Sulfate: a neglected (but potentially highly relevant) anion.

Sulfate is an important anion as sulfonation is essential in modulation of several compounds, such as exogens, polysaccharide chains of proteoglycans, cholesterol or cholesterol derivatives and tyrosine residues of several proteins. Sulfonation requires the presence of both the sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) and a sulfotransferase. Genetic disorders affecting sulfonation, associated with skeletal abnormalities, impaired neurological development and endocrinopathies, demonstrate the importance of sulfate. Yet sulfate is not measured in clinical practice. This review addresses sulfate metabolism and consequences of sulfonation defects, how to measure sulfate and why we should measure sulfate more often.

The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Assessment of Kidney Function in Children.

A good understanding of kidney function tests is essential for patient care. Urinalysis is the commonest used test for screening purposes in ambulatory settings. Glomerular function is assessed further by urine protein excretion and estimated glomerular filtration rate and tubular function by various tests such as urine anion gap and excretion of sodium, calcium, and phosphate. In addition, kidney biopsy and/or genetic analyses may be required to further characterize the underlying kidney disease. In this article, we discuss maturation and the assessment of kidney function in children.

Carboplatin Dosing in Children Using Estimated Glomerular Filtration Rate: Equation Matters.

Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3-89.5% versus 76.3-78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.

Concordance between creatinine- and cystatin C-based eGFR in clinical practice.

The mean of GFR-estimates based on serum creatinine (eGFRcrea) and cystatin C (eGFRcys) has superior accuracy than each estimate alone. Recent studies have shown that agreement between eGFRcrea and eGFRcys is an indicator for the accuracy of the mean of the two estimates. As long as the difference between the two (|ΔeGFR|) is below 40%, a high P30 accuracy rate of more than 90% was documented in research settings using gold-standard GFR measurements. This was the case in approximately 80% of the measurements. The study was set out to explore |ΔeGFR| in a broader pediatric nephrological population and identify factors influencing the discrepancy between eGFRcrea and eGFRcys. We retrospectively analyzed 1596 simultaneous cystatin C and creatinine measurements in 649 unique patients at the pediatric nephrology outpatient clinic of VU university medical center. The FASage equation was used to calculate eGFRcrea, FAScys for eGFRcys. |ΔeGFR| was calculated as 100x(|eGFRcrea-eGFRcys|)/(0.5x(eGFRcrea+eGFRcys). ΔeGFR below 40% was considered high agreement. Patient characteristics like age, diagnosis, glucocorticosteroid use, eGFR, BMI and sex were analyzed for their effect on ΔeGFR below or above 40% using non-parametric tests and a potential explanation for measurements with low agreement was sought. Eighty-seven percent of the population had a |ΔeGFR| lower than 40%. Measurements with |ΔeGFR| above 40% were significantly more frequent from patients with neural tube defects. In 102 out of 208 measurements with low agreement, a potential explanation was found. In a broad pediatric nephrological population, |ΔeGFR| is below 40% in the vast majority of measurements. In this group, the mean of eGFRcrea and eGFRcys can be used as an accurate estimate of GFR.

Evidence for shrunken pore syndrome in children.

The link between cystatin C and mortality independent of glomerular filtration rate (GFR) in adults has prompted the "Shrunken Pore Syndrome" (SPS) hypothesis, where high serum cystatin C with normal creatinine is explained by smaller glomerular pores, through which creatinine can pass freely, while the larger cystatin C, beta-trace protein (BTP) and pro-inflammatory molecules are retained. This study set out to apply the definition of SPS to children. In 294 children who underwent inulin clearance (Cin) test, serum creatinine, cystatin C and BTP were measured. For all three markers eGFRx was calculated using the full age spectrum equations. The ratio eGFRcys/eGFRcrea was plotted against the error of eGFRBTP(%) (i.e. eGFRBTP-Cin)/Cin*100%). Patients with and without SPS according to different cut-off points of eGFRcys/eGFRcrea and eGFRcys/Cin (i.e. ≤0.6,0.7,0.8) were compared in terms of eGFRx, Cin, error of eGFRx(%) and eGFRBTP/eGFRcrea-ratio. The ratio eGFRcys/eGFRcrea and error of eGFRBTP(%) were positively correlated. The prevalence of SPS by eGFRcys/eGFRcrea with a cut-off of 0.6 was 4.8%. Patients with SPS had a more negative error of eGFRcys(%) and eGFRBTP(%) and higher Cin regardless of the definition. Overestimation of eGFRcrea in patients with SPS was only present when using the eGFRcys/eGFRcrea rather than the eGFRcys/Cin definition. Cystatin C and BTP are related independent of creatinine, suggesting glomerular pore size as a common denominator. The prevalence of SPS in children is comparable to adults. For research in SPS, a definition based on eGFRcys/exogenous clearance study may be useful to study the effect of SPS on creatinine metabolism.

Estimation of GFR in children using rescaled beta-trace protein.

