Chronic Renal Failure in Children and Adolescents

Chronic Renal Failure in Children and Adolescents
Dr Ian Ramage Consultant Paediatric Nephrologist Glasgow

Definition Epidemiology Aetiology Clinical Nutrition Growth Bones Anaemia Blood Pressure Cardiovascular Disease Neurodevelopment Psychosocial Pharmacy Treatment Outcome

Definition - Adults

Definition - Children (a) Kidney damage for > 3 months, as defined by structural or functional abnormalities determined by kidney biopsy, imaging tests or composition of the blood or urine, with or without decreased GFR; AND (b) GFR < 60ml/min/1.73m2 for ≥ 3 months, with or without the signs of kidney damage listed above

Epidemiology Increases with age ESRF 9.9 (MARP) Higher in males
9 (MARP) 0-4 years 14 (MARP) years 28 (MARP) years ESRF 9.9 (MARP) Prevalence increased 22.9 in 1980 62.1 in 2000 Higher in males Higher in Blacks/Indigenous This slide shows the epidemiology of ESRD. Data relating to the prevalence of CKD compared to ESRD in children is vague. Looking at adult data from the NHANES study demonstrated a prevalence of CKD of 10.8% compared to 0.2% for ESRD so CKD is 50 times more common than ESRD in adults. Males to females 1.72 to 1 and remains higher in the Italian study even after the removal of those diagnosed with PUV. In black north americans the rate of ESRD is 2-3 times higher than white children irrespective of gender.

Aetiology

Nutrition Feeding Disorders Dietician Protein Calcium and Phosphate
Calories Lipids Fluids Vitamins & Minerals Iron, Copper, Zinc Feeding Disorders

Growth Prenatal Infantile Childhood Pubertal Nutrition > GH
Max growth from >25cm/yr at birth 18cm/yr age 1yr 10cm/yr age 2 yr Childhood GH and Thyroid hormone dependent Children grow along percentile achieved at the end of 2 years of life (Van Dyck M Pediatr Nephrol 1999) Pubertal Delayed peak height velocity of ~ 2.5 years Growth spurt delayed & shortened with reduced growth velocity Only 65% of healthy children Loss of pulsatile hypothalamic release ofGnRH Normal growth can be divided into four important phases: prenatal, infantile, childhood and pubertal. Nutrition is important at all phases of growth, but particularly so during the infantile phase because the rate of growth is higher than at any other time of life (other than prenatally) and is less dependent on growth hormone (GH) than during other phases. Rate of growth gradually decreases from >25 cm/year at birth to an average of 18 cm/year at age 1 year and 10 cm/year by the age of 2. Half of adult height is achieved by the age of 2 years, so that irrecoverable loss of growth potential can occur during this phase. At birth, 170 kcal/day are stored in new tissue, falling to 50–60 at 6 months, 30–40 by 1 year and 20–30 by the age of 2 years. During the childhood phase, growth becomes more dependent on the GH/insulin-like growth factor-1 (IGF-1) axis; growth rate decelerates continuously until the pubertal phase. The pubertal phase results from the coordination of GH and sex steroid production. Together they have an anabolic effect on muscle mass, bone mineralization and body proportions. It is another phase of rapid growth so that nutrition can again modify the genetic growth potential [1].

Growth Children with CKD fail to reach adult height potential (Haffner D N Eng J Med 2000) 36% of CKD patients have growth impairment Average Ht SDS at transplantation – 1.85 Greatest in Males Greatest in Younger Patients Increased morbidity and mortality (Furth NL Pediatr Nephrol 2002) Each SDS decrease associated with a 14% increase in death (Wong CS A J Kid Dis 2000) Normal growth can be divided into four important phases: prenatal, infantile, childhood and pubertal. Nutrition is important at all phases of growth, but particularly so during the infantile phase because the rate of growth is higher than at any other time of life (other than prenatally) and is less dependent on growth hormone (GH) than during other phases. Rate of growth gradually decreases from >25 cm/year at birth to an average of 18 cm/year at age 1 year and 10 cm/year by the age of 2. Half of adult height is achieved by the age of 2 years, so that irrecoverable loss of growth potential can occur during this phase. At birth, 170 kcal/day are stored in new tissue, falling to 50–60 at 6 months, 30–40 by 1 year and 20–30 by the age of 2 years. During the childhood phase, growth becomes more dependent on the GH/insulin-like growth factor-1 (IGF-1) axis; growth rate decelerates continuously until the pubertal phase. The pubertal phase results from the coordination of GH and sex steroid production. Together they have an anabolic effect on muscle mass, bone mineralization and body proportions. It is another phase of rapid growth so that nutrition can again modify the genetic growth potential [1].

