Iron therapy for renal anemia : how much needed , how much harmful ? Iron deficiency is the most common cause of hyporesponsiveness to erythropoiesis-stimulating agents -LRB- ESAs -RRB- in end-stage renal disease -LRB- ESRD -RRB- patients . Iron deficiency can easily be corrected by intravenous iron administration , which is more effective than oral iron supplementation , at least in adult patients with chronic kidney disease -LRB- CKD -RRB- . Iron status can be monitored by different parameters such as ferritin , transferrin saturation , percentage of hypochromic red blood cells , and/or the reticulocyte hemoglobin content , but an increased erythropoietic response to iron supplementation is the most widely accepted reference standard of iron-deficient erythropoiesis . Parenteral iron therapy is not without acute and chronic adverse events . While provocative animal and in vitro studies suggest induction of inflammation , oxidative stress , and kidney damage by available parenteral iron preparations , several recent clinical studies showed the opposite effects as long as intravenous iron was adequately dosed . Thus , within the recommended international guidelines , parenteral iron administration is safe . Intravenous iron therapy should be withheld during acute infection but not during inflammation . The integration of ESA and intravenous iron therapy into anemia management allowed attainment of target hemoglobin values in the majority of pediatric and adult CKD and ESRD patients . Introduction Iron-restricted erythropoiesis is a common clinical condition in patients with chronic kidney disease -LRB- CKD -RRB- . The causes underlying this pathology and the subsequent contribution of absolute or functional iron deficiency to renal anemia include : Inadequate intake of dietary ironBlood loss during the extracorporeal procedure in hemodialysis patientsBlood loss from the gastrointestinal tract -LRB- bleeding -RRB- -LRB- Too -RRB- frequent diagnostic blood testsInadequate intestinal iron absorption and inhibition of iron release from macrophages -LRB- anemia of chronic disease -RRB- Increased iron requirements during therapy with erythropoiesis-stimulating agents -LRB- ESAs -RRB- . In iron deficiency without anemia , reduction in iron storage is not sufficiently large enough to decrease the hemoglobin level . In CKD patients with absolute iron-deficient anemia , however , iron deficit is so severe that it aggravates renal anemia . Iron supplementation is mandatory in the majority of patients with end-stage renal disease -LRB- ESRD -RRB- , particularly in those receiving ESA therapy . Evaluation of iron status In patients with normal kidney function , absolute iron deficiency is characterized by low serum ferritin concentration -LRB- < 30 μg/l -RRB- . The ferritin cut-off level for absolute iron deficiency in CKD patients is 100 μg/l -LSB- 1 -RSB- by the experience that chronic inflammation increases serum ferritin levels approximately three-fold . The Kidney Disease Outcomes Quality Initiative -LRB- K/DOQI -RRB- guidelines recommend serum ferritin levels > 200 μg/l for the adult hemodialysis patient population -LSB- 2 -RSB- . The European Best Practice Guidelines define the optimal range for serum ferritin as 200 -- 500 μg/l in adult patients with ESRD -LSB- 1 -RSB- . A normal ferritin level -LRB- ≥ 100 μg/l -RRB- can not exclude iron deficiency in uremic children -LSB- 3 , 4 -RSB- , but a serum ferritin < 60 μg/l is a specific predictor of its presence -LSB- 5 -RSB- . An upper ferritin level of 500 μg/l is recommended for adults and children with CKD -LSB- 2 -RSB- . Serum ferritin is an indicator of storage iron . Iron deficiency is accompanied by reductions in serum iron concentration and transferrin saturation -LRB- TSAT -RRB- and by elevations in red cell distribution width , free erythrocyte protoporphyrin concentration , total serum iron binding capacity -LRB- TIBC -RRB- , and circulating transferrin receptor -LSB- 6 -RSB- . Serum soluble transferrin receptor , however , reflects ongoing erythropoiesis but not iron availability in ESA-treated chronic dialysis patients -LSB- 7 -RSB- . Typically , TSAT -LRB- the ratio of serum iron to TIBC -RRB- is 15 % or less -LRB- normal 16 -- 40 % -RRB- with iron deficiency , but TSAT also decreases in the presence of acute and chronic inflammation -LRB- functional iron deficiency -RRB- . TSAT is raised with bone marrow dysfunction due to alcohol , cancer chemotherapy , or a megaloblastic process . TSAT is also affected by diurnal variations , being higher in the morning and lower in the evening -LSB- 8 -RSB- . Even a TSAT > 20 % or a serum ferritin level > 200 μg/l does not exclude iron deficiency in ESRD patients . In a study by Chuang et al. -LSB- 9 -RSB- , 17 % of iron-deficient hemodialysis patients had serum ferritin levels greater 300 μg/l . Clinically , functional iron deficiency is confirmed by the erythropoietic response to a course of parenteral iron and is excluded by the failure of erythroid response to intravenous iron administration -LSB- 10 -RSB- . Erythrocyte and reticulocyte indices , such as the percentage of hypochromic red blood cells and the reticulocyte hemoglobin content -LRB- CHr -RRB- provide direct insight into bone marrow iron supply and utilization . Determination of the percentage of hypochromic red blood cells , i.e. , those with a cellular hemoglobin concentration < 28 g/dl , provides important information on functional iron deficiency in ESA-treated dialysis patients -LSB- 11 -RSB- . Tessitore et al. -LSB- 12 -RSB- found that hypochromic red blood cells > 6 % are the best marker to identify adult ESRD patients who will have the best response to intravenous iron . CHr has been proposed as a surrogate marker of iron status and as an early predictor of response to iron therapy in adult dialysis patients -LSB- 13 , 14 -RSB- . Combined use of CHr and high-fluorescence reticulocyte count predicts with a very high sensitivity and specificity the response to intravenous iron in adult dialysis patients -LSB- 8 -RSB- . There are , however , only few studies in the pediatric renal literature on the use of CHr -LSB- 15 , 16 -RSB- . In children with ESRD , an increase from baseline CHr levels was observed in response to oral and intravenous iron , but cut-off values for the use of CHr in the pediatric CKD population are not clear . This measure has proven to be of value with adult ESRD patients . Detection of both absolute and functional iron deficiency is important because iron deficiency is the most common cause of hyporesponsiveness to ESAs . In clinical practice , an increased erythropoietic response to iron supplementation is the most widely accepted reference standard of iron-deficient erythropoiesis . For pharmacological therapy of iron deficiency , both oral and parenteral iron preparations are available . Intravenous iron is more effective than oral iron supplementation , at least in CKD patients . Iron is not only a prerequisite for effective erythropoiesis but also an essential element in all living cells . Elemental iron serves as a component of oxygen-carrying molecules and as a cofactor for enzymatic processes . Its redox potential , however , limits the quantity of iron that can be safely harbored within an individual . Oral iron therapy Oral iron is best absorbed if given without food . Side-effects of oral iron therapy include constipation , diarrhea , nausea , and abdominal pain . In the treatment of iron deficiency with ferrous sulphate , the usual adult dose is one 300 mg tablet -LRB- containing 60 mg elemental iron -RRB- three to four times daily . The pediatric dose is 2 -- 6 mg/kg per day of elemental iron in 2 -- 3 divided doses -LSB- 17 , 18 -RSB- . Intestinal iron absorption is enhanced in patients with iron deficiency and declines with the correction of iron deficiency and reaccumulation of iron stores . If side-effects limit compliance , the medication can be