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:

image

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

Presenting complaint

Reason for current admission

Past history of underlying kidney disease

Initial diagnosis (when was kidney disease diagnosed; when was the chronic nature clarified; where; what were the presenting symptoms; initial investigations—which tests, e.g. MCU, MAG3, DTPA, DMSA, renal biopsy, cystoscopy; aetiology), number of hospitalisations, sequence/tempo of development of complications (growth failure, anaemia, bone disease) and their management.

Current symptoms

Essentially, this is an extensive systems review, relating to CKD:

1. General health (e.g. tiredness, coping at school, sports, poor exercise tolerance).

2. Urinary (e.g. polyuria, nocturia, anuria, bed wetting).

3. Gastrointestinal (e.g. anorexia, nausea, vomiting, abdominal pain, diarrhoea).

4. Neurological (e.g. headache, paraesthesiae, seizures, confusion).

5. Cardiovascular (e.g. hypertension, cardiac failure symptoms: dyspnoea, oedema).

6. Growth (e.g. monitoring weight, height, causes attributed to poor growth).

7. Skin (e.g. itching [from microscopic subcutaneous calcium deposits], bruising).

8. Skeletal (e.g. bone pain, muscle cramps, muscular weakness).

9. Fluid intake, particularly need for night-time drinks.

Family history

Other members of the immediate family affected (e.g. siblings), renal problems (e.g. nephronophthisis, polycystic kidney disease, cystinosis), deafness (e.g. Alport’s syndrome).

Current management

Current diet, medications, dialysis routine, management problems, present treatment in hospital, usual treatment at home, sequence of prior treatment changes, use of growth hormone, erythropoietin, drug side effects (e.g. steroid effects), diet, compliance, degree of self-management (e.g. with CAPD), future treatment plans (e.g. ‘living related donor’ [LRD] transplant, home haemodialysis), usual follow-up (by whom, where, how often, routine investigations done), use of identification bracelet, use of alternative therapies or medications.

Social history

• Disease impact on child: for example, amount of school missed, limitations on lifestyle, body image, self-esteem, peer reactions, future plans, education, career, educational difficulties related to development and/or time lost from school.

• Impact on family: for example, financial considerations such as the cost of frequent hospitalisations, drugs (especially post-transplant if not eligible for [in Australia] a health care card—a problem for those over 16 years of age), special feeds (low-phosphate, high-calorie, low-protein, designed for renal patients—in Australia, Kindergen is now on the Pharmaceutical Benefits Scheme [PBS] and is useful for infants, but other feeds such as Suplena and Nephro have to be bought from the hospital and can be expensive), pumps and disposables (many children are on nasogastric or feeds via gastrostomy overnight), surgery (renal transplant), treatment for other affected children, time lost from parents’ work, transport, private health insurance.

• Parents, other family members, as potential kidney donors; who will be the donor and what they understand about their own potential morbidity; financial considerations.

• Impact on siblings: for example, sibling as kidney donor, sibling rivalry, sibling neglect.

• Benefits received, social supports (e.g. social worker, extended family, Kidney Health Australia [previously Australian Kidney Foundation], dialysis and renal transplant associations).

• Discussion on transition from paediatric to adult renal services by 18 years of age. (In Australia, dialysis machines and disposables are provided by the government.)

• Compliance with and understanding of medications by child/family.

Understanding of disease

Both the child’s and the parents’ understanding. Ask about the degree of previous education (e.g. in hospital, by local paediatrician) and contingency plans (e.g. who to contact first when child unwell).

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:

1. For the conscious patient:

(a) Clonidine (central sympatholytic action; given orally).
(b) Nifedipine (calcium channel blocker, given orally).
(c) Minoxidil (vasodilator, given orally).
(d) ACE inhibitors (given orally).

2. For hypertensive encephalopathy (all given intravenously):

(a) Clonidine (central action).
(b) Labetolol (alpha and beta blocker).
(c) Nitroprusside (vasodilator).
(d) Diazoxide (vasodilator).
(e) Hydralazine (vasodilator).

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.

The avoidance of transfusions, with their attendant risks of sensitisation and transmission of infective agents, and the amelioration of anaemia, are the main advantages of using r-HuEPO. Disadvantages include the cost and the potential side effects of r-HuEPO: hypertension, hyperkalaemia (remember that the first symptom of hyperkalaemia is death), iron deficiency and vascular access thrombosis.

