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Medical Affairs Department of Pediatrics Clinical Practice Guideline

MANAGEMENT OF CHRONIC KIDNEY DISEASE IN CHILDREN

Document # Date CPG Formulated Next Review Date

PEDS-NEPRHO# 011 JULY 17, 2011 JULY 2013

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Definition of CKD: Disorder that lasts 3 months with either kidney damage defined by structural or functional renal abnormalities. Classification: Is based on GFR for children older than 2 years as follows: - CKD1 Normal GFR ( 90 mL/min per 1.73 m2) with kidney damage** CKD2 GFR between 60 and 89 mL/min per 1.73 m2 CKD3 GFR between 30 and 59 mL/min per 1.73 m2 CKD4 GFR between 15 and 29 mL/min per 1.73 m2 CKD5 GFR of less than 15 mL/min per 1.73 m2 or end-stage renal disease (ESRD)

** Kidney damage: (chronic) pathologic abnormalities in blood or urine tests or imaging studies related to the kidney. GFR can be calculated as per the Schwartz formula: GFR = k X Height (cm) / sCreat - K is 0.33 in premature infants and 0.45 for term infants <1 year. K is 0.55 in children and adolescent girls, and 0.7 in adolescent boys.

Normal GFR in Children Mean GFR SD Age (Gender) mL/min/1.73m2 1 week 40.6 14.8 2-8 weeks 65.8 24.8 >8 weeks 95.7 21.7 2-12 years 133.0 27.0 13-21 years (males) 140.0 30.0 13-21 years (females) 126.6 22.0 GENERAL PRINCIPLES: Treat reversible kidney dysfunction, Prevent or slow the progression of kidney disease, Treat the complications of CKD, Identify and adequately prepare the child/family in whom renal replacement therapy will be required. CKD Complications: Sodium and intravascular volume: - In CKD 4/5 water and sodium retention may result in volume overload which needs sodium restriction.

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- Salt wasters (i.e. obstructive uropathy or dysplastic kidneys) require ongoing fluid and sodium replacement. Hyperkalemia: Hyperkalemia does not usually occur until the GFR is < 10%. Special attention should be paid to serum potassium in patients receiving ACEi/ARBs when approaching CKD5. Management consists of: a) Low potassium diet, b) administration of a loop diuretic, c) correction of metabolic acidosis and sodium polystyrene sulfonate (Kayexalate). Metabolic acidosis: Overt acidosis is characteristically present in CKD 4/5. It is associated with growth impairment. The aim is to maintain the serum bicarbonate level 22 mEq/L. Sodium bicarbonate can be given to correct acidosis. Bone metabolism and bone disease: Subtle signs of renal osteodystrophy begin to be observed when the GFR decreases to 50% of normal (CKD3). Physical findings may include muscle pain, weakness, and bony changes such as varus and valgus deformities of the long bones. Laboratory abnormalities of bone metabolism (e.g., elevated PTH) are common in CKD3 and require therapeutic interventions. Types: - Osteitis fibrosa cystica (high bone turnover) results from secondary hyperparathyroidism. Adynamic bone disease (low bone turnover) and is related to excessive suppression of the parathyroid gland. Mixed osteodystrophy

Diagnosis: - Bone biopsy is the gold standard; consider if persistent hypercalcemia with a serum intact PTH between 42 and 63 pmol/L. Radiology is only helpful for monitoring severe cases, as it may be normal even with moderate hyperparathyroidism. PTH level >21 pmol/L and ca <2.5 mmol/L identified patients with high turnover bone disease. PTH <21 pmol/L and ca >2.5 mmol/L identified patients with adynamic bone lesions.

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Children on hemodialysis: all patients with a serum PTH concentration >13 pmol/L and a serum calcium value <2.5 mmol/L have either osteitis fibrosa or mixed osteodystrophy. Tertiary HPT will be caused by a cycle of PTH stimulation as increased hydroxylation of Vit D induced by PTH stimulation will increase not only Ca but also PO4 absorption from the gut.

Management: Level of PTH aimed for in CRF to maintain normal bone turnover are the following: - CKD 2/3: 3.7 to 7.4 pmol/L (normal range 0.5 to 6 pmol/L) CKD4: 7.4 to 11.6 pmol/L (~up to 2x the upper NL) CKD 5: 21 to 32 pmol/L (or 3-5 times normal value) to allow normal growth.

Monitoring: For calcium and phosphorus the recommendations for measurements are at least: - CKD 2 yearly CKD3 q 6 months CKD 4 q 3 months CKD5 monthly

For PTH and alkaline phosphatase measurements: - CKD2 yearly. CKD3 q 6 months CKD4/5 q 3 months

Phosphate: - In CKD4 hyperphosphatemia will usually occur unless appropriate therapy is given. The targeted goals: to avoid serum phosphorus below the target range because of the potential adverse effects of hypophosphatemia on linear growth. CKD 5: The serum phosphorus should be maintained between 1.3 to 1.9 mmol/L in children 1 to 12 years of age and between 1.1 to 1.8 mmol/L in adolescents. CaCO3 can decrease absorption to 30-40 % if given before or during the meals. Non-calcium phosphate binder (Sevelamer) should be added if hypercalcemia (s Ca >2.55 mmol/L).

