028), total calcium (p=0.01), ionized calcium (p=0.003) and parathyroid hormone (P ≤ 0.001) Serum aldosterone and parathyroid hormone levels were correlated positively in patients with primary hyperparathyroidism (r=0.509, p < 0.05). A statistically significant positive correlation between renin and parathyroid hormone (r=0.688, p < 0.05) and renin and calcium (r=0.673, p < 0.05) was determined in hyperparathyroid patients. In multivariate regression analysis, the strongest predictive variable of aldosterone secretion was parathyroid hormone (p=0.011). An independent relationship between parathyroid hormone and aldosterone in patients with primary hyperparathyroidism and the correlation between renin and parathyroid hormone as well as with calcium indicate not only the direct but also the indirect associations between parathyroid hormone and aldosterone in primary hyperparathyroidism. These findings may represent another possible model of renin-angiotensin-aldosterone-induced organ damage.

Interobserver reproducibility of mercaptoacetyltriglicine renography in children and adults with suspected obstruction: parameters of drainage and function calculated by International Atomic Energy Agency software.

OBJECTIVE: The aim of this study was to estimate interobserver reproducibility of Tc-99m mercaptoacetyltriglycine renography in children and adults by assessing the parameters of the International Atomic Energy Agency (IAEA) software for the analysis of dynamic renal studies. METHODS: The renograms of 65 children and 65 adults covered a wide age range, different quality of drainage, overall function and differential renal function (DRF). Three observers were processing parameters of the IAEA software. Normalized residual activity at 20 min (NORA20), NORA on the postmicturition acquisition (NORApm), PM to maximum renal count ratio (PM/max), output efficiency at 20 min (OE20), OE 20 min after diuretic stimulation (OEF + 20), whole kidney mean transit time (MTT) and DRF by integral and Rutland-Patlak were calculated by observers. RESULTS: The overall agreement between three observers was almost perfect [the average intraclass correlation coefficient (ICC) above 0.99] in children and adults, with no significant difference between the parameters of renal drainage, transit and DRF. ICCs for all parameters were higher than 0.980 in children under 12 months, even slightly greater for PM/max and OEF+20. In children with poor/incomplete drainage and DRF below 40%, ICCs were above 0.98. In the subgroup of adults with impaired overall tubular extraction rate, level of reproducibility was almost perfect. Slightly lower but still insignificant values of ICC were presented in adults with poor/incomplete drainage. CONCLUSION: Our results indicate an excellent interobserver reproducibility for all quantitative parameters of IAEA software in both pediatric and adult patients.

Fractional excretion of magnesium and kidney function parameters in nondiabetic chronic kidney disease.

AIM: Elevated fractional excretion of magnesium (FEMg) is a noninvasive biomarker of kidney damage, but its association with kidney functional parameters in nondiabetic chronic kidney disease (CKD) patients has not been sufficiently explored thus far. METHODS: We enrolled 111 adult patients with nondiabetic CKD and 30 controls. To precisely investigate kidney function, the following parameters were assessed measured glomerular filtration rate (mGFR), effective renal plasma flow (ERPF), Cystatin C, albuminuria, and fractional excretion of magnesium (FEMg). All the CKD patients were divided into two groups according to the values of mGFR (mL/min/1.73m2): the first group consisted of those with GFR≥ 60 mL/min/1.73m2, whereas the second group included those with GFR< 60 mL/min/1.73m2. RESULTS: FEMg (%) was significantly higher in the group of nondiabetic patients with CKD compared to the healthy subjects [6.3 vs. 5.3 %, P=0.013]. There was also significant difference in the value of FEMg between the first and second groups of CKD patients. Increased FEMg was significantly correlated with all the investigated kidney function parameters, mGFR, ERPF, Cystatin C and albuminuria (r=-0.62; r=-0.60; r=0.77; r=0.39; p<0.01 for all). In multiple regression analyses based on observed parameters of kidney function, only cystatin C was independently and significantly associated with FEMg (multiple correlation coefficients: 0.738, p < 0.001)). Nondiabetic CKD patients with GFR< 60 mL/min/1.73m2 have increased FEMg above 6.1% with 78.7 % specificity and 83.7% sensitivity. CONCLUSION: Highly significant association between kidney functional parameters and FEMg may indicate significance of this parameter in clinical practice.

Cystatin C, vascular biomarkers and measured glomerular filtration rate in patients with unresponsive hypertensive phenotype: a pilot study.