INTRODUCTION: Beta-trace protein (BTP) is a low molecular weight protein, produced mainly in the cerebrospinal fluid. It has been proposed as a marker for kidney function. Recently, a new method for GFR estimation using mean normal values to rescale GFR marker concentrations has been described for creatinine and cystatin C, two commonly used endogenous markers for kidney function. The aim of this study is to apply this approach to BTP in children. METHOD: We retrospectively analyzed serum concentrations of creatinine, cystatin C and BTP measured during inulin clearance tests in children. BTP was measured using a particle-enhanced immunonephelometric assay (Siemens Healthcare). A novel BTP-based eGFR equation was developed using published normal values for children: eGFRBTP[ml/min/1.73m2] = 107.3/BTP/QBTP with QBTP = 0.69. Performance of this equation was compared to the established creatinine-based full age spectrum equation FASage and the cystatin C-based FAScys equations as well as the BTP-based Benlamri equation in terms of bias, % prediction error and P30 and P10 accuracy rates. RESULTS: 322 inulin clearance tests were studied. Overall, our novel equation performed comparably to the creatinine-based FASage and the BTP-based Benlamri equations but was less accurate than FAScys (P30: 79.2 vs 86.3%, p = .008). Combining markers significantly enhanced performance compared to the single marker equations, with the exception of FAScys. CONCLUSION: Rescaled BTP concentrations are a simple method for estimating GFR in children. However, the additional value of BTP for the estimation of GFR compared to rescaled creatinine and cystatin C still remains to be demonstrated.

GFR-estimation by serum creatinine during glucocorticosteroid therapy.

BACKGROUND: While glucocorticosteroids (GCS) are widely used in patients with kidney disease, little is known about their effect on serum creatinine, the most commonly used endogenous marker of kidney function. METHODS: We assessed the effect of GCS on the relationship between estimated GFR using the Schwartz equation (eGFR) and measured GFR using a single-injection inulin clearance (Cin) in children both in a paired analysis and a cross-sectional study. Primary outcome variable was the difference between eGFR and Cin (ΔGFR) in a paired analysis involving 22 patients during and off GCS treatment (mean GFR 103.8 ml/min/1.73 m2, mean prednisone dose 34.8 mg/m2/day). In a cross-sectional analysis in 42 patients receiving GCS (mean dose of 25.7 mg/m2/day), a dose-dependent effect was explored using univariate and multivariate linear regression of various variables including GCS dosage with serum creatinine as dependent variable. RESULTS: The paired analysis showed no significant difference in ΔGFR with or without GCS [- 23 (SD 53) vs. - 9 (SD 41) ml/min/1.73 m2, p = 0.203]. Stepwise multivariate linear regression analysis showed a significant correlation between age and Cin, while GCS dose was not related to serum creatinine. CONCLUSION: GCS use had no significant effect on serum creatinine as a marker for kidney function in a mixed population of renal outpatient clinic children.

Combining GFR estimates from cystatin C and creatinine-what is the optimal mix?

BACKGROUND: Combining estimated glomerular filtration rate (eGFR) equations based on creatinine and cystatin C has been shown to improve the accuracy of GFR estimation. This study aims to optimize this strategy for height-independent GFR estimation in children. METHODS: Retrospective study of 408 inulin clearance tests with simultaneous International Federation of Clinical Chemistry-calibrated measurements of creatinine, cystatin C, and urea in children (mean age 12.5 years, GFR 91.2 ml/min/1.73m2) comparing the arithmetic (meanarith) and geometric means (meangeom) of a height-independent creatinine-based (full age spectrum, based on age (FASage)) and a cystatin C-based equation (FAScys), with the complex height-dependent CKiD3 equation incorporating gender, height, cystatin C, creatinine, and urea. RESULTS: Meangeom had a P30 accuracy of 89.2% compared to meanarith 87.7% (p = 0.030) as well as lower bias and %precision error and performed almost as well as CKiD3 (P30 accuracy 90.9%). Modifying the weight of FASage and FAScys when calculating the means showed that an equal contribution was most accurate in most patients. In spina bifida patients, FAScys alone outperformed any combination. Malignancy or nephritis patients had slightly higher accuracy with weighted means favoring cystatin C or creatinine, respectively. Disagreement between FAScys and FASage was inversely correlated with the accuracy of meangeom. When disagreement exceeded 40%, application of weighted means based on diagnosis improved the performance of eGFR. CONCLUSIONS: In the absence of height data, the optimal strategy for estimating GFR in children is by using the geometric mean of FASage and FAScys. When there is large disagreement between the two, weighted means based on diagnosis improve accuracy.

Endogenous markers for kidney function in children: a review.

Although glomerular filtration rate (GFR) in children can be measured using a gold-standard technique following injection of an exogenous marker, this invasive and cumbersome technique is not widely available and GFR is commonly estimated using serum levels of endogenous markers. Creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin are well-established endogenous markers of kidney function. These markers differ in site of production and effects of diet and medication, as well as renal-tubular handling and extra-renal elimination. For each marker, different methods are available for measurement. Importantly, the measurements of creatinine and cystatin C have recently been standardized with the introduction of international reference standards. In order to allow estimation of GFR from serum marker concentrations, different equations for estimated GFR (eGFR) have been developed in children, using simple or more complex regression strategies with gold standard GFR measurements as a dependent variable. As a rule, estimation strategies relying on more than one marker - either by calculating the average of single parameter equations or by using more complex equations incorporating several parameters - outperform eGFR estimations using only a single marker. This in-depth review will discuss the physiology, measurement and clinical use of creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin in children. It will also address the generation of eGFR equations in children and provide an overview of currently available eGFR equations for the pediatric age group.

Accurate eGFR reporting for children without anthropometric data.

INTRODUCTION: Reporting estimated glomerular filtration rate (eGFR) instead of serum concentrations is advised in current guidelines. Most creatinine-based eGFR equations for children require height, a parameter not readily available to laboratories. Combining height-dependent creatinine- and cystatin C-based eGFR improves performance. Recently, a height-independent creatinine-based eGFR equation has been developed. AIM: To compare the combination of height-independent creatinine- and cystatin C-based equations with a combination of equations using anthropometric data. METHODS: Retrospective analysis of 408 pediatric inulin clearance studies with simultaneous height, creatinine, cystatin C and urea measurements. eGFR calculation using the recalibrated Schwartzcrea (height-dependent), FASage (height-independent) and the Schwartzcys equation. The means (Schwartzcrea+Schwartzcys)/2 and (FASage+Schwartzcys)/2 were compared with the CKiD3 equation incorporating cystatin C, creatinine, urea, height and gender in terms of %prediction error and accuracy. RESULTS: All three single parameter equations performed similarly (P30 accuracy around 80%). (FASage+Schwartzcys)/2 (P30 89.2%) and (Schwartzcrea+Schwartzcys)/2 (P30 89.0%), performed comparably to CKiD3 (P30 90.0%). If the difference between the creatinine- and the cystatine C based eGFR was <40%, P30 accuracy of the mean exceeded 90%. CONCLUSION: Combining the height-independent FASage and SchwartzCys equations substantially improves accuracy and performs comparably to height-dependent equations. This allows laboratories to directly report eGFR in children.

Estimating glomerular filtration rate (GFR) in children. The average between a cystatin C- and a creatinine-based equation improves estimation of GFR in both children and adults and enables diagnosing Shrunken Pore Syndrome.

Estimating glomerular filtration rate (GFR) in adults by using the average of values obtained by a cystatin C- (eGFRcystatin C) and a creatinine-based (eGFRcreatinine) equation shows at least the same diagnostic performance as GFR estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparison of eGFRcystatin C and eGFRcreatinine plays a pivotal role in the diagnosis of Shrunken Pore Syndrome, where low eGFRcystatin C compared to eGFRcreatinine has been associated with higher mortality in adults. The present study was undertaken to elucidate if this concept can also be applied in children. Using iohexol and inulin clearance as gold standard in 702 children, we studied the diagnostic performance of 10 creatinine-based, 5 cystatin C-based and 3 combined cystatin C-creatinine eGFR equations and compared them to the result of the average of 9 pairs of a eGFRcystatin C and a eGFRcreatinine estimate. While creatinine-based GFR estimations are unsuitable in children unless calibrated in a pediatric or mixed pediatric-adult population, cystatin C-based estimations in general performed well in children. The average of a suitable creatinine-based and a cystatin C-based equation generally displayed a better diagnostic performance than estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparing eGFRcystatin and eGFRcreatinine may help identify pediatric patients with Shrunken Pore Syndrome.

Barriers to conducting effective obstetric audit in Ifakara: a qualitative assessment in an under-resourced setting in Tanzania.

OBJECTIVE: To explore barriers to and solutions for effective implementation of obstetric audit at Saint Francis Designated District Hospital in Ifakara, Tanzania, where audit results have been disappointing 2 years after its introduction. METHODS: Qualitative study involving participative observation of audit sessions, followed by 23 in-depth interviews with health workers and managers. Knowledge and perceptions of audit were assessed and suggestions for improvement of the audit process explored. RESULTS: During the observational period, audit sessions were held irregularly and only when the head of department of obstetrics and gynaecology was available. Cases with evident substandard care factors were audited. In-depth interviews revealed inadequate knowledge of the purpose of audit, despite the fact that participants regarded obstetric audit as a potentially useful tool. Insufficient staff commitment, managerial support and human and material resources were mentioned as reasons for weak involvement of health workers and poor implementation of recommendations resulting from audit. Suggestions for improvement included enhancing feedback to all staff and managers to attend sessions and assist with the effectuation of audit recommendations. CONCLUSION: Obstetric staff in Ifakara see audit as an important tool for quality improvement. They recognise, however, that in their own situation, insufficient staff commitment and poor managerial support are barriers to successful implementation. They suggested training in concept and principles of audit as well as strengthening feedback of audit outcomes, to achieve structural health care improvements through audit.