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1.  Microalbuminuria in children with urinary tract infection 
Korean Journal of Pediatrics  2010;53(9):840-844.
Microalbuminuria is defined as increased urinary albumin excretion (30-300 mg/day) or microalbumin/creatinine ratio (30-300 mg/g) in a spot urine sample. Although microalbuminuria is a predictor of clinical nephropathy and cardiomyopathy, few studies have investigated microalbuminuria in children with urinary tract infection (UTI).
Therefore, we compared the spot urine microalbumin/creatinine ratio in pediatric UTI patients with that of control subjects. We investigated the correlation between the ratio in children with UTI and age, height, weight, blood pressure, glomerular filtration rate (GFR), hematuria, vesicoureteral reflux, renal parenchymal defect, and renal scar, and its predictability for UTI complications.
We studied 66 patients (42 boys, 24 girls) and 52 healthy children (24 boys, 28 girls). The mean microalbumin/creatinine ratio in UTI patients was statistically significantly increased compared to the control group (340.04±321.36 mg/g (38.47±36.35 mg/mmol) in patient group vs. 225.68±154.61 mg/g (25.53±17.49 mg/mmol) in control group, P=0.0141). The mean value of spot urine microalbumin/creatinine ratio (384.70±342.22 mg/g (43.47±37.67 mg/mmol) in patient group vs. 264.92±158.13 mg/g (29.94±17.86 mg/mmol) in control group, P=0.0341) in 1-23 months age patient group showed statistically significant increase compared to control group. Microalbumin/creatinine ratio showed negative correlation to age (r=-0.29, P=0.0167), body surface area (BSA) (r=-0.29, P=0.0173) and GFR (r=-0.26, P=0.0343). The presence of hematuria (P=0.0169) was found to be correlated.
The spot urine microalbumin/creatinine ratio in children with UTI was significantly greater than that in normal children, and it was positively correlated with GFR. This ratio is a potential prescreening and prognostic marker in UTI patients. Further studies are required to validate the predictability of microalbuminuria in pediatric UTI patients.
PMCID: PMC3005216  PMID: 21189969
Microalbuminuria; Child; Urinary tract infection
2.  Microalbuminuria in Normal Korean Children 
Yonsei Medical Journal  2011;52(3):476-481.
Although microalbuminuria is known as a predictor of clinical nephropathy and cardiomyopathy, few studies have investigated the incidence and reference range of microalbuminuria in healthy children. This study aimed to establish a reference range and to study the age-related trend for spot urine microalbumin/creatinine ratio in a Korean pediatric population.
Materials and Methods
352 healthy children were studied from July 2007 through March 2010. Height, weight, serum creatinine, spot urine microalbumin/creatinine ratio, and glomerular filtration rate (GFR) were obtained for each subject. We divided the study population into 5 groups according to age, and compared the spot urine microalbumin/creatinine ratio with other variables using one-way analysis of variance (ANOVA), regression analysis and Pearson's correlation analysis.
In this study, the data showed that the spot urine microalbumin/creatinine ratio decreased with age: 1-12 months, 22.72±13.80 mg/mmol (2SD: 3.33-54.40 mg/mmol); 13-28 months, 16.34±9.58 mg/mmol (2SD: 3.16-35.19 mg/mmol); 29-48 months, 13.12±9.74 mg/mmol (2SD: 3.01-41.57 mg/mmol); 4-6 years, 10.58±8.13 mg/mmol (2SD: 0.00-30.19 mg/mmol); and 7-19 years, 5.13±5.44 mg/mmol (2SD: 0.45-14.45 mg/mmol). The spot urine microalbumin/creatinine ratio showed correlation with age, height, height z-score, weight, weight z-score, GFR, body mass index (BMI) and body surface area (BSA).
The spot urine microalbumin/creatinine ratio in normal Korean children decreased with age. This ratio could potentially be used to establish reference ranges and cutoff values for Korean children and to predict nephropathy and cardiomyopathy.
PMCID: PMC3101047  PMID: 21488191
Microalbuminuria; children
3.  Audit of Microalbumin Excretion in Children with Type I Diabetes 
Objective: To investigate prevalence, persistence and clinical correlates of increased microalbumin excretion in random urine samples collected in a paediatric diabetes clinic.
Method: Random urine samples were collected annually in patients >10 years attending the diabetes clinic in the Royal Hospital for Sick Children, Edinburgh. Albumin excretion is expressed as albumin:creatinine ratio (ACR) and classified as normal (10mg/mmol), or macroalbuminuria (>47 mg/mmol in females, >35 mg/mmol in males). We analyzed retrospectively results on 421 urine samples collected from 217 patients (109 males), of a median age of 12.3 years (94% 10−16 years) over 3 years. For each sample, the corresponding mean HbA1c over the previous year was calculated.
Results: Prevalence of micro− and macro−albuminuria in individual samples was 1% and 0.5% respectively. ACR was equivocal in 10.1% and 4.7% in samples from females and males respectively (p=0.03). HbA1c showed borderline significant differences across ACR groups (p=0.06). Equivocal ACR excretion was associated with slightly higher mean HbA1c (9.5±1.3%) compared to normal albuminuria (9.0±1.1%, p3.5 mg/mmol. The 14−16 years age group patients were most likely to have ACR >3.5 mg/mmol (p=0.05).