administered with food , or the dose can be reduced . One 500-mg ferrous sulphate dose nightly at bedtime may be an effective therapy in adults -LSB- 19 -RSB- . Uremia is a chronic inflammatory state -LSB- 20 , 21 -RSB- . Even in the absence of overt infection or inflammation , many ESRD patients show increased levels of acute-phase proteins , such as C-reactive protein -LRB- CRP -RRB- , ferritin , fibrinogen , and/or interleukin-6 -LRB- IL-6 -RRB- , associated with low serum albumin levels -LSB- 22 -RSB- . The interaction of proinflammatory cytokines with hepcidin in mediating functional iron deficiency may explain why CKD patients have high ferritin levels , poor intestinal iron absorption , and disturbed iron release from the reticuloendothelial system -LSB- 23 -RSB- . In the duodenum and proximal jejunum , the nonheme dietary Fe3 + is reduced to Fe2 + by the cytochrome b-like ferrireductase Dcytb . Fe2 + is gathered from the lumen of the intestine and crosses the apical enterocyte brush border membrane through the divalent metal transporter-1 -LRB- DMT1 -RRB- . The expression of both Dcytb and DMT1 is strongly affected by the iron concentration within the enterocyte . Circulating levels of hepcidin negatively regulate intestinal iron absorption by the enterocyte DMT1 . Hypoxia , anemia , iron deficiency , and/or stimulated erythropoiesis strongly down-regulate hepatic hepcidin release , allowing intestinal iron absorption , while iron overload or inflammation/infection stimulates hepcidin production , resulting in inhibition of intestinal iron absorption . Hepcidin controls the whole-body iron content . It also inhibits the release of iron by the iron exporter ferroportin -LRB- iron-regulated transporter-1 -RRB- located along the entire basolateral membrane of enterocytes and also in the intracellular vesicular compartment of tissue macrophages . Hepcidin is primarily produced in the liver in response to acute-phase reactions . Any further expression depends on the degree of hepatic iron storage -LRB- for review , see -LSB- 24 -RSB- -RRB- . Thus , the inflammatory state associated with uremia and less uremia per se is predominantly responsible for poor intestinal iron absorption in ESRD patients . In iron-depleted peritoneal dialysis patients with normal CRP values , high-dose oral iron is well absorbed -LSB- 25 -RSB- . The European Pediatric Peritoneal Dialysis Working Group recommended that anemia treatment should aim for a target hemoglobin concentration of at least 11 g/dl accomplished by administration of ESA and iron . Oral iron should be preferred in pediatric peritoneal dialysis patients -LSB- 18 -RSB- . The majority of pediatric hemodialysis patients are also supplemented with oral iron . The 2001 North American Pediatric Renal Transplant Cooperative Study -LRB- NAPRTCS -RRB- annual report showed that 84 % of pediatric peritoneal dialysis and 72 % of pediatric hemodialysis patients at 12 months of dialysis were receiving oral iron therapy -LSB- 26 -RSB- . Intravenous iron therapy Since oral iron therapy is often not sufficient in ESRD patients , parenteral administration of iron is necessary to optimally care for these patients . Intravenous iron can be given safely to CKD patients -LSB- 27 -- 34 -RSB- as long as the therapy is performed according to international recommendations and guidelines -LSB- 1 , 2 -RSB- . This therapy is unequivocally superior to oral iron supplementation -LSB- 35 -RSB- . All forms of intravenous iron may be associated with acute adverse events -LSB- 1 , 2 -RSB- . Potential risk factors associated with intravenous iron therapy include acute allergic reactions such as rash , dyspnoea , wheezing , or even anaphylaxis , as well as long-term complications caused by the generation of powerful oxidant species , initiation and propagation of lipid peroxidation , endothelial dysfunction , propagation of vascular smooth muscle cell proliferation , and/or inhibition of cellular host defense . Allergy is believed to relate to dextran moiety . Iron dextran therapy is associated with a higher risk for serious type I reactions compared with newer intravenous iron products . Iron sucrose carries the lowest risk for hypersensitivity reactions -LSB- 36 -RSB- . In our clinical experience with more than 100,000 intravenous injections of iron sucrose and ferric gluconate within the last 15 years , we detected no significant differences in efficacy or adverse events between both intravenous iron preparations . Serious reactions to iron dextran are unpredictable and possibly life threatening . Labile - or free-iron reactions are more frequent with nondextran forms -LSB- 37 -RSB- . Recommended doses of iron sucrose or ferric gluconate appear safe , at least in adult CKD patients -LSB- 32 , 34 , 38 -RSB- . Parenteral therapy with iron sucrose or ferric gluconate is also safe and effective in the management of anemia in adult hemodialysis patients sensitive to iron dextran -LSB- 29 , 39 -RSB- . Iron sucrose safety data are sparse in the pediatric CKD literature -LSB- 2 -RSB- . It should be considered that the iron load administered intravenously to CKD patients based on international recommendations is more than ten times less than the iron load by repeated blood transfusions at times when no ESA therapy was available for ESRD patients . Iron deficiency in CKD patients develops primarily during the correction of renal anemia by ESA treatment . Approximately 150 mg of iron is necessary for an increase of 1 g/dl in hemoglobin level . In adult hemodialysis patients , annual blood losses up to 4 l of blood , equivalent to 2 g iron , should be considered -LSB- 40 -RSB- . Thus , intravenous iron prevents iron-restricted erythropoiesis during ESA therapy . Parenteral treatment strategies depend on the availability of iron products in respective countries . Hemodialysis patients should receive at least one dose of intravenous iron every 2 weeks -LSB- 1 -RSB- . Careful monitoring of iron status is mandatory in order to avoid iron overload . In patients with anemia of chronic disease -LRB- and inflammation -RRB- , a major part of iron administered intravenously is transported into the reticuloendothelial system , where it is not readily available for erythropoiesis -LSB- 41 -RSB- . Intravenous iron therapy is underused in pediatric ESRD patients . Chavers et al. -LSB- 42 -RSB- compared anemia prevalence in US Medicare pediatric and adult dialysis patients treated with ESAs from 1996 to 2000 . Prevalence of anemia -LRB- defined as hemoglobin values less than 11 g/dl -RRB- was found in pediatric and adult hemodialysis patients during 54.1 % versus 39.8 % patient years as well as in pediatric and adult peritoneal dialysis patients during 69.5 % versus 55.1 % patient years , respectively . The percentage of patient years with intravenous iron was low , especially for pediatric peritoneal dialysis patients : 33.9 % -LRB- age group 0 -- 4 years -RRB- and 71 % -LRB- age group 5 -- 19 years -RRB- versus 0.3 % and 19.4 % among pediatric hemodialysis patients in these age categories , respectively . Among pediatric hemodialysis and peritoneal dialysis patients , intravenous iron was not administered among 34 % and 85 % of patient years -LSB- 42 -RSB- . Data obtained from the US Centers for Medicare and Medicare Services on hemodialysis patients in an age range between 12 and < 18 years indicate that 37 % of these patients are anemic , defined as hemoglobin < 11 g/dl . Dialyzing < 6 months , a low serum albumin , and a mean TSAT < 20 % were identified as predictors of anemia in these children . Despite the prescription of iron supplements in almost all pediatric patients , there was evidence for low TSAT and/or low ferritin in many children . In this study , approximately 60 % of all children received intravenous iron therapy -LSB- 43 -RSB- . An international multicenter study investigated the safety and efficacy of two dosing regimens -LRB- 1.5 mg/kg or 3 mg/kg -RRB- of ferric gluconate during eight consecutive hemodialysis sessions in iron-deficient pediatric hemodialysis patients receiving concomitant ESA therapy . Efficacy and safety profiles were comparable , with no unexpected adverse events with either dose -LSB- 16 -RSB- . Initial recommended ferric gluconate therapy is 1.5 mg/kg for eight doses for iron-deficient pediatric hemodialysis patients and 1 mg/kg per week for iron-replete pediatric hemodialysis patients , with subsequent dose adjustments made according to TSAT and/or ferritin levels -LSB- 16 , 44 -RSB- . In children , iron sucrose in a high dose -LRB- 5 mg/kg -RRB- should be given over 90 min and in a low dose -LRB- up to 2 mg/kg -RRB- over 3 min -LSB- 45 -RSB- . An other recommendation for pediatric patients is to inject 6 mg iron/kg per month during iron deficiency , with subsequent dose adjustments according to serum ferritin -LSB- 46 -RSB- . Nonrandomized intravenous iron -LRB- 1 -- 4 mg/kg per week -RRB- trials in children on hemodialysis and nondialyzed or transplanted children showed an increase in hemoglobin or hematocrit and a decrease in ESA requirements between 5 % and 62 % per week or per dose of ESA -LSB- 3 , 4 , 47 , 48 -RSB- . De Palo et al. -LSB- 49 -RSB- reported an excessive increase in hemoglobin with severe hypertension in children on maintenance hemodialysis after the first month of darbepoetin alpha therapy combined with intravenous ferric gluconate in a very high dose of 10 -- 20 mg/kg per week . The patients had already been on erythropoietin therapy for at least 6 months with adequate iron status -LRB- serum ferritin 220 ± 105 μg/l ; TSAT 24.2 ± 11.5 % -RRB- . The complications observed in this study are not surprising , as such a high-dosed intravenous iron therapy is not justified , either in adult or in pediatric dialysis patients with `` adequate iron status '' . The current practice of intravenous iron therapy in pediatric hemodialysis patients is often performed on extrapolation from adult data and not based on data obtained from prospective multicenter trials performed in children -LSB- 50 -RSB- . Even if exposure to intravenous iron may lead to oxidative stress , renal injury , infection , and/or cardiovascular disease , the magnitude of these complications is not really clear . The overall risk -- benefit ratio favors the use of intravenous iron in CKD patients in order to optimize erythropoiesis and prevent iron deficiency -LSB- 51 -RSB- . Intravenous iron therapy is still underutilized in the adult hemodialysis population -LSB- 52 -RSB- , but its use increased from 1997 to 2002 . Ferric gluconate and iron sucrose have become the predominant form of intravenous iron therapy -LSB- 53 -RSB- . Iron and inflammation/infection Intravenous iron therapy may adversely impact CKD patients via a potentiation of systemic inflammation . In animals , even a single ultra-high-dosed intravenous injection of available iron preparations -LRB- 2 mg iron for mice with a body weight of 25 -- 35 g , corresponding to 5,000 mg iron for a 75-kg adult patient -RRB- does not independently raise plasma levels of tumour necrosis factor-α -LRB- TNF-α -RRB- . Systemic inflammation experimentally induced by intraperitoneal endotoxin injection -LRB- 2 or 10 mg/kg in mice -RRB- resulted in a dramatic increase in plasma TNF-α levels . Interestingly , 2 h following concomitant injection of endotoxin and ferric gluconate -LRB- 2 mg -RRB- or iron dextran -LRB- 2 mg -RRB- , a decrease of plasma TNF-α levels was observed . In contrast , combined endotoxin and iron sucrose injection resulted in a further increase in plasma TNF-α compared with endotoxin alone -LSB- 54 -RSB- . However , a 75-kg CKD patient will neither receive 5,000 -- 25,000 mg endotoxin intraperitoneally nor concomitant 5,000 mg iron sucrose injection intravenously in order to demonstrate that under these artificial conditions , TNF-α mRNA and TNF-α release are stimulated . It is therefore of particular importance that relevant clinical studies demonstrated that intravenous iron sucrose therapy within recommended doses may even display anti-inflammatory effects -LSB- 55 , 56 -RSB- . Intravenous iron sucrose therapy affects positively circulating cytokine levels in hemodialysis patients : IL-4 levels increase , while TNF-α levels decrease -LSB- 55 -RSB- . There is a direct correlation between IL-4 and TSAT but an inverse correlation between TNF-α and TSAT . Hemoglobin levels increase with an increase of IL-4 and a decrease of TNF-α , while ESA dose decreases with an increase of IL-4 and a decrease of TNF-α -LSB- 55 -RSB- . In other words , adequately dosed intravenous iron therapy in hemodialysis patients results in down-regulation of proinflammatory immune effector pathways and stimulation of the expression of the anti-inflammatory cytokine IL-4 . By these mechanisms , in addition to its well-known stimulatory effects on erythropoiesis , iron therapy contributes to an increase in hemoglobin levels and to a decrease in the need of ESAs . The anti-inflammatory properties of intravenous iron therapy have also been demonstrated in patients with rheumatoid arthritis -LSB- 56 -RSB- . In contrast , iron-mediated weakening of the Th-1 immune effector function -LRB- estimated by lowered TNF-α production -RRB- with a subsequent strengthening of Th-2-mediated immune effector function -LRB- estimated by increased IL-4 production -RRB- is an unfavorable condition for ESRD patients in the case of an acute infection or malignant disease -LSB- 55 -RSB- . Moreover , intravenous administration of iron increases the availability of this essential nutrient for microorganisms -LSB- 57 -RSB- associated with an increased incidence of infectious complications in ESRD patients . Teehan et al. -LSB- 58 -RSB- followed 132 hemodialysis patients for up to 1 year after the initiation of intravenous iron therapy for the outcome of bacteremia . Iron-replete patients -LRB- those with a TSAT value ≥ 20 % and a ferritin level ≥ 100 ng/ml -RRB- had a significantly higher risk of bacteremia -LRB- hazard ratio 2.3 in the univariate analysis and 2.5 in the multivariate analysis -RRB- compared with adult hemodialysis patients who were not iron replete -LSB- 58 -RSB- . Inhibition of intracellular killing of bacteria by polymorphonuclear leukocytes -LRB- PMNL -RRB- due to iron sucrose therapy in high-ferritin hemodialysis patients has been reported -LSB- 59 -RSB- . Peritoneal dialysis patients receiving high-dose intravenous iron sucrose also displayed short-term inhibition of bacterial killing by PMNL -LSB- 60 -RSB- . Finally , iron sucrose as well as ferric gluconate inhibit in vitro migration of PMNL through endothelial cells -LSB- 61 -RSB- . All these data suggest a risk for infectious complications , at least in patients overtreated with iron . However , clinical studies on intravenous iron therapy in ESRD patients reported controversial results -LSB- 62 -- 64 -RSB- . According to the published cohort study , among 32,566 hemodialysis patients , there was no association between iron administration and mortality . This study by Feldman and coworkers -LSB- 64 -RSB- supports intravenous administration of iron ≥ 1,000 mg over 6 months if needed to maintain target hemoglobin levels . This is , however , an adult and not a pediatric recommendation . Intravenous iron therapy should be withheld in the presence of acute infection until the infection has successfully been treated and resolved -LSB- 65 -RSB- . Intravenous iron is ineffective and may increase the virulence of bacterial and viral pathogens . On the other hand , ESRD patients with chronically infectious complications may develop absolute iron deficiency if iron supplementation is withheld over months . In such a situation , iron should be administered intravenously as soon as ferritin levels drop below 100 μg/l -LRB- personal opinion -RRB- . ESA-stimulated erythropoiesis of chronically infected adult ESRD