Nephrology

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Chapter 12 Nephrology

Long Cases

Chronic kidney disease (CKD)

There has been much progress in the last few years in paediatric nephrology. Nomenclature has changed recently, to enable more precision when describing the nature and progression of paediatric renal disease. Chronic renal failure (CRF) has been renamed chronic kidney disease (CKD), and is divided into six stages (CKD 1–5, 5D). The first stage has a normal glomerular filtration rate (GFR); the sixth stage requires renal replacement therapy (RRT) by dialysis and renal transplantation (RTx). The stages in between describe mild, moderate and severe reductions in renal function. RTx is the treatment of choice for end-stage renal disease (ESRD) and many children receive renal allografts without prior dialysis (pre-emptive RTx). Pre-emptive RTx avoids the morbidity and mortality associated with dialysis. Many of the multiple long-term problems of CKD involving growth and neurocognitive development are improved with RTx.

Medical progress has included incorporating into management of paediatric CKD the findings of a landmark randomised 5-year trial, the ESCAPE trial (Effect of Strict Blood Pressure Control and ACE [Angiotensin-Converting Enzyme] Inhibition on the Progress of CRF in Pediatric Patients), which was published in the NEJM in October 2009. It showed that intensified blood pressure control (keeping ambulatory blood pressure below the 50th centile) in children aged 3–18 with CKD stages 3–5 delayed progression of kidney disease, compared to those treated to a conventional target blood pressure [BP] (50th to 95th percentile). All children received ACE inhibition at a standard dose, so additional medications such as calcium channel blockers were used to achieve blood pressure targets. Blood pressure control improved 5-year renal survival by 35% in children with CKD.

Technical progress has been made towards improved renal supportive therapy for those requiring RRT. Proposed alternatives to dialysis include: a wearable system, termed the ‘Human Nephron Filter (HNF)’, which has a biocompatible nano-membrane with a solute clearance profile superior to haemodialysis; a bioartificial kidney, which contains a renal tubule-cell cartridge and can deliver some functions of a normal kidney that dialysis does not provide; the ‘Vincenza wearable artificial kidney (VAK)’, which is a wearable form of peritoneal dialysis; and cellular therapies, utilising stem cells to repair or regenerate damaged kidney tissue. At present, none of these technologies is used in clinical practice.

The concept of prenatal programming of renal disease has become established: being born with low birth weight (from IUGR [intrauterine growth retardation], being born SGA [small for gestational age] or from being born prematurely) increases the risk of CKD in adulthood. It is now postulated that an adverse intrauterine environment decreases the final number of nephrons; hence the job for the paediatrician is to identify children at risk, avoiding nephrotoxic drugs (e.g. aminoglycosides, non-steroidal, anti-inflammatory drugs), obesity counselling starting in the neonatal period—other risk factors should be discussed with parents of IUGR/SGA or premature babies to minimise exposure to smoking, encourage healthy diet—and monitoring blood pressure to prevent hypertension, early recognition of proteinuria (and treatment with ACE inhibitors or angiotensin blockers) and obesity.

Genetic aspects of adult and paediatric CKD have been discussed widely. In adults, genes associated with CKD include the gene ACTN4 (actinin alpha 4), which encodes for a non-muscle alpha actinin isoform—mutations in this gene are associated with an inherited form of focal segmental glomerulosclerosis (FSGS); and the gene UMOD (uromodulin), which encodes for uromodulin, the most abundant protein in urine—mutations in this gene are associated with medullary cystic kidney disease-2 (MCKD2), and familial juvenile hyperuric nephropathy and, finally, associated with CKD in the general population by genome-wide association. In children, mutations in the genes (NPHS1, NPHS2) encoding for the proteins nephrin and podocin in the slit diaphragm between podocyte foot processes result in congenital nephrotic syndrome and FSGS respectively. Mutations in at least 10 different genes have been identified in children with juvenile nephrophthisis.

Children with CKD often appear in the long-case section of the clinical examination, most having ESRD, and requiring renal supportive (dialysis) or (transplant) therapy to survive. The principles of management should be well understood, and the candidates should be fully conversant with treatment modalities such as automated peritoneal dialysis (APD; also called continuous cycling peritoneal dialysis, CCPD), continuous ambulatory peritoneal dialysis (CAPD), haemodialysis, RTx and the commonly used immunosuppressive drugs and biological agents.

Background information

Aetiology

1. Glomerulonephritis: 30%.

2. Malformation (structural) of kidney/urinary tract: 30%.

3. Hereditary nephropathies (e.g. nephronophthisis, cystinosis): 20%.

4. Others (e.g. haemolytic uraemic syndrome [HUS], nephrotoxins): 20%.

Causes can be divided into congenital and acquired. Congenital nephropathies and maldevelopments of the urinary tract tend to cause ‘delayed’ ESRD, by 5–15 years, with a protracted course of (perhaps subclinical) CKD, causing poor growth. Acquired conditions (rarer in infancy and early childhood) tend to progress faster, affected children having previously had normal growth before their illness. In general, congenital causes equate with groups 2 and 3 and acquired with groups 1 and 4.

At present, the most common form of glomerular disease causing ESRD is focal segmental glomerulosclerosis. In some populations, around 30% of patients with sporadic forms of the disease have mutations in the gene encoding for podocin. However in African American populations with FSGS, detection of mutations is uncommon. Other causes of ESRD are SLE, rapidly progressive glomerulonephritis, IgA nephropathy, Henoch–Schönlein purpura nephritis and mesangiocapillary glomerulonephritis.

Hereditary nephropathies are numerous (around 50 types at present—refer to the standard tomes).

There are two important points to remember:

1. Structural problems tend to cause salt- and water-losing forms of CKD.

2. Glomerular disease tends to cause oliguria, salt retention and hypertension.

Many children have dysplastic disease (structural), which leads to polyuric renal failure, so they may drink large amounts of fluid, and do not have any problems with oedema or hypertension. This is quite different to adults with CKD, most of whom are oliguric or anuric. Irrespective of the original cause of kidney damage, once CKD supervenes, there is relentless progression towards kidney failure, but the rate of this is quite variable. Risk factors for rapid decline include lower levels of kidney function at presentation, higher levels of proteinuria, and hypertension. Increased protein in urine causes injury to tubular cells, which leads to interstitial inflammation and fibrosis; in patients with CKD, blocking the RAS decreases proteinuria and slows the deterioration to ESRD. Systemic hypertension causes intraglomerular hypertension, which leads to glomerular hypertrophy and injury; intensified BP control slows progression of renal failure.

Glomerular filtration rate (GFR) and clinical correlates

In general, asymptomatic kidney disease is correlated with a GFR of above 30 mL/min/1.73 m² and symptomatic with a GFR below 30 mL/min/1.73 m², but this depends on the cause of CKD. For example, children with FSGS and nephrotic syndrome are symptomatic with significantly reduced quality of life at minor reductions in GFR. At a GFR below normal (normal being 100–120 mL/min/1.73 m²) but above 30 mL/min/1.73 m², serum creatinine is usually up to 0.2 mmol/L (this depends on the size of the patient). This corresponds to the group of children with CKD who are monitored regularly (for their growth, development, blood pressure, serum creatinine, evidence of renal bone disease and calculated GFR) and may receive specific treatment for their specific diagnoses (e.g. cysteamine for cystinosis). They may also require antihypertensive agents, sodium supplements, bicarbonate supplements, calcitriol and phosphate binders. However, the majority of this group will progress to ESRD. Clinical problems are usually not evident until GFR falls below 25–30 mL/min/1.73 m².

At a GFR between 30 and 15 mL/min/1.73 m², the serum creatinine level is usually between 0.2 and 0.8 mmol/L, depending on the size of the child. This corresponds to a group who require medical manipulation, but not yet dialysis or transplantation. In children in this group who are undiagnosed, symptoms develop (e.g. anorexia, fatigability) and finally bring the child to medical attention.

At a GFR below 15 mL/min/1.73 m², serum creatinine is usually above 0.8 mmol/L in older children, but small children may require RRT at creatinine levels of 0.35–0.5 mmol/L. This group requires dialysis or transplantation. If the GFR is below 5 mL/min/1.73 m², symptoms such as nausea, vomiting and oedema become severe, and, without treatment, pericarditis, bleeding diatheses and uraemic encephalopathy will supervene. The new staging is as follows:

• Stage 1: normal or increased GFR (≥ 90 mL/min/1.73 m²), with some evidence of kidney damage.

• Stage 2: mildly decreased GFR (60–89 mL/min/1.73 m²); the emphasis is on prevention of disease progression.

• Stage 3: moderately decreased GFR (30–59 mL/min/1.73 m²); the emphasis is on prevention of disease progression, plus managing complications.

• Stage 4: severely decreased GFR (15–29 mL/min/1.73 m²); the emphasis is on treating complications, and preparing for dialysis or transplant.

• Stage 5: very little GFR left (<15 mL/min/1.73 m²); dialysis imminent.

• Stage 5D: RRT required.

End-stage renal disease (ESRD) refers to the time when medical management is insufficient and renal supportive/replacement therapy is needed (dialysis or transplant).

Aide-mémoire for GFR

An easy way to remember these stages is to think of two numbers: 30 and 15 (mL/min/1.73 m²). Thus:

• Above 30: monitor (stages 1, 2 and 3); each stage 30 below the last.

• Between 15 and 30: medical manipulation (stage 4); symptomatic.

• Below 15: renal replacement imminent or commenced (stages 5 and 5D); waiting for a transplant.

Useful calculations

Calculation of GFR

The GFR can be approximated by an empirically derived formula, the Schwartz formula, based on the relationship between muscle mass and serum creatinine:

The calculation for a child who is 120 cm tall and has a serum creatinine level of 1000 micromol/L would be: GFR = 40 × 120/1000 = 4.8.

Thus, that child’s GFR would be 4.8 mL/min/1.73 m². Note that this formula is less useful in children under 2 years. Also, the Schwarz formula is not valid for patients with abnormal body proportions or markedly reduced muscle mass, and can overestimate GFR at lower levels of GFR. It is not valid in children with acute renal failure or where renal function is not stable.

GFR also can be measured by DTPA (Tc99m diethylene triamine penta-acetic acid) clearance, or by iohexol plasma disappearance.

Assessment of rate of evolution of renal failure

The use of the reciprocal of creatinine to measure this has fallen out of favour. A graph was plotted of the reciprocal of the serum creatinine (on the vertical axis) against time (on the horizontal axis) for one year; at least five measurements over that time were needed, and the patient had to be stable (no development of hypertension, urinary tract infections or such like) for it to be more accurate. This was thought to give the rate of decline of renal function, and the stage at which a given child will develop ESRD could be determined by extrapolating the graph to where it intersected the time axis.

History

Examination

See the short case on renal examination in this chapter. Some of the findings mentioned there will be of no relevance to the case you see, but the framework should be helpful.

Management

The main goal is for the child to have as normal a life as possible, free of uraemic symptoms, and able to be involved with the usual activities of daily living. The candidate should avoid getting ‘bogged down’ in the acute management of electrolyte problems and should discuss issues such as bone disease, growth including use of rhGH, development and psychosocial issues (especially schooling in chronic patients, transition). Discuss schooling in particular, as children on dialysis often miss key parts of their education (especially maths) and have major problems at school later, often with some acting-out behaviour. Ask about schooling during haemodialysis treatment in children on in centre haemodialysis.

In patients with lesser degrees of CKD, discuss slowing of progression, such as controlling hypertension, excluding urinary tract infections, obstruction, use of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) in patients with proteinuria with aim to reduce proteinuria as close to normal as possible by increasing medications as tolerated.

The candidate should recognise that CKD and ESRD are not synonymous.

The management of CKD can be divided into 12 main areas, comprising the following, organised within the mnemonic URAEMIAS:

U. Uraemic complications (includes monitoring for development of neuropathy, encephalopathy; measuring serum urea and creatinine)

R. Renal replacement therapy (dialysis, RTx)

A. Acid–base status

E. Electrolytes and fluids: this includes serum potassium; this is very important, but the candidate should not go directly to this unless the child is already on dialysis; it is usually not the most important problem in CKD; also includes salt and water balance (including hypertension).

M. Mineral and bone disease.

I. Intake: nutrition/Immunisation/Immunosuppression

A. Anaemia

S. Stature (growth)/Social/School

The examiners expect the candidate to be familiar with the standard management of all these areas. The following presents discussion in order of priority and chronicity, not in the order of the mnemonic.

Electrolytes and fluid: (a) control of serum potassium

Hyperkalaemia

The potassium (K⁺) level should be kept in the normal range. This is usually not difficult, as renal excretion of potassium remains fairly satisfactory in CKD. If the level rises above 5.0 mmol/L, dietary potassium restriction and administration of sodium polystyrene sulphonate may be adequate temporarily. However, if there is an acute rise in the potassium level (e.g. with intercurrent bacterial infection or haemolysis) above 7.0 mmol/L, this is poorly tolerated, and more acute intervention is needed.

The treatment of acute hyperkalaemia (serum potassium level above 7.0 mmol/L) should be known by all candidates. Note that dosages have deliberately been omitted, as it is unwise to try to quote doses in the examination unless you are absolutely conversant with the particular drug used. It is always safer to say that you would look up the dosage, based on weight or surface area.

Treatment of acute hyperkalaemia

1. Salbutamol, given nebulised (same doses as in asthma) or intravenously, works quickly and lasts a couple of hours. This is the easiest treatment to give in a paediatric service.

2. Calcium gluconate 10%, or calcium chloride 10% (cardioprotective) intravenously over 2–5 minutes, with electrocardiographic monitoring. This modifies myocardial cells’ action potential, and protects for around 30 minutes.

3. Sodium bicarbonate intravenously over 30 minutes. Alkalosis shifts K⁺ into cells. The effect lasts 2 hours.

4. An intravenous infusion of 50% dextrose with soluble insulin over 30 minutes. This shifts K⁺ into cells. The effect lasts 2 hours.

5. Sodium polystyrene sulphonate orally in 70% sorbitol (or in water), or rectally in 1% methylcellulose suspension (or 20% sorbitol). This binds K⁺ with ion exchange resin. This takes 1–2 hours to take effect, and lasts 4–6 hours.

6. Acute dialysis.

The above measures are temporary only. If chronic hyperkalaemia cannot be managed with dietary restriction and oral sodium polystyrene sulphonate, definitive treatment (dialysis and eventually transplant) is needed.

Electrolytes and fluids: (b) control of salt and fluid balance

Be careful here not to mix up CKD with ESRD. Most children with ESRD, regardless of cause, require restriction.

In CKD (but not ESRD), there are two main groups to consider: those who require fluid restriction, a low-salt diet, diuretics and dialysis for fluid overload; and those who waste salt and water well into the disease process, requiring a high fluid intake (often waking for fluids at night), and require salt supplementation and intravenous hydration if vomiting with intercurrent illnesses. The former group commonly have a glomerular cause for their CRF and the latter group a structural cause, with tubular dysfunction and decreased concentrating ability. Consideration of the history (e.g. salt craving), examination (blood pressure, weight, oedema) and urinary sodium excretion help determine into which group the child falls.

Salt and fluid restriction

This is required for the majority of patients with ESRD and for some with advanced CKD. However, note that all patients with ESRD are thirsty (because hyperosmolality makes anyone thirsty, even if there is increased intravascular volume), and that all ESRD patients drink too much, leading to problems with oedema, hypertension and increased weight. Candidates should recognise this problem, but know that in practice it is unwise to confront the patient, as it is unhelpful (although some children will admit to drinking too much). The diet should have no added salt, but not be so restrictive that the child stops eating.

High salt and fluid intake

Some children, particularly those in whom CKD is caused by congenital renal disease, have high output problems and require high fluid intake and salt supplementation. The amount given is guided by parameters such as urinary sodium excretion and weight. This is not a common problem in ESRD, as most children retain sodium and water, although a few continue to have a large urine output.

Hypertension

Tight control of hypertension is important to slow progression of CKD. Hypertension is common in oliguric forms of CKD (e.g. chronic glomerulonephropathies, reflux nephropathy, haemolytic uraemic syndrome [HUS]). Fluid overload is the main cause of the hypertension in advanced CKD, so that when a child is finally on dialysis, antihypertensive agents (optimally) should not be needed, as dialysis should be able to manage fluid overload. If a patient is oedematous (i.e. fluid-overloaded), blood pressure cannot be controlled.

In children being medically managed, before needing dialysis, salt restriction and antihypertensive drugs can be used. The drugs used ideally will slow progress to renal failure, and block the RAS: ACE inhibitors (e.g. ramipril, lisinopril); angiotensin receptor blockers (ARBs, e.g. irbesartan). Other drugs used have included diuretics, and calcium channel blockers (e.g. amlodipine). Less frequently used drugs include beta blockers (e.g. atenolol, metoprolol, propranolol) and prazosin (alpha₁ post-synaptic blocker). Different nephrologists have different preferences for the order in which various drugs are tried. One suggested general plan is as follows:

1. No-added-salt diet.

2. ACE inhibitors (e.g. lisinopril, an easy-to-use tablet that can be dissolved and dose titrated for small children) or ARBs (e.g. irbesartan). They can cause hyperkalaemia, which limits their use in children with severe reductions in GFR or ESRD.

3. Diuretics (e.g. frusemide); these lose effectiveness once 70% of renal function is lost.

4. Calcium channel blockers (e.g. nifedipine, amlodipine, diltiazem).

Acute hypertensive crisis

The following may be useful:

Differentiate between CKD and ESRD. Hypertension in ESRD is fluid overload until proved otherwise, and in compliant patients it is manageable with dialysis to remove fluid. Antihypertensive administration makes fluid removal on haemodialysis more difficult because of vasodilation.

CKD may require diuretics (e.g. glomerulonephritides), but reflux nephropathy is usually better controlled with nifedipine, or with ACE inhibitors (again, remember to beware of hyperkalaemia here). Amlodipine is an easy drug to use for longer-term control of blood pressure, as a 5 mg tablet can be dissolved in water and then the required dose given. Breaking a nifedipine tablet turns it into a shorter-acting agent, so it is difficult to titrate the dose in small children.

Remember that tight control of hypertension can decrease the rate of decline of renal function. The ESCAPE study used a fixed dose of ramipril, but added non-ACE inhibitor antihypertensives to achieve the target BP measurements in both groups. Anti-RAS antihypertensives are preferred. Be sure to know the side effects of any drug that you mention in your presentation. For completion, here is a more comprehensive list of antihypertensives that can be used in children:

• Alpha and beta blocker: labetolol (IV)—also available orally.

• ACE inhibitors: ‘prils’—benzapril, captopril, enalapril, fosinopril, lisinopril, quinapril + enalaprilat (IV). Lisinopril is easy to use, as a tablet can be dissolved in water and then the required dose administered as a liquid.

• Angiotensin receptor blockers: ‘sartans’—irbesartan, losartan.

• Beta blockers: ‘olols’—atenolol, bisoprolol, esmolol (IV), metoprolol, propranolol.

• Calcium channel blockers: diltiazem + ‘dipines’—amlopdipine, felodipine, isradipine, nifedipine, nicardipine (IV).

• Central alpha agonist: clonidine.

• Diuretics: hydrochlorothiazide, chlorthalidone, frusemide (loop diuretic), spironolactone, triamterene, amiloride. Note that the latter three may be associated with hyperkalaemia because of their site of action.

• Dopamine 1 receptor agonist: fenoldopam (IV).

• Peripheral alpha agonists: ‘azosins’—doxazosin, prazosin, terazosin.

• Vasodilators: hydralazine (IV, IM), minoxidil, sodium nitroprusside (IV).

Acid–base balance

Acidosis in CKD is caused by an inability to excrete acids (approximately 2—3 mEq/kg of H⁺ ions produced from metabolism, daily) and an inability to retain bicarbonate. In advanced CKD and ESRD, metabolic acidosis is mainly related to problems with ammonium ion production and titrable acidity. Despite this, alkaline bone salts acting as buffers keep the plasma bicarbonate level stable at levels of between 14 and 18 mEq/L.

Acute severe acidosis is preferably treated by dialysis, as the patients are often fluid-overloaded and hypertensive, such that intravenous sodium bicarbonate administration would not be optimal.

For chronic acidosis, management includes administration of alkali (2—3 mEq/kg/day), which can be given as sodium bicarbonate tablets or liquid (1 mL of 8.4% sodium bicarbonate solution is equivalent to 1 mmol).

If acidosis is intractable, treat with dialysis.

Patients with ESRD on dialysis will not need bicarbonate supplements, as dialysis alone corrects acidosis.

Bone disease: CKD-mineral and bone disorder (CKD-MBD)—renal osteodystrophy; renal rickets plus hyperparathyroidism

Bone disease can be detected histologically within 6 months of the onset of ESRD, in almost all patients. It is due to a combination of lack of 1,25(OH)₂ vitamin D₃ (calcitriol), secondary hyperparathyroidism and acidosis leading to the use of alkaline bone salts as buffers. Secondary hyperparathyroidism is invariably present once there is a 50% reduction in GFR. Histological descriptions include a spectrum from high-turnover disease (osteitis fibrosa) to low-turnover disease (osteomalacia and adynamic lesion of bone), but there are no clear clinical correlates.

Clinical features tend to be fairly non-specific, and may include muscle weakness, bone pain, bone deformity and growth retardation. Bone deformities can lead to slipped epiphyses, bow legs or knock knees. Dental anomalies may occur, including defective enamel and malformed teeth, especially in those with congenital renal disease. Soft-tissue calcification can occur if serum phosphorus levels are too high. This can involve ischaemic necrosis of skin, muscle or subcutaneous tissues (termed ‘calciphylaxis’), and occasionally visceral calcification (e.g. pulmonary involvement, causing restrictive lung disease).

A major objective of managing bone disease is preventing pain and deformity. Assessment includes measurement of serum calcium, serum phosphate, serum alkaline phosphatase and parathyroid hormone (PTH) levels, and taking bone X-rays. Serum alkaline phosphatase is used to monitor the success of treatment. Radiologically, the findings of renal osteodystrophy include widened growth plates, with fraying and cupping of metaphyses (renal rickets), plus subperiosteal bone resorption and osteopenia (secondary hyperparathyroidism). The rachitic components are best seen at the ends of rapidly growing bones (e.g. proximal tibia, distal femur) and the hyperparathyroid components on the radial aspects of the second and third digits. Delay in skeletal maturation also occurs. The overall plan of management is as follows.

Control of serum phosphate

This is important, as hyperphosphataemia can lead to a rapid decline in renal function. It is best to correct the hyperphosphataemia before trying to increase the serum calcium level. A low-phosphate diet is recommended (avoiding ice cream, milk, dairy). Calcium carbonate (e.g. Caltrate, or Cal-Sup chewable) or sevelamer hydrochloride (non-calcium-based) can be used as a phosphate binder, but need to be given with food to be effective. Phosphate binders can be increased in dosage until the calcium level is also returning towards normal. Sevelamer hydrochloride, which is much more expensive than calcium carbonate, is indicated where phosphate levels cannot be controlled with calcium carbonate without causing hypercalcaemia.

Calcium supplementation

The preparation of choice is calcium carbonate, which acts as a phosphate binder as well (as mentioned above). Note that when used as a calcium supplement, it is better given between meals. The serum calcium is not restored to normal until after the hyperphosphataemia is under control, because of the risk of metastatic calcification if hyperphosphataemia persists.

Vitamin D supplementation

This is usually given as 1,25(OH)₂ D₃ (calcitriol), once a day, but can be given as ‘pulse’ therapy 2–3 times a week. Serum PTH is used to monitor treatment, aiming for PTH to be twice the upper limit of normal. Higher levels indicate healing and the risk of overshooting, with resultant hypercalcaemia. Lower levels of PTH are associated with adynamic bone disease, with reduced bone turnover. Serum alkaline phosphatase can also be used to monitor treatment. The main problem with management is non-compliance. In patients receiving haemodialysis, IV forms of vitamin D analogues can be given to improve compliance and decreased number of oral medications needed; these include paricalcitol (a synthetic vitamin D analogue) and doxercalciferol (vitamin D2).

X-ray bones annually

Once a year, (a) check bone age and (b) X-ray hips, knees and ankles (weight-bearing joints are usually the most severely affected).

Stature (growth)

There are many factors that can adversely affect growth in CKD:

1. Deficient caloric intake: a most important factor in infants and young children.

2. Salt wasting: another important factor in infants and young children.

3. Disease onset (e.g. CKD from infancy [congenital renal diseases] leads to an attained height of −3 Height Standard Deviation Score (SDS) at 3 years of age— probably one third of reduction in height occurs in the first 3 months of life, as most children with CKD have normal birth weights and lengths).

4. Disease type (e.g. cystinosis, or nephrotic syndrome requiring high-dose corticosteroids, may lead to particularly poor growth).

5. Abnormalities in insulin-like growth factor-1 (IGF-1) and IGF-binding proteins (IGFBPs, especially IGFBP-3).

6. Growth hormone resistance, secondary to point 3 above.

7. Poor protein synthesis and low protein turnover.

8. CKD-mineral and bone disorder (renal osteodystrophy).

9. Glucose intolerance (on steroids).

10. Acidosis.

11. Polyuria (decrease in extracellular volume).

12. Infection.

As noted above, growth problems are worse if the disease causing CKD dates from (before) birth. These children may have several problems, especially sodium wasting, leading to significant undernutrition in the first two years of life. Growth problems are also significant around puberty.

Each case may have several factors operating. Optimum nutrition, monitoring of bone disease, correction of acidosis and anaemia, avoidance of high-dose steroids and provision of adequate salt (especially in young children) may improve growth. Poor growth can have a devastating effect on the child’s self-image and cause severe problems (e.g. being teased at high school). It may be the major issue in some cases.

Recombinant human growth hormone (rhGH)

A major breakthrough was the finding that supraphysiological doses of recombinant human growth hormone (rhGH) are very effective in increasing height velocity: for example, in one study, from a baseline median of 4.1 cm/year to 9.2 cm/year after 12 months, and to 6.6 cm/year after 2 years of treatment. (The reduced GH-stimulating effect in the second year is also seen in children with idiopathic GH deficiency.) RhGH is used in children with CKD and a GFR below 30 mL/min/1.73 m², whose height is below the 25th centile for age, or whose height velocity is below the 25th centile for bone age. The maximum dose is 28 units/m² per week. If growth velocity fails to increase to at least the 50th centile for bone age, rhGH may be discontinued. Prepubertal patients respond particularly well to rhGH.

Mechanism: CKD causes decreased renal clearance of IGFBP-3, which binds 95% of IGFs. IGFBP-3 increases and binds to IGF-1, decreasing available, free, active IGF-1, and hence causing uraemic GH resistance and growth impairment. RhGH is safe and effective in CKD, in patients with ESRD on dialysis (although slightly less effective) and in growth-retarded paediatric allograft recipients. RhGH should be continued until epiphyseal closure or renal transplantation occurs. Potential complications of rhGH therapy include hypercalciuria, aseptic necrosis of the femoral head, pseudotumour cerebri and suggestions of possible (although no evidence for this) induction of malignancy. The last of these, if correct, could be a consideration for those who have received cytotoxics, or have ESRD from Wilms’ tumour.

Intake: nutrition

The diet in CKD is a difficult therapy problem and depends on the stage of CKD. If CKD is advanced and dialysis is imminent, protein restriction may be used to keep urea at acceptable levels. Protein intake is no longer reduced to slow the progression to ESRD, as it has now been shown that it does not work in children, and there is a risk of reduced growth. Also, ACE inhibitors are effective and better tolerated than the previously recommended diet. Optimum nutrition is needed for these children with nutritional and growth failure, who are anorectic too.

A further problem is the intake of milk in infants. Milk has a high phosphate content and hyperphosphataemia is deleterious to renal function, so milk intake should be limited. Infant formulae can be used with added calories (e.g. polyjoule) and salt, or special formulae designed for renal patients (with high calories, and with low-phosphate and high-salt content).

Different units have different philosophies on diet. Candidates should learn (and understand) the regimen used by their training hospital and be able to discuss this.

Children with CKD have an inadequate intake of energy. Energy supplementation aims to raise this intake to the recommended daily allowance (RDA) calculated at mean weight for age. This can be achieved by adding glucose polymer to feeds, oral or flavoured supplements, but avoiding standard energy supplements (e.g. Ensure, Osmolyte), as these have high protein and phosphate content unsuitable for CKD. For infants, standard infant formulas can be supplemented with Polyjoule and Calogen (a long-chain fatty acid preparation).

In some children, volume constraints will limit the amount of nutritional supplementation that can be given. For younger children with structural disease, nutrition can be optimised by supplemental feeding (e.g. overnight by gastrostomy, or nasogastric feeding), as volume overload is not a problem. Should fluid restriction be necessary, high-calorie supplements (e.g. Suplena, Nutrison Energy Plus or Nepro) can be used for overnight feeds. If overnight feeds are not tolerated because of coexistent gastro-oesophageal reflux, fundoplication may be needed.

The general principle is to encourage a normal, balanced diet, in order to maximise growth potential, while correcting electrolyte and acid–base imbalances by medications where needed. Nutritional supplementation by itself does not lead to catch-up growth, but does allow stabilisation of growth rates.

Anaemia

This is mainly due to lack of erythropoietin. Other contributing factors include increased red blood cell destruction, blood loss (nose, gut, skin), decreased erythropoiesis by uraemic toxins, marrow suppression by drug treatment, poor intake of protein, iron and vitamins, and defective utilisation of iron. Anaemia can be alleviated by treatment with r-HuEPO (SC), aiming for a haemoglobin level of 110–120 g/L. A patient probably should be transfused when the haemoglobin drops below 60 g/L, to avoid the risk of cardiac decompensation. For maximum efficiency of r-HuEPO, a child needs to be iron-replete. In most children pre-dialysis or on peritoneal dialysis, this can be achieved with oral iron therapy. However, children on haemodialysis usually require iron supplements intravenously, to maximise their response to r-HuEPO. The aim should be that the ferritin level should exceed 100 ug/L and the transferrin saturation should exceed 20%.

Recombinant human erythropoietin (r-HuEPO)

Erythropoietin increases the terminal differentiation of erythroid progenitor cells, increases cellular haemoglobin synthesis and increases reticulocyte release from bone marrow. Several symptoms previously attributed to uraemia are definitely improved by r-HuEPO, including fatigue, poor exercise tolerance, anorexia, pruritis, uraemic bleeding, sleep disturbance, cold intolerance and cognitive dysfunction (typical problems being difficulties staying on task, concentrating, poor short-term memory and suboptimal performance at school). The benefits of r-HuEPO are improved overall well-being, increased energy levels, increased exercise tolerance, improved school attendance, increased physical activity and improved overall cognitive functioning. Other improvements have included regression of ventricular hypertrophy and normalisation of impaired brain-stem auditory evoked responses.

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Examination Paediatrics

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