BACKGROUND: Biomarkers are commonly used to estimate the presence of subclinical cardiovascular disease (CVD) in patients with essential arterial hypertension (HT). In addition to known association between cystatin C and glomerular filtration rate (GFR), elucidating the association between cystatin C and vascular biomarkers (intima-media thickness of common carotid arteries (CCIMT), carotid plaque and renal artery resistance index (RRI)) in patients with unresponsive hypertensive phenotype could be of significant clinical interest. METHODS: Participants (n = 200, median age 58 (52-64) years, 49% female) under treatment with antihypertensive drugs were stratified into two subgroups based on their blood pressure level as having responsive hypertension (RHT - compliant and responsive to treatment, n = 100), or nonresponsive (URHT - compliant but nonresponsive to treatment, n = 100). GFR was measured by isotopic (slope-intercept) method (99m Tc diethylene triamine penta-acetic acid - mGFR). RESULTS: The URHT group had significantly higher median cystatin C serum concentration (p = 0.02) and CCIMT (p = 0.00) compared to the RHT group, with no significant difference in RRI (p = 0.51) and mGFR among subgroups [69.9 ± 28.2 vs 76.74 ± 23.61 ml/min/1.73m2, p = 0.27]. In the URHT group, cystatin C was found to be associated with CCIMT (p = 0.02), hsCRP (p = 0.01) and duration of HT (p = 0.02), independently of mGFR and age. Independent predictors of URHT phenotype were CCIMT (p= 0.02) and hsCRP (p= 0.04). CONCLUSION: In addition to GFR, cystatin C serum concentration is positively and independently associated with CCIMT in patient with URHT phenotype and subclinical CVD. Prospective larger studies should further investigate the clinical importance of this relationship.

PLASMA ENDOTHELIN-1 LEVELS AND ALBUMINURIA IN PATIENTS WITH TYPE 2 DIABETES MELLITUS.

INTRODUCTION: Microalbuminuria is a very important independent risk factor for the progression of renal diseases as well as diseases of the cardiovascular system. Pathophysiological mechanisms that lead to the development ofmicroalbuminuria in patients with diabetes are complex and they are a result of numerous factors. In the past decade, endothelin-1, the most potent vasoconstrictor peptide, was identified as animportant factor that significantly contributes to the functional and structural renal changes. The objective of this study was to investigate the relationship between plasma concentration of endothelin-1 and urinary albumin excretion in patients with type 2 diabetes mnellitus. MATERIAL AND METHODS: There were 76 patients with type 2 diabetes who were divided into those having normoalbuminuria (n-33), microalbuminuria (n=29) and macroalbuinuria (n=14), and 30 healthy controls. Plasma levels of endothelin-1 were measured by enzyme-linked immunosorbent assay. RESULTS: There were significant differences in plasma concentration of endothelin-1 among groups (P<0.01). The correlation between endothelin-1. albuminuria. proteinuria and glomercular filtration rate was significant. In multiple regression analyses the plasma concentration of endothelin-l was independently and significantly associated with albuminuria (ß=0.01, p=0.009), proteinuria =.02, p<0.001) and glon.erular filtration rate (P3=0ßl. pO-.P=)6).0Conclu- sion. Higher plasma concentrations of endothelin-1 are independently associated with the levels of urinary, excretion of albumin Whicw May morroborate tlse hpothesis of apotenstial role of this peptide inl th de- vepment of microalbUminuriauin diabetic necphrpathy.

RELIABILITY OF POSITRON EMISSION TOMOGRAPHY-COMPUTED TOMOGRAPHY IN EVALUATION OF TESTICULAR CARCINOMA PATIENTS.

INTRODUCTION: The study was aimed at assessing the reliability of 18F-fluorodeoxyglucose positron emission tomography-computed tomography scan in evaluation of testicular carcinoma patients. MATERIAL AND METHODS: The study sample consisted of 26 scans performed in 23 patients with testicular carcinoma. According to the pathohistological finding, 14 patients had seminomas, 7 had nonseminomas and 2 patients had a mixed histological type. In 17 patients, the initial treatment was orchiectomy+chemotherapy, 2 patients had orchiectomy+chemotherapy+retroperitoneal lymph node dissection, 3 patients had orchiectomy only and one patient was treated with chemotherapy only. Abnormal computed tomography was the main cause for the oncologist to refer the patient to positron emission tomography-computed tomography scan (in 19 scans), magnetic resonance imaging abnormalities in 1 scan, high level oftumor markers in 3 and 3 scans were perforned for follow-up. Positron emission tomography-computed tomography imaging results were compared with histological results, other imaging modalities or the clinical follow-up of the patients. RESULTS: Positron emission tomography-computed tomography scans were positive in 6 and negative in 20 patients. In two patients, positron emission tomography-computed tomography was false positive. There were 20 negative positron emission omography-computed tomography scans perforned in 18 patients, one patient was lost for data analysis. Clinically stable disease was confirmed in 18 follow-up scans performed in 16 patients. The values of sensitivty, specificity, accuracy, and positive- and negative predictive value were 60%, 95%, 75%, 88% and 90.5%, respectively. CONCLUSION: A hgh negative predictive value obtained in our study (90.5%) suggests that there is a small possibility for a patient to have future relapse after normal positron emission tomography-computed tomography study. However, since the sensitivity and positive predictive value of the study ire rather low, there are limitations of positive positron emission tomography-computed tomography scan to suggest persistent disease.

