European Journal of Pediatrics

, Volume 171, Issue 11, pp 1579–1588 | Cite as

Educational Paper: Progression in chronic kidney disease and prevention strategies

Review

Abstract

Chronic kidney disease (CKD) in children is a rare but devastating condition. Once a critical amount of nephron mass has been lost, progression of CKD is irreversible and results in end-stage renal disease (ESRD) and need of renal replacement therapy. The time course of childhood CKD is highly variable. While in children suffering from congenital anomalies of the kidneys and the urinary tract, progression of CKD in general is slow, in children with acquired glomerulopathies, disease progression can be accelerated resulting in ESRD within months. However, irrespective of the underlying kidney disease, hypertension and proteinuria are independent risk factors for progression. Thus, in order to prevent progression, the primary objective of treatment should always aim for efficient control of blood pressure and reduction of urinary protein excretion. Blockade of the renin–angiotensin–aldosterone system preserves kidney function not only by lowering blood pressure, but also by reducing proteinuria and exerting additional anti-proteinuric, anti-fibrotic, and anti-inflammatory effects. Besides, intensified blood pressure control, aiming for a target blood pressure below the 50th percentile, may exert additive renoprotective effects. Additionally, other modifiable risk factors, such as anemia, metabolic acidosis, dyslipidemia, and altered bone-mineral homeostasis may also contribute to CKD progression. In conclusion, beyond strict blood pressure control and reduction of urinary protein excretion, identification and treatment of both, renal disease-related and conventional risk factors are mandatory in children with CKD in order to prevent deterioration of kidney function.

Keywords

Chronic kidney disease Renal disease progression Hypertension Proteinuria Anemia Dyslipidemia Bone mineral metabolism Inflammation Nutrition Children 

Introduction

Chronic kidney disease (CKD) commonly progresses towards end-stage renal disease (ESRD) and need of renal replacement therapy (RRT) once a critical impairment of renal function has occurred. However, the time course of CKD progression can be quite variable and suggests the influence of several modifiable but also of unmodifiable factors, such as the etiology of underlying kidney disease itself, the stage of kidney disease, comorbidities, ethnicity, and the genetic background.

CKD not only bears the risk of progressive loss of renal function, but also of cardiovascular disease (CVD). Childhood onset CKD is associated with an excessive mortality rate compared to healthy age-matched controls, as demonstrated by Oh et al. [46] in a single center analysis comprising 283 patients; 35 % of these children died within 25 years, 57 % out of these due to cardiovascular disease. Thus, successful strategies to slow down the rate of renal disease progression and to delay ESRD and the need for RRT will also have impact on the expectancy and quality of life of these patients. The purpose of this review is to discuss factors influencing the time course of CKD and potential treatment strategies to slow down renal disease progression.

Factors influencing CKD progression

“Renal disease progression” describes the whole process from minimal kidney injury (CKD stage 1) to end-stage renal disease (i.e., CKD stage 5) and the need for renal replacement therapy. According to the Brenner hypothesis, a critical reduction of functioning renal mass—either by inborn or acquired kidney disease—results in hyperfiltration of the remaining glomeruli. In addition, hypertension and proteinuria are key players of renal disease progression [24,29,34]. Increased blood pressure leads to elevated intraglomerular pressure, hyperfiltration, and increased urinary protein excretion. Proteinuria itself (independent of the presence of hypertension) exerts local pro-inflammatory and pro-sclerotic effects resulting in glomerular hypertrophy and sclerosis. In parallel to the glomerular alterations, tubular and tubulointerstitial changes (hypertrophy, fibrosis, and finally atrophy) occur (Figs. 1 and 2). Within this vicious circle, the renin–angiotensin–aldosterone system (RAAS) plays a pivotal role: local angiotensin II increases intraglomerular pressure and proteinuria, stimulates local release of cytokines, and activates inflammatory pathways, aggravating glomerular hypertrophy and sclerosis, tubulointerstitial inflammation, and fibrosis as well as enhancing central nervous sympathetic tone by renal afferent nerve stimulation.
Fig. 1

Risk factors modifying renal disease progression

Fig. 2

Pathophysiology and current treatment strategies of hypertension and proteinuria in chronic renal failure. RAAS renin–angiotensin–aldosterone system; non-DHP CCB non-dihydropyridine calcium channel blockers; up tacksymbol inhibitory effect

Other factors potentially contributing to renal disease progression are genetic predisposition, renal anemia, altered bone-mineral metabolism, dyslipidemia, hyperuricemia, chronic inflammation, nutrition, and oxidative stress as well as general cardiovascular risk factors such as diabetes mellitus, smoking, and obesity (Fig. 1).

Several principal renoprotective strategies have recently emerged, these are based mainly on clinical evidence established in adults, but growing evidence supports their efficacy also in the pediatric population (Table 1).
Table 1

Therapeutic strategies targeting renal disease progression

Therapeutic Target

Agents

Action

Treatment aim

Renoprotective studies in children

Renin–angiotensin–aldosterone system

ACE inhibitors

RAAS blockade: antiproteinuric, antihypertensive, anti-fibrotic, and anti-inflammatory effects

Blood pressure control

Yes (ACEi) [16,61,65,73]

ARBs

Reduction of proteinuria

Aldosterone antagonists

Attenuation of glomerular sclerosis and tubulointerstitial fibrosis

Renin inhibitors

Hypertension

All antihypertensive drug classes

Antihypertensive

Strict blood pressure control [35,40,73]:

Yes (ACEi) [73]

