Chronic kidney disease

Best practice management Dr Fiona Mackie

2016

• Strategies to delay progression of disease

• Management of chronic kidney disease Anaemia Nutrition/fluids Growth failure Calcium/phosphate balance

When the horse has bolted ………

Anaemia • Prevalence data- children/adolescents with

CKD (Wong H KI 2006)

• Current definitions (KDIGO 2012)

CKD Stage Prevalence % Hb <12 mg/dl or treatment for anaemia

1-2 30%

3 66

4-5 93

Age Hb g/dl (g/L)

6 mo-5 yrs 11.0 (110)

5-12 yrs 11.5 (115)

12-15 yrs 12 (120)

Non pregnant females >15 yrs 12 (120)

Males >15 13 (130)

Causes of anaemia

• Multifactorial: Erythropoetin deficiency, lack of iron availability, inflammation, blood loss, hyperparathyroidism, B12 and folate deficiency

www.kyoto-u.ac.jp

Usually lower O2 availability induces EPO production. As GFR, decreases there is a decrease in fractional Na reabsorption, therefore a decrease in oxygen use and therefore a decrease in EPO production

Impact of anaemia in children

• Decreased Hb levels are independently associated with the development of LVH in children with CKD ( Mitsnefes JASN 2010)

• 52% increase in mortality risk in patients with hematocrit <33% at dialysis institution- NAPRTCS Warady et al Ped Neph 2003

• IPPN: increase in patient mortality of 5 vs 2% at 12 mths, 8 vs 4% at 24 mths with Hb <11g/dL (JASN 2013)

• Increased rate of hospitalisations

• Poorer school performance

Treatment of anaemia- iron deficiency; absolute and functional

• How often should we measure?: KDIGO recommends measuring transferrin saturation (TSAT) and ferritin every 3 mths or more often if starting or adjusting ESA’s

• What should we measure?: KDIGO recommends Transferrin- indicator of total iron binding capacity but has diurnal variation and is nutritionally dependent

Serum ferritin- stored iron; but also an acute phase reactant • Most acceptable in children- TSAT ( serum iron/total

iron binding capacity x 100. Is derived from transferrin level x 1.4. Best predictor of iron deficiency TSAT <20%

How should we treat iron deficiency?

• Iron target: KDIGO 2012 target saturation >20% and ferritin >100 ng/mL. Use oral iron first unless on HD- then use IV iron (trial data suggests more effective in children on HD)

• IV iron formulations- can have anaphylaxis (more common with iron dextran). Must be monitored appropriately with resuscitation facilities available. Problem if IV tissues (tattoo)

Treating iron deficiency

• KDIGO 2012 recommendations for children (RCT evidence) If on HD: ferric gluconate 1.5 mg/kg weekly for 8 doses if iron deficient If on HD and iron replete 1 mg/kg/week and adjust according to iron studies

• If using oral iron- dose recommended for treatment in children is 2-6 mg/kg/day (elemental) in 2 divided doses

Sometimes oral iron is not successful in PD or CKD patients

Sydney Children’s Hospital protocol for iron polymaltose Use pre-meds; monitor

Iron polymaltose dosing for HD patients

Erythropoietin analogues • KDIGO targets Hb 11-12

Available:

• Infants and young children may require much higher doses- much higher than adults. HD patients require more than PD patients (greater blood losses)

• Dose modification no more frequently than every 2 weeks

T 1/2 Dose Dosing frequency

Epoetin alfa 150 u/kg/wk 3 times per wk-weekly

Shorter half life

Darbopoetin IV 25 h; sc 48 h 0.45 µg/kg weekly or 0.75µg/kg q 2 weeks

1-2 weeks Painful on injection

Methoxy polyethylene glycol-epoietin beta (Mircera)

135 hrs 1.2 mcg/kg monthly

monthly Less painful; can be given monthly

ESA resistance

• Either from the start or it develops over time • Possible causes

iron deficiency inflammation (increased hepcidin levels limits GI absorption in gut and liver release) bone disease ACEI/ARB acidosis vitamin C or folate deficiency malnutrition antibody to ESA- pure red cell aplasia- rare and hard to diagnose

Fluids and nutrition

http://blog-health-nutrition.extension.umn.edu/2015/07/stay-hydrated-with-healthy-beverages-in.html

Management of chronic kidney disease- Fluids

• KDIGO 2013 recommendations: Supplemental free water and sodium supplements should be given to children with CKD and polyuria to avoid chronic intravascular depletion and promote growth (Level 1C evidence)

