Increased Plasma Hcy Levels Research Articles

Causal effects of homocysteine levels on the components of sarcopenia: A two-sample mendelian randomization study.

Background: Currently, it is unclear whether there is a causal association between genetically predicted plasma homocysteine (Hcy) levels and the risk of sarcopenia. We performed a Mendelian randomization (MR) study to assess the association between circulating Hcy levels and the components [grip strength, walking pace, and appendicular lean mass (ALM)] of sarcopenia. Methods: Independent single nucleotide polymorphisms (SNPs) significantly associated with plasma Hcy levels served as instrumental variables. Summary-level data regarding the components of sarcopenia. Were obtained from the UK Biobank. Inverse variance weighted (IVW) as the primary method was used for Mendelian randomization (MR) analysis. We also use four models, weighted median, MR-Egger regression, Maximum likelihood, and Penalised weighted median, as supplementary methods to IVW. The MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of the causal association between Hcy levels and the components of sarcopenia. Results: The IVW-MR analysis suggested significant negative associations of increased plasma Hcy levels with grip strength (right: effect = -0.036, SE = 0.032, p = 5.53E-4; left: effect = -0.045, SE = 0.010, p = 1.45E-5), walking pace (effect = -0.038, SE = 0.011, p = 3.18E-4), and ALM (effect = -0.058, 0.013, p = 1.03E-5). However, there were no significant associations of decreased plasma Hcy levels with grip strength (right: effect = 0.005, SE = 0.021, p = 0.82; left: effect = -0.006, SE = 0.014, p = 0.64), walking pace (effect = 0.01, 0.020, p = 0.61), or ALM (effect = -0.034, SE = 0.018, p = 0.06).The accuracy and robustness of these findings were confirmed by sensitivity tests. Conclusion: Increased circulating Hcy levels were associated with lower grip strength, slower walking pace, and decreased ALM.

A compound reflects the level of homocysteine based on Rhodamine B and its ability to respond to homocysteine in the plasma of diabetic patients.

BackgroundThe level of homocysteine (Hcy) is significantly elevated in the plasma of patients with diabetes. The increased plasma Hcy level is positively correlated with the severity of the disease and is one of the important causes of diabetic complications.MethodsWe designed and synthesized a compound could reflect the level of Hcy based on rhodamine B, and the structure was verified by 1H‐NMR and EI‐HRMS. Then, the linearity, repeatability, selectivity, and cellar toxicity, the effects of the fluid viscosity and pH of compound on Hcy were measured; meanwhile, the response of Hcy level in the plasma of diabetic patients was detected.ResultsThis is a novel compound that has never been reported. The compound showed a satisfactory linear range and repeatability at the viscosity and pH of physiological fluid. In addition, the compound was capable of evading the interference from other amino acids and metal ions, and it exhibited high selectivity toward Hcy.ConclusionThe compound showed increased responsiveness to plasma Hcy in patients with diabetes in comparison with healthy individuals and effectively reflected plasma Hcy levels in healthy individuals and diabetic patients. Therefore, the compound is expected to be used in the diagnosis of diabetes mellitus.

Link between Homocysteine and Cardiovascular Diseases

Purpose of Review Numerous studies have shown a positive correlation between serum Hcy level and various pathological conditions such as coronary, carotid, and peripheral vascular disease. Increased plasma Hcy levels are associated not only with an increased risk of arteriosclerosis but also with atherosclerosis and thrombosis. The aim of this review is to review biochemical mechanisms responsible for development and progression of cardiovascular diseases (CVD).