Additional antiproteinuric effect by blood pressure control

- BP target <75th Pct in non-proteinuric children

- BP target <50th Pct in proteinuric children

Proteinuria

ACE inhibitors, some CCBs (nondihydropyridines) and ß-blockers (e.g. carvediolol),

Antiproteinuric

Minimization of proteinuria: urinary protein excretion <300 mg/m2/d [27,54]

No

Dyslipidemia

Statins

Lipid lowering

Normalization of lipid profile

No

Anemia

Erythropoietin

Improved oxygen supply, reduced oxidative stress, direct protective effects

Normalization of hemoglobin levels

No (no benefit in adults with advanced CKD)

Calcium-Phosphate metabolism, Hyperparathyroidism

Phosphate binders (calcium-free)

Renoprotective

Calcium, phosphate, PTH and vitamin D levels within target range for CKD patients [1]

No

Vitamin D

Anti-fibrotic (vitamin D)

Calcimimetics

Reduction of proteinuria, blood pressure, glomerular sclerosis (calcimimetics)

Metabolic acidosis

Bicarbonate

Renoprotective

Serum bicarbonate level >22 mmol/l [13]

No

Hyperuricemia

Allopurinol

Renoprotective

Normalization of serum uric acid levels [59]

No

Renal disease progression

Low protein diet (0.8–1.1 g/kg/day) [69]

Reduction of serum urea levels

Reduction of serum urea levels, delay of end-stage renal disease

Yes (effects inconclusive, no benefit in children)

RAAS renin–angiotensin–aldosterone system; ACE angiotensin-converting enzyme; ACEi ACE inhibitor; ARBs angiotensin receptor blockers; CCBs calcium channel blockers; BP blood pressure; Pct percentile; CKD chronic kidney disease

Effect of hypertension and proteinuria on renal disease progression

Hypertension is an independent predictor for renal disease progression in adult patients [24,29,34]. In pediatric nephropathies, hypertension is a common finding—the prevalence varies from 20 % to 80 % depending on the underlying kidney disease and the degree of renal dysfunction—and even children with CKD stage 2 (glomerular filtration rate 60–90 ml/min/1.73 m2) or renal hypodysplasia may exhibit high blood pressure [56]. However, hypertension is usually less severe than in the adult CKD population. In line with adult studies, the “European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood” reported a significant association between systolic blood pressure >120 mmHg and more rapid progression in children with CKD [69].

Several studies in adults could demonstrate that antihypertensive therapy slows down the decline in glomerular filtration rate (GFR) [6]. The clear evidence of the beneficial effect of intensified blood pressure control in patients with CKD has led to generally lower target blood pressure recommendations. In recent guidelines by the Joint National Committee in the US (JNC7) [11] and the Guidelines of the European Hypertension Society [64], 120/80 mmHg has been defined as the upper limit of the “optimal” blood pressure range. If proteinuria is present, any blood pressure greater than 130/80 mmHg should actively be reduced by therapeutic intervention [42].

According to the final results of the ESCAPE Trial (Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of Chronic Renal Failure in Pediatric Patients), intensified blood pressure control, i.e., targeting 24-h mean arterial blood pressure levels below the 50th percentile provides beneficial renoprotective effect over the conventional target range (50th to 95th percentile) [73]. In this international investigator-initiated, randomized clinical trial, the angiotensin converting enzyme (ACE) inhibitor ramipril was administered at a fixed dose (6 mg/m²/day) to 385 CKD children. Patients were subsequently randomized to either conventional or intensified blood pressure control group, achieved by administration of additional antihypertensive drugs not affecting the RAAS. Within the 5-year observation period, only 29.9 % of the patients in the strict blood pressure control group, as compared to 41.7 % in the conventional treatment group, attained the composite endpoint of doubling of serum creatinine, GFR decline to <10 ml/min/1.73 m² or need for RRT. This difference corresponded to a risk reduction by 35 % [73].

Population-based studies in healthy individuals have revealed that proteinuria is a powerful predictor of end-stage renal disease and overall mortality [25,62]. Proteinuria predicts renal prognosis not only in animal CKD models but also in adults with diabetic or non-diabetic kidney disorders [51].

The spectrum of underlying kidney diseases in children differs markedly from adults. Congenital renal hypodysplasia with or without urinary tract abnormalities is the leading cause of CKD in children, affecting more than 60 % of the patients. However, the European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood could demonstrate that also in pediatric nephropathies, proteinuria and elevated blood pressure are major independent risk factors for the deterioration of kidney function [69]; these findings could be confirmed by the ItalKid Study [3]. In addition, there is evidence from the ESCAPE trial that residual proteinuria during ACE inhibition is quantitatively associated with renal failure progression [73]. Even in children with normal kidney function, persistent proteinuria in the nephrotic range is a risk factor for progressive renal injury; therefore, early detection and therapeutic intervention is mandatory. However, in children with non-glomerular origin of CKD and nil-to-moderate proteinuria, the level of protein excretion does not appear to play a role in renal disease progression [33].

Minimizing proteinuria results in a reduced GFR loss in the long run. In the REIN study, a reduction in proteinuria at 3 months of ACE inhibitor therapy by 1 g/day led to slowing down of GFR decline by 2 ml/min per year [54]. This degree of proteinuria reduction appears to be associated with the maximal renoprotective effect. Thus, the goal of any antiproteinuric treatment is to reduce proteinuria—ideally below 300 mg/m²/day.