R-HuEPO can be given intravenously (IV) or subcutaneously (SC). Previously, it was given intraperitoneally (IP), but this increased the risk of peritonitis. It may be given SC, twice a week, if the haemoglobin level is below 100 g/L. This is continued until the Hb level is around 110g/L, at which stage once a week is enough. The child’s B12, folate and iron status should also be checked.

There are three forms of r-HuEPO:

• Epoetin alfa (Eprex): this can be given 2–3 times per week as SC injection, or in those on haemodialysis, given IV on dialysis days, although the IV route is less effective than the SC route.

• Darbepoetin alfa (Aranesp): this can be given SC or IV, has a longer half-life, and so needs to be given only weekly or less frequently (fortnightly or even monthly). The main problem with this is pain at the injection site.

• Epoetin beta (Neorecormon): this can be given once weekly, but can be required more frequently. Its advantage is being less painful SC than darbepoetin.

Suboptimal responses (persistent anaemia) occur with several conditions: iron deficiency, aluminium intoxication, blood loss, hyperparathyroidism, inflammation and infection, or the dose being too low or not administered correctly. If there is such a response, check the ferritin, iron and total iron-binding capacity (TIBC) and transferrin saturation (iron/TIBC). If there is iron deficiency (transferrin saturation of <20% is the most useful indicator), replacement oral iron is given. If the oral preparation is insufficient to replete iron stores, IV iron sucrose (this is the only IV preparation available now) may be warranted; this is a common problem in haemodialysis patients. Also, check parathyroid hormone (PTH) levels to exclude hyperparathyroidism, as increased PTH causes some resistance to hormone action.

Renal support and replacement

Dialysis

Dialysis is only waiting for a transplant. Occasionally, parents are not aware of this, so make a point of assessing their understanding of this point. Dialysis only provides around one tenth the clearance function of normal kidneys.

Dialysis is commenced when the complications of CKD can no longer be managed by medical therapy. It is usually started when the GFR is below 15 mL/min/1.73 m2. Indications include inability to control the main management headings (electrolytes, hypertension, oedema, acidosis, bone disease) and uraemic symptoms not corrected by treatment with r-HuEPO. Other considerations include availability of donors. Some children can have a transplant as their initial renal replacement therapy, this being known as a ‘pre-emptive transplantation’ (PET) (see below). Overall, it is an individual clinical decision for each child. It is better if the child is still fairly stable and reasonably well, when first started on dialysis, rather than waiting until he or she becomes very ill.

A child may be excluded from the transplant program if there are congenital malformations with very poor functional prognosis. Infants under 6 months may be excluded for technical reasons, including size (usually, a child must weigh at least 10 kg to receive an adult kidney). It is a joint decision made by the doctor, child and parents.

The modality of dialysis varies—haemodialysis, continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD; also known as continuous cycling peritoneal dialysis [CCPD]). Most young children are started on peritoneal dialysis unless this is specifically contraindicated; most patients in the long-case setting thus will be on home-based peritoneal dialysis (although more and more children, especially adolescents, are on inpatient haemodialysis). CAPD uses gravity to instill prefilled bags of dialysate into the peritoneal cavity three or four times a day. It has the advantages of not causing any pain and providing continuous dialysis. CAPD is a simple portable procedure and is relatively cheap. Disadvantages include no days off, the requirement for repeated connections and disconnections, and the attendant risk of peritonitis (usually from Staphylococcus aureus or Staphylococcus epidermidis).

APD involves use of an automated cycler for overnight instillation and drainage of dialysate fluid. APD has the advantages of only one connection and disconnection between the cycler and the peritoneal catheter per day, and hence less risk of infection, and decreased time demands on the family. It does interfere with the child’s social life, especially for teenagers. APD in the form of continuous cycling peritoneal dialysis (CCPD) is performed nightly and then fluid remains in the peritoneal cavity during the day. Most children need an additional bag change in the late afternoon for optimum dialysis.