Conclusions: Female sex and increasing age, but not HbA1c, were independently associated with increased ACR. A robust mechanism for collection of repeat early morning urine samples from patients with increased ACR in random urine samples, and follow−up of those patients who have persistently high microalbumin excretion are important. It is also important to confirm the usefulness of ACR measurements in random urine samples as a marker of incipent nephropathy.
Conflict of interest:None declared.
PMCID: PMC3005646  PMID: 21274398
type 1 diabetes; Microalbuminuria; children and adolescents
4.  Clinical Significance of Subjective Foamy Urine 
Chonnam Medical Journal  2012;48(3):164-168.
Foamy urine is widely regarded as a sign of proteinuria. However, there is no objective definition of foamy urine and there are no reports on the proportion of involved patients who have overt proteinuria or microalbuminuria. We performed this study to investigate this proportion and to identify possible risk factors for these two conditions. We reviewed all new outpatients from 1 November 2011 to 30 April 2012 and identified patients complaining of foamy urine. Their demographic data and medical records were examined. In particular, we tabulated the patients' spot urinary protein to creatinine ratio, spot urinary microalbumin to creatinine ratio (ACR), blood urea nitrogen (BUN), and serum levels of creatinine (Cr), uric acid, calcium, phosphate, and glucose. In addition, we calculated estimated glomerular filtration rates (eGFRs) by using the CKD-EPI equation. We also performed risk factor analysis with the Chi-squared test and by logistic regression. Seventy-two patients (6.3% of total new outpatients) complained of foamy urine; of these, there were 59 males with a median age of 65.5 years (range, 36-87 years). Of the 72 patients, 16 (22.2%) had overt proteinuria. We found that diabetes, poor renal function (high Cr, BUN, low eGFR), increased serum phosphate, and increased serum glucose were associated with overt proteinuria. Multiple logistic regression analysis showed that serum Cr and serum phosphate were associated with overt proteinuria. The ACR was available for 38 patients, and in this subgroup, 12 (31.6%) showed microalbuminuria or overt proteinuria. In this subgroup, a high serum Cr was the only statistically significant risk factor. Among patients who complained of foamy urine, approximately 20% had overt proteinuria, and increased serum Cr and phosphate were statistically significant risk factors.
PMCID: PMC3539097  PMID: 23323222
Proteinuria; Creatinine; Phosphates
5.  Cystatin C as an Early Biomarker of Nephropathy in Patients with Type 2 Diabetes 
Journal of Korean Medical Science  2011;26(2):258-263.
This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C-reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m2 estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m2 estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria.
PMCID: PMC3031011  PMID: 21286018
Cystatin C; Diabetic Nephropathies; Albuminuria
6.  Prevalence of Microalbuminuria among Rural North Indian Population with Diabetes Mellitus and its Correlation with Glycosylated Haemoglobin and Smoking 
Introduction: Macrovascular and microvascular complications of diabetes mellitus are a consequence of metabolic derangement mainly hyperglycemia. Diabetic nephropathy being one of them causes end stage renal disease. Hence, to detect renal involvement, microalbuminuria can be considered as an early marker.
Aim: To study mean albumin creatinine ratio (ACR) in type 1 and type 2 diabetes mellitus with respect to HbA1c, duration of diabetes and smoking.
Materials and Methods: Two hundred cases of type 1 and type 2 diabetes mellitus and 100 controls, age and sex matched were included in this study and measured for spot urinary albumin, spot urinary creatinine, fasting plasma glucose and HbA1c.
Results: It was observed that mean ACR was significantly elevated in type 1 and type 2 diabetes mellitus as compared to the controls. Mean ACR increases in diabetics with poor glycemic control, duration of diabetes and smoking.
Conclusion: The early detection of microalbumin in diabetics can significantly reduce the progression of renal complications and before the development of proteinuria.
PMCID: PMC4149067  PMID: 25177561
ACR; Diabetes mellitus; Diabetic nephropathy; HbA1c; Microalbuminuria
7.  Physical Activity Alters Urinary Albumin/ Creatinine Ratio in Type 1 Diabetic Patient 
While the best way to identify microalbuminuria is to determine albumin excretion rate (AER) in a 24 h urine sample. Published data have shown that calculation of an albumin/creatinine ratio (ACR) in a spot urine sample has reasonable rate of sensitivity and specificity. We aimed to evaluate the effect of daily exercise on ACR and estimate the best time for the examination of the ACR in a spot urine sample. Sixteen eligible patients with Type 1 diabetes mellitus were asked to perform varying degree of exercise periods. Urinary albumin and creatinine excretion rates during each period were determined. ACR and AER of timed urinary samples were compared with the 24 hour urinary AER. We found significant correlations between timed and 24 hour urinary AER. According to diagnostic performance tests, ACR and AER of timed urine samples were both found to be significantly more sensitive during resting period when compared with mild or moderate active periods. It is concluded that ACR and AER of a timed urine sample are sensitive and specific methods for determining microalbuminuria, while overnight resting samples give the impression of being more diagnostic.
Key PointsTimed urine samples can predict microalbuminuria but because of the erroneous urine collections, microalbuminuria measurement should be calculated with creatiniuria measurement.With increasing physical activity during urine collection diagnostic performances of the cut-off values go downhill.For detecting microalbuminuria best results are reached with the early-morning urine samples.