patients may benefit from low-dose intravenous iron supplementation -LRB- 10 -- 20 mg iron sucrose or ferric gluconate per hemodialysis session -RRB- , even if serum ferritin is normal or slightly elevated . The level of serum ferritin at which ESRD patients are considered to be in an iron overload state is still not defined . Inflammatory states should not be considered indiciations to withhold the benefits of intravenous iron therapy in general -LSB- 65 -RSB- . However , a clinical problem is the diagnosis of chronic anemia associated with inflammation and true iron deficiency , as serum ferritin concentration increases rather than decreases . Iron and kidney function Intravenous administration of 100 mg iron sucrose in CKD patients caused transient proteinuria and tubular damage -LSB- 37 -RSB- , but ferric gluconate did not -LRB- 125 mg infused over 1 h or 250 mg infused over 2 h -RRB- -LSB- 66 -RSB- . Induction of passive Heymann nephritis in rats resulted in a marked increase in nonheme iron content of kidney cortex and tubules , while a iron-deficient diet caused a significant reduction of nonheme iron level in glomeruli and also a significant reduction of proteinuria in these animals -LSB- 67 -RSB- . Pediatric thalassemia patients have a high prevalence of renal tubular abnormalities , probably caused by the anemia and increased oxidative stress induced by excess iron deposits . Significantly higher levels of urinary N-acetyl-beta-d-glucosaminidase , malondialdehyde , and beta-2-microglobulin were found in these children compared with normal children -LSB- 68 -RSB- . Under artificial experimental conditions -LRB- intravenous injection of 2 mg iron sucrose or ferric gluconate into mice with a body weight of 25 -- 35 g -RRB- , induction of monocyte chemoattractant protein-1 -LRB- MCP-1 -RRB- in renal and extrarenal tissues has been observed . Since MCP-1 has profibrotic properties , implications for CKD progression in case of intravenous iron therapy has been suggested -LSB- 69 -RSB- . However , in a recent article , Mircescu et al. -LSB- 70 -RSB- reported that intravenous iron sucrose therapy -LRB- 200 mg elemental iron per month for 12 months -RRB- resulted in an increase in hemoglobin from 9.7 ± 1.1 to 11.3 ± 2.5 g/dl in nondiabetic patients with CKD and a mean glomerular filtration rate -LRB- GFR -RRB- of 36.2 ± 5.2 ml/min per 1.73 m2 , estimated by the formula of Cockcroft and Gault . The majority of these CKD patients had preexisting iron deficiency -LRB- mean ferritin 98.0 μg/l , range 24.8 -- 139.0 μg/l -RRB- . An important finding of this study was that GFR -LRB- final values at the end of the study 37.2 ± 0.9 ml/min per 1.73 m2 -RRB- remained completely stable over a period of 12 months despite 2,400 mg of intravenous iron sucrose administration . The CKD patients had relatively high blood pressure -LRB- 140 ± 32/82 ± 20 mmHg at baseline -RRB- , which did not change throughout the investigation -LSB- 70 -RSB- . Agarwal -LSB- 71 -RSB- found that a single dose of 100 mg iron sucrose results in a transient increase of MCP-1 in plasma and urine of CKD patients . Those who believe that 100 mg iron sucrose administered to CKD patients may negatively affect kidney function should simply administer a lower intravenous iron dose , e.g. , 50 mg iron sucrose intravenously . Iron and oxidative stress Zager et al. -LSB- 72 -RSB- compared in vitro parenteral iron toxicity induced by three commercially available iron preparations -LRB- iron dextran , ferric gluconate , iron sucrose -RRB- using renal tubular cells and renal cortical homogenates . Each test agent induced massive and similar degrees of lipid peroxidation . Under the in vitro conditions used , iron sucrose caused markedly higher cell death than ferric gluconate , and ferric gluconate caused higher cell death than iron dextran . This relative toxicity profile was also observed in cultured aortic endothelial cells . Again , it should be stressed that the study of Mircescu et al. -LSB- 70 -RSB- demonstrated that intravenous iron sucrose therapy administered within international recommendations -LRB- none of the 58 CKD patients exceeded serum ferritin of 500 μg/l -RRB- does not cause a decline in kidney function in CKD patients over a period of 1 year . Intravenous iron therapy may enhance symptoms of oxidative stress -LSB- 73 -- 75 -RSB- . Drüeke et al. -LSB- 75 -RSB- demonstrated that advanced oxidation protein products -LRB- AOPPs -RRB- correlated with iron exposure and carotis artery intima thickness in dialysis patients . In hemodialysis patients , oxidative stress as a result of intravenous iron therapy caused serum albumin oxidation -LSB- 76 -RSB- . Ferric gluconate modifies fibrinogen and β2-microglobulin as a marker of oxidative stress in adult hemodialysis patients -LSB- 77 , 78 -RSB- . Intravenous administration of 100 mg iron sucrose in CKD patients increased malondialdehyde as a marker of lipid peroxidation -LSB- 37 -RSB- . Hemodialysis patients with ferritin levels above 650 μg/l showed an enhanced oxidative burst in PMNL -LSB- 59 -RSB- . However , not all studies found evidence for enhanced oxidative stress caused by parenteral iron therapy in ESRD patients . Hemodialysis therapy per se was found to cause a significant increase in peroxide concentration . Interestingly , this rise in plasma total peroxides was not additionally influenced by concomitant intravenous injection of 100 mg iron sucrose -LSB- 79 -RSB- . These data confirm increased oxidative stress associated with hemodialysis -LSB- 80 -RSB- . Whether intravenous iron therapy results in an additional oxidative stress reaction needs to be further evaluated . Increased blood levels of non-transferrin-bound iron -LRB- NTBI -RRB- and/or its redox-active part have been reported in adult ESRD patients receiving intravenous iron therapy -LSB- 79 , 81 , 82 -RSB- . Intravenous infusion of 300 mg iron sucrose in ESRD patients also caused peripheral vasodilation , which was confirmed by increased forearm blood flow . NTBI and redox-active iron were considered to be , at least in part , responsible for endothelial dysfunction observed in ESRD patients . However , an increase in NTBI and redox-active iron caused by intravenous iron sucrose infusion did not influence vascular reactivity to intra-arterial acetylcholine , glycerol-trinitrate , or L-N-mono-methyl-arginine -LRB- L-NMMA -RRB- -LSB- 82 -RSB- . Vitamin C and iron ESRD patients undergoing regular hemodialysis or hemodiafiltration may develop vitamin C deficiency -LSB- 83 -RSB- . Vitamin C deficiency may cause oxidative stress and vascular complications as well as impairment of intestinal iron absorption and iron mobilization from iron stress . Moretti et al. -LSB- 84 -RSB- measured iron absorption in young women from test meals fortified with isotopically labeled ferric pyrophosphate and ferrous sulfate . The addition of ascorbic acid at a molar ratio of 4:1 to iron increased iron absorption from ferric pyrophosphate to 5.8 % and that from ferrous sulfate to 14.8 % . In the fasting state , ferrous ascorbate is better absorbed than ferric hydroxide-polymaltose complex -LSB- 85 -RSB- . High-dose oral vitamin C may increase intestinal aluminium absorption -LSB- 86 -RSB- . Oxidative stress can cause hyporesponsiveness to ESA therapy in ESRD patients . Vitamin C may improve erythropoiesis through its antioxidative properties -LSB- 87 -RSB- . Intravenous ascorbic acid therapy facilitates iron release from inert deposits , resulting in a decrease of soluble transferrin receptor and an increase of TSAT -LSB- 88 -RSB- . In contrast , oral vitamin C supplementation -LRB- 250 mg three times per week for 2 months -RRB- did not influence oxidative/antioxidative stress and inflammation markers in adult hemodialysis patients -LSB- 89 -RSB- . In adult hemodialysis patients on maintenance intravenous iron sucrose therapy , intravenous administration of 500 mg ascorbic acid three times a