Blood pressure control per se has an anti-proteinuric effect as demonstrated by several large trials [51,57,72]. A low blood pressure target, i.e., <125/75 mmHg in adults, either reduced proteinuria absolutely by 50 % [51] or prevented the two- to threefold increase in proteinuria observed in patients with the “conventional” blood pressure target of 140/90 mmHg [57]. This low blood pressure target appears to be well tolerated by the majority of patients, and in terms of cardiovascular outcomes, the “J curve” phenomenon (a slight increase of cardiovascular events in patients with very low blood pressure levels) appears to be confined to older patients with advanced atherosclerosis.

The various classes of antihypertensive drugs are comparable with respect to their blood pressure lowering effect; they, however, differ markedly regarding their effects on proteinuria and renal progression [11].

Antihypertensive drugs blocking the renin–angiotensin system such as ACE inhibitors (ACEi) and angiotensin II type I receptor blockers (ARB), are meanwhile first choice pharmacotherapeutics in adults [42] and in children with CKD [35]. In addition to their antihypertensive effect, they also exert antiproteinuric properties and have an excellent safety profile, which is almost indistinguishable from placebo.

RAAS antagonists suppress the local angiotensin II tone (ACEi) or action (ARB). This leads to a reduction of intraglomerular pressure and proteinuria, diminished local release of cytokines and alleviated activation of inflammatory pathways, with consequently attenuated glomerular hypertrophy and sclerosis, tubulointerstitial inflammation and fibrosis as well as to a normalized central nervous sympathetic tone by reduced renal afferent nerve stimulation. Moreover, the extent of oxidative stress is reduced independently of the blood pressure lowering effect.

Several randomized trials in adults either with diabetic or non-diabetic kidney disease demonstrated a higher reduction of proteinuria (30–40 %) by ACE inhibition as compared to placebo and/or other antihypertensive drugs [26], significantly reducing renal disease progression rate [23,26,37,49,53,63,66]. Similar results were obtained in randomized studies comparing ARBs with placebo or conventional antihypertensive agents in adults with diabetic nephropathy [50]. The extent of the advantage of RAAS antagonists over other antihypertensive drugs is still under debate [8]. The risk of doubling serum creatinine or achieving ESRD is reduced by 30–40 %, but the superiority of RAAS antagonists is related to the degree of proteinuria [26].

The ESCAPE trial has demonstrated efficient blood pressure control and diminished proteinuria by the ACE inhibitor ramipril in almost 400 children with CKD [73]. However, a gradual rebound of proteinuria after the second treatment year has been observed. This effect was dissociated from a persistently good blood pressure control and may limit the long-term renoprotective efficacy of ACEi monotherapy in pediatric CKD. In several studies, subsets of patients appear to develop partial secondary resistance to ACE inhibitors (“aldosterone escape”) [7], characterized by compensatory upregulation of ACE-independent angiotensin II production. It is currently an open issue whether such patients would benefit from the primary use of ARBs alone or in combination with ACE inhibitors.

While the maximal antiproteinuric and renoprotective effects of ACEi and ARBs appear to occur at doses which are by far higher than the doses required for the maximal antihypertensive action, regulatory authority approval is usually available only for the indication of hypertension in the respective dose range. Therefore, it is generally recommended to administer these drugs, after confirming tolerability in a short run-in period, at their highest approved doses.

Several studies are available with respect to the efficacy of RAAS antagonists for renoprotection in children with CKD. Small uncontrolled studies demonstrated stable renal function in children with sequelae of hemolytic uremic syndrome during long-term ACE inhibition [65], stable GFR during 2.5 years of losartan therapy in children with proteinuria [16], and attenuated histopathological disease progression in children with IgA nephropathy receiving combined RAAS blockade treatment [61], while the ItalKid Study did not reveal significant effect on renal disease progression by ACEi therapy in children with hypodysplastic kidneys [4] compared to matched untreated patients.

In children and adults with Alport syndrome, a hereditary nephropathy caused by mutations in type IV collagen genes resulting in structural changes of the glomerular basement membrane, ACEi are effective in slowing down renal disease progression. In a large European Study following almost 300 Alport patients, early ACEi treatment in young patients significantly delayed onset of renal replacement therapy and improved life expectancy compared to later or no therapy [22].

Aldosterone antagonists also act by RAAS suppression resulting in reduced blood pressure. The use of spironolactone is limited by its endocrine side effects; however, the new aldosterone antagonist eplerenone has minimal affinity for progesterone and androgen receptors; apart from the risk of hyperkalemia, reported side effects are similar to placebo [68]. Combined therapy of eplerenone and an ACEi increased patient survival in adults with congestive heart failure. However, the combination therapy of both appears to be limited in CKD patients due to the potentiated risk of hyperkalemia.

The renin antagonist, aliskiren, which blocks the conversion from angiotensinogen to angiotensin I, has been shown to effectively reduce blood pressure in animals, as well as in humans. Preliminary data showed a blood pressure-lowering effect comparable to that of ARBs, and the combination therapy of aliskiren and valsartan at maximum recommended doses provided significantly higher reductions in blood pressure than did monotherapy [48]. However, due to the higher risk of cardiovascular complications found in the ALTITUDE study the combination therapy of aliskiren with ACEi or ARBs in patients with diabetes or reduced renal function is not recommended [18].

Calcium channel blockers (CCBs), antihypertensive agents not affecting the RAAS, are also efficient to achieve blood pressure goal in patients with CKD. However, CCBs of the dihydropyridine type (amlodipine, nifedipine) fail to reduce progression of chronic kidney disease and may even increase proteinuria and promote more rapid CKD progression. Therefore, dihydropyridine CCBs should be used as first line antihypertensive monotherapy in non-proteinuric patients only and should be avoided unless in combination with RAAS antagonists to improve blood pressure control in proteinuric patients.

CKD is often a state of overactivation of the sympathetic nervous system, and antiandrenergic agents play an important role in its management. Beta-blockers are effective in reducing blood pressure in CKD patients by the blockade of the post-synaptic beta-receptors resulting among others in a reduction of pulse rate, cardiac output, afterload, and renal renin release.

Metoprolol and atenolol were the first antihypertensive drugs for which beneficial effects on renal progression were demonstrated. Metoprolol had an antiproteinuric effect almost comparable to ramipril [72]. The antiproteinuric action may be due to sympathicoplegic effects. Newer beta-blockers such as carvedilol have even improved antiproteinuric effects as compared to atenolol [19].

Hypertension is a multifactorial disorder, thus monotherapy is often not effective in lowering blood pressure or reducing proteinuria to the target range. Treatment with a single antihypertensive agent usually controls blood pressure in less than half of the patients. Patients with severe hypertension (>20/10 mmHg above the normal range) should be started on combination therapy [11]. In CKD patients, RAAS antagonists are most commonly combined with a diuretic or a calcium channel blocker. Fixed-dose combination preparations are becoming increasingly popular in antihypertensive therapy and may help maximize treatment adherence and efficacy.

Combined RAAS blockade using ACEi and ARB concomitantly has only a minor effect on blood pressure (3–4 mmHg vs. monotherapy) but increases the antiproteinuric effect of ACEi or ARB monotherapy by 30–40 % [14,36]. However, recent findings of the ONTARGET Study in adult populations with high cardiovascular risk (CKD and diabetes) do not support dual therapy with telmisartan and ramipril over monotherapy in patients with low glomerular filtration rate or albuminuria [47].

Other modifiable risk factors influencing renal disease progression

Dyslipidemia is an independent predictor not only of cardiovascular disease but also of the progression of chronic kidney disease [39]. The dyslipidemic pattern varies according to the underlying kidney disease [55], and the degree of dyslipidemia correlates with the degree of renal function deterioration. A high-fat diet causes macrophage infiltration and foam cell formation in rats, leading to glomerulosclerosis. In addition, damage of the glomerular capillary endothelial, the podocytes, and mesangial cell proliferation through the production of chemokines, cytokines, growth factors, and increased oxidative stress have been described [1].

Recently, a positive correlation between serum cholesterol and GFR loss was demonstrated in adults with diabetic nephropathy [38]; patients with a total cholesterol level above 7 mmol/L showed an at least three times faster decline in GFR than subjects with lower cholesterol levels. The Arteriosclerosis Risk in Communities Study demonstrated that elevated triglycerides and low HDL, but not LDL cholesterol, were associated with an increased risk of renal impairment in healthy middle-aged adults [39].

Insulin resistance may also mediate the association between lipids and loss of renal function and the metabolic syndrome is strongly associated with the risk for microalbuminuria and chronic renal disease in the general population [10].

In patients with CKD, general measures to obviate dyslipidemia include prevention or treatment of malnutrition, correction of metabolic acidosis, hyperparathyroidism, and anemia, all of which may contribute to dyslipidemia. In addition, referring to evidence from the general population, therapeutic life style modification is recommended for adults and children with CKD-related dyslipidemia [41], although the lipid-lowering effect of lifestyle modifications in CKD patients is usually not impressive.

Based on the evident benefit of prevention of cardiovascular disease in the general adult population, lipid lowering medical treatment is commonly prescribed in adult CKD patients. Statin therapy is effective in reducing cardiovascular morbidity and mortality in adults with moderate to severe CKD, although not in patients with ESRD [67] and with respect to renoprotection, experimental evidence suggests that statins may retard renal progression not only by their lipid lowering but also by lipid-independent pleiotropic effects [17].

No studies have evaluated the efficacy of statins in children with progressive nephropathies to date.

There is increasing evidence that anemia is also linked to renal disease progression. In patients with reduced kidney mass, tissue hypoxia is favored by an increase of oxygen consumption by tubular cells of the remaining nephrons, a decrease in the number of the interstitial capillaries, and an accumulation of extracellular matrix between interstitial capillaries and tubular cells, blocking the diffusion of oxygen. Hypoxia leads not only to increased production of pro-fibrotic molecules by the tubular cells, such as transforming growth factor β or endothelin-1, but stimulates the synthesis of extracellular matrix. Moreover, hypoxia enhances the production of reactive oxygen species, which may also play a role in the progression of CKD.

The renoprotective effect of erythropoietin (EPO) in CKD might be partially explained by improved oxygen supply with attenuation of interstitial fibrosis and tubuloepithelial cell loss and reduced oxidative stress via anemia correction. In addition, EPO might exert direct protective effects on tubular cells and might help to maintain the integrity of the interstitial capillary network and to stimulate regenerative progenitor cells [5] and to reduce apoptotic cell death [58].

In a recently published clinical trial, early initiation of recombinant human EPO (rhuEPO) therapy in adult patients with CKD and mild to moderate anemia significantly slowed down the progression of kidney disease and delayed the need for renal replacement therapy [21]. However, other data in patients with more advanced CKD and high-dose rhuEPO treatment revealed no beneficial effect on renal survival [15]. The role of EPO in pediatric CKD progression has not yet been defined.

Increased oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and endogenous levels of antioxidant substances may be both the cause and consequence of renal damage in CKD patients. High oxidative stress and low availability of the substrate of nitrogen oxide (NO) synthase, l-arginine, as well as an accumulation of endogenous NO inhibitors such as asymmetric dimethylarginine (ADMA) may induce endothelial dysfunction. Several studies demonstrated an increased level of reactive oxygen species in patients with CKD. Increased oxidative stress appears to correlate with the progression of chronic kidney disease [28].

Metabolic acidosis is common in patients with CKD and may contribute to the development and worsening of proteinuria and tubulointerstitial fibrosis, thus accelerating the rate of decline in renal function. In a recent randomized controlled trial evaluating the renoprotective potential of oral bicarbonate supplementation in adult patients with CKD, only 4 of 67 patients receiving bicarbonate progressed to dialysis as compared to 22 of 67 patients in the untreated control group [13]. There was a significant reduction of the CKD progression rate to 1 ml/min/year in patients with serum bicarbonate levels ≥22 mmol/L compared with >2.5 ml/min/year in patients with uncorrected low bicarbonate levels. Thus, tight control of metabolic acidosis may become an important component of renoprotective therapy in patients with progressive CKD.

Another biomarker of progressive CKD is serum uric acid. There is increasing evidence that uric acid is not only a marker but also a contributor to renal disease progression and mediates the development of hypertension. In a study randomizing patients with CKD II–IV and hyperuricemia to allopurinol treatment, renal outcome was improved within 12 months of follow-up, without a change in blood pressure [59].

Low protein diet had been prescribed for prevention of renal progression for decades. However, the effects and consequences of this diet on CKD progression and delay of end-stage renal disease are still inconclusive. One of the largest trials could not prove efficacy of a low protein diet on progression in non-diabetic kidney disease [31], whereas a recent review [20] found a risk reduction of renal death in patients with protein restriction. Thus, the progression rate was not significantly influenced by protein restriction, whereas renal replacement therapy could be postponed.

In children, reduced protein intake to the maximal acceptable lower limit did not slow down renal progression [9,69]. Further reductions may be effective but not acceptable for patients. Furthermore, therapeutic strategies of protein reduction in children may be conflicting, since a low protein diet bears the risk of low calorie intake, while a high calorie intake is needed for optimal growth. Therefore, at present, it seems not to be justified to prescribe low protein diet.

Several studies in adults with CKD suggested that dietary phosphorus restriction may stabilize kidney function [30]. However, conclusions in this regard could not be drawn from studies in children [43].

A high calcium–phosphorus product may be detrimental to renal survival by aggravating intrarenal vasculopathy as well as by causing tubulointerstitial calcifications, which may stimulate tubulointerstitial inflammation and fibrosis. In view of these pathophysiological associations, calcium-free phosphate binders may have some renoprotective potential in patients with CKD.

Non-hypercalcemic doses of active vitamin D attenuate renal progression in uremic rats. This effect may be mediated by the immune-modulatory and anti-fibrotic properties of vitamin D. In addition, there is increasing evidence for interactions between vitamin D, FGF23 (fibroblast growth factor 23), and klotho, regulating calcium phosphate homeostasis. Disturbances of this hormonal axis may contribute to renal disease progression by activation of the RAAS, vitamin D deficiency, reduced renal production of klotho, and reduced FGF23 signaling [12]. FGF23 levels are independently associated with progression of CKD and may serve as a biomarker and mechanism for cardiovascular disease [70].

Regarding vitamin D metabolism, a negative endocrine regulation of the RAAS through 1,25-dihydroxyvitamin D3 has been reported, and oral paracalcitol exerted an antiproteinuric effect in adult CKD patients [2,32]. These experimental and early clinical findings beyond close monitoring of mineral metabolism provide an additional rationale for early treatment of bone disease to maintain mineral, vitamin D, and parathyroid hormone (PTH) homeostasis in CKD patients [43].

The first calcimimetic agent, cinacalcet (R-568), which has been approved for treatment of secondary hyperparathyroidism, efficiently reduces plasma PTH, calcium and phosphate levels in adult patients [60]. Cinacalcet acts by allosteric modification of the calcium sensing receptor increasing its sensitivity to extracellular calcium. This receptor is expressed not only on PTH-producing cells but also on the podocytes. Both in vitro and in vivo studies have shown further beneficial effects beyond control of mineral homeostasis; cinacalcet stabilizes the actin cytoskeleton of the podocyte and reduces apoptosis [45]. In addition, animal studies have shown that cinacalcet markedly reduces proteinuria, blood pressure, glomerulosclerosis, and the progression of kidney disease [44]. However, clinical data on the effect of cinacalcet treatment on proteinuria and renal disease progression in adults or children have not yet been reported.

Recent studies in adults suggest a common genetic predisposition for progression of both renal and cardiovascular disease. The physiologic cytokine pathways are complex, sharing common genes for renal progression and cardiovascular alterations. Gene polymorphisms in the RAAS–cytokine pathway may influence gene expression and secretion of inflammatory cytokines and thereby modulate the rate of CKD progression and CVD in patients with CKD [52]. Ongoing genome-wide association studies through the evaluation of thousands of single nucleotide polymorphisms will offer further insight into the pathophysiologic mechanisms of these polygenic diseases [71]. These investigations provide hope for future drug targets to delay progression and to modify the individual risk. Early interventions in patients with high-risk genotypes may slow the deterioration of renal function and decrease the incidence of end-stage renal failure and cardiovascular disease.

Conclusion

Therapeutic strategies to prevent renal disease progression in pediatric CKD should comprise strict blood pressure control and lowering of proteinuria. In this context, RAAS antagonists preserve kidney function not only by lowering blood pressure but also through antiproteinuric and anti-fibrotic properties. Other modifiable factors contributing to renal disease progression in a multifactorial way include anemia, dyslipidemia, metabolic acidosis, and disorders of vitamin D and mineral metabolism. Thus, measures to preserve renal function should also comprise the maintenance of hemoglobin, serum bicarbonate, serum lipid, and calcium-phosphorus ion product levels in the normal range.

References

  1. 1.
    Abrass CK (2004) Cellular lipid metabolism and the role of lipids in progressive renal disease. Am J Nephrol 24:46–53PubMedCrossRefGoogle Scholar
  2. 2.
    Agarwal R, Acharya M, Tian J, Hippensteel RL, Melnick JZ, Qui P, Williams L, Batlle W (2005) Antiproteinuric effect of oral paracalcitol in chronic kidney disease. Kidney Int 68:2823–2828PubMedCrossRefGoogle Scholar
  3. 3.
    Ardissino G, Testa S, Dacco V, Vigano S, Taioli E, Claris-Appiani A, Procaccio M, Avolio L, Ciofani A, Dello Strologo L, Montini G (2004) Proteinuria as a predictor of disease progression in children with hypodysplastic nephropathy. Pediatr Nephrol 19:172–177PubMedCrossRefGoogle Scholar
  4. 4.
    Ardissino G, Vigano S, Testa S, Dacco V, Paglialonga F, Leoni A, Belingheri M, Avolio L, Ciofani A, Claris-Appiani A, Cusi D, Edefonti A, Ammenti A, Cecconi M, Fede C, Ghio L, la Manna A, Maringhini S, Papalia T, Pela I, Pisanello L, Ratsch IM, on behalf of the ItalKid Project (2007) No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy - report from the ItalKid Project database. Nephrol Dial Transplant 22:2525–2530PubMedCrossRefGoogle Scholar
  5. 5.
    Aydin Z, Duijs J, Bajerna IM, van Zonneveld AJ, Rabelink TJ (2007) Erythropoietin, progenitors, and repair. Kidney Int 72:516–520CrossRefGoogle Scholar
  6. 6.
    Bakris GL, Williams M, Dworkin L, Elliot WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J (2000) Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 36:646–661PubMedCrossRefGoogle Scholar
  7. 7.
    Bomback AS, Klemmer PJ (2007) The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 3:486–492PubMedCrossRefGoogle Scholar
  8. 8.
    Casas JP, Weiliang C, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, MacAllister RJ (2005) Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 366:2026–2033PubMedCrossRefGoogle Scholar
  9. 9.
    Chaturvedi S, Jones C (2007) Protein restriction for children with chronic renal failure. Cochrane Database Syst Rev 17:CD006863Google Scholar
  10. 10.
    Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J (2004) The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 140:167–174PubMedGoogle Scholar
  11. 11.
    Chobanian AV, Barkis GL, Black DL, Cushman WC, Green LA, Izzo JLJ, Jones DW, Materson BJ, Oparil S, Wright JTJ, Roccella EJ (2003) The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289:2560–2571PubMedCrossRefGoogle Scholar
  12. 12.
    De Borst MH, Vervloet MG, ter Wee PM, Navis G (2011) Cross talk between the renin–angiotensin–aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. J Am Soc Nephrol 22:1603–1609PubMedCrossRefGoogle Scholar
  13. 13.
    de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM (2009) Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 20:2075–2084PubMedCrossRefGoogle Scholar
  14. 14.
    Doulton TW, He FJ, MacGregor FA (2005) Systemic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension 45:880–886PubMedCrossRefGoogle Scholar
  15. 15.
    Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A, Investigators CREATE (2006) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355:2071–2084PubMedCrossRefGoogle Scholar
  16. 16.
    Ellis D, Vats A, Moritz ML, Reitz S, Grosso MJ, Janosky JE (2003) Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria. J Pediatr 143:89–97PubMedCrossRefGoogle Scholar
  17. 17.
    Epstein M, Campese VM (2005) Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on renal function. Am J Kidney Dis 45:2–14PubMedCrossRefGoogle Scholar
  18. 18.
  19. 19.
    Fassbinder W, Quarder O, Waltz A (1999) Treatment with carvedilol is associated with a significant reduction in microalbuminuria: a multicenter randomized study. Int J Clin Pract 53:519–522PubMedGoogle Scholar
  20. 20.
    Fouque D, Laville M (2009) Low-protein diets for chronic kidney disease in non diabetic adults. Cochrane database of systematic reviews, Issue 3, Art.No. CD001892. doi:10.1002/14651858.CD001892.pub3
  21. 21.
    Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC (2004) Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 66:753–760PubMedCrossRefGoogle Scholar
  22. 22.
    Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tönshoff B, Höcker B, Wygoda S, Erich JHH, Pape L, Konrad M, Rascher W, Dötsch J, Müller-Wiefel DE, Hoyer P, and Study Group Members of the Gesellschaft für Pädiatrische Nephrologie (GPN), Knebelmann B, Pirson Y, Grunfeld J-P, Niaudet P, Cochat P, Heidet L, Lebbah S, Torra R, Friede T, Lange K, Müller GA, Weber M (2012) Early angiotensin converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int 81:494–501PubMedCrossRefGoogle Scholar
  23. 23.
    Hannedouche T, Landais P, Goldfarb B, el Esper N, Fournier A, Godin M, Durand D, Chanard J, Mihnin F, Suo JM (1994) Randomised controlled trial of enalapril and beta blockers in non-diabetic chronic renal failure. BMJ 309:833–837PubMedCrossRefGoogle Scholar
  24. 24.
    Iseki K, Ikemiya Y, Iseki C, Takishita S (2003) Proteinuria and the risk of developing end-stage renal disease. Kidney Int 63:1468–1474PubMedCrossRefGoogle Scholar
  25. 25.
    Iseki K, Kinjo K, Iseki C, Takishita S (2004) Relationship between predicted creatinine clearance and proteinuria and the risk of developing ESRD in Okinawa, Japan. Am J Kidney Dis 44:806–814PubMedGoogle Scholar
  26. 26.
    Jafar TH, Schmid CH, Landa M, Giatras J, Toto R, Remuzzi G, Maschio G, Brenner BM, Kamper A, Zucchelli P, Becker G, Himmelmann A, Bannister K, Landais P, Shahinfar S, DeJong P, DeZeeuw D, Lau J, Levey AS, for the ACE Inhibition in Progressive Renal Disease Study Group (2001) Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med 135:73–87PubMedGoogle Scholar
  27. 27.
    Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, de Zeeuw D, Shahinfar S, Toto R, Levey AS, AIPRD study group (2003) Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-meta-analysis. Ann Intern Med 139:244–252PubMedGoogle Scholar
  28. 28.
    Karamouzis I, Sarafidis PA, Karamouzis M, Illiadis S, Haidich A-M, Sioulis A, Triantos A, Vavatsi-Christaki N, Grekas DM (2008) Increase in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease. Am J Nephrol 28:397–404PubMedCrossRefGoogle Scholar
  29. 29.
    Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, Shulman NB, Stamler J (1996) Blood pressure and end-stage renal disease in men. N Engl J Med 334:13–18PubMedCrossRefGoogle Scholar
  30. 30.
    Klahr S, Levy AD, Beck GJ (1994) The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 330:877–884PubMedCrossRefGoogle Scholar
  31. 31.
    Levey AS, Greene T, Sarnak MJ, Wang X, Beck GJ, Kusek JW, Collins AJ, Kopple JD (2006) Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis 48:876–888CrossRefGoogle Scholar
  32. 32.
    Li YC, Kong J, Wei M, Chen Z-F, Liu SQ, Cao L-P (2002) 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin–angiotensin system. J Clin Invest 110:229–238PubMedGoogle Scholar
  33. 33.
    Litwin M (2004) Risk factors for renal failure in children with non-glomerular nephropathies. Pediatr Nephrol 19:178–186PubMedCrossRefGoogle Scholar
  34. 34.
    Locatelli F, Marcelli D, Comelli M, Alberti D, Graziani G, Buccianti G, Redaelli B, Giangrande A (1996) Proteinuria and blood pressure as causal components of progression to end-stage renal failure. Northern Italien Cooperative Study Group. Nephrol Dial Transplant 11:461–467PubMedCrossRefGoogle Scholar
  35. 35.
    Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti C, Kuznetsova T, Laurent S, Mancia G, Morales-Olivas F, Rascher W, Redon J, Schaefer F, Seeman T, Stergiou G, Wühl E, Zanchetti A (2009) Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens 27:1719–1742PubMedCrossRefGoogle Scholar
  36. 36.
    MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD (2006) Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 48:8–20PubMedCrossRefGoogle Scholar
  37. 37.
    Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P (1996) Effect of angiotensin-converting-enzme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334:939–945PubMedCrossRefGoogle Scholar
  38. 38.
    Mulec H, Johnson SA, Bjorck S (1990) Relation between serum cholesterol and diabetic nephropathy. Lancet 335:1537–1538PubMedCrossRefGoogle Scholar
  39. 39.
    Muntner P, Coresh J, Clinton Smith J, Eckfeldt J, Klag MJ (2000) Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int 58:293–301PubMedCrossRefGoogle Scholar
  40. 40.
    National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576CrossRefGoogle Scholar
  41. 41.
    National Kidney Foundation (2003) K/DOQI Clinical practice guidelines for managing dyslipidemias in patients with kidney disease. Am J Kidney Dis 41:S1–S91 (Suppl 3)Google Scholar
  42. 42.
    National Kidney Foundation (2004) K/DOQI Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 43:S1–S290 (Suppl 1)Google Scholar
  43. 43.
    National Kidney Foundation (2005) K/DOQI Clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease. Am J Kidney Dis 46:S12–S122 (Suppl 1)Google Scholar
  44. 44.
    Ogata H, Ritz E, Odoni G, Amann K, Orth SR (2003) Beneficial effects of calcimimetics on progression of renal failure and cardiovascular risk factors. J Am Soc Nephrol 14:959–967PubMedCrossRefGoogle Scholar
  45. 45.
    Oh J, Beckmann J, Bloch J, Hettgen V, Mueller J, Li L, Hoemme M, Gross ML, Penzel R, Mundel P, Schaefer F, Schmitt CP (2011) Stimulation of the calcium-sensing receptor stabilizes the podocyte cytoskeleton, improves cell survival, and reduces toxin-induced glomerulosclerosis. Kidney Int 80:483–492PubMedCrossRefGoogle Scholar
  46. 46.
    Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100–105PubMedCrossRefGoogle Scholar
  47. 47.
    ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleigth P, Anderson C (2008) Renal outcomes with telmisartan, ramipril, or both, in patients at high vascular risk (The ONTARGET Study): a multicenter, randomized, double-blind, controlled trial. N Engl J Med 358:1547–1559PubMedCrossRefGoogle Scholar
  48. 48.
    Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A (2007) Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized, double-blind trial. Lancet 370:221–229PubMedCrossRefGoogle Scholar
  49. 49.
    Parving HH, Andersen AR, Smidt UM, Svendsen PA (1983) Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1:1175–1179PubMedCrossRefGoogle Scholar
  50. 50.
    Parving HH, Hommel E, Smidt UM (1988) Protection of kidney function and decrease in albuminuria by captopril in insulin-dependent diabetics with nephropathy. BMJ 297:1086–1091PubMedCrossRefGoogle Scholar
  51. 51.
    Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter LJ (1995) Blood pressure control, proteinuria, and the progression of renal disease: the modification of diet in renal disease study. Ann Intern Med 123:754–762PubMedGoogle Scholar
  52. 52.
    Rao M, Wong C, Kanetsky P, Girndt M, Stenvinkel P, Reilly M, Raj DSC (2007) Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int 72:549–556PubMedCrossRefGoogle Scholar
  53. 53.
    Ruggenenti P, Perna A, Gherardi G, Garini G, Zocalli C, Salvadori M, Scolari F, Schena FP, Remuzzi G (1999) Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 354:359–364PubMedCrossRefGoogle Scholar
  54. 54.
    Ruggenenti P, Perna A, Remuzzi G (2003) Retarding progression of chronic renal disease: the neglected issue of residual proteinuria. Kidney Int 63:2254–2261PubMedCrossRefGoogle Scholar
  55. 55.
    Saland MJ, Ginsberg H, Fisher EA (2002) Dyslipidemia in pediatric renal disease: epidemiology, pathophysiology, and management. Curr Opin Pediatr 14:197–204PubMedCrossRefGoogle Scholar
  56. 56.
    Schaefer F, Mehls O (2004) Hypertension in chronic kidney disease. In: Portman RJ, Sorof JM, Ingelfinger JR (eds) Pediatric hypertension. Humana Press, Totowa, pp 371–387Google Scholar
  57. 57.
    Schrier RW, Estacio RO, Esler A, Mehler P (2002) Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 61:1086–1097PubMedCrossRefGoogle Scholar
  58. 58.
    Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Shaeff M, Kieswich J, Allen D, Harwood S, Raftery M, Thiemermann C, Yaqoob MM (2004) Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 15:2115–2124PubMedCrossRefGoogle Scholar
  59. 59.
    Siu YP, Leung KT, Tong MK, Kwan TH (2006) Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 47:51–59PubMedCrossRefGoogle Scholar
  60. 60.
    Strippoli GF, Palmer S, Tong A, Elder G, Messa P, Craig JC (2006) Meta-analysis of biochemical and patient-level effects of calcimimetic therapy. Am J Kidney Dis 47:715–726PubMedCrossRefGoogle Scholar
  61. 61.
    Tanaka H, Suzuki K, Nakahata T, Tsugawa K, Konno Y, Tsuruga K, Ito E, Waga S (2004) Combined therapy of enalapril and losartan attenuates histologic progression in immunoglobulin A nephropathy. Pediatr Int 46:576–579PubMedCrossRefGoogle Scholar
  62. 62.
    Tarver-Carr M, Brancati F, Eberhardt M, Powe N (2000) Proteinuria and the risk of chronic kidney disease (CKD) in the United States. J Am Soc Nephrol 11:168AGoogle Scholar
  63. 63.
    The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia) (1997) Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephroptahy. Lancet 349:1857–1863CrossRefGoogle Scholar
  64. 64.
    The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) (2007) 2007 Guidelines for the Management of Arterial Hypertension. J Hypertens 25:1105–1187Google Scholar
  65. 65.
    Van Dyck M, Proesmans W (2004) Renoprotection by ACE inhibitors after severe hemolytic uremic syndrome. Pediatr Nephrol 19:688–690PubMedCrossRefGoogle Scholar
  66. 66.
    van Essen GG, Apperloo AJ, Rensma PL, Stegeman CA, Sluiter WJ, de Zeeuw D (1997) Are angiotensin converting enzyme inhibitors superior to beta blockers in retarding progressive renal function decline? Kidney Int Suppl 63:S58–S62PubMedGoogle Scholar
  67. 67.
    Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E, German Study Group for Growth Hormone Treatment in Chronic Renal Failure (2005) Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353:238–248PubMedCrossRefGoogle Scholar
  68. 68.
    White WB, Carr AA, Krause S, Jordan R, Roniker B, Oigman W (2003) Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension. [Abstract]. Am J Cardiol 92:38–42PubMedCrossRefGoogle Scholar
  69. 69.
    Wingen AM, Fabian-Bach C, Schaefer F, Mehls O (1997) Randomised multicentre study of a low-protein diet on the progression of chronic renal failure in children. European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood. Lancet 349:1117–1123PubMedCrossRefGoogle Scholar
  70. 70.
    Wolf M (2012) Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int, May 23 [Epub ahead of print]Google Scholar
  71. 71.
    Wong C, Kanetsky P, Raj D (2008) Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease. Pediatr Nephrol 23:1037–1051PubMedCrossRefGoogle Scholar
  72. 72.
    Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG (2003) African American study of kidney disease and hypertension: effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 288:2421–2431CrossRefGoogle Scholar
  73. 73.
    Wühl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, Testa S, Jankauskiene A, Emre S, Caldas-Afonso A, Anarat A, Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen A-M, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, Hohbach-Hohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Möller K, Wigger M, Peruzzi L, Mehls O, Schaefer F (2009) Strict blood pressure control and renal failure progression in children. The ESCAPE Trial Group. N Engl J Med 361:1639–1650PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Division of Pediatric Nephrology, Center for Pediatrics and Adolescent MedicineUniversity of HeidelbergHeidelbergGermany

Personalised recommendations