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Calcium: - The total serum calcium should be maintained within a normal range. If the total serum calcium value exceeds 2.55 mmol/L, the dose of calcium-based phosphate binders should be reduced and/or therapy changed to Sevelamer. Vitamin D therapy should also be discontinued until the serum calcium returns to the targeted range.

Vitamin D: - Deficiency of 25-hydroxyvitamin D is common in children with CKD. The patients with CKD 2 to 4 and serum PTH values above the target range, serum 25-hydroxyvitamin D concentrations should be measured yearly. If the PTH remains elevated after having the phosphate within the normal range, the serum calcium level is <2.37 mmol/L and the serum 25-hydroxyvitamin D is >75 nmol/L, the recommended starting dose for Calcitriol is based on the body weight of the child: o Weight <10 kg: 0.05 mcg q 48 hrs. o Weight 10 - 20 kg: 0.1 - 0.15 mcg/d. o Weight > 20 kg: 0.25 mcg/d. o Alfacalcidol (1mo-12 yr): 15-30 ng/kg/d (max 500 ng or 0.5 mcg/d) Once Calcitriol/Alfacalcidol is started, serum PTH should be measured at least every three months.

Hypertension: - The prevalence of hypertension in children with CKD is high, even when the GFR is only mildly reduced. Aggressive blood pressure control slows the progression of CKD. Based on that the target BP goals are: The NHBPEP recommended a reduction in PB to below the 90th percentile based upon the age, gender, and height of the patient. Target ABPM is a mean BP <50th percentile (ESCAPE trial). Ambulatory blood pressure monitoring (ABPM) should be considered with the following indications: Suspected white coat hypertension, Resistant hypertension, Hypotensive symptoms while taking antihypertensive medications, Episodic hypertension and Autonomic dysfunction.

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Left ventricular hypertrophy: - LVH is commonly seen in children with CKD especially patients on dialysis as a response to mechanical or hemodynamic overload. Echocardiograms should be performed in all patients: a) at the initiation of dialysis, b) once patients have achieved dry weight (ideally within 13 months of dialysis initiation), and c) at 3-yearly intervals thereafter.

Anemia: - Anemia due to reduced kidney erythropoietin production develops when the GFR is below 30 mL/min/ 1.73 m2. The anemia of CKD is principally normocytic and normochromic.

Treatment: - The target hemoglobin is 11 - 12 g/dL. Serum ferritin should be kept between 100 to 800 ug/l and TSAT 20, All patients receiving therapy with erythropoiesis stimulating agent (ESA) require iron supplementation to prevent the development of iron deficiency. The initial rHuEPO is 80 to 120 u/kg per week in 2-3 divided doses (up to 300 u/kg per week for <5 years of age or children on dialysis). Darbepoetin alfa is a long-acting erythropoietic agent can be used at a dose of 0.5 (range 0.25 to 0.75) mcg/kg/week. In PD patient it can be given q 2 weeks and in CKD 4 it can be given once a month.

Monitoring: - The expected increase in Hgb (Hct) after the initiation of rHuEPO therapy or after a dose change is between 2 - 8% over a 2 - 4 week period. Monitor the Hgb (Hct) every 1-2 weeks until a stable target Hgb (Hct) and then every 4 weeks. Growth: - Growth retardation occurs in up to 50% of children with GFR<50ml/min/1.73m2. The most important cause of poor growth is inadequate intake of calories and protein leading to malnutrition. Water, electrolyte, and acid-base imbalance, renal osteodystrophy, and growth hormone resistance are also important. The criteria for initiating recombinant human growth hormone (rHuGH) in children with CKD include all of the following:

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1. Height SDS that is <-1.88 and/or a height velocity SDS <-2 persists beyond 3 months despite treatment of nutritional deficiencies and metabolic abnormalities. 2. Growth potential that is documented by open epiphyses. 3. There are no contraindications for rHuGH. 4. The use of rHuGH is continued until the child a) reaches the 50th percentile for mid-parental height, b) achieves a final adult height with closed epiphyses, or c) receives a kidney transplant. Dyslipidemia: - Abnormal lipid metabolism is common in patients with CKD and adds to the risk for cardiovascular disease (CVD) in children with CKD. Evaluation should be performed at presentation, and annually thereafter or 2-3 months following a change in treatment or subsequent to the presentation of another condition known to cause dyslipidemia.

Nutrition: Refer to separate CPG on TOL (in process). Immunization: Refer to separate CPG on TOL (in process). References: - www.uptodate.com, as of July 2011 Oxford Handbook of Pediatric Nephrology by Lesley Rees, Nicholas J.A. Webb, Paul A. Brogan, 1st edition 2007. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) Clinical Practice Guidelines (http://www.kidney.org/professionals/kdoqi, as of July 2011). Bajo MA et. al. Nefrologia. 2009; 29 (2):136-42 (Changing the frequency of administration of darbepoetin alfa (from weekly to fortnightly) maintains the hemoglobin levels in patients undergoing peritoneal dialysis).

Prepared by: Dr Issam Abou Najab, Pediatric Nephro Specialist Dr Ibrahim Al Attrach. Consultant Pediatric Nephrologist

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Approval: Name Head of the Department: Dr. Aiman Al Rahmani Other Involved Department Head/Manager: Division Chief Dr. Ibrahim Al Attrach Dr. Issam Abou najab Tawam/JHopkins CMO Dr. Walid Kaplan Reviewed By Johns Hopkins Member: Yes Johns Hopkins Member Signature Date

No

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