week for 6 months resulted in an increase of TSAT and hemoglobin in approximately 65 % of the patients -LSB- 90 -RSB- . In contrast , neither oral nor intravenous ascorbic acid changed TSAT or hemoglobin levels in a study performed by Chan et al. -LSB- 91 -RSB- . Ascorbic acid increases the intracellular labile iron pool and iron mobilization to transferrin in human hepatoma HepG2 cells only in the presence of iron sucrose but not in the presence of iron dextran or ferric gluconate -LSB- 92 -RSB- . Several studies reported an increase in hemoglobin and/or a decrease in adult ESA dose during adjuvant ascorbic acid therapy three times per week in ESRD patients -LSB- 93 -- 99 -RSB- . Measurements of plasma oxalate concentration are needed in ESRD patients supplemented with ascorbic acid -LSB- 100 -RSB- . Studies on vitamin C and iron in children with ESRD are not available so far . Iron therapy after kidney transplantation Anemia is observed in 21 -- 39.7 % of adult renal transplant patients -LSB- 101 -- 104 -RSB- . The prevalence may be even higher in pediatric transplant recipients : 84.3 % of children were anemic in the first month after kidney transplantation , and prevalence of anemia was not below 64.2 % between 6 months and 6 years after transplantation . Iron deficiency was identified in 27 -- 56 % of children between 1 and 60 months posttransplantation -LSB- 105 -RSB- . Fourteen pediatric and young adult renal transplant recipients received single iron gluconate infusions ranging from 1.9 to 6.4 mg/kg . The mean hemoglobin level increased significantly from 10.1 ± 1.6 to 11.4 ± 2.1 g/dl following ferric gluconate therapy . Adverse events were observed in three children -LSB- 106 -RSB- . A recent study by Morii and coworkers showed that oral coadministration of ferrous sulphate markedly decreased the absorption of mycophenolate mofetil in healthy Japanese subjects -LSB- 107 -RSB- . However , a randomized crossover trial failed to confirm this observation in European transplant patients receiving long-term mycophenolate mofetil therapy -LSB- 108 -RSB- . In line with this observation , an in vitro study showed that iron ions did not interact with mycophenolate mofetil -LSB- 109 -RSB- . Conclusions The integration of ESA and intravenous or oral iron therapy into standard anemia management resulted in target hemoglobin levels -LRB- as established by international guidelines -RRB- in the vast majority of ESRD patients -LSB- 110 -RSB- . Correction of renal anemia reduced morbidity and mortality as well as hospitalization in ESRD patients . It also improved quality of life , cognitive function , and physical activity . Using a balanced approach to iron supplementation within international recommendations allowed the attainment of benefits of intravenous iron therapy at storage iron levels far below those generally seen with transfusions in the pre-ESA era -LSB- 110 -RSB- .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

iron supplementation
iron status
inflammation
infection


Hypertension in children with chronic kidney disease : pathophysiology and management Arterial hypertension is very common in children with all stages of chronic kidney disease -LRB- CKD -RRB- . While fluid overload and activation of the renin -- angiotensin system have long been recognized as crucial pathophysiological pathways , sympathetic hyperactivation , endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension . Moreover , several drugs commonly administered in CKD , such as erythropoietin , glucocorticoids and cyclosporine A , independently raise blood pressure in a dose-dependent fashion . Because of the deleterious consequences of hypertension on the progression of renal disease and cardiovascular outcomes , an active screening approach should be adapted in patients with all stages of CKD . Before one starts antihypertensive treatment , non-pharmacological options should be explored . In hemodialysis patients a low salt diet , low dialysate sodium and stricter dialysis towards dry weight can often achieve adequate blood pressure control . Angiotensin-converting enzyme -LRB- ACE -RRB- inhibitors and angiotensin receptor blockers are first-line therapy for patients with proteinuria , due to their additional anti-proteinuric properties . Diuretics are a useful alternative for non-proteinuric patients or as an add-on to renin -- angiotensin system blockade . Multiple drug therapy is often needed to maintain blood pressure below the 90th percentile target , but adequate blood pressure control is essential for better renal and cardiovascular long-term outcomes . Introduction Hypertension is one of the most common sequelae of chronic kidney disease -LRB- CKD -RRB- in children -LSB- 1 -RSB- . CKD-associated hypertension develops by a large variety of pathophysiological mechanisms . Blood pressure is one of the most critical determinants of the progression rate of renal failure in children -LSB- 2 , 3 -RSB- , and cardiovascular mortality in childhood onset renal failure -LSB- 4 -RSB- . Therefore , good antihypertensive management can substantially contribute to better renal and patient survival of adults with childhood-onset CKD . As in many other complications of chronic renal failure , patients often do not report symptoms of hypertension , so an active screening approach is needed to prevent end-organ damage . This article aims to give a short overview of the different pathophysiological pathways that lead to hypertension in CKD in order to explain how these can be targeted by different therapeutic approaches . Pathophysiology of hypertension in CKD Fundamentally , increased blood pressure is caused by an increase in cardiac output and/or of total peripheral resistance . Both can be altered by a plethora of different mechanisms in uremia and renal failure . Additionally , children with certain underlying diseases , e.g. glomerulopathies and polycystic kidney disease , are especially susceptible to hypertension -LSB- 3 , 5 -RSB- . Figure 1 gives an overview of the most important pathways involved . Fig. 1Interplay of different factors in the generation of hypertension in chronic kidney disease -LRB- BP blood pressure , CO cardiac output , TPR total peripheral resistance , PTH parathyroid hormone , Na sodium -RRB- Activation of the renin -- angiotensin -- aldosterone system plays a pivotal role in renal hypertension . While plasma renin activity is typically found to be markedly elevated only in patients with renal artery stenosis , many patients with CKD have ` inappropriately normal ' renin levels -LRB- i.e. lower levels would be expected , considering their degree of hypertension and fluid overload -LSB- 6 , 7 -RSB- -RRB- . Hyper-reninemia occurs probably due to renin secretion in poorly perfused areas such as cysts and scars or after microangiopathic damage or tubulo-interstitial inflammation -LSB- 8 , 9 -RSB- and leads to angiotensin II-mediated vasoconstriction as well as aldosterone-mediated salt retention , thus increasing both total peripheral resistance and blood volume . Additional delayed effects of a high angiotensin II tone include inflammation , cardiac hypertrophy and endothelial cell damage , mesangial cell proliferation and fibrosis -LSB- 10 -RSB- , which contribute further to hypertension and end-organ damage . Sodium retention and consequent fluid overload have long been recognized as causes of hypertension in CKD . Hypertensive children on dialysis have lower residual urine output than their normotensive peers have -LSB- 5 -RSB- . While inter-dialytic weight gain is correlated with the inter-dialytic increase in ambulatory blood pressure , the correlation is rather weak -LRB- in children r = 0.41 -LSB- 11 -RSB- -RRB- . This may be due to delayed effects -LSB- 12 -RSB- but also points to important volume-independent factors regulating blood pressure -LRB- BP -RRB- in patients on hemodialysis . This is also illustrated by the fact that nephrectomy in