Therapeutic strategies to slow chronic kidney dise

Authors: Elke Wühl Franz Schaefer

Publish Date: 2008/03/12

Volume: 23, Issue: 5, Pages: 705-

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Abstract

Childhood chronic kidney disease commonly progresses toward endstage renal failure largely independent of the underlying disorder once a critical impairment of renal function has occurred Hypertension and proteinuria are the most important independent risk factors for renal disease progression Therefore current therapeutic strategies to prevent progression aim at controlling blood pressure and reducing urinary protein excretion Reninangiotensinsystem RAS antagonists preserve kidney function not only by lowering blood pressure but also by their antiproteinuric antifibrotic and antiinflammatory properties Intensified blood pressure control probably aiming for a target blood pressure below the 75th percentile may exert additional renoprotective effects Other factors contributing in a multifactorial manner to renal disease progression include dyslipidemia anemia and disorders of mineral metabolism Measures to preserve renal function should therefore also comprise the maintenance of hemoglobin serum lipid and calciumphosphorus ion product levels in the normal rangeProgression of chronic kidney disease CKD toward endstage renal failure is common in CKD patients and once significant impairment of renal function has occurred it tends to progress irrespectively of the underlying kidney disorder However information on the natural course of CKD progression in children is still limited The prospective populationbased ItalKid registry including almost 1200 CKD children with various renal diseases over a 10year period reported a prevalence of 23 of patients suffering from severe kidney disease with chronic renal insufficiency CRI The incidence of renal replacement therapy was 73 per year per 100 patients with CRI and the risk of developing endstage renal disease ESRD by age 20 was 68 1 The decline of renal function was not linear but rather characterized by a sharp decline during puberty and at early postpubertal age This finding supports the general clinical impression that in many children with renal hypodysplasia kidney function deteriorates more rapidly around the time of puberty This notion received further support by a recently published retrospective analysis of 176 children with renal hypodysplasia 2 The authors postulated that the natural course of chronic renal failure in these patients can be divided into three time periods an initial period usually lasting the first 3 years of life characterized by an improving renal function a subsequent period of stable renal function attained by 50 of patients for a mean of 8 years and a phase with renal function gradually deteriorating toward ESRD The latter period started just after infancy in 48 and around puberty in 23 In 30 of patients renal function remained stable even beyond pubertyPathophysiology consequences and treatment options of hypertension and proteinuria in chronic kidney disease EPO erythropoietin P reduction serum phosphate reduction RAS renin angiotensin system NonDHP CCP non dihydropyridine calcium channel blockers TGFβ transforming growth factor β TIMP tissue inhibitors of metalloproteinases ET1 endothelin 1 PAI plasminogen activator inhibitor ⊥ inhibitory effectHypertension is an independent risk factor of renal failure progression in adults 3 4 5 Whereas the degree of hypertension correlates with the severity of the underlying renal disease interventional studies have provided evidence that high blood pressure actively contributes to renal failure progression in human CKD In pediatric nephropathies renal hypertension is common although typically less severe than in adult kidney disorders Hypertension prevalence estimates in children with CKD range from 20 to 80 depending on the degree of renal dysfunction and underlying renal disease 6 7 However even children with CKD stage 2 or renal hypodysplasia may present with significantly elevated blood pressure 8 The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood demonstrated that in CKD children a systolic blood pressure greater than 120 mmHg was associated with a significantly faster glomerular filtration rate GFR decline 9Numerous studies in adults have provided proof to the concept that consequent antihypertensive therapy slows down the rate of renalfailure progression 10 A close linear relationship between the blood pressure level achieved by antihypertensive treatment and the rate of renal failure progression in adult CKD patients has been noted which appears to persist well into the normal range of blood pressure 11 12The firm evidence of a favorable effect of intensified blood pressure control in patients with CKD has resulted in generally lower