Mesenchymal Stem Cells Derived Exosomes Promotes Bone Regeneration through Cystathionine‐β‐synthase Enhanced Angiogenesis and Osteogenesis during Bone Development

It is critical that bone formation and angiogenesis are tightly coordinated during bone development and fracture healing, but the molecular regulator of such intercellular communication in bone microenvironment are not well studied. Cystathionine‐β‐synthase (CBS), an enzyme in homocysteine (Hcy) metabolic pathway play crucial role in osteoblast differentiation. Therefore, we hypothesize that CBS as a novel molecular regulator in osteoblasts, which regulates vascularization during bone development in osteoblast derived exosome. To test this hypothesis, we have used 7–10 weeks old male mice in our study; wild type mice (C57BL/6, WT) and CBS+/− mice. Blocking the CBS function was done by either inhibitor hydroxylamine (HA) or SiRNA prevented osteoblast differentiation and mineralization. This was supported by studies using osteoblasts cultured from bone marrow of CBS deficient (CBS+/−) mice. Exosomes of mesenchymal stem cell derived osteoblasts cultured stimulated endothelial migration and angiogenesis, which was prevented by blocking CBS in osteoblasts using HA or SiRNA. Mass spectrometry analysis and ELISA assay identified among others vascular endothelial growth factor (VEGF)‐A and VEGF homolog placental growth factor (PIGF) to be present in control osteoblasts culture medium and CBS(+/+) mice osteoblasts but not in osteoblasts treated with HA and CBS+/− osteoblasts. Immunostaining and metatarsal angiogenesis assay showed retarded vascularization in bone tissue of CBS+/− mice. However, osteopenia phenotype was confirmed in CBS+/− mice by microCT analysis. CBS+/− mice showed significantly reduced bone mineral density (BMD) and bone volume/tissue volume (BV/TV) and showed increased plasma Hcy levels compared to CBC+/+ mice (WT). However, CBS+/− mice exhibited a more significant increase in the number of TRAP‐positive osteoclasts and higher levels of RANKL than CBS+/+ mice. This suggests that Hcy levels may be associated with osteoclast activity. Furthermore, real‐time PCR and western blot analyses revealed significant decreases Alkaline phosphatase (ALP) and Runt‐related transcription factor 2 (RUNX2) expression in CBS‐deficient (CBS+/−) mouse bone marrow cells. In conclusion, we demonstrate that CBS in osteoblasts is at the crossroad of osteoblast differentiation/mineralization and angiogenesis. These findings uncover the previously undefined molecular understanding of CBS that promote angiogenesis and osteogenesis in bone development and fracture repair.Support or Funding InformationThis work is financial supported from National Institute of health grant AR‐067667 and HL‐107640‐NT are greatly acknowledged.

Hyperhomocysteinemia is associated with decreased apolipoprotein AI levels in normal healthy people.

BackgroundHyperhomocysteinemia (HHcy) is an independent risk factor for various cardiovascular diseases. Animal studies have shown that homocysteine (Hcy) inhibits hepatic expression of apolipoprotein AI (apoAI). Our recent clinical study showed that increased plasma Hcy levels were associated with decreased apoAI levels in patients with impaired glucose tolerance. In this study, we assessed a potential association between Hcy and apoAI levels in normal healthy people.MethodsA total of 1768 normal healthy individuals were divided into two groups: the control group (subjects without HHcy) and the HHcy group (subjects with HHcy).ResultsHHcy subjects exhibited significantly lower high-density lipoprotein cholesterol (HDL-C) and apoAI levels than the control group (HDL-C: 1.18 ± 0.25 vs. 1.29 ± 0.32 mmol/L; apoAI: 1.38 ± 0.19 vs. 1.47 ± 0.25 g/L; all P < 0.01). Plasma Hcy levels were negatively associated with HDL-C and apoAI levels after adjustments for age, BMI and TG (HDL-C: r = –0.10; apoAI: r = –0.11; all P < 0.05). Multivariate regression analysis showed that the plasma Hcy levels were an independent influencing factor for apoAI (β = –0.065, P < 0.05).ConclusionsIncreased plasma Hcy levels were associated with decreased apoAI levels in normal healthy people, and the inhibition of apoAI synthesis might be a mechanism through which Hcy is linked with the development of atherosclerosis in HHcy subjects.