PMCID: PMC3896114  PMID: 24497821
Microalbuminuria; albumin/creatinine ratio; type 1 diabetes mellitus; exercise; nephropathy
8.  Wilm's Tumor-1 Protein Levels in Urinary Exosomes from Diabetic Patients with or without Proteinuria 
PLoS ONE  2013;8(3):e60177.
Podocyte injury is an early feature of diabetic nephropathy (DN). Recently, urinary exosomal Wilm's tumor-1 protein (WT1), shed by renal epithelial cells, has been proposed as a novel biomarker for podocyte injury. However, its usefulness as biomarker for early diabetic nephropathy has not been verified yet. We investigated urinary exosomal WT1 in type-1 diabetic patients to confirm its role as a non-invasive biomarker for predicting early renal function decline.
The expression of WT1 protein in urinary exosomes from spot urine samples of type-1 diabetes mellitus patients (n = 48) and healthy controls (n = 25) were analyzed. Patients were divided based on their urinary albumin excretion, ACR (mg/g creatinine) into non- proteinuria group (ACR<30 mg/g, n = 30) and proteinuria group (ACR>30 mg/g, n = 18). Regression analysis was used to assess the association between urinary exosomal levels of WT1 with parameters for renal function. Receiver Operating Characteristic (ROC) curve analysis was used to determine the diagnostic performance of exosomal WT-1.
WT1 protein was detected in 33 out of 48 diabetic patients and in only 1 healthy control. The levels of urinary exosomal WT1 protein is significantly higher (p = 0.001) in patients with proteinuria than in those without proteinuria. In addition, all the patients with proteinuria but only half of the patients without proteinuria were positive for exosomal WT1. We found that the level of exosomal WT1 were associated with a significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio, and serum creatinine as well as a decline in eGFR. Furthermore, patients exhibiting WT1-positive urinary exosomes had decreased renal function compared to WT1-negative patients. ROC analysis shows that WT-1 effectively predict GFR<60 ml. min-1/1.73 m2.
The predominant presence of WT1 protein in urinary exosomes of diabetic patients and increase in its expression level with decline in renal function suggest that it could be useful as early non-invasive marker for diabetic nephropathy.
PMCID: PMC3609819  PMID: 23544132
9.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine is correlated with muscle mass, and low muscle mass is also associated with CVD. Whether low urine creatinine in the denominator of the ACR contributes to the association of ACR with CVD is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
6,770 community-living individuals without CVD.
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Incident CVD events.
During a mean of 7.1 years’ follow-up, 281 CVD events occurred. Geometric means for spot urine creatinine, urine albumin and ACR were 95 ± 2 (SD) mg/dl, 0.7 ± 3.7 mg/dl and 7.0 ± 3.1 mg/g. Adjusted HRs per 2-fold higher increment in each urinary measures with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). Urine creatinine was lower in older, female, and low weight individuals. ACR ≥10 mg/g was more strongly associated with CVD events in individuals with low weight (HR for lowest vs. highest tertile: 4.34 vs. 1.97; p for interaction=0.006). Low weight also modified the association of urine albumin with CVD (p for interaction=0.06), but 1/urine creatinine did not (p for interaction=0.9).
We lacked 24-hour urine data.
While ACR is more strongly associated with CVD events among persons with low body weight, this association is not driven by differences in spot urine creatinine. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin and less by urine creatinine.
PMCID: PMC3783582  PMID: 23830183
10.  A Comparative Study of Clinical Utility of Spot Urine Samples with 24-h Urine Albumin Excretion for Screening of Microalbuminuria in Type 2 Diabetic Patients 
Twenty-four hour urinary albumin excretion (UAE) is considered as gold standard method for albuminuria measurement, but collection of 24-h urine is inconvenient. The aim of present study was to evaluate whether albumin: creatinine ratio (ACR) and urinary albumin concentration (UAC) in different spot urine samples correlate or not with 24-h UAE for screening of microalbuminuria in type 2 diabetic patients. We collected first morning void (FMV), random urine sample (RUS) and 24-h urine, separately on consecutive days from 104 type 2 diabetic patients. ACR and UAC in each spot urine sample compared with 24-h UAE with regard to Pearson correlation coefficient. Pearson’s correlation of albumin: creatinine ratio (ACR) with 24-h UAE was (r = 0.802 and 0.623) in first morning void (FMV) and random urine sample (RUS), respectively. Pearson’s correlation coefficient of urinary albumin concentration (UAC) compared with 24-h UAE was (r = 0.943 and 0.920), in FMV and RUS, respectively, P < 0.01. Results revealed that values in first morning void (FMV) were better correlated with 24-h urinary albumin excretion (UAE), than the values in random urine sample (RUS). We conclude that the first morning void (FMV) may be able to replace 24-h urine collection, preferably urinary albumin concentration (UAC) in the initial screening of microalbuminuria in diabetic patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s12291-011-0136-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3162961  PMID: 22754194
Diabetes mellitus; Microalbuminuria; Screening; Spot urine sample; Urinary albumin concentration
11.  A genome-wide association for kidney function and endocrine-related traits in the NHLBI's Framingham Heart Study 
BMC Medical Genetics  2007;8(Suppl 1):S10.
