8-2. Management of chronic renal failure. Isidro Salusky (eng)

Management of Chronic Renal Failure in Infants and Children

Isidro B. Salusky, M.D.Distinguished Professor of Pediatrics

Chief, Division of Pediatric NephrologyDirector, Clinical Translational Research Center

Associate Dean of Clinical ResearchDavid Geffen School of Medicine at UCLA

Normal Growth Curve

Leading Causes of Death in General Pediatric Population and Children with CKD

Mitsnefes MM JASN 23:578, 2012

CVD Mortality by Age, Race, and Gender in the General Population and in ESRD Patients

NKF Task Force on Cardiovascular Disease. Am J Kidney Dis. 1998;32(suppl 3):S115.Sarnak MJ, Levey AS. Am J Kidney Dis. 2000;35(suppl 1):S117-S131.

% A

nn

ual

mo

rtal

ity

Age (yr)

GP MaleGP FemaleGP BlackGP WhiteDialysis MaleDialysis FemaleDialysis BlackDialysis White

25-34 35-44 45-54 55-64 65-74 75-84 >85

100

10

1

0.1

0.01

0

Dialysis Population

General Population

Pediatric Patients at Higher Risk for Cardiovascular Disease

(American Heart Association Statement)

• Homozygous hypercholesterolemia• Kawasaki disease• Diabetes type I and II• Chronic kidney disease • Congenital heart disease/ Pediatric heart transplant • Chronic inflammatory disease (SLE & RA)• Childhood cancer

Kavey REW et al. Circulation 114:2710, 2006

Growth Retardation in Kidney Disease: Factors Involved

–Protein and Calorie Malnutrition–Acidosis/Electrolyte Abnormalities–Primary kidney disease–Anemia–Renal bone diseases–Hormonal Factors –Immunosuppressive Medications

Stages of Chronic Kidney Disease

Stage Description

GFR(mL/min/1.73 m2)

1

2

3

4

5

Kidney damage with normal or GFR

Kidney damage with mild GFR

Moderate GFR

Severe GFR

Kidney failure

90

60-89

30-59

15-29

15 or dialysis

K/DOQI: Evaluation, classification and stratification. AJKD 39: 2001K/DOQI: Evaluation, classification and stratification. AJKD 39: 2001

Prevalence of Complications According to KDOQI Stages of CKD

Wong H et al. KI 70:585, 2006

n=366

Anemia in CKD- Simple Version• Renal insufficiency = EPO deficient state

Extended Dosing of ESAs

Causes of Anemia in CKD Patients (1 of 3)

• Renal insufficiency– Decreased production

of erythropoietin

– Accumulation of uremictoxins

Kidney

Decreased erythropoietin production

Bone

Bone marrow

Inhibition of erythropoiesis

Erythroidprogenitor cells

Adapted from Weiss et al. N Eng J Med. 2005;352:1011-1023.

Anemia in CKD Complicated version

• EPO resistance– Iron deficiency– Hyperparathyroidis

m– High dose ACE

inhibition– Aluminum toxicity– Antibodies to ESA

– Inflammation– Folate/B12 deficiency– Hemoglobinopathies– Hemolysis– Chronic Blood Loss– Chronic infection

Anemia Treatment

• Erythropoietin Stimulating factors (ESA) • Iron• Diagnose and treat underlying cause of

Epogen resistance

Kaplan-Meier Survival Curves in Children on PD with Hgb. Above or Below 11 g/dl

Borzych-Buzalka D et al. JASN 24:665, 2013

Mean Epogen Dose in Children on PD

NAPRTCS 2011

Protein-Calorie Malnutrition

• Loss of appetite-may manifest early in the course of kidney disease

• Spontaneous food intake decreases with worsening kidney failure

• Calorie Malnutrition-seen during the first years of life

• Protein Malnutrition-not frequently seen in children with kidney failure

Management of Poor Growth in Chronic Kidney Disease

• Adequate caloric intake– Infants-growth rates during this period are

correlated with calorie intake • Nasogastric (NG) or Gastrostomy (G) Tube Feeding

– Older children- intake should not be less than 80% of the Recommended Daily Allowance (RDA)

• Therapy with recombinant human growth hormone

Effects of Nasogastric (NGT) and Gastrostomy (GS) Feedings on Growth in Infants on CPD (IPPN)

Rees L et al. JASN 22:2302, 2011

Regional Variations on Nutritional Status

(n=153)

Rees L et al. JASN 22:2302, 2011

Regional Variations on Linear Growth

Rees L et al. JASN 22:2303, 2011

Regional Factors that Influence Growth and Development

• North America: Oligo-anuric, high glucose exposure and treatment with RhGH

• Europe: Biocompatible PD fluids

• Turkish: Lower serum albumin levels, higher serum P levels and use of amino-acids containing solutions

• Latin America: Persistent residual renal function, higher use of phosphate binders and lowest rate of NaCl supplementation

Rees L et al. JASN 22:2302, 2011

Acidosis and Electrolyte Abnormalities

• Many congenital kidney diseases lead to loss of electrolytes and decreased ability of the kidneys to concentrate urine

• Infants with kidney failure due to renal dysplasia-high urinary losses of sodium

• Metabolic acidosis- kidney function below 50%• The specific effect of bicarbonate therapy on

growth in CKD remains to be defined • Correction prior to treatment with rhGH

Renal OsteodystrophyImplications on the Growing Skeleton

• Effects on bone remodeling and modeling– Skeletal fracture and microfracture repair– Bone deformities– Growth retardation

• Relationship to:– Osteopenia / osteoporosis– Changes in bone mass over time during long-term dialysis– Vascular calcifications

• Bone loss after renal transplantation and cardiovascular disease

CKD Stage

% o

f Sub

ject

s

2 3 4

0

20

40

60

80

100

CKD: Abnormalities in Turnover and PTH

Bone turnover

PTH

Wesseling-Perry K CJASN (2012) 7:146

0

50

100

150

200

BF

R (

um3 /

um2 /

y)

0

250

500

750

1000

PT

H (

pg/m

l)

Low/nl BFR High BFR Low/nl BFR High BFR

GH GH GHGH

rhGH Increases BFR out of Proportion to PTH in Dialyzed Patients: Randomized Trial

Bacchetta J et al CJASN 2013

*

*

GH No GH

Long-term Consequences of Childhood Renal Osteodystrophy

Groothoff JW KI 63 (2003) 266–275

Height < -2 SD 153 (61.9%)

Clinical manifestations of bone disease 91 (36.8%)

Deformities 63 (25.5%)

Pathological fractures 33 (13.4%)

Aseptic bone necrosis 32 (13.0%)

Mild disabling bone disease 26 (10.5%)

Severe disabling bone disease 18 (7.3%)

Invalidating bone disease (all) 44 (17.8%)

Lumen

Intimal Atherosclerotic Plaque

From Passive Deposits to Active Processes

New Definition of Renal Osteodystrophy CKD-Mineral Bone Disease (CKD-MBD)

A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:

– Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism

– Abnormalities in bone turnover, mineralization, volume, linear growth, or strength

– Vascular or other soft tissue calcification

Moe et al Kidney International 2006

Vascular Calcification in Patients With CKD

• Patients with Stage 5 CKD are at high risk for vascular calcification

• Vascular calcifications are present in almost 50% of patients with stage 4 CKD and new dialysis patients

• Vascular calcification can be quantified• Vascular calcification is associated with modifiable risk

factors– Ca intake from calcium-based binders– S-P, S-Ca and Ca P product

• Vascular calcification results in arterial stiffening and increased pulse pressure and adynamic bone disease

Therapeutic Options for the Treatment of CKD-MBD

Phosphate Binders D2-D3 1,25(OH)D

CalcimimeticDrugs

Cinacalcet

Calcitriol

Paricalcitol

Doxercalciferol

Sevelamer:Ca free – Metal Free

Ca-Salts

Lanthanum Ca:Ca free - Metal +

Ergocalciferol

KDIGO Focus: Consider Normal Limit for PTH

Stage Treatment Target Range

3KDIGO: Upper Limit of Normal* (2C)KDOQI: 35-70 pg/mL

4KDIGO: Upper Limit of Normal* (2C) KDOQI: 70-110 pg/mL

5KDIGO: Upper Limit of Normal* (2C)KDOQI: 150-300 pg/mL

5DKDIGO: 2 to 9 times Upper Limit of Normal (2C)KDOQI: 150-300 pg/mL Europe Children: 2 to 3 x upper Limit of Normal

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int. 2009;76(suppl 113):S1-S130.

2. Adapted from National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

Treatment

*In patients with CKD stages 3-5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with calcitriol or vitamin D analogs is suggested. (2C)

Coronary Artery Calcification According to Length of Follow-up (Meta-analysis)

Favors Non-Ca Favors Ca

Jamal SA et al. Lancet, 2013

(n=3409) (n= 4026)

-3

-2.5

-2

-1.5

-1

-0.5

0

Height SDS: Pediatric Dialysis and Transplantation

Months on Dialysis

0

Months post Transplantation

12 24 0 24 48 72

NAPRTCS 2010/2011

GH/IGFSystem

Vitamin D/PTH/FGF23 Axis

VascularCalcificationBone Health

OptimizeGrowth and

Survival