children on dialysis lowers mean blood pressure , despite causing anuria -LSB- 13 -RSB- . It has been proposed that fluid overload leads to hypertension only in those patients in whom peripheral resistance fails simultaneously to fall , i.e. when additional factors interfere with vascular autoregulation -LSB- 14 -RSB- . A growing body of evidence suggests that increased activity of the sympathetic nervous system -LRB- SNS -RRB- is an important volume-independent cause of hypertension . Campese et al. demonstrated that renal denervation improves both hypertension and increased sympathetic activity caused by phenol injection into rat kidneys -LSB- 15 -RSB- . Muscle sympathetic nerve activity is also elevated in hypertensive patients with chronic renal failure -LSB- 16 -RSB- . The underlying mechanisms of this phenomenon are , as yet , unclear and may include afferent signals from the failing kidney as well as dopaminergic abnormalities and the accumulation of leptin in CKD -LSB- 17 , 18 -RSB- . Interestingly , not only beta blockade but also angiotensin-converting enzyme -LRB- ACE -RRB- inhibition can reduce the sympathetic hyperactivation of CKD -LSB- 16 , 19 -RSB- . However , as sympathetic hyperactivity is also a feature of renovascular hypertension -LSB- 20 -RSB- , essential hypertension and hypertensive patients with polycystic kidney disease -LSB- 13 -RSB- , it appears that sympathetic activation also occurs independently of renal function . The most established cause for sympathetic over-activation is renal ischemia caused by renal artery stenosis -LSB- 20 , 21 -RSB- , but renal cysts might also cause local renal ischemia . While children with end-stage renal disease -LRB- ESRD -RRB- usually have normal plasma noradrenaline and adrenalin concentrations , hemodialysis per se leads to substantial increase in both plasma renin activity and catecholamines , which can contribute to hypertension -LSB- 22 -RSB- . Recent experimental evidence suggests that renalase -- an amine oxidase specifically expressed by the kidney -- lowers blood pressure and heart rate . Its activity is markedly reduced in patients with ESRD -LSB- 23 -RSB- . However , whether the cardiovascular effects of this enzyme are really due to its catecholamine-metabolizing activity is still controversial -LSB- 24 -RSB- . There has been debate about the role of nitric oxide -LRB- NO -RRB- in mediating endothelial cell damage and hypertension in CKD . Newer studies have demonstrated that , in uremic patients , reduced NO stimulation leads to reduced agonist-induced endothelium-dependent vasodilatation , whereas other vasodilatory pathways are not affected . Renal failure leads to the accumulation of endogenous NO synthase inhibitors such as asymmetric dimethyl-L-arginine -LRB- ADMA -RRB- , which appears to be due to increased generation and decreased metabolism rather than decreased clearance -LSB- 25 -RSB- . ADMA independently predicts overall mortality and cardiovascular events in patients with ESRD -LSB- 26 -RSB- , as well as progression of CKD -LSB- 27 -RSB- . While ADMA is related to blood pressure in animal models of CKD , clinical studies have not found differences in blood pressure -LSB- 25 -RSB- . Endothelial NO synthase is also suppressed by hyperparathyroidism in rats with CKD -LSB- 28 -RSB- . In contrast to ADMA levels , those of serum parathyroid hormone -LRB- PTH -RRB- correlate highly with blood pressure in patients with CKD -LSB- 29 -RSB- . Whereas acute infusion of PTH has a hypotensive effect , chronic hyperparathyroidism leads to accumulation of calcium inside vascular smooth muscle cells , enhancing their sensitivity to calcium and norepinephrine -LSB- 30 , 31 -RSB- . This effect can be blocked by calcium channel antagonists . A number of drugs commonly administered in CKD can cause iatrogenic hypertension . For example , erythropoietin -LRB- EPO -RRB- causes blood pressure elevation over several weeks . This may be via arterial wall remodeling , causing increased vascular resistance -LSB- 32 -RSB- . Vaziri et al. have proposed that EPO acts directly on voltage-independent calcium channels in smooth muscle cells , leading to a decreased sensitivity to the vasodilatory action of nitric oxide -LSB- 33 -RSB- . The resulting possibility of calcium channel antagonists as ` specific ' therapy for EPO-induced hypertension has been successfully tested in rats -LSB- 34 -RSB- . Glucocorticoids lead to fluid retention by their mineralocorticoid effect . Cyclosporine A causes vasoconstriction of glomerular afferent arterioles and hyperplasia of the juxtaglomerular apparatus , with subsequent increased release of renin and angiotensin II -LSB- 35 -RSB- . Increased circulating catecholamines and endothelin-1 precursors , and increased renal sodium absorption via the Na-K-2Cl co-transporter in the loop of Henle -LSB- 36 -RSB- , have also been demonstrated after cyclosporine A treatment . Tacrolimus appears to be less pro-hypertensive than cyclosporine in children after renal transplantation -LSB- 37 -RSB- , but , for other reasons , it is less commonly used prior to transplantation -LSB- 38 -RSB- . Treatment with growth hormone leads to water and sodium retention by the distal nephron -LSB- 39 -RSB- , mediated by increased intra-renal insulin-like growth factor -LRB- IGF -RRB- -1 . However , growth hormone -LRB- GH -RRB- does not appear to increase blood pressure in children with CKD or Turner syndrome , despite both groups being prone to hypertension -LSB- 40 , 41 -RSB- . Management Owing to the lack of acute symptoms and to the serious long-term consequences of hypertension , an active screening approach is necessary to detect elevated blood pressures early and to prevent end-organ damage -LSB- 42 -RSB- . In contrast to other complications of CKD , which become prevalent only in later stages of CKD , hypertension is already very common in CKD stage 1 , with over 63 % of children affected . In CKD stages 4 and 5 the incidence increases further to 80 % -LSB- 1 -RSB- . More than 50 % of children with ESRD have uncontrolled hypertension , despite widespread use of antihypertensive drugs -LSB- 5 , 43 -RSB- . The frequency of blood pressure measurement during screening and during therapy should be appropriate to the patient 's risk of developing uncontrolled hypertension . A routine for this is suggested in the flow chart in Fig. 2 . In general , we would consider all children with CKD to be at least at intermediate risk , and , therefore , we recommend 3-monthly clinic blood pressure -LRB- CBP -RRB- measurements ; children with ESRD , multiple pro-hypertensive medications or confirmed hypertension should be considered as at high risk . In our experience 24 h ambulatory blood pressure measurement -LRB- ABPM -RRB- is a very valuable tool and should be performed annually in high-risk populations such as renal transplant recipients or those with rapidly progressive renal disease . ABPM is also useful to exclude white-coat hypertension , which is a problem even in children under long-term medical care -LSB- 44 -RSB- . While there are equivocal results about the long-term consequences of white-coat hypertension , end-organ damage could be clearly demonstrated in children with masked hypertension , i.e. elevated ABPM but normal CBP -LSB- 45 -RSB- , underlining the usefulness of this method . Fig. 2Flow diagram for the choice of method to measure blood pressure during screening , follow up and treatment -LRB- CBP clinic blood pressure ABPM 24 h ambulatory blood pressure monitoring , HBP home blood pressure measurement BP blood pressure , BMI body mass index -RRB- Whichever method is used , techniques should be in accordance with international consensus statements , and the appropriate pediatric reference ranges are very important . These are now available for clinic -LSB- 46 , 47 -RSB- , ambulatory -LSB- 48 -RSB- and home blood pressure measurements -LSB- 49 -RSB- . The diagnosis of hypertension