Plasma endothelin-1 level, measured glomerular filtration rate and effective renal plasma flow in diabetic nephropathy.

BACKGROUND: Endothelin-1 (ET-1) is potent vasoconstrictor peptide which is able to contribute to the functional and structural renal changes. The aim of this study was to investigate the relationship between plasma concentration of ET-1 and indices of renal function in patients with diabetic nephropathy. METHODS: We measured plasma ET-1 levels in 99 patients with type 2 diabetes, divided into two groups according to the values of their glomerular filtration rate (GFR): group I (GFR ≥ 60 mL/min/1.73 m(2); n = 50), group II (GFR ≥ 60 mL/min/1.73 m(2), n = 49), and the control group (n = 30) with clinically healthy subjects who were matched by age and sex. GFR and effective renal plasma flow (ERPF) were measured by the radioisotopic clearance. Other renal function parameters, such as serum concentrations of cystatin C, urea, creatinine, uric acid, 24-h albuminuria and proteinuria were additionally measured. RESULTS: There were significant differences in plasma concentration of ET-1 among groups I, II and the control group (1.45 vs. 2.40 vs. 0.80 pg/mL, p < 0.001). The correlation between ET-1 and mGFR (r = -0.52, p < 0.001), ERPF (r = -0.42, p < 0.001), albuminuria and proteinuria (r = 0.36, p < 0.001; r = 0.48, p < 0.001) and cystatin C (r = 0.42, p < 0.001) was significant. In multiple regression analyses, only plasma concentration of ET-1 (p < 0.001) and duration of hypertension (p < 0.05) were independently and significantly associated with mGFR. CONCLUSION: A higher plasma concentration of ET-1 is independently associated with a decreased value of GFR in patients with diabetic nephropathy.

The effect of angiotensin converting enzyme inhibition on effective renal plasma flow in patients with diffuse renal parenchymal diseases and hypertension.

INTRODUCTION: Angiotensin converting enzyme inhibitors are commonly used to treat various hypertensive conditions and in addition to lowering blood pressure these drugs affect the local renal hemodynamic status, thereby influencing the glomerular filtration rate and effective renal plasma flow. The study was aimed at determining whether angiotensin converting enzyme inhibitors can produce significant changes in effective renal plasma flow in patients with parenchymal renal disease and to assess whether the changes depend on the pre-existing functional status of the kidney. MATERIAL AND METHODS: The study included 80 subjects, 40 subjects with hypertension associated with diffuse renal parenchymal disease and 40 subjects with essential hypertension. All study subjects underwent the baseline effective renal plasma flow measurement and the repeated effective renal plasma flow measurement after administration of captopril. Effective renal plasma flow was determined by 131 I-hippuran clearance in blood samples taken at 20 and 30 minutes. RESULTS: Angiotensin converting enzyme inhibitors caused significant effective renal plasma flow changes in 55% of subjects with diffuse renal parenchymal disease and in 75% of subjects with essential hypertension. The effective renal plasma flow changes were more significant in subjects with preserved renal function (normal baseline effective renal plasma flow) compared to subjects with reduced baseline effective renal plasma flow. CONCLUSION: The application of angiotensin converting enzyme inhibitors in patients with diffuse renal parenchymal disease and in individuals with essential hypertension may result in significant hemodynamic changes in the kidney, accompanied by changes in effective renal plasma flow. The extent of the changes caused by angiotensin converting enzyme inhibitors depends on the preexisting functional status of the kidney.

Lung tumors: early and delayed ratio of 99mTc-methoxy-2-isobutylisonitrile accumulation.