Growth Dietician Nutrition Growth Hormone (Haffner D N Eng J Med 2000)
Supplemental Feeding Gastro-oesophageal reflux NG/Gastrostomy Fundoplication Growth Hormone (Haffner D N Eng J Med 2000) Everything Else Normal growth can be divided into four important phases: prenatal, infantile, childhood and pubertal. Nutrition is important at all phases of growth, but particularly so during the infantile phase because the rate of growth is higher than at any other time of life (other than prenatally) and is less dependent on growth hormone (GH) than during other phases. Rate of growth gradually decreases from >25 cm/year at birth to an average of 18 cm/year at age 1 year and 10 cm/year by the age of 2. Half of adult height is achieved by the age of 2 years, so that irrecoverable loss of growth potential can occur during this phase. At birth, 170 kcal/day are stored in new tissue, falling to 50–60 at 6 months, 30–40 by 1 year and 20–30 by the age of 2 years. During the childhood phase, growth becomes more dependent on the GH/insulin-like growth factor-1 (IGF-1) axis; growth rate decelerates continuously until the pubertal phase. The pubertal phase results from the coordination of GH and sex steroid production. Together they have an anabolic effect on muscle mass, bone mineralization and body proportions. It is another phase of rapid growth so that nutrition can again modify the genetic growth potential [1].

Renal Osteodystrophy Nutrition Dietician Pharmacist Psychologist
Nurse Specialist Doctor

Renal Osteodystrophy CKD – Mineral and Bone Disorder (Moe S Kidney Int 2006) Abnormalities of calcium, phosphorous, PTH and vitamin D metabolism Abnormalities in bone turnover, mineralisation, volume, linear growth or strength Vascular and other soft tissue calcification

Renal Osteodystrophy Abnormalities of calcium, phosphorous, PTH and vitamin D metabolism (Wesseling K Pediatr Nephrol 2008) Kidneys hydroxylate vitamin D to calcitriol Reduction in calcitriol early in CKD Decreased intestinal Calcium absorption Increased PTH release Initially N or low PO4 Later ↓ GFR ↓ PO4 excretion with ↓ hydroxylation and ↑ PTH Renal and skeletal PTH resistance Increased PTH Antagonised by Vitamin D If unchecked Parathyroid hyperplasia Autonomous unregulated Parathyroid growth and hormone release

Renal Osteodystrophy Abnormalities in bone turnover, mineralisation, volume, linear growth or strength (Wesseling K Pediatr Nephrol 2008) Bone Turnover Characteristically “High Turnover” Increased Osteoclastic and Osteoblastic Activity Can occur early in CKD “Low Turnover” – Adynamic bone disease Only reported in dialysis patients Excess of Vitamin D and Calcium with PTH suppression Increased fractures and growth retardation

Renal Osteodystrophy Abnormalities in bone turnover, mineralisation, volume, linear growth or strength (Wesseling K Pediatr Nephrol 2008) Bone Mineralisation Increased Osteoid (unmineralised bone) Defective mineralisation Increased Fractures Growth retardation Bone Abnormalities Bone Volume PTH is anabolic to trabecular bone Increased bone volume Steroid therapy

Renal Osteodystrophy Abnormalities in bone turnover, mineralisation, volume, linear growth or strength (Wesseling K Pediatr Nephrol 2008) Linear Growth Target PTH level unclear GH Resistance ↓ IGF1 Bioactivity Strength Epiphyseal widening Slipped Epiphysis Genu Valgum Femoral and wrist abnormalities Avascular necrosis Pathological fractures - NKF K/DOQI 2005 Am J Kid Dis 41 – Klaus G EWPDG 2006 Pediatr Nephrol

Renal Osteodystrophy Vascular and other soft tissue calcification (Wesseling K Pediatr Nephrol 2008)
Vascular calcification is present in children (Milliner DS 1990 Kidney Int, Goodman WG N Eng J Med 2000) Risk factors* (Russo D Am J Kid Dis 2004, Mitsnefes MM JASN 2005) Hypercalcaemia Hyperphosphataemia Increased Ca x Po4 product High dose vitamin D Pathophysiology Menchymal to osteoblast conversion Upregulation of Na dependent PO4 transporter Upregulation of pro mineralisation factors Calcium based PO4 binders – PREVENTABLE (Chertow GM Kidney Int 2002, Block GA Kidney Int 2005) * 40% of adults without these risk facorts have evidence of vascular disease and there is evidence of carotid intimal thickening even in children with low grade CKD