Glomerular filtration rate (GFR) and urinary albumin excretion (UAE) are markers of kidney function that are known to be heritable. Many endocrine conditions have strong familial components. We tested for association between the Affymetrix GeneChip Human Mapping 100K single nucleotide polymorphism (SNP) set and measures of kidney function and endocrine traits.
Genotype information on the Affymetrix GeneChip Human Mapping 100K SNP set was available on 1345 participants. Serum creatinine and cystatin-C (cysC; n = 981) were measured at the seventh examination cycle (1998–2001); GFR (n = 1010) was estimated via the Modification of Diet in Renal Disease (MDRD) equation; UAE was measured on spot urine samples during the sixth examination cycle (1995–1998) and was indexed to urinary creatinine (n = 822). Thyroid stimulating hormone (TSH) was measured at the third and fourth examination cycles (1981–1984; 1984–1987) and mean value of the measurements were used (n = 810). Age-sex-adjusted and multivariable-adjusted residuals for these measurements were used in association with genotype data using generalized estimating equations (GEE) and family-based association tests (FBAT) models. We presented the results for association tests using additive allele model. We evaluated associations with 70,987 SNPs on autosomes with minor allele frequencies of at least 0.10, Hardy-Weinberg Equilibrium p-value ≥ 0.001, and call rates of at least 80%.
The top SNPs associated with these traits using the GEE method were rs2839235 with GFR (p-value 1.6*10-05), rs1158167 with cysC (p-value 8.5*10-09), rs1712790 with UAE (p-value 1.9*10-06), and rs6977660 with TSH (p-value 3.7*10-06), respectively. The top SNPs associated with these traits using the FBAT method were rs6434804 with GFR(p-value 2.4*10-5), rs563754 with cysC (p-value 4.7*10-5), rs1243400 with UAE (p-value 4.8*10-6), and rs4128956 with TSH (p-value 3.6*10-5), respectively. Detailed association test results can be found at . Four SNPs in or near the CST3 gene were highly associated with cysC levels (p-value 8.5*10-09 to 0.007).
Kidney function traits and TSH are associated with SNPs on the Affymetrix GeneChip Human Mapping 100K SNP set. These data will serve as a valuable resource for replication as more SNPs associated with kidney function and endocrine traits are identified.
PMCID: PMC1995611  PMID: 17903292
12.  Persistent Microalbuminuria in Human Immunodeficiency Virus Infected Children in Kano, Nigeria 
Microalbuminuria has been reported to be a precursor of HIV related renal disease, which if detected early and coupled with appropriate intervention may slow or retard the progress of the disease. One hundred and seventy-eight HIV infected children aged 15 years and below were recruited from the Paediatric Infectious Disease Clinic of Aminu Kano Teaching Hospital (AKTH), Kano, to determine the prevalence of persistent microalbuminuria using the albumin creatinine ratio (ACR). Early morning urine samples and spot urine samples were analyzed using a dipstick specific for microalbumin. Those who tested positive had their samples reanalyzed in the laboratory using immunometric assay and Jaffe reaction method for albumin and creatinine, respectively. Patients that had ACR of 30–300 mg/g were said to have microalbuminuria and had their urine samples retested after 6 to 8 weeks. Twelve children (6.7%) had persistent microalbuminuria and had a mean age of 7.5 ± 3.3 years, with a male to female ratio of 1 : 1. There was no significant relationship between the finding of microalbuminuria and age, sex, duration of infection, and the use of highly active antiretroviral therapy. Periodic screening for microalbuminuria using albumin specific dipstick should be considered for children with HIV infection.
PMCID: PMC3958656  PMID: 24724027
13.  Relationship between Sialic acid and metabolic variables in Indian type 2 diabetic patients 
Plasma sialic acid is a marker of the acute phase response. Objective is to study the relationship between sialic acid relationship with metabolic variables in Indian type 2 diabetes with and without microvascular complications.
Research design and Methods
Fasting Venous blood samples were taken from 200 subjects of which 50 were of diabetes mellitus (DM) and nephropathy patients, 50 patients with type 2 diabetes and retinopathy, 50 patients with type 2 diabetes without any complications and 50 healthy individuals without diabetes. The Indian subject's aged 15–60 years with type 2 diabetes were recruited for the study. Simultaneously urine samples were also collected from each of the subjects. All the blood samples were analyzed for total cholesterol, triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), fasting and postprandial glucose on fully automated analyzer. Serum and urine sialic acid along with microalbumin levels were also estimated.
There was a significantly increasing trend of plasma and urine sialic acid with severity of nephropathy (P < 0.001) and with degree of urinary albumin excretion (P < 0.001). Serum sialic acid correlated with increasing serum creatinine concentration (P < 0.001). Elevated serum sialic acid concentrations were also associated with several risk factors for diabetic vascular disease: diabetes duration, HbA1c, serum triglyceride and cholesterol concentrations, waist-to-hip ratio and hypertension. Significant correlations were found between sialic acid concentration and cardiovascular risk factors like LDL and TG in the diabetic subjects.
The main finding of this study is that elevated serum and urinary sialic acid and microalbumin concentrations were strongly related to the presence of microvascular complications like diabetic nephropathy and retinopathy and cardiovascular risk factors in Indian type 2 diabetic subjects. Further study of acute-phase response markers and mediators as indicators or predictors of diabetic microvascular complications is therefore justified.