BACKGROUND/AIM: Currently used radiopharmaceuticals are nonspecific and most of them are accumulated by benign tumors as well as inflammatory lesions, abscess or granulomatous lesions. Some factors such as the choice of radiopharmaceutical applied, histopathologic type of tumor, its size, location or previous tumor treatment could influence tumor imaging sensitivity. The aim of this study was to investigate accumulation of 99mTc-methoxy-2-isobutylisonitrile (99mTc-MIBI) by counting early/delayed uptake and release of this radiopharmaceutical inside lung tumors and evaluating possible factors which could be involved in its accumulation. METHODS: Two-phase 99mTc-methoxy-2-isobutylisonitrile single photon emission computed tomography scan (early and delayed scan) was performed in 60 patients with lung tumors (the group 1 - 30 benign, and the group 2 - 30 malignant tumors). We calculated the uptake ratio on early (early ratio - ER), delayed images (delayed ratio - DR) and retention index (RI). Individual influence of etiology, diameter, localization, and histological type on uptake/release values was evaluated with regression analysis. RESULTS: The values of ER and DR were significantly different in both groups (p < 0.01), showing lower values in benign vs malignant lung tumors (ER 1.36 ± 0.094 and DR 1.25 ± 0.089 vs ER = 1.93 ± 0.106 and DR = 1.7 ± 0.095 respectively). Tumor size showed a significant influence on the change of ER and DR values (p < 0.01), with greater uptake in tumors > 3 cm. RI values showed no significance between the two groups (P > 0.05). CONCLUSION: The uptake ratio of 99mTc-methoxy-2-isobutylisonitrile could be a useful index in differentiating lung tumors, while RI has no influence on this. Among the evaluated factors, ER and DR values are significantly influenced only by the diameter of lung tumor, while localization or different histological types between the groups has no influence on this.

[Polyostotic Paget's disease of bone: diagnostic dilemma in detection of bone metastases from prostate cancer].

INTRODUCTION: Paget's disease of bone (osteitis deformans) is a rare metabolic disorder of bone remodeling with complex etiology. In the most cases, it is detected by coincidence, during nuclear medicine and radiological diagnostic procedures. Herein we report a case of advanced prostate cancer coexisting with asymptomatic Paget's disease. CASE REPORT: We present a 69-year-old patient, with biochemical recurrence two years after radical prostatectomy for localized prostate cancer and period of stable remission. During the evaluation of metastatic spread of prostate cancer, the bone scintigraphy with technetium diphosphonate showed diffuse areas of increased radiotracer uptake in the left leg long bones and focal changes in the axial part of the skeleton. Scintigraphic findings led to a differential diagnostic dilemma regarding etiology of bone changes, so it was supplemented by standard radiologic methods and laboratory evaluation of bone metabolism parameters. The existence of asymptomatic polyostotic Paget's disease and metastatic bone changes was found at the same time. CONCLUSION: Metastatic bone lesions, in this case from prostate cancer, and asymptomatic Paget's disease may closely resemble each other. They both need careful evaluation in order to determine the proper stages of malignant disease and selection of appropriate therapies for patients.

Lung 99mTc-MIBI scintigraphy: impact on diagnosis of solitary pulmonary nodule.

Most of today available non-invasive procedures cannot clearly determinate between benign and malignant solitary pulmonary nodules (SPN). The purpose of the study was to assess the possibility of using 99mTc labeled hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) to differentiate benign from malignant SPN. Sixty patients were included in the study if the CT scan showed indeterminate SPN. Prior to definitive diagnosis 99mTc-MIBI single photon emission computerized tomography (SPECT) was performed: early scan 10 minutes and delayed 60-120 minutes after the intravenous injection of 740 MBq 99mTc-MIBI using dual-headed Gamma camera. The results were considered positive if there was an increased accumulation of the radiopharmaceutical in the area of the lung corresponding to the location of the lesion. The mean nodule size ± SD measured on CT scan was 2.96 cm. Lung cancer was diagnosed in 30/60 patients (14 squamocellular, 10 adenocarcinoma, 3 large-cell and 3 microcellular lung carcinomas). Of the 30 patients with malignant lesions, 27 patients (90%) had positive 99mTc-MIBI scan results by qualitative assessment. Among benign lesions, 23/30 (76.7%) were negative on 99mTc-MIBI scan. The size and PH report of SPN is statistically significantly influencing on 99mTc-MIBI accumulation in the SPN (p<0.01). The sensitivity, specificity, accuracy, positive and negative predictive value were 90%, 76.6%, 79.4%, 88.5% and 83.3% respectively. 99mTc-MIBI SPECT is an inexpensive non-invasive diagnostic procedure which might be useful diagnostic modality in the evaluation of SPN. Easy availability and low cost makes 99mTc-MIBI SPECT an attractive method in evaluating SPN.

[The importance of homocysteinemia measurement in chronic renal failure].

INTRODUCTION: Hyperhomocysteinemia is an independent risk factor for premature cardiovascular disease. In this study we examined the prevalence of high plasma levels of homocysteine in different stages of chronic renal failure. MATERIAL AND METHODS: We examined 105 subjects: 73 patients in different stage of chronic renal failure, 31 of them on hemodialysis, and 32 subjects as a control group. RESULTS: The results show high prevalence of hyperhomocysteinemia in chronic renal failure patients, especially with reduction of glomerular filtration rate over 50% of the surface normalized value. CONCLUSION: We can conclude that hyperhomocysteinemia is important risk factor for cardiovascular diseases in chronic renal failure patients, according to its high prevalence in these patients.