• If hypertension >95 pc then sodium should be restricted to age based sodium requirement levels

Age Upper limit Na per day

<1 yr No data

1-3 yrs 1500 mg

4-8 1900

9-13 2200

14-18 2300

KDIGO 2013

Protein energy wasting PEW (“malnutrition” in CKD)

Protein energy wasting

uremia

Orexigenic hormones

eg acyl grelin

Desacyl ghrelin,

adinopectin, letpin

GI losses eg vomiting from GOR; albumin

losses on PD or nephrotic

Altered taste Inadequate

caloric intake

anabolism

Risk factors for PEW

• Infants

• Reduced residual renal function; inadequate dialysis dose

• Metabolic acidosis

• Low birth weight, small for gestational age

• Psychosocial factors

• Co-morbidity- neurological disease, CVS

• PD losses (of amino acids and proteins)

Evaluation of nutrition in children with CKD

• Any unit looking after children with CKD should have access to a dietitian

• Why is it so important: For every 2 SDS above or below a BMI of 0.5 the risk of mortality increases by 26% in children ( u shape curve; Wong CS AM J KD 2000- ESKD children from USRDS data))

What to evaluate and how?

• 3 day diet records from family

Evaluation of nutrition

• nPCR is calculated from the intradialytic increase in BUN between HD sessions. A low nPCR predicts weight loss in adolescents on HD (evidence); recommended to measure monthly in adolescents on HD. Can use online calculators eg hsls.pitt.edu

• No good biochemical marker but albumin does correlate with mortality in children and adults so helps with severity

Management of nutrition- few detailed guidelines

• CARI (Australia) 2005 Ensure the energy intake is that of a healthy child of the 50th percentile height of the same age to allow catch-up growth. If this can not be maintained orally, commence feeds nasogastric or gastrostomy

• Many studies have demonstrated improved growth especially in infants <2 yrs with MG/gastrostomy feeds in CKD (however not NAPRTCS study)

Nutrition guidelines

• The net glucose intake from PD is 8% energy requirements per day- take this into account if overweight (Salusky 1983)

• Gastrostomy tubes should not be inserted at the time of a PD dialysis catheter (either well before or after) because of peritonitis risk

• KDOQI recommends measuring water soluble vitamins, zinc and copper every 4 months in dialysis patients and supplementing (not adult doses)

Growth

Short stature

• Definition: height of 2 SD’s below mean for age and sex (below the 2.5 percentile)

• Worse if infant onset of CKD • ESPN Data: 45% of children starting dialysis <

19yrs had a final adult height <3rd centile age/sex matched. However there have been improvements over the last 2 decades.

• Consequences: Increased mortality (complex includes influences of nutrition, bone disease etc); reduced QOL; poorer school performances and reduced income

Risk factors for poor linear growth

• Infant onset of CKD

• Low birth weight and small for gestational age

• Protein energy wasting

• Incompatible dialysate solutions

• Inadequate dialysis dose (daily HD better growth than conventional)

Growth hormone therapy

• GH stimulates linear growth, increases muscle mass and improves bone density

• Insensitivity to GH, reduced transcription of IGF1 • Effect of supraphysiological doses of GH- does

have a positive effect on final height. Better pre-dialysis; effect decreases after 1st year

• Metanalysis data: safe to use post transplant (no increased risk of rejection)

• Caution not to use in children with severe renal osteodystrophy- manage this first

Simplified diagram showing muti-organ interactions in regulation of phosphate homoeostasis

FGF23 produced in the bone cells can suppress renal NaPi-2a and NaPi-2c co-transporter

activities to increase the urinary excretion of phosphate.

M. Shawkat Razzaque Clin. Sci. 2011;120:91-97 © 2011 by Portland Press Ltd

CKD Mineral Bone Disorder CKD-MBD

Suppression of renal alpha hydroxylase by FGF23/Klotho leads to reduced 1,25 OH2D

FGF23 elevation

• Independent risk factor for mortality in adults with CKD and general population

• Why is it elevated in CKD? Not fully understood possibly oral phosphate loading transient increases in PTH reduced Klotho iron deficiency stimulates FGF 23 transcription in osteocytes

Calcium based binders either have no effect or increase FGF 23

The appropriate therapy to minimise FGF23 rise and prevent CVS morbidity remains to be defined Salusky Ped Neph 2015