PMCID: PMC1201167  PMID: 16092968
Sialic acid; Microalbuminuria; microvascular; and type-2 diabetes mellitus
14.  Endogenous Markers for Estimation of Renal Function in Peritoneal Dialysis Patients 
♦ Objective: This method comparison study, conducted at the peritoneal dialysis (PD) outpatient clinic of the Department of Renal Medicine, Aarhus University Hospital, Denmark, set out to evaluate the accuracy and reproducibility of methods for estimating glomerular filtration rate (GFR) based on endogenous markers in PD patients.
♦ Patients: The 12 consecutive patients included in the study were examined twice while in a stable condition. All patients finished the study. Inclusion criteria were age 18 years or older, ability to collect 24-hour urine, and urine production greater than 300 mL in 24 hours.
♦ Main Outcome Measures: The methods for estimating GFR using endogenous markers included the average of urinary clearances of creatinine and urea [U-Cl(crea-urea)] and two equations using the serum concentration of cystatin C [eGFR(CysC)]. The resulting GFR estimates were compared with those obtained using urinary and corrected plasma clearances of 51Cr-EDTA [U-Cl(EDTA) and cP-Cl(EDTA)], the corrected plasma clearance being plasma clearance minus dialysate clearance.
♦ Results: Compared with the U-Cl(EDTA), the U-Cl(crea-urea) GFR estimate was 12% higher [95% confidence limits (CL): 3%, 21%]. Although significantly different (p = 0.01), the latter two methods showed the best agreement. The estimates obtained using the eGFR(CysC) methods were skewed from y = x compared with the estimates obtained using other methods, indicating strong bias, probably because of extrarenal elimination. The cP-Cl(EDTA) estimate was 34% (95% CL: 26%, 42%), higher than the U-Cl(EDTA) estimate (p < 0.001). The reproducibility (coefficients of variation) differed significantly between methods: cP-Cl(EDTA), 7%; U-Cl(EDTA), 14%; U-Cl(crea-urea), 18%; and both eGFR(CysC) methods, 3%.
♦ Conclusions: In PD patients, GFR may be estimated as U-Cl(crea-urea) when complete urine collection is performed, taking into account an overestimation of approximately 12%. The available equations for eGFR(CysC) seem to be inaccurate; further development and validation is desirable. Omitting the eGFR(CysC) methods, cP-Cl(EDTA) was the most reproducible method and might be useful in certain situations.
PMCID: PMC3598110  PMID: 23032085
Chromium radioisotopes; creatinine; cystatin C; glomerular filtration rate; urea
15.  Relationship between inflammatory markers, metabolic and anthropometric variables in the Caribbean type 2 diabetic patients with and without microvascular complications 
Serum sialic acid and C reactive protein are the markers for inflammation. The main objective of this study was to determine the sialic acid level in Caribbean type 2 diabetic patients with and without microvascular complications and its relationship with metabolic and anthropometric variables.
Research design and methods
The Caribbean subjects aged 15–60 years with type 2 diabetes were recruited for the study. Fasting venous blood samples were collected from 162 subjects of which 44 were healthy individuals, 44 were of type 2 diabetes, 44 were of type 2 diabetes with nephropathy and 30 were of diabetes with retinopathy. Simultaneously urine samples were also collected from each of the subjects. All the blood samples were processed for lipid profile, glucose, HbA1C, C-reactive protein and sialic acid. The urine samples were analysed for sialic acid and microalbumin.
Serum sialic acid concentrations were significantly higher among diabetic subjects (66.0 ± 11.7 mg %) as compared to controls (55.2 ± 8.3 mg %). There was a significantly increasing trend of serum sialic acid with severity of nephropathy (71.6 ± 23.6 mg %) and degree of urinary albumin excretion (794.3 ± 805.9). The diabetic retinopathy patients also demonstrated significantly higher values of serum sialic acid (77.9 ± 29.0) and urine microalbumin (351.1 ± 559.9). Elevated serum sialic acid microalbumin concentrations were associated with cardiovascular risk factors such as hypertension, increased waist to hip ratios. (P < 0.05). Sialic acid had no correlation with CRP or any component of the lipid profile.
The increased serum sialic acid and microalbumin were strongly related to the presence of microvascular complications like diabetic nephropathy and diabetic retinopathy and cardiovascular risk factors like hypertension and waist to hip ratios in Caribbean type-2 diabetic patients. The serum sialic acid may be used as an inflammatory marker and possible indicator of microvascular complications in type-2 diabetic patients.
PMCID: PMC1764741  PMID: 17187674
16.  Biomarkers in chronic kidney disease, from kidney function to kidney damage 
World Journal of Nephrology  2015;4(1):57-73.