Children are admitted to hospital, have a peritoneal (e.g. Tenckhoff) catheter inserted and are trained (along with their parents) in the management of APD and CAPD, usually for 3 weeks. All get cyclers, but they need to know CAPD for holidays or machine breakdowns. The volume of dialysis fluid instilled into the peritoneal cavity on each occasion is usually between 40 and 60 mL/kg (this partly depends on the child’s tolerance). In CAPD, bags are changed three or four times a day. The bag sizes are 500 mL, 1000 mL, 1500 mL and 2000 mL. In APD, there are a variable number of bags overnight, 5–8 cycles, and fluid dwells in the abdomen during the day.

The available solution strengths (different glucose concentrations) are 1.5%, 2.3% and 4.25%. Which one is used depends on the amount of fluid one wishes to remove. Of all dialysis modalities, CCPD is associated with the best growth, the best control of anaemia and the best patient tolerance. When started on dialysis, the child is usually put on the transplant program.

Common complications of APD or CAPD include peritonitis, exit-site and catheter-tunnel infections, and catheter blockage. To treat peritonitis, which occurs in about 1 in 8 patient months, or three times every 2 years, the standard IP antibiotics are cephazolin and gentamicin. Antibiotics are added once daily to fluid that dwells in the abdomen all day. The insertion of catheters can be covered with antibiotics. If the child develops abdominal pain and the fluid becomes cloudy, a culture of peritoneal dialysis fluid should be obtained and intraperitoneal antibiotics commenced. Antibiotic treatment may be altered once the culture result is available. Catheter life varies, averaging about 9 months.

Haemodialysis (HD) takes 5 hours, 3–4 times a week. In the USA, haemodialysis accounts for 35% of children on dialysis. It is usually undertaken in a tertiary renal centre, and access is via a central venous double lumen catheter designed for HD, or via an arterio-venous fistula. Central venous haemodialysis catheters are percutaneously inserted for acute HD and the short term, or inserted like Hickman catheters for the longer term. Infection and obstruction are the main catheter problems. Fistulae and vein grafts are used in long-term HD patients if the child has suitable veins. A schoolteacher and a play therapist are essential to support children on haemodialysis.

Renal transplantation (RTx)

RTx is the treatment of choice for ESRD. The donor is usually a relative (‘living related donor’, LRD) who has a compatible blood group. RTx is particularly beneficial in terms of growth. Once the RTx is performed, the usual medications treating CKD are stopped, and the immunosuppressants are started. The latter must be continued indefinitely; in adolescence, issues with compliance can be the single greatest threat to graft survival. LRD grafts are preferable to cadaveric donor (CD) grafts (also called deceased donor [DD] grafts), as they give a better rate of patient survival at 5 years (95% for LRD, versus 80% for CD) and of graft survival at 5 years (80% for LRD, versus 65% for CD: less difference with newer immunosuppressives such as tacrolimus). The allograft half-life (time for half of the transplanted kidneys from a particular cohort to be lost) for a LRD graft is more than 25 years, versus 16 years for a CD graft. Adult kidneys can be used, even in children under 5 years of age. The use of LRDs has increased steadily; now around 60% of RTx in children have used LRD allografts. Over 80% of LRD allografts come from a parent.

Pre-emptive transplantation (PET) is where children have a transplant as their initial renal replacement therapy, if there is a living related donor. PET is performed before reaching ESRD and dialysis, and has become increasingly popular, with around 30% of transplants in the USA being PETs. Recipients of PETs have improved patient and allograft survival.

Pretransplantation native nephrectomy may need consideration if the diseases causing the renal failure are likely to cause ongoing problems in the transplanted kidney. In Australia today, it is rare that paediatric renal units need to consider native nephrectomy before transplant. If necessary, one or both native kidneys can be removed at transplant. The most common reason for this to be done is to make room for a transplant. For completeness, the conditions that very rarely may require pretransplantation are listed here:

1. Very large kidneys: one or both are removed to provide adequate space for a new transplant.

2. Very significant polyuria (e.g. obstructive uropathies, dysplastic kidneys). Polyuria can persist in the native kidney, causing dehydration and exacerbating nephrotoxic effects of post-RTx immunosuppressive regimens.

3. Significant electrolyte disturbance.

4. Persistent proteinuria (e.g. FSGS, SLE, MPGN, congenital nephrotic syndrome). Oedema, poor nutritional status, hyperlipidaemia and hypercoagulability can all increase the risk of allograft thrombosis.