target blood pressure recommendations in this patient group In the most recent guidelines by the Joint National Committee in the US JNC7 13 and the Guidelines of the European Hypertension Society 14 120/80 mmHg has been defined as the upper limit of the ‘optimal’ blood pressure range particularly when proteinuria is present and any blood pressure 130/80 in CKD patients should be actively lowered by therapeutic intervention 15 These blood pressure targets are equivalent to the 50th to 75th distribution percentile in the general young adult population It is as yet unknown whether these blood pressure targets hold true for the pediatric population and whether glomerular damage in children correlates with absolute or agespecific relative blood pressure The Kidney Disease Outcomes Quality Initiative K/DOQI guidelines on blood pressure control in CKD children 15 adopted the recommendations of the task force that target blood pressure should be 90th percentile for normal values 16 adjusted for age gender and height percentile Assuming that equivalent blood pressure percentiles should be targeted in children as in adults the adult recommendations would for instance correspond to an acceptable upper blood pressure level of 106/66 mmHg 75th percentile in an 8year old child with CKD The final results of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of Chronic Renal Failure in Pediatric Patients ESCAPE trial to become available in mid2008 will provide pediatric evidence as to whether intensified blood pressure control targeting to below the 50th percentile of 24h mean arterial pressure will confer a renoprotective advantage over a more conventional target 50th to 95th percentile 17 The integrity of the normal diurnal blood pressure pattern may play a significant role in renal failure progression in addition to and independent of the absolute blood pressure level Nondipping a well known independent cardiovascular risk factor and common characteristic of renoparenchymal hypertension is associated with more rapid progression of renal failure in adult CKD patients 18 19 and nondipping is believed to reflect sympathetic hyperactivation in CKDPopulationbased studies in healthy individuals have demonstrated that proteinuria is a powerful independent risk factor for ESRD and overall mortality 20 21 22 Proteinuria is certainly predictive of the renal prognosis in adults with diabetic and nondiabetic kidney disorders 23 24 25 Urinary protein excretion was the only baseline variable correlated with GFR decline and progression to ESRD in the Ramipril Efficacy in Nephropathy REIN trial 26 However the spectrum of underlying renal disorders in children differs markedly from adults In the pediatric CKD population congenital renal hypodysplasia with or without urinary tract abnormalities is the leading underlying renal disorder affecting more than 60 of children The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood first demonstrated in 200 children with CKD stage 3–4 that proteinuria and hypertension are major independent determinants of GFR decline in pediatric nephropathies 9 The ItalKid Project confirmed that proteinuria predicts renal disease progression in children with renal hypodysplasia 27 In addition there is evidence from the ESCAPE trial that residual urinary protein excretion during angiotensinconverting enzyme ACE inhibition is quantitatively associated with renal failure progression 28 Even in children with normal kidney function persistent proteinuria in the nephrotic range is a risk factor for progressive renal injury and early detection and treatment of proteinuria is essential 29 In nonproteinuric children with CRI of nonglomerular origin the level of protein excretion does not appear to play a major role in CKD progression which seems to be best predicted by rapid somatic growth age and blood pressure 30In line with evidence from animal models multiple clinical studies have confirmed that proteinuria is not only a marker but also an important mechanism of CKD progression Reduction of proteinuria is associated with a slowing of GFR loss in the long term 25 31 32 33 In the Modification of Diet in Renal Disease MDRD trial for each 1 g/d reduction in proteinuria observed within 4 months of antiproteinuric treatment ie blood pressure reduction and dietary interventions the subsequent GFR decline was slowed by about 1 ml/min per 173 m2 per year 25 In the REIN study reduction of proteinuria at 3 months of ACE inhibitor therapy by 1 g/d resulted in slowing down GFR decline by 2 ml/min per year 34 This degree of proteinuria reduction appears to be associated with the maximal renoprotective effect 35 36 Hence the goal of any antiproteinuric treatment is to reduce proteinuria as much as possible ideally to 300 mg/m2/day

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