Folic Acid Mitigates Angiotensin-II-Induced Blood Pressure and Renal Remodeling

Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension increases plasma Hcy levels and contributes to renovascular remodeling. We also tested whether folic acid (FA) treatment reduces plasma Hcy levels by enhancing Hcy remethylation and thus mitigating renal remodeling. Hypertension was induced in WT mice by infusing Ang II using Alzet mini osmotic pumps. Blood pressure, Hcy level, renal vascular density, oxidative stress, inflammation and fibrosis markers, and angiogenic- and anti-angiogenic factors were measured. Ang II hypertension increased plasma Hcy levels and reduced renal cortical blood flow and microvascular density. Elevated Hcy in Ang II hypertension was associated with decreased 4, 5-Diaminofluorescein (DAF-2DA) staining suggesting impaired endothelial function. Increased expression of Nox-2, -4 and dihydroethidium stain revealed oxidative stress. Excess collagen IV deposition in the peri-glomerular area and increased MMP-2, and -9 expression and activity indicated renal remodeling. The mRNA and protein expression of asymmetric dimethylarginine (ADMA) was increased and eNOS protein was decreased suggesting the involvement of this pathway in Hcy mediated hypertension. Decreased expressions of VEGF and increased anti-angiogenic factors, angiostatin and endostatin indicated impaired vasculogenesis. FA treatment partially reduced hypertension by mitigating HHcy in Ang II-treated animals and alleviated pro-inflammatory, pro-fibrotic and anti-angiogenic factors. These results suggest that renovascular remodeling in Ang II-induced hypertension is, in part, due to HHcy.

Study on correlation between plasma homocysteine levels and TCM syndromes of dementia

Objective To investigate the relationship between plasma homocysteine (Hcy) levels and TCM syndromes of dementia.Methods 250 cases were divided into a dementia group (120 cases) and non-dementia group (130 cases).120 cases in the dementia group include 36 Alzheimer dementia(AD) patients and 84 vascular dementia (VaD) patients.The plasma levels of Hcy were measured in all 250 cases.The relationship between Hcy levels,TCM syndromes and dementia was analyzed.Results The level of plasma Hcy was significantly higher in the dementia group (17.13 ± 9.01) nmol/ml than that in the non-dementia group (12.81 ± 7.94) nmol/ml,and it was highest in the VaD patients (P＜0.01).The mean of Hcy concentration in obstruction of phlem-turbid syndrome was higher(18.43±7.81)nmol/ml than syndromes [Tanyuzuluo (5.38 ± 8.91)nmol/ml,Shenxusuikui (16.44 ± 9.05)nmol/ml,Shenyinkuixu(16.19 ± 9.24)nmol/ml,Ganjinghuowang (15.92 ± 7.28)nmol/m1,Pishen-Yangxu(12.26 ± 5.17) nmol/ml (P ＜ 0.01)].Conclusion Increased plasma Hcy levels may be one of the risk factors leading to AD or VaD. Key words: Dementia; Homocysteine; TCM syndromes

Akut İskemik İnmeli Hastalarda Plazma Homosistein Seviyeleri: Kesitsel Bir Çalışma

Objective: In this study, we aimed to investigate plasma homocysteine (Hcy) changes in patients within the acute period of ischemic stroke. Material and Methods: In this cross-sectional study, a total of 110 patients with acute ischemic stroke presenting within 48 hours of onset and 45 age and gender-matched healthy subjects were evaluated. Hcy was measured on 2nd, 4th, 7th, 10th and 14th days of the hospitalization. Control samples were also collected after a 12-hour fasting period. Results: Statistically significantly lower Hcy levels were found in acute ischemic stroke patients on the 2nd day compared to the control group (p<0.001). No significant difference was found in the 4th day between the groups (p=0.478). In all other days on which test was performed, Hcy levels were statistically significantly higher in acute ischemic stroke group compared to the control group (p<0.001 for all). Conclusion: This study suggests that Hcy levels are not significantly elevated after recent ischemic stroke, but rise in the 2nd week of admission, and our findings do not support the hypothesis that raised plasma Hcy levels predate ischemic stroke. Therefore, increased plasma Hcy level is a consequence of disease process, and has no value as a predictor of ischemic stroke.

Plasma phospholipid polyunsaturated fatty acids and homocysteine in Chinese type 2 diabetes patients.