Renal Osteodystrophy - Treatment
Dietician Phosphate Binders Calcium based binders used most commonly Aim to keep Ca intake < double DRI If ↑ Ca stop binder ± Vitamin D Sevelamer Non calcium based Halts progression of vascular calcification (Block GA Kidney Int 2005) Lower mortality rates (Block GA Kidney Int 2007) Lanthanum Accumulation in liver, bone and growth plate (Spasovski GB Nephrol Dial Transpl 2006, Slatopolsky E Kidney Int 2005) Intensive Dialysis * 40% of adults without these risk facorts have evidence of vascular disease and there is evidence of carotid intimal thickening even in children with low grade CKD

Renal Osteodystrophy - Treatment
Secondary Hyperparathyroidism Vitamin D Ergocalciferol/Cholecalciferol Calcitriol Paracalcitriol* Calcimimetics Cinacalcet 25(OH) vitamin D deficiency is common in children with CKD, and assessment and repletion is recommended for all children in stages 2 to 4 CKD with secondary hyperparathyroidism. After repletion of native vitamin D stores, therapy with active vitamin D sterols is effective in suppressing PTH levels to the target range for the stage of CKD. Vitamin D sterols suppress PTH levels by two mechanisms: indirectly, through increased intestinal calcium absorption, and directly, via suppression of PTH gene transcription. Calcitriol and alfacalcidol are widely used in children, have been shown to be effective in suppressing PTH when given in daily or intermittent doses, and improve growth in children with CKD [39, 40]. However, hypercalcemia has been linked to their administration, particularly when given with calcium-containing phosphate binders. Thus, newer vitamin D analogues have been developed to maximize affinity for parathyroid tissue, while minimizing effects on intestinal calcium and phosphorus absorption. Three new vitamin D analogues are available for use in patients with CKD: 22-oxacalcitriol (OCT) in Japan, as well as 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) and 1α-hydroxyvitamin D2 (doxercalciferol) in the USA. Oral forms of paricalcitol and doxercalciferol have been approved for CKD 3 through 5 in adults, though not yet in children. Doxercalciferol and paricalcitol are effective in lowering PTH levels and may have a lower calcemic potential than calcitriol in both adults and children with CKD [35, 106]. Calcimimetic agents, which act as allosteric activators of the calcium sensing receptor (CaSR), are also available for the treatment of secondary hyperparathyroidism in the adult dialysis population. By increasing the sensitivity of the CaSR, these small organic molecules are able to reduce PTH levels, decrease the calcium–phosphorus product, and may provide a medical means of halting the progression of parathyroid gland hyperplasia [107]. Cinacalcet has been shown to be effective in the control of secondary hyperparathyroidism in adults with CKD [108], in those treated with maintenance dialysis [109–112], and in those with functioning renal allografts [113]. These agents have not been approved for use in children, and, due to the presence of the CaSR on the growth plate [114], studies are required to confirm their safety and efficacy in young patients.

CKD - Anaemia Adequately treated anaemia (Morris KP Arch Dis Child 1994, Morris KP Arch Dis Child 1993, Jabs K Pediatr Nephrol 1996, Warady BA Pediatr Nephrol 2003) Mortality Quality of life Exercise tolerance Growth Cardiovascular Function

CKD - Anaemia Published success (Children v Adults) (Chavers BM Kidney Int 2004) Haemodialysis - 54% v 40% Peritoneal Dialysis 69% v 55% CKD – 36.6% (Wong H Kidney Int 2006) CKD 1 – 31% CKD 4/5 – 93% Even with treatment with EPO the success of anaemia management is less in children than adults

CKD – Anaemia (Hollowell JG 2005)
Initiate anaemia work-up when Hb < 5th percentile (NKF – K/DOQI 2006 AM J Kid Dis)

CKD – Anaemia Erythropoeitin Deficiency Iron Deficiency
Blood Loss Phlebotomy Haemodoalysis Menses GI Dietary insufficiency or poor absorption Depletion during EPO therapy Decreased RBC survival Bone Marrow suppression Inadequate dialysis Malnutrition Infection and Inflammation Hyperparathyroidism B12 or Folate Deficiency Carnitine Deficiency Medications EPO levels innappropriate for degree of anemia and also fall further when CKD progress’. Some studies suggest only get significant anaemia when GFR 25-35ml/min/1.73m2. RBC’s in CKD have reduced life span. May be due to carnitine deficiency, maybe EPO deficiency. BM suppression occurs with serum form children with CKD. Exact inhibitor unclear but it is removed by dialysis and hence comparison with dose delivery. Of note children dialysed via a fistula have better Kt/V, HB and albumin than those dialysed via a cvl.