should be based on at least three clinic blood pressure measurements above the 95th percentile -LSB- 46 -RSB- . As white-coat hypertension is very common , and the effects of thorough investigation and treatment can be far-reaching , we feel ABPM is advisable in nearly all newly diagnosed hypertensive children . In countries where health care providers do not cover the cost of ABPM , home blood pressure measurements may be helpful in confirming the diagnosis , but they do not pick up the nocturnal blood pressure dynamics -LSB- 44 -RSB- . Once hypertension has been confirmed , good management should not focus only on pharmacological therapy , but also on detection and treatment of end-organ damage and , where appropriate , improvement of the dialysis regime and consideration of therapeutic life-style changes . Echocardiography and ophthalmological examination are the most important assessments of end-organ damage in hypertensive children . Left ventricular hypertrophy -LRB- LVH -RRB- is common in children with CKD , even during antihypertensive therapy -LSB- 50 -RSB- . LVH in patients with normal clinic blood pressure may indicate masked hypertension in untreated children -LSB- 45 -RSB- or insufficient efficacy of antihypertensive drug therapy in treated children -LRB- e.g. insufficient dose , non-compliance , or short duration of action of selected antihypertensive drugs -RRB- . Echocardiography and ophthalmological evaluation should be repeated at regular intervals in children with initial signs of end-organ damage -LSB- 46 -RSB- . From personal experience we would also recommend follow-up examination in children with persistent hypertension or in those at high risk -LRB- e.g. ESRD -RRB- . Additional assessments of end-organ damage include measurement of carotid intima media thickness and of pulse wave velocity , which reflect functional alterations of arterial wall properties caused by hypertension and other factors such as hyperparathyroidism -LSB- 51 -RSB- . These investigations are still mainly used for research purposes , but clinical use has been facilitated by the recent provision of pediatric reference ranges -LSB- 52 -RSB- . In hypertensive patients who are undergoing renal replacement therapy , improvement of the dialysis prescription should be the primary therapeutic approach to hypertension , before pharmacological treatment is started.Extracellular volume overload can be efficiently reduced by adequately long dialysis times . Even though the reduction of fluid overload may take several weeks to translate into normalized blood pressure , drug-free control of hypertension is possible in many , if not most , hemodialysis patients -LSB- 12 -RSB- . A number of studies have shown improved BP control with short daily , long intermittent or nocturnal hemodialysis -LSB- 53 -RSB- . While conventional dialysis schedules can also improve control of hypertension by targeting dry weight more aggressively -LSB- 54 -RSB- , this tends to be tolerated less well , with more intra-dialytic hypotensive episodes . Lower concentrations of dialysate sodium also produce a moderate fall in blood pressure on a population level , with best results in patients with previously high blood pressure -LSB- 55 -RSB- . In addition to intensified dialysis , dietary sodium restriction is a useful adjunct to intensified dialysis in avoiding sodium overload , and it reduces intra-dialytic hypotensive episodes . Indeed , some authors find dietary sodium restriction plus low sodium dialysate to be equally effective as time-intensified dialysis , and they maintain that with good dietary advice a low salt diet need not be unpalatable -LSB- 56 -RSB- . However , restriction of fluid and salt intake requires considerable patient motivation , which is often a problem in the adolescent population . Therapeutic life-style changes can be effective in lowering blood pressure if obesity contributes to the patient 's hypertension . Obesity in children with CKD is uncommon and usually associated with steroid treatment ; however , it is seen more commonly in populations with a higher background risk of obesity -LSB- 3 -RSB- . While weight loss can be effective in reducing blood pressure in overweight children with normal renal function -LSB- 57 -RSB- , unfortunately , there are no controlled studies of life-style interventions in children with CKD . In our experience calorie-reduced diets are rarely effective in this population , probably due to the multifactorial etiology of hypertension in renal disease . Also , the recommended intake of fresh fruit and vegetables may be hard to achieve if a potassium - and phosphate-reduced diet is also necessary . Interestingly , weight loss improves salt-induced increases in blood pressure in obese children -LSB- 58 -RSB- ; therefore , combined calorie - and sodium-reduced diets may be particularly effective in obese CKD children who are salt retainers . Pharmacological treatment remains the mainstay of antihypertensive management in all stages of CKD . In approximately 75 % of children with CKD stages 2 -- 4 , blood pressure control below the 95th percentile can be achieved by antihypertensive monotherapy , but 50 -- 60 % of children need more than one drug if intensified BP control -LRB- < 50th percentile -RRB- is targeted -LSB- Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CRF in Pediatric Patients -LRB- ESCAPE -RRB- trial , unpublished results -RSB- . In children with ESRD adequate control is much harder to achieve : a review of the North American Pediatric Renal Transplant Cooperative study -LRB- NAPRTCS -RRB- database also showed that over 50 % of children on dialysis have uncontrolled hypertension -LSB- 43 -RSB- , and a Polish nationwide survey found that in only 57 % of children with ESRD was hypertension adequately controlled , despite the use of multiple drug therapy in 65 % -LSB- 5 -RSB- . Even though multiple drug therapy is often required , it is advisable to start with a single drug at a low dose and to titrate upward until blood pressure is controlled -LSB- 46 -RSB- . Exceptions are hypertensive emergencies , such as hypertensive encephalopathy , when intravenous -LRB- i.v. -RRB- treatment should be started promptly . ACE inhibitors and angiotensin II type 1 receptor blockers -LRB- ARBs -RRB- are the most useful drugs , as they are not only antihypertensive but also slow down the progression of renal failure more efficiently than do other antihypertensive treatments -LSB- 59 -RSB- . Surveys among pediatric nephrologists from both sides of the Atlantic show that ACE inhibitors are increasingly popular and are now the most commonly used drugs for pediatric hypertension -LSB- 60 , 61 -RSB- . The renoprotective effect of renin -- angiotensin system -LRB- RAS -RRB- blockade is due to a combination of reduced proteinuria , lower intra-glomerular pressure through selective dilatation of the glomerular efferent arteriole , and anti-inflammatory and anti-fibrotic effects -LSB- 10 -RSB- . Additionally , RAS inhibition reduces the sympathetic hyperactivity seen in CKD -LSB- 16 -RSB- . There is convincing evidence from studies of adults that all proteinuric patients should receive renin -- angiotensin system blockade , even if they do not have hypertension -LSB- 42 -RSB- . Major side effects are a moderate increase of potassium and creatinine ; these should be monitored more closely with declining renal function . Sexually active adolescent girls must use contraception . ACE inhibitor-induced cough appears to be less common in children than in adults -LSB- 62 -RSB- . There is no clear evidence suggesting clinical superiority of ARBs over ACE inhibitors -LSB- 63 -RSB- , and a number of drugs in both classes are labeled for children . Food and Drug Administration -LRB- FDA -RRB- approval for children under 6 years old is expected soon for a number of ARBs . Combination therapy with an ACE inhibitor and an ARB should be considered for patients