The main aim of the present study was to investigate the plasma phospholipids (PL) fatty acids status and its association with plasma Hcy in patients with type 2 diabetes mellitus (T2DM). One hundred and four T2DM (aged 57.3±13.4 y) and 150 healthy subjects (aged 48.4±8.7 y) were recruited. Plasma Hcy and PL fatty acids were determined by standard methods. Plasma Hcy concentration in T2DM was significantly higher than that in healthy subjects (p<0.001). The prevalence of hyperhomocysteinemia was significantly higher in T2DM (36.54%) than that in healthy subjects (17.32%) (p=0.012). Plasma PL 20:4n-6 (r=0.303, p=0.012), 22:5n-3 (r=0.312, p=0.01), total PUFA (r=0.303, p=0.012), n-6 PUFA (r=0.261, p=0.032) were significantly positively associated with plasma Hcy concentration in T2DM. While, plasma PL n-3:n-6 PUFA (r=-0.400, p=0.046) was negatively associated with plasma Hcy in T2DM. In healthy subjects, plasma PL 22:6n-3 (r=-0.201, p=0.042) was negatively associated with plasma Hcy. In addition, plasma PL 22:6n-3 (r=0.193, p=0.044) and 22:5n-6 (r=0.234, p=0.038) were significantly negatively associated with plasma vitamin B-12 in healthy subjects. Our results suggested that increased plasma Hcy levels in T2DM associated with low n-3:n-6 ratio intake. We suggest that T2DM increase their long chain n-3 PUFA intake from fish or fish oil while decrease n-6 PUFA intake.

Thrombosis and risk factors: A comment

We read with great interest the recent publication by Akar related to thrombosis and risk factors, in which he reached in conclusion that in case of need only homocysteine (Hcy) levels should be routinely analyzed and not the 5, 10-methylenetetrahydrofolate reductase (mTHFr) 677 T polymorphism [1]. The methylation of Hcy to methionine is catalyzed by the mTHFr enzyme. As far as is known, genetic deficiency of mTHFr is one cause leading to increased plasma Hcy levels [2]. But, it should not be forgotten that Hcy rises in many acquired and genetic conditions (Table) [3]. There are three main indications for determining plasma total Hcy: (a) to diagnose homocystinuria; (b) to identify individuals with or at risk of developing cobalamin or folate deficiency; (c) to assess total Hcy as a risk factor for cardiovascular and other disorders [4]. There is an involved question in this point: Is increased plasma total Hcy level related to both venous and arterial occlusive disease? And, if is it true, are polymorphism and mutation of mTHFr directly playing a role to augment the level of Hcy for cardiovascular disease (CvD)? As reviewed elsewhere, moderately increased plasma Hcy is associated with venous and arterial occlusion [5]. moreover, as it is known, the presence of mTHFr 677C→T polymorphism is a strong risk factor for increased plasma Hcy level but not for CvD [4]. In a metaanalysis including 11.162 CvD cases and 12.758 controls, with high Hcy levels in a state of low folate levels, the TT genotype was associated with a 16% increase in coronary heart disease risk [6]. Concordantly, previous studies had shown that the mTHFr 677C→T polymorphism is only associated with high Hcy levels or increased CvD risk in a setting of low folate status [6]. Hence, at higher dietary intakes of folate, the effect of the mTHFr 677C→T genotype has no adverse effect on plasma Hcy levels or on subsequent risk of CvD. The results support the hypothesis that impaired folate metabolism, resulting in high Hcy concentrations, plays a causal role in the occurrence of CvD. In view of cost effectiveness, do not investigate routinely mTHFr 677C→T polymorphism in the general or CvD population seems to be reasonable, but the other mutations of mTHFr could be still influential for high plasma Hcy levels.

Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives

Nicotinamide and catecholamines are both degraded by S-adenosylmethionine-dependent methylation. Whether excess nicotinamide affects the degradation of catecholamines is unknown. The aim of this study was to investigate the effect of nicotinamide on the methylation status of the body and methylation-mediated catecholamine degradation in both normotensives and hypertensives. The study was conducted in 19 normotensives and 27 hypertensives, using a nicotinamide-loading test (100 mg orally). Plasma nicotinamide, N(1)-methylnicotinamide, homocysteine (Hcy), betaine, norepinephrine, epinephrine, normetanephrine and metanephrine levels before and 5 h after nicotinamide loading were measured. Compared with normotensives, hypertensives had higher baseline (fasting) levels of plasma nicotinamide, Hcy and norepinephrine, but lower levels of plasma normetanephrine, a methylated norepinephrine derivative. Nicotinamide loading induced a significant increase in the levels of plasma N(1)-methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives. Moreover, nicotinamide-loading significantly increased plasma Hcy levels, but decreased plasma normetanephrine levels in normotensives. The baseline levels of plasma epinephrine in hypertensives were similar to those of normotensives, but the post-nicotinamide-loading levels of plasma epinephrine in hypertensives were higher than those of normotensives. This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease.

The 894G &gt; T (Glu298Asp) Variant in the Endothelial NOS Gene and MTHFR Polymorphisms Influence Homocysteine Levels in Patients with Cognitive Decline

The presence and severity of cerebrovascular pathological findings have been shown to increase the risk and stage of cognitive decline observed in Alzheimer's disease and vascular dementia. Thus, the modification of vascular risk factors seems useful to reduce the risk of dementia regardless of type. Hyperhomocysteinemia has long been known as a major independent risk factor for vascular dysfunction. In this study, we evaluated the relationships between plasma homocysteine levels and genetic risk factors for hyperhomocysteinemia, i.e., the presence of gene variants for methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (eNOS) in patients with cognitive impairment. Genotyping for MTHFR C677T and eNOS 894G>T polymorphisms was carried out in 69 patients with probable diagnosis of AD and anamnestic mild cognitive impairment, matched for age and gender with 69 healthy volunteers. Patients with MTHFR TT677 genotype showed higher plasma Hcy levels than controls, even after adjustment for folate levels (P<0.05). Moreover, Hcy plasma levels were higher in cases than controls for any given eNOS genotype. In particular, the presence of eNOS TT894 genotype in patients with cognitive decline resulted significantly associated with increased plasma Hcy levels when compared with controls having the same genotype or patients having other eNOS genotypes (P=0.02). These data suggest that both MTHFR C677T and eNOS G894T variants should be regarded as genetic risk factors for hyperhomocysteinemia in patients with cognitive decline.

High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway

BackgroundHyperhomocysteinemia (HHcy) causes increased oxidative stress and is an independent risk factor for cardiovascular disease. Oxidative stress is now believed to be a major contributory factor in the development of non alcoholic fatty liver disease, the most common liver disorder worldwide. In this study, the changes which occur in homocysteine (Hcy) metabolism in high fat-diet induced non alcoholic fatty liver disease (NAFLD) in rats were investigated.Methods and resultsAfter feeding rats a standard low fat diet (control) or a high fat diet (57% metabolisable energy as fat) for 18 weeks, the concentration of homocysteine in the plasma was significantly raised while that of cysteine was lowered in the high fat as compared to the control diet fed animals. The hepatic activities of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGS), the enzymes responsible for the breakdown of homocysteine to cysteine via the transsulphuration pathway in the liver, were also significantly reduced in the high fat-fed group.ConclusionsThese results indicate that high fat diet-induced NAFLD in rats is associated with increased plasma Hcy levels caused by down-regulation of hepatic CBS and CGL activity. Thus, HHcy occurs at an early stage in high fat diet-induced NAFLD and is likely to contribute to the increased risk of cardiovascular disease associated with the condition.