CKD – Anaemia Koshy SM & Geary DF Pediatr Nephrol 2008
EPO levels innappropriate for degree of anemia and also fall further when CKD progress’. Some studies suggest only get significant anaemia when GFR 25-35ml/min/1.73m2. RBC’s in CKD have reduced life span. May be due to carnitine deficiency, maybe EPO deficiency. BM suppression occurs with serum form children with CKD. Exact inhibitor unclear but it is removed by dialysis and hence comparison with dose delivery. Of note children dialysed via a fistula have better Kt/V, HB and albumin than those dialysed via a fistula. Koshy SM & Geary DF Pediatr Nephrol 2008

CKD – Anaemia Treatment
Measure pre-dialysis ? Measurement Monthly if stable 1-2 weeks if changes made ? (Greenbaum LA, Comprehensive Pediatric Nephrology, Elsvier 2008) Iron Erythropoeitin Darbopoeitin Mircera

CKD – Anaemia Treatment
Iron Monitoring Iron stores Ferritin Acute phase protein ESA’s cause functional iron deficiency Normal or elevated level doesn’t exclude deficiency TSAT – Serum Iron/TIBC - <20% Iron therapy Oral IV Age specific

CKD - Hypertension Very common (Wong H Kidney In 2006)
CKD I – 63% CKD 4/5 – 80% ESDR 50% uncontrolled (Tcakzyk K 2006 Nephrol Dial Transplant, Mitsnefes MM J Am Soc Nephol 2005) Progression of CKD (Wingen AM Lancet 1997, Mitsnefes MM J Am Soc Nephol 2003) Cardiovascular mortality (Kroothoff JW Kidney Int 2002) Aetiology ↑BP = ↑ CO X ↑ TPR Only really get hyper-reninism in RAS, but what you do see is an innappropraitley normal level of renin excretion (i.e. would expect lower levels given degree of hypertension and fluid overload) probably from areas of damage, inflammation,scarring cysts etc. The increase in renin has a direct pressor effect through Angiotensin II and salt and water retention through aldosterone. Hadstein C & Schaefer F Ped Nephrol 2008

CKD – Hypertension Aetiology
↑BP = ↑ CO X ↑ TPR RAS Fluid Overload Sympathetic system Catecholamines & Renalase Nitrous Oxide NO synthetase ADMA (Zocalli C Lancet 2001, Fliser D 2002 J Am Soc Nephrol) Drugs Only really get hyper-reninism in RAS, but what you do see is an innappropraitley normal level of renin excretion (i.e. would expect lower levels given degree of hypertension and fluid overload) probably from areas of damage, inflammation,scarring cysts etc. The increase in renin has a direct pressor effect through Angiotensin II and salt and water retention through aldosterone. Fluid overload is a significant factor with inter dialystic weight gain associated with interdialytic increase ABPM but less so that on adults (r=o.41 in children) It has been shown that BP falls in nephrectomised children who then become anuric unless there are other factors preventing a fall in TPR. Campese demonstrated that denervated kidneys resulted in a fall in BP. Synergistic role for ACE and beta blockers in treating sympathetic overactivity ADMA asymetric dimethyl L arginine Hadstein C & Schaefer F Ped Nephrol 2008

CKD Hypertension Surveillance

CKD Hypertension Treatment
Fluid management Dialysis prescription Lifestyle changes Salt Calories Exercise

CKD Hypertension Treatment
ACE ARB ACE/ARB Calcium Channel Blockers β – blockers Diuretics Others Escape Trial Group N Eng J Med 2009 CONCLUSIONS: Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition.

CKD – Cardiovascular Disease
CKD Patient Survival 40-60 yrs less for dialysis 20-25 yrs less for transplants CV Disease 40-50% (Oh J Circulation 2002, Groothoff JW Kidney Int 2002, McDonald SP 2004 N Eng J Med) Sudden Cardiac Death Arrythmias Dilated Hypertrophic Cardiomyopathies LVH Ischaemic Heart Disease ? Mitsnefes MM 2008 Ped Nephrol

CKD – Cardiovascular Disease
Treatment - Minimise Risk Factors Transplantation ↓ Cardiac Death by 80% ↑ Life expectancy by years Hypertension, Hyperlipidaemia, CAN Hypertension Proteinuria Anaemia Dyslipidaemia Renal Osteodystrophy Therapeutic Lifestyle Changes (TLC) No evidence for hyperhomocysteinaemia or chronic inflammmation

CKD Neurodevelopment Neuroimaging Electrophysiology Cognitive Function
12-23% Cerebral atrophy Chronic Infarct lesions Electrophysiology EEG abnormalities 30-40% Predominantly slow wave increase Cognitive Function Variable Results Largest deficit in infants* Lower IQ particularly non-verbal Variable Improvement post transplantation Studies of children ESRF have demonstrated a high prevalence of abnormalities in neuroimaging. There have however never been any studies of “genaral” CKD patients as they tend to be of specific groups, Cystinosis, Lowe’s Nephrotic ect the latter of whom are more prone to thromboembolic phenomena which may explain the neuroimaging findings.