Current CK-MBD recommendations • There are new guidelines to be released by KDIGO this year • Existing recommendations for phosphate are to maintain no higher

than age limits for CKD stages 1-4; lower targets for CKD stage 5 • Initially dietary restriction – even lower if raised PTH • 0 to 0.5 years – 100 mg/day • ●0.5 to 1 year – 275 mg/day • ●1 to 3 years – 460 mg/day • ●4 to 8 years – 500 mg/day • ●9 to 19 years – 1250 mg/day

• Phosphate binders- calcium containing vs non-calcium containing

(sevelemar)

Calcium absorption from phosphate binders is increased if taken between meals and also if taking active vitamin D as well

Problem of hypercalcemia

• 2 studies in children comparing sevelemar to calcium acetate. Equal reduction in phosphate, less hypercalcemia with sevelemar.

• Use both calcium and non-calcium containing binders to reduce cost.

Management of CK-BMD

• PTH goals: if elevated reduce phosphate and then if still elevated start calcitriol

• PTH targets are controversial

• IPPN- for children on PD target PTH 1.7-3 times upper limit of normal

• Measure 25 hydroxyvitamin D and replace if low

How often to measure?

• For calcium and phosphorus measurements, the KDOQI guidelines recommend [1]:

• ●Stage 2 disease – Measurements at least yearly • ●Stage 3 disease – Measurements at least every six months • ●Stage 4 disease – Measurements at least every three months • ●Stage 5 disease – Measurements at least monthly • For PTH and alkaline phosphatase measurements, the KDOQI

guidelines recommend: • ●Stage 2 disease – Measurements at least yearly • ●Stage 3 disease – Measurements at least every six months • ●Stage 4 and 5 disease – Measurements at least every three

months Bone biopsy rarely indicated or done

Lipids

• Current KDIGO guidelines for adults- recommend statins for adults >50 with GFR <60 ml/min/1.73 m2 or post kidney transplant but not those on dialysis (lack of supporting trial data)

• We know the atherosclerotic process begins in childhood • KDIGO recommends baseline measurement of lipids in

children to exclude familial hypertriglyceridemia or rare inherited lipid disorders

• First line treatment: lifestyle modification/dietary ? Fish oil for hypertriglyceridemia- 3 trials in pediatrics showing it reduces TG

• No recommendations for statins in children- lack of trial evidence and outcome data

Wingen AM et al Randomised multicentre study of a low protein diet on the progression of chronic renal failure in children Lancet 349:1117-1123

Hypertension is an independent risk factor for progression of renal disease in children

Hypertension

Progression of Renal Disease, According to Blood-Pressure-Control Group

The ESCAPE Trial Group. N Engl J Med 2009;361:1639-1650

ESCAPE trial 2009

Intensive BP target below the 50th percentile compared with conventional 50-95th pc resulted in significantly less reduction in GFR

Endpoint was >50 % decline in GFR or ESKD

Antihypertensives

• Ideally agents that target RAAS- added benefit of antiproteinuric ACE inhibitors- ESCAPE trial AT Receptor antagonists Combined ACEI andATRA- minor additional effect on BP (4 mmHg) vs monotherapy but significantly increased anti-proteinuric effect 30%. Caution in adults (ONTARGET study high risk CVS disease adults no additional benefit in combination and more adverse events) Aldosterone inhibition- could help with aldosterone escape that occurs with chronic ACEI. Spironolactone not ideal as endocrine effects; can use eplerenone if available.

• Calcium channel blockers- no antiproteinuric effect- only use with ACEI/AT RA in early stages of CKD. May need to be used alone in more advanced CKD because of hyperkalemia

• Beta blockers- metoprolol in older studies equivalent antiproteinuric effect to ACEI.

Vaccination

• CKD children are at risk of more serious consequences of vaccine preventable infections (including Influenza)

• They should receive all standard immunisations- especially pre-transplant

• Ensure Hep B levels remain adequate –recommended >10 (measure annually). Require adult doses of Hep B vaccine

• Give influenza vaccine annually • HPV (papilloma) virus vaccine important-as at long term increased

risk (especially post transplant) of HPV related cancers. We recently demonstrated adequate initial response in immunosuppressed children (Vaccine 2016)

• Live vaccines should not routinely be given post transplant- there are a few published studies of use with varicella. Use only with extreme caution- should always try to vaccinate pre transplant

Overall management of the child with CKD

• Close attention to detail, regular follow up

• A multidisciplinary team that includes dietitians, nurses, social workers, psychologists

• Good patient and parent education- information about dialysis and benefits of living kidney donation