Chronic kidney disease (CKD) typically evolves over many years, with a long latent period when the disease is clinically silent and therefore diagnosis, evaluation and treatment is based mainly on biomarkers that assess kidney function. Glomerular filtration rate (GFR) remains the ideal marker of kidney function. Unfortunately measuring GFR is time consuming and therefore GFR is usually estimated from equations that take into account endogenous filtration markers like serum creatinine (SCr) and cystatin C (CysC). Other biomarkers such as albuminuria may precede kidney function decline and have demonstrated to have strong associations with disease progression and outcomes. New potential biomarkers have arisen with the promise of detecting kidney damage prior to the currently used markers. The aim of this review is to discuss the utility of the GFR estimating equations and biomarkers in CKD and the different clinical settings where these should be applied. The CKD-Epidemiology Collaboration equation performs better than the modification of diet in renal disease equation, especially at GFR above 60 mL/min per 1.73 m2. Equations combining CysC and SCr perform better than the equations using either CysC or SCr alone and are recommended in situations where CKD needs to be confirmed. Combining creatinine, CysC and urine albumin to creatinine ratio improves risk stratification for kidney disease progression and mortality. Kidney injury molecule and neutrophil gelatinase-associated lipocalin are considered reasonable biomarkers in urine and plasma to determine severity and prognosis of CKD.
PMCID: PMC4317628  PMID: 25664247
Chronic kidney disease; Estimated glomerular filtration rate; Kidney damage; New biomarkers; MicroRNA
17.  TNF-α and Microalbuminuria in Patients with Type 2 Diabetes Mellitus 
Journal of Diabetes Research  2014;2014:394206.
Aim. Recent evidence suggests that chronic subclinical inflammation plays a key role in the pathogenesis and progression of diabetic nephropathy. Aim of the present study was to investigate possible correlation between the presence and degree of microalbuminuria and markers of inflammation in patients with type 2 diabetes mellitus (DM). Patients-Methods. Eighty patients were enrolled and clinical and laboratory data were recorded. Albumin-creatinine ratio (ACR) was calculated in first-morning urine samples. Serum and urinary tumor necrosis factor-α (TNF-α) levels were determined by ELISA. Results. Forty-five patients had normoalbuminuria, 33 microalbuminuria, and 2 macroalbuminuria. Patients with microalbuminuria were older, with higher glycosylated hemoglobin levels (HbA1c) and they more frequently had diabetic retinopathy, neuropathy, and cardiovascular disease and were on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). ACR was significantly correlated with the presence of cardiovascular disease, hypertension, and HbA1c levels and the administration of clopidogrel and ACEi or ARBs. ACR was not correlated with C-reactive protein, fibrinogen, or serum TNF-α levels but had a strong correlation with urinary TNF-α levels. Conclusions. In patients with type 2 DM, urinary, but not serum, TNF-α levels are associated with the presence and severity of microalbuminuria.
PMCID: PMC4284977  PMID: 25587544
18.  Cystatin C, Albuminuria, and Mortality Among Older Adults With Diabetes 
Diabetes Care  2009;32(10):1833-1838.
Albuminuria and impaired glomerular filtration rate (GFR) are each associated with poor health outcomes among individuals with diabetes. Joint associations of albuminuria and impaired GFR with mortality have not been comprehensively evaluated in this population.
This is a cohort study among Cardiovascular Health Study participants with diabetes, mean age 78 years. GFR was estimated using serum cystatin C and serum creatinine. Albumin-to-creatinine ratio (ACR) was measured in single-voided urine samples.
Of 691 participants, 378 died over 10 years of follow-up. Cystatin C–estimated GFR <60 ml/min per 1.73 m2, creatinine-based estimated GFR <60 ml/min per 1.73 m2, and urine ACR ≥30 mg/g were each associated with increased mortality risk with hazard ratios of 1.73 (95% CI 1.37–2.18), 1.54 (1.21–1.97), and 1.73 (1.39–2.17), respectively, adjusting for age, sex, race, diabetes duration, hypoglycemic medications, hypertension, BMI, smoking, cholesterol, lipid-lowering medications, prevalent cardiovascular disease (CVD), and prevalent heart failure. Cystatin C–estimated GFR and urine ACR were additive in terms of mortality risk. Cystatin C–estimated GFR predicted mortality more strongly than creatinine-based estimated GFR.
Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes; a focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both; and further consideration of cystatin C use in clinical care.
PMCID: PMC2752913  PMID: 19587367
19.  Changes in Albumin Excretion in the Diabetes Prevention Program 
Diabetes Care  2009;32(4):720-725.
Increased urinary albumin excretion rates have been linked to nephropathy and macrovascular disease. We here describe the baseline prevalence and effect of Diabetes Prevention Program (DPP) interventions on the development and reversal of elevated albumin excretion.
Urine albumin-to-creatinine ratios (ACRs) were calculated from untimed urine collections. Analyses compared participants by treatment group, diabetes and hypertension status, and use of ACE inhibitors or angiotensin II receptor blockers (ARBs).
Elevated ACR levels (≥30 mg/g creatinine) were present at baseline in 198 (6.2%) of 3,188 participants: placebo 5.3%, metformin 6.5%, and intensive lifestyle (ILS) 6.8%. Of the 2,802 with ACR measurements at baseline and at the end of the study, the percentage with elevated levels declined (incident and regression) from 6.2 to 6.1%, with no significant differences between the groups even with adjustment for ACE inhibitor and ARB use. The odds of developing an elevated ACR were 59% higher for a participant who developed diabetes compared with one who did not.