CKD Neurodevelopment Specific Neurocognitive Functions (Hulstijn-Dirkmaat GM 1995 Ped Nephrol, Ledermann 2000 J Pediatr, Warady BA 1999 Ped Nephrol) Attention and executive functions Language Visual-spatial Memory Academic Achievement and School Performance Poorer Performance than peers (Brouhard PH 2000 Ped Transplant) Transplanted patients perform better (Gipson DS 2006 Child Neuropsychol) 15% Special Educational Needs 77% had CNS Infarcts (Qvist E 2002Ped Tansplant) Assessment and early intervention key Studies of children ESRF have demonstrated a high prevalence of abnormalities in neuroimaging. There have however never been any studies of “genaral” CKD patients as they tend to be of specific groups, Cystinosis, Lowe’s Nephrotic ect the latter of whom are more prone to thromboembolic phenomena which may explain the neuroimaging findings.

CKD - Progression Age of attainment of renal mass deficit Gender
Underlying Disease & Genetic Pathology Polymorphic Genetic Variation Dyslipidaemia and Insulin Resistance Nutrition Anaemia Disorders of Calcium & Phosphate Proteinuria Hypertension It is recognised that infants born with a single kidney are at a higher risk of hypertension, proteinuria etc than adults underging unilateral nephrectomy for trauma. I patients with unilateral nephrectomy for Wimls tumour, those undergoing nephrectomy at a younger age had a higher incidence of microalbuminuria. With morphometric studies showing glomerular volumes 5-6x greater than normal. Men get it worse, but the survival benefit does not seem to extend to post-menopausal women suggesting a role for female sex hormones. The acceleration of GFR loss around puberty would theoretically be expected to prejudice males but there is no published evidence to confirm this. Underlying Disease (explain graphic). In addition if one had an RPGN then progression would be expected to be faster than a static anatomical lesion. Even within disease there is genetic heterogeneity depending on the specific gene defect e.g. in ADPD PKD1 defects generally progress faster than PKD2 mutations, similarly with nephronopthisis the NPHP1 gene is associated with ESRD aged 13 as opposed to 19 for the NPHP3 gene and 8 months for the NPHP2 gene. Alports too is another example. Polymorphic variations in the ACE gene have shown a poorer prognosis for the DD genotype similarly variations in the Ang II type 1 receptor and haem oygenase 1 promoter. There’s not a lot we can do about that but we can do something about those in red Gonzalez Celedon C Pediatr Nephrol

CKD Progression - Proteinuria
REIN Study (Kramer BK 1997 Lancet) ItalKid Study (Ardissino G 2004 Ped Nephrol) Escape Study (2009 N Eng J Med) Summary 1G/day reduction in proteinuria reduces GFR decline by 2ml/min/year Target < 300mg/m2/day Associated benefit of treating BP Wingen AM Lancet 1997

CKD Progression - Blood Pressure
ACE Inhibition 30-40% reduction in doubling creatinine or ESRD in those with proteinuria (Jaffar TH 2001 Ann Intern Med, Remuzzi G 2001 Lancet) “Aldosterone Escape” Gradual introduction Initial response predictive of long term benefit May see 10-15% drop in GFR Positive predictor of renoprotection May not persist in children (Wuhl E 2006 Pediatr Nephrol) Wingen AM Lancet 1997

CKD Progression - Blood Pressure
Calcium Channel Blockers Dihydropyridine (Remuzzi G 1997 Kidney Int) Amlodipine, Nifedipine Non Dihydropiridine Diltiazem, Verapamil β- blockers Metoprolol & Atenolol (Parving HH 1983 Lancet, Wright JT 2003 JAMA) Carvedilol (Marchi F 1995 Adv Ther, Tanaka H 2004 Pediatr Int) Combination Therapies ACE/ARB Dose escalation “Ultra-high” dose Antihypertensive Chronotherapy (Svensson P 1001 Hypertension, Hermida RC 2005 Hypertension) Wingen AM Lancet 1997

CKD - Progression

Chronic Renal Failure in Children and Adolescents

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