5. Hypertension (many glomerulonephritides). Pretransplant native nephrectomy can lead to improved blood pressure control, less reliance on antihypertensives, and improved surgical and long-term graft survival. In general, however, native kidneys are removed post-transplant if hypertension is difficult to control.

6. Recurrent pyelonephritis (can occur particularly with bladder dysfunction, obstructive uropathy and reflux nephropathy).

The initial work-up for transplantation includes adding the name of the child to the cadaveric waiting list and sending blood, monthly, to the blood bank. The average waiting time for RTx in Australia is around 4 years: in New South Wales, children under 15 have a priority rating, which operates once they have been on dialysis for more than a year, so that children are waiting around 18 months for a cadaveric transplant. It is expected that this age limit will increase to 17 years and that these criteria will extend to all states. Blood grouping and tissue typing are done on suitable family members if an LRD is considered, this being increasingly the case. Donors must be ABO blood group compatible; otherwise pre-formed isohaemagglutinins interact with renal vascular endothelium, leading to loss of the graft. HLA matching clearly is beneficial in LRD transplants, although there is less evidence for its importance in cadaver donor grafts. HLA matching does improve the outcome of second or subsequent transplants.

Pretransplant immunisation is very important. Varicella vaccination should be given before RTx if possible, while pretransplant viral surveillance for serological evidence of any prior exposure to cytomegalovirus, herpes simplex virus, hepatitis B, hepatitis C, HIV and Ebstein–Barr virus is essential, although currently only prevention of CMV disease is possible by using prophylactic valganciclovir therapy. Work-up also involves assessing the bladder for vesicoureteric reflux and outlet obstruction. Recipients must weigh at least 10 kg, which can be a problem. For example, in a very small 2-month-old infant with ESRD, transplant would be preferable to dialysis, so if there is a related donor available, the best plan would be to supplement the child’s caloric intake (such as by nasogastric tube) and ‘feed up’ the child to 10 kg.

Immunosuppressive therapy

A major problem with transplantation is the need for long-term immunosuppressive therapy, with the associated risk of opportunistic infection and an increased risk of malignancy later in life. Corticosteroids are still used. The most common standard treatment used is prednisone, mycophenolate mofetil (MMF) and tacrolimus; cyclosporine A (CSA) is significantly less effective in preventing rejection compared with tacrolimus in a systematic review.

There has been a rapid expansion in the number of newer immunosuppressants. The following agents may be used to prevent graft rejection. They are arranged as the ABC of immunosuppression for mnemonic purposes only. The main side effects are listed.

Antiproliferatives

1. Azathioprine (AZA) is a prodrug of 6-mercaptopurine, which inhibits growth of immune cells. It is being used less in RTx, replaced by MMF. Side effects are bone marrow suppression, susceptibility to viruses, pancreatitis, alopecia, malignancy and gastrointestinal upset.

2. Mycophenolate mofetil (MMF) is an antimetabolic agent that interferes with purine metabolism in B- and T-lymphocytes. It is metabolised to mycophenolic acid, which blocks conversion of inosine monophosphate (IMP) to guanosine IMP. It is more effective than AZA in preventing acute rejection in the first year post-transplant, and has similar toxicities to AZA.

3. Sirolimus is a product of Streptomyces hygroscopicus. It forms a complex with FK binding proteins in lymphocytes, which interrupts second messenger signalling, leading to blockage of cytokine-mediated proliferation of T- and B-cells. With the combination of sirolimus and CSA, there is a synergistic effect that allows a lower dose of CSA to be given. Sirolimus is not nephrotoxic, and has no adverse effect on blood pressure. There is a competitive drug interaction with CSA and sirolimus, such that sirolimus should not be given within 4 hours of CSA. Sirolimus is an alternative to CSA or tacrolimus, as it has less nephrotoxicity, but it is also less potent than either of these; thus there is a slightly higher rate of rejection early. Side effects include mouth ulcers, hypercholesterolaemia, pneumonia and rash.

Biological agents

1. Monoclonal antibodies:

Basiliximab is a chimeric human/murine antibody directed against the CD 25 antigen (the interleukin-2 [IL-2] receptor alpha chain on the surface of activated T-cells), which causes IL-2 receptor blockade. It is used instