Assessment of kidney function : clinical indications for measured GFR

We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charite´– Universitätsmedizin Berlin. Publisher Copyright: © The Author(s) 2021.In the vast majority of cases, glomerular filtration rate (GFR) is estimated using serum creatinine, which is highly influenced by age, sex, muscle mass, body composition, severe chronic illness and many other factors. This often leads to misclassification of patients or potentially puts patients at risk for inappropriate clinical decisions. Possible solutions are the use of cystatin C as an alternative endogenous marker or performing direct measurement of GFR using an exogenous marker such as iohexol. The purpose of this review is to highlight clinical scenarios and conditions such as extreme body composition, Black race, disagreement between creatinine- and cystatin C-based estimated GFR (eGFR), drug dosing, liver cirrhosis, advanced chronic kidney disease and the transition to kidney replacement therapy, non-kidney solid organ transplant recipients and living kidney donors where creatinine-based GFR estimation may be invalid. In contrast to the majority of literature on measured GFR (mGFR), this review does not include aspects of mGFR for research or public health settings but aims to reach practicing clinicians and raise their understanding of the substantial limitations of creatinine. While including cystatin C as a renal biomarker in GFR estimating equations has been shown to increase the accuracy of the GFR estimate, there are also limitations to eGFR based on cystatin C alone or the combination of creatinine and cystatin C in the clinical scenarios described above that can be overcome by measuring GFR with an exogenous marker. We acknowledge that mGFR is not readily available in many centres but hope that this review will highlight and promote the expansion of kidney function diagnostics using standardized mGFR procedures as an important milestone towards more accurate and personalized medicine.Peer reviewe

The Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 kidney analysis examined long-term glomerular dysfunction in childhood cancer survivors

This investigation aimed to evaluate glomerular dysfunction among childhood cancer survivors in comparison with matched controls from the general population. In the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, 1024 survivors five or more years after diagnosis, aged 18 or more years at study, treated between 1963-2001 with nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation participated. In addition, 500 age- and sex-matched controls from Lifelines, a prospective population-based cohort study in the Netherlands, participated. At a median age of 32.0 years (interquartile range 26.6-37.4), the glomerular filtration rate was under 60 ml/min/1.73m2 in 3.7% of survivors and in none of the controls. Ten survivors had kidney failure. Chronic kidney disease according to age-thresholds (glomerular filtration rate respectively under 75 for age under 40, under 60 for ages 40-65, and under 40 for age over 65) was 6.6% in survivors vs. 0.2% in controls. Albuminuria (albumin-to-creatinine ratio over3 mg/mmol) was found in 16.2% of survivors and 1.2% of controls. Risk factors for chronic kidney disease, based on multivariable analyses, were nephrectomy (odds ratio 3.7 (95% Confidence interval 2.1-6.4)), abdominal radiotherapy (1.8 (1.1-2.9)), ifosfamide (2.9 (1.9-4.4)) and cisplatin over 500 mg/m2 (7.2 (3.4-15.2)). For albuminuria, risk factors were total body irradiation (2.3 (1.2-4.4)), abdominal radiotherapy over 30 Gy (2.6 (1.4- 5.0)) and ifosfamide (1.6 (1.0-2.4)). Hypertension and follow-up 30 or more years increased the risk for glomerular dysfunction. Thus, lifetime monitoring of glomerular function in survivors exposed to these identified high risk factors is warranted.</p

Hypertension in long-term childhood cancer survivors after treatment with potentially nephrotoxic therapy; DCCSS-LATER 2:Renal study

Purpose: To evaluate the prevalence of and risk factors for hypertension in childhood cancer survivors (CCSs) who were treated with potentially nephrotoxic therapies. Methods: In the Dutch Childhood Cancer Survivor Study LATER cohort part 2 renal study, 1024 CCS ≥5 years after diagnosis, aged ≥18 years at study participation, treated between 1963 and 2001 with nephrectomy, abdominal radiotherapy, total body irradiation (TBI), cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide (≥1 g/m2 per single dose or ≥10 g/m2 total) or haematopoietic stem cell transplantation participated and 500 controls from Lifelines. Hypertension was defined as blood pressure (BP) (mmHg) systolic ≥140 and/or diastolic ≥90 or receiving medication for diagnosed hypertension. At the study visit, the CKD-EPI 2012 equation including creatinine and cystatin C was used to estimate the glomerular filtration rate (GFR). Multivariable regression analyses were used. For ambulatory BP monitoring (ABPM), hypertension was defined as BP daytime: systolic ≥135 and/or diastolic ≥85, night time: systolic ≥120 and/or diastolic ≥70, 24-h: systolic ≥130 and/or diastolic ≥80. Outcomes were masked hypertension (MH), white coat hypertension and abnormal nocturnal dipping (aND). Results: Median age at cancer diagnosis was 4.7 years (interquartile range, IQR 2.4–9.2), at study 32.5 years (IQR 27.7–38.0) and follow-up 25.5 years (IQR 21.4–30.3). The prevalence of hypertension was comparable in CCS (16.3%) and controls (18.2%). In 12% of CCS and 17.8% of controls, hypertension was undiagnosed. A decreased GFR (<60 ml/min/1.73 m2) was associated with hypertension in CCS (OR 3.4, 95% CI 1.4–8.5). Risk factors were abdominal radiotherapy ≥20 Gy and TBI. The ABPM-pilot study (n = 77) showed 7.8% MH, 2.6% white coat hypertension and 20.8% aND. Conclusion: The prevalence of hypertension was comparable among CCS who were treated with potentially nephrotoxic therapies compared to controls, some of which were undiagnosed. Risk factors were abdominal radiotherapy ≥20 Gy and TBI. Hypertension and decreased GFR were associated with CCS. ABPM identified MH and a ND

A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects

Background Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects. Methods In th

Coding of coronary arterial origin and branching in congenital heart disease: The modified Leiden Convention

Objectives: Variations in coronary anatomy are common and may relate to the position of the coronary ostium relative to the aortic sinus, the angle of coronary take-off, or the course of the coronary arterial branches. Several classification systems have been proposed. However, they all lack a simple rationale that is applicable irrespective of the relative position of the great arteries, as well as in bicuspid aortic valves. We present a modification of a relatively simple system introduced in the early 1980s, designated the “Leiden Convention.” Methods: The first step of the Leiden Convention is that the clinician takes position in the nonfacing sinus of the aorta looking toward the pulmonary orifice. The right-hand facing sinus is sinus 1, and the left-hand facing sinus is sinus 2. The coronary branches arising from sinus 1 are annotated proceeding in a counterclockwise fashion toward sinus 2. “Usual” (normal) coronary anatomy would be 1R-2LCx. Given their clinical relevance, single sinus coronary arteries are discussed separately. Results: This system was originally designed and highly applicable in hearts with an altered great artery relationship, such as in the var

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.publishedVersio

Genes in the Ureteric Budding Pathway: Association Study on Vesico-Ureteral Reflux Patients

Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p<0.005 were included in a follow-up study in 202 cases and 892 controls. Of the total cohort, ∼50% showed a clear-cut primary VUR phenotype and ∼25% had both a duplex collecting system and VUR. We also looked for association in these two extreme phenotype groups. None of the SNPs reached a significant p-value. Common genetic variants in four genes (GREM1, EYA1, ROBO2 and UPK3A) show a trend towards association with the development of primary VUR (GREM1, EYA1, ROBO2) or duplex collecting system (EYA1 and UPK3A). SNPs in three genes (TGFB1, GNB3 and VEGFA) have been shown to be associated with VUR in other populations. Only the result of rs1800469 in TGFB1 hinted at association in our study. This is the first extensive study of common variants in the genes of the ureteric budding pathway and the genetic susceptibility to primary VUR

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

peer reviewed("[en] BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.","[en] ",""