Étude des marqueurs du stress oxydatif chez les coronariens tabagiques tunisiens

Summary Objective The present study was undertaken to evaluate the variation of the parameters of antioxidant and oxidant status in coronary smokers Tunisian patients. Patients and methods We made this study on 72 patients with unstable angina (UA) compared to 30 healthy control subjects. The measured parameters are: homocysteine (Hcy), total antioxidant status (SAT), as well as enzymatic activities of superoxide dismutase (SOD), and glutathion peroxidase (GPx). Results Compared with healthy control subjects, coronary smokers patients had significantly higher Hcy concentration and significant decrease of antioxidant activities. The SAT was positively correlated with the antioxidant enzyme (SOD and GPx). However, Hcy concentration was negatively correlated with the SAT. Conclusion The present study shows clearly the significant reduction of antioxidant system with the concomitant increase in the parameter of oxidant status in smokers patients with UA. Smoking is known to be associated with an increased plasma Hcy level. Both are associated with an increased risk of cardiovascular disease.

Daily rhythms in plasma levels of homocysteine.

BackgroundThere is accumulated evidence that plasma concentration of the sulfur-containing amino-acid homocysteine (Hcy) is a prognostic marker for cardiovascular morbidity and mortality. Both fasting levels of Hcy and post methionine loading levels are used as prognostic markers. The aim of the present study was to investigate the existence of a daily rhythm in plasma Hcy under strictly controlled nutritional and sleep-wake conditions. We also investigated if the time during which methionine loading is performed, i.e., morning or evening, had a different effect on the resultant plasma Hcy concentration.MethodsSix healthy men aged 23–26 years participated in 4 experiments. In the first and second experiments, the daily rhythm in Hcy as well as in other amino acids was investigated under a normal or an inverse sleep-wake cycle. In the third and fourth, Hcy concentrations were investigated after a morning and evening methionine loading. To standardize food consumption in the first two experiments, subjects received every 3 hours 150 ml of specially designed low-protein liquid food (Ensure® formula).ResultsIn both the first and second experiments there was a significant daily rhythm in Hcy concentrations with a mid-day nadir and a nocturnal peak. Strikingly different 24-h patterns were observed in methionine, leucine, isoleucine and tyrosine. In all, the 24-h curves revealed a strong influence of both the sleep-wake cycle and the feeding schedule. Methionine loading resulted in increased plasma Hcy levels during both morning and evening experiments, which were not significantly different from each other.ConclusionsThere is a daily rhythm in plasma concentration of the amino acid Hcy, and this rhythm is independent of sleep-wake and food consumption. In view of the fact that increased Hcy concentrations may be associated with increased cardiovascular risks, these findings may have clinical implications for the health of rotating shift workers.

Hyperhomocysteinemia in children on renal replacement therapy.

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis in adult patients on dialysis or after kidney transplantation. There are few data on homocysteine (Hcy) concentrations in children under these circumstances. The aim of our study was to evaluate plasma Hcy levels and their determining factors in children on renal replacement therapy. In 29 children and adolescents on chronic dialysis therapy and in 34 children after renal transplantation (Tx) fasting total plasma Hcy, red blood cell (RBC) folate, and serum vitamin B(12) levels were measured. The plasma Hcy levels were expressed as number of standard deviations (SD) from mean level in age- and gender-matched controls. In dialysis patients the mean plasma Hcy level was elevated (4.4+/-0.8 SDs), without significant difference between patients on hemodialysis or continuous cycling peritoneal dialysis. In the dialysis patients a negative correlation ( r=-0.49) between plasma Hcy levels and RBC folate concentrations was found. Oral folate supplementation was given to 8 of 21 dialysis patients, resulting in high RBC folate levels (>800 micro g/ml) and normalization of the plasma Hcy levels (0.4+/-0.5 SDs). In Tx patients the mean plasma Hcy level was 5.6+/-1.4 SDs. Multivariate regression analysis revealed that the main factor determining Hcy level after kidney Tx was creatinine clearance. Patients with normal kidney function had a mean Hcy concentration of 1.69+/-0.86 compared with 10.0+/-2.2 in children with decreased function. Folate and cyclosporine levels had less significant effects on Hcy concentrations. Seven patients who were evaluated while on dialysis and after a successful kidney Tx demonstrated a significant reduction in Hcy levels. Children and adolescents on dialysis therapy and with impaired renal function after renal Tx have significant hyperhomocysteinemia. Oral folate supplementation normalizes the increased plasma Hcy levels and should be added to the medical treatment of all children with impaired renal function.