who continue to show proteinuria while undergoing monotherapy , since it is effective in further reducing proteinuria -LRB- and progression of CKD -RRB- in adults -LSB- 63 , 64 -RSB- . Experience in children is positive but very limited -LSB- 65 -- 68 -RSB- , and the increased risk of hyperkalemia and renal failure should be realized -LSB- 69 -RSB- . Therefore , for improved control of hypertension without proteinuria , the combination of single RAS blockade with a diuretic is preferable . The use of fixed-dose combinations of RAS antagonists with a thiazide diuretic may be an option in adolescents where compliance is an issue , but less so in younger children where frequent dose adjustments are required -LSB- 46 -RSB- . From trials in hypertensive patients without renal disease it appears that the blood pressure lowering effect , per se , is relevant for cardiovascular risk protection , without any class-specific benefits . Therefore , in essential hypertension , the choice of agents should be guided by the matching of the side effects profile of the individual drugs to the patient-specific risk factor profile -LSB- 47 -RSB- . In patients with CKD , meta-analyses of adult trials demonstrated superior renoprotection by ACE inhibitors , even after adjustment for blood pressure and urine protein excretion -LSB- 70 -RSB- . There is no conclusive evidence as to whether the inhibition of the renin -- angiotensin system is superior to other antihypertensives in non-proteinuric CKD patients -LSB- 59,71,72 -RSB- . Recommendations for adults prefer to err on the side of caution and suggest a low threshold for considering CKD patients proteinuric -LRB- 200 mg protein/g creatinine in spot urine -RRB- -LSB- 42 -RSB- . Diuretics are less commonly used in children with CKD than in adults with CKD , due to the preponderance of hypodysplastic kidney disorders , which frequently present as salt-losing nephropathies . In patients with evidence of hypervolemia , thiazides and loop diuretics have proven most useful for controlling volume overload , and they have a very good side-effects profile . It should be remembered that , while thiazides are a popular first-line therapy in mild-to-moderate CKD , they are less effective when glomerular filtration rate -LRB- GFR -RRB- falls below 60 ml/min per 1.73 m2 body surface area , and they are ineffective below 30 ml/min per 1.73 m2 . Therefore , furosemide should be preferred and used in adequate doses for CKD stages 4 and 5 . Mineralocorticoid receptor antagonists -LRB- e.g. spironolactone -RRB- are theoretically attractive in CKD , due to their synergistic actions with RAS antagonists , and the new selective receptor blocker eplerenone is devoid of anti-androgenic side effects . However , monotherapy -LRB- and , even more , combination therapy with RAS antagonists -RRB- is limited by the potentiated risk of hyperkalemia . During diuretic therapy , patients should be monitored for volume depletion and electrolyte disturbances . Long-acting formulations help to increase patient compliance -LSB- 42 -RSB- . Calcium channel blockers are very potent anti-hypertensive drugs and , therefore , useful as add-on therapy in children with resistant hypertension . Dihydropyridine -LRB- DHP -RRB- drugs -LRB- e.g. nifedipine , amlodipine -RRB- act mainly as vasodilators and do not have cardiac side effects . Amlodipine has pediatric labeling and is available as a suspension , and doses need not to be adjusted to renal function . However , DHP-type calcium channel blockers -LRB- CCBs -RRB- increase intra-glomerular pressure and proteinuria , while non-DHP-type calcium channel blockers -LRB- e.g. verapamil and diltiazem -RRB- have an additional anti-proteinuric effect . In a long-term clinical trial of elderly patients with type II diabetic nephropathy , non-DHP calcium channel blockers showed as equally an effective slowing of CKD progression , reduction of proteinuria and antihypertensive efficacy as did the ACE inhibitor lisinopril -LRB- while both were superior to the beta blocker atenolol -LSB- 73 -RSB- -RRB- . However , there are no published safety data on any of the non-DHPs in children with hypertension , so they should be used with caution due to their known prolongation of the PR interval in adults -LSB- 74 -RSB- . Intravenous administration of nicardipine is an option for controlling hypertensive crises , especially when the level of renal function is unclear or changing rapidly . It has been used safely , even in very small children with hypertension , despite reports of hypotension in normotensive newborns with asphyxia -LSB- 74 -RSB- . Beta blockers can be used as second-line therapy for renal hypertension in children . However , they are contraindicated in asthma and can cause fatigue . All beta blockers require dose reduction with progression of CKD . They should be used with caution in heart failure , and their adverse metabolic effects make them less suitable for diabetics . The largest clinical experience , especially for infants , is available for propranolol . A sustained-release form of this drug allows once daily administration in larger children . However , other agents , such as atenolol , which have the advantage of being both long acting and β1-selective , may be preferred in clinical practice . Other drugs are used less commonly , mainly due to their more severe side-effects profiles . Alpha blockers -LRB- such as prazosin -RRB- can be used in patients who also require them for control of bladder emptying or Raynaud 's phenomenon . Centrally acting alpha agonists -LRB- such as clonidine -RRB- act via reduction of sympathetic nervous outflow . Rebound hypertension after discontinuation is a major problem of this drug . The vasodilators hydralazine and minoxidil are less suitable in CKD as they are less effective and cause salt and water retention . The aim of antihypertensive management is the regression of end-organ damage -LRB- especially LVH -RRB- and the lowering of blood pressure below target values while minimizing drug side effects . The currently recommended treatment goal in hypertensive patients with CKD is a blood pressure of < 130/80 mmHg in adults -LSB- 42 , 47 -RSB- and < 90th percentile in children -LSB- 46 -RSB- . However , a meta-analysis of 11 randomized trials in non-diabetic adults with CKD showed differing results for proteinuric and non-proteinuric patients : while there was no increase in adverse renal outcomes with higher blood pressure in non-proteinuric patients , ideal systolic blood pressure for proteinuric patients -LRB- > 1 g per day -RRB- was 110 -- 129 mmHg . In proteinuric patients , renal survival decreased , with systolic blood pressures below 110 mmHg and above 130 mmHg . These data are hard to interpret conclusively , as persistent hypertension during treatment may also be a reflection of more severe underlying disease -LSB- 70 -RSB- . In children , the pending results of the ESCAPE trial may help us to elucidate optimal blood pressure targets . Conclusion Adequate management of hypertension in CKD requires an active screening approach in order to prevent the significant renal deterioration and cardiovascular morbidity and mortality associated with high blood pressure . Owing to the plethora of different pathophysiological mechanisms involved , a whole range of therapeutic options is available . Non-pharmacological options should not be disregarded for obese children or for children on hemodialysis . Inhibitors of the renin -- angiotensin system should be preferred for proteinuric patients and , probably , also for non-proteinuric patients . Multiple drug therapy is often necessary to reach target blood pressure below the 90th percentile . For this , diuretics and calcium channel blockers are the most suitable options .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

hypertension
children
chronic kidney disease
pathophysiology

antihypertension therapy
life-style changes