At entry into the DPP, an elevated ACR was present in 6.2%. Despite the marked decrease in progression to diabetes and the improvement in insulin resistance and other cardiovascular risk markers in the ILS and metformin groups, there was no improvement in ACR, on average, in those two groups. However, the frequency of an elevated ACR was higher in participants who developed diabetes. An increased ACR may have multiple causes, thus obscuring the improvements that might have been expected with the reduction in insulin resistance seen in the DPP.
PMCID: PMC2660489  PMID: 19131464
20.  Urinary Cystatin C and Acute Kidney Injury After Cardiac Surgery 
Acute Kidney Injury (AKI) is common following cardiac surgery and is associated with adverse patient outcomes. Urinary cystatin C (CysC) is a biomarker of proximal tubule function and may rise earlier in AKI than serum creatinine.
Study Design
Prospective cohort study
Settings & Participants
The TRIBE AKI (Translational Research Investigating Biomarker Endpoints in AKI) Consortium prospectively enrolled 1,203 adults and 299 children at 8 institutions from 2007–2009.
Index Test
Urinary CysC (mg/L) within the first 12 hours after surgery
Serum Creatinine based AKI was defined as AKI Network stage 1 (Mild AKI) as well as a doubling of serum creatinine from the pre-operative value or the need for dialysis during hospitalization (Severe AKI).
Other Measurements
Analyses were adjusted for characteristics used clinically for AKI risk stratification including age, sex, race, eGFR, diabetes, hypertension, heart failure, non-elective surgery, cardiac catheterization within 72 hours, type of surgery, myocardial infarction, and cardiopulmonary bypass time greater than 120 minutes.
Urinary CysC measured in the early post-operative period (0–6 and 6–12 hours postoperatively) correlated with both mild and severe AKI in adults and children. However after analyses were adjusted for other factors the effect was attenuated for both forms of AKI in both cohorts.
Limited numbers of patients with severe AKI and short-term dialysis
Urinary CysC values are not significantly associated with the development of AKI following cardiac surgery in adults and children.
PMCID: PMC3627833  PMID: 23332602
Acute kidney injury Biomarkers; Cystatin C; Dialysis; Peri-operative
21.  Estimating the glomerular filtration rate from serum creatinine is better than from cystatin C for evaluating risk factors associated with chronic kidney disease 
Kidney international  2013;83(6):1169-1176.
Chronic kidney disease risk factors may associate with the estimated glomerular filtration rate (eGFR) differently than with the measured GFR. To examine this, we evaluated 1150 patients (mean age 65) in two community cohorts for risk factors, measured GFR by iothalamate clearance, and eGFR based on creatinine (Cr), cystatin C (CysC), or both. The interaction between each risk factor and eGFR (relative to measured GFR) identified risk factor associations with eGFR along non-GFR pathways. In a subset of 40 patients with two visits, the mean coefficient of variation was 8.2% for measured GFR, 6.4% for eGFRCr, 8.2% for eGFRCr-CysC, and 10.7% for eGFRCysC. The measured GFR was better correlated with eGFRCr-CysC (r, 0.74) than eGFRCr (r, 0.70) or eGFRCysC (r, 0.68). Lower measured GFR associated with lower 24-hour urine creatinine, albuminuria, hypertension, diabetes, higher triglycerides, and higher uric acid. Lower eGFRCr had these same associations except for an association with higher 24-hour urine creatinine along a non-GFR pathway. Lower eGFRCysC and eGFRCr-CysC also had these same associations but also associated with obesity, albuminuria, hypertension, diabetes, higher triglycerides, higher C-reactive protein, and higher uric acid along non-GFR pathways. Thus, cystatin C improves estimation of GFR over creatinine alone; however, the association between most of the risk factors and GFR was more accurate by eGFR based on creatinine alone. This is explained by the association of these risk factors with the non-GFR determinants of cystatin C.
PMCID: PMC3661736  PMID: 23423253
22.  The Effects of Blocking Angiotensin Receptors on Early Stages of Diabetic Nephropathy 
This study aimed to investigate the beneficial effects of angiotensin receptor blockers (ARBs) on markers of endothelial function in patients with early stage of diabetic nephropathy (DN).
This cross-sectional study was conducted on 32 participants with IDDM from January 2010 until May 2011 in Isfahan, Iran. The participants were candidate for receiving ARBs or angiotensin-converting enzyme inhibitors (ACEIs) to decrease microalbuminuria. The inclusion criteria were as follows: the age of onset of insulin-dependent diabetes mellitus (IDDM)less than 15 years; normal glomerular filtration rate (GFR); normal blood pressure; normal cardiovascular examination; negative urine culture, receiving no medications except insulin. Microalbuminuria was measured in two fasting urine samples with a sampling interval of at least 1–2 months by ELISA method. Patients with two abnormal results were included. Microalbumin to creatinin ratio equal to or more than 30 mg/gm was considered abnormal. The fasting blood samples to determine serum nitric oxide (NO) and vascular cell adhesion molecule (VCAM) were obtained at the time 0 (before starting the study), and after 2 months of receiving ARBmedication. Valsartan tablet (Diovan, Novartis Company) with a dose of 1 mg/kg/day up to 80 mg/day in a single dose was administered.
Urine microalbumin to creatinin ratio after valsartan consumption was lower than microalbumin level before the medication, P < 0.05. After valsartan consumption, serum VCAM-1 level reduced and NO level increased significantly, P < 0.05.
Angiotensin receptor blockers may reduce VCAM-1 and microalbuminuria and may increase NO levels in early stages of DN. Thus administration of ARBs might be considered even in early stages of DN.
PMCID: PMC3415188  PMID: 22891149
Angiotensin receptor blocker; diabetic nephropathy; endothelial dysfunction; valsartan
23.  Genetic modulation of diabetic nephropathy among mouse strains with Ins2 Akita mutation 
Physiological Reports  2014;2(11):e12208.
Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end‐stage renal disease. DN is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty‐eight Akita strains were generated by breeding this panel to DBA/2.Akita mice. Male F1 diabetic and nondiabetic littermates were evaluated for DN‐related traits. Urine albumin‐to‐creatinine ratios (ACRs), volume and cystatin C as well as blood urea nitrogen and lipoprotein levels varied significantly among the diabetic strains. For most Akita strains, ACR values increased 2‐ to 6‐fold over euglycemic control values. However, six strains exhibited changes in ACR exceeding 10‐fold with two strains (NOD/ShiLt and CBA) showing 50‐ to 83‐ fold increases. These increases are larger than previously reported among available DN mouse models establishing these strains as useful for additional studies of renal function. ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and an interstitial tubular marker associated with DN onset in humans suggesting that tubule damage as well as podocyte‐stress contributed to reduced kidney function assessed by ACR. Although large changes were seen for ACRs, severe nephropathology was absent. However, glomerular hypertrophy and collagen IV content were found to vary significantly among strains suggesting a genetic basis for early onset features of DN. Our results define the range of DN phenotypes that occur among common inbred strains of mice.
Diabetic nephropathy (DN) is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty‐eight Akita strains on different genetic backgrounds were evaluated for DN‐related traits and the results define the range of DN phenotypes that occur among common inbred strains of mice.
PMCID: PMC4255814  PMID: 25428948
Akita; Animal models; Albuminuria; Diabetic nephropathy; Genetics
24.  Serum C peptide level and renal function in diabetes mellitus 
Indian Journal of Nephrology  2010;20(1):25-28.
C peptide is an active peptide hormone with potentially important physiological effects. C peptide has the capacity to diminish glomerular hyperfiltration and reduce urinary albumin excretion in both experimental and human type 1 diabetes. The present study is aimed at correlating the serum C peptide level with that of renal clearance, urinary albumin excretion and duration of diabetes. This is a prospective cross sectional study. Patients with diagnosis of type 2 diabetes mellitus were evaluated for their baseline clinical and laboratory profile. Both males and females above the age of 18 years were included in the study. The laboratory investigations include fasting serum C peptide, HbA1C, serum creatinine, blood urea nitrogen, urine albumin and creatinine. Creatinine clearance was calculated using modification of diet in renal disease formula from serum creatinine value. A total of 168 patients were included in the study, among them 90 were females (53.57%) and 78 males (46.43%). Mean age of the patients was 57.64 years. Pearson correlation test showed negative correlation of serum C peptide level with creatinine clearance, though statistically not significant. Negative correlation was also seen between serum C peptide, and urine albumin, urine albumin creatinine ratio, HbA1C and duration of diabetes. Mean urine albumin was higher in patients with subnormal C peptide level. Duration of disease was more in patients with lower serum C peptide level. The study has shown weak association of serum C peptide level with microalbuminuria and creatinine clearance. Risk of albuminuria is more in patients with low serum C peptide level.
PMCID: PMC2878407  PMID: 20535267
C peptide; creatinine clearance; microalbuminuria
25.  Correlation of microalbumin and sialic acid with anthropometric variables in type 2 diabetic patients with and without nephropathy 
The objective of this study is to correlate microalbumin and sialic acid levels with anthropometric variables in type 2 diabetic patients with and without nephropathy.
This study was a case control study and included 108 Trinidadian subjects (aged 15–60 years) of which 30 were healthy individuals, 38 had type 2 diabetes, and 40 were of type 2 diabetic patients with nephropathy. Blood pressure and waist to hip ratio were recorded. Fasting venous blood samples and urine samples were collected from all the subjects. Blood samples were analysed for the glucose, C-reactive protein, and sialic acid. Urine sample was analysed for microalbumin and sialic acid.
Urinary microalbumin was higher among diabetic subjects (28.9 ± 30.3 mg/L) compared with controls (8.4 ± 10.2 mg/L) and was significantly higher in diabetic patients with nephropathy (792.3 ± 803.9 mg/L). Serum sialic acid was higher in subjects with diabetic nephropathy (71.5 ± 23.3 mg/dL) compared to diabetics (66.0 ± 11.7 mg/dL) and controls (55.2 ± 8.3 mg/dL). Increased microalbumin and sialic acid were correlated with other cardiovascular risk factors such as hypertension and waist to hip ratios (p < 0.05).
From these results it can be concluded that the increased microalbumin and sialic acid were strongly correlated with hypertension and waist to hip ratios in Trinidadian type-2 diabetic patients. Measurement of sialic acid, microalbumin, and waist to hip ratio along with the blood pressure is recommended for all type 2 diabetic patients to reduce the cardiovascular risk.
PMCID: PMC2464761  PMID: 18629366
sialic acid; microalbumin; diabetes

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