Educational Paper: Progression in chronic kidney disease and prevention strategies
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.
KeywordsChronic kidney disease Renal disease progression Hypertension Proteinuria Anemia Dyslipidemia Bone mineral metabolism Inflammation Nutrition Children
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.  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
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).
Therapeutic strategies targeting renal disease progression
Renoprotective studies in children
RAAS blockade: antiproteinuric, antihypertensive, anti-fibrotic, and anti-inflammatory effects
Blood pressure control
Reduction of proteinuria
Attenuation of glomerular sclerosis and tubulointerstitial fibrosis
All antihypertensive drug classes
Yes (ACEi) 
Additional antiproteinuric effect by blood pressure control
- BP target <75th Pct in non-proteinuric children
- BP target <50th Pct in proteinuric children
ACE inhibitors, some CCBs (nondihydropyridines) and ß-blockers (e.g. carvediolol),
Normalization of lipid profile
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)
Calcium, phosphate, PTH and vitamin D levels within target range for CKD patients 
Anti-fibrotic (vitamin D)
Reduction of proteinuria, blood pressure, glomerular sclerosis (calcimimetics)
Serum bicarbonate level >22 mmol/l 
Normalization of serum uric acid levels 
Renal disease progression
Low protein diet (0.8–1.1 g/kg/day) 
Reduction of serum urea levels
Reduction of serum urea levels, delay of end-stage renal disease
Yes (effects inconclusive, no benefit in children)
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 . 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 .
Several studies in adults could demonstrate that antihypertensive therapy slows down the decline in glomerular filtration rate (GFR) . 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)  and the Guidelines of the European Hypertension Society , 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 .
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) . 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 % .
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 .
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 ; these findings could be confirmed by the ItalKid Study . In addition, there is evidence from the ESCAPE trial that residual proteinuria during ACE inhibition is quantitatively associated with renal failure progression . 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 .
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 . 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 %  or prevented the two- to threefold increase in proteinuria observed in patients with the “conventional” blood pressure target of 140/90 mmHg . 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 .
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  and in children with CKD . 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 , 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 . The extent of the advantage of RAAS antagonists over other antihypertensive drugs is still under debate . 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 .
The ESCAPE trial has demonstrated efficient blood pressure control and diminished proteinuria by the ACE inhibitor ramipril in almost 400 children with CKD . 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”) , 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 , stable GFR during 2.5 years of losartan therapy in children with proteinuria , and attenuated histopathological disease progression in children with IgA nephropathy receiving combined RAAS blockade treatment , while the ItalKid Study did not reveal significant effect on renal disease progression by ACEi therapy in children with hypodysplastic kidneys  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 .
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 . 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 . 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 .
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 . The antiproteinuric action may be due to sympathicoplegic effects. Newer beta-blockers such as carvedilol have even improved antiproteinuric effects as compared to atenolol .
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 . 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 .
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 . The dyslipidemic pattern varies according to the underlying kidney disease , 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 .
Recently, a positive correlation between serum cholesterol and GFR loss was demonstrated in adults with diabetic nephropathy ; 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 .
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 .
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 , 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  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 .
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  and to reduce apoptotic cell death .
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 . However, other data in patients with more advanced CKD and high-dose rhuEPO treatment revealed no beneficial effect on renal survival . 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 .
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 . 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 .
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 , whereas a recent review  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 . However, conclusions in this regard could not be drawn from studies in children .
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 . FGF23 levels are independently associated with progression of CKD and may serve as a biomarker and mechanism for cardiovascular disease .
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 .
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 . 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 . In addition, animal studies have shown that cinacalcet markedly reduces proteinuria, blood pressure, glomerulosclerosis, and the progression of kidney disease . 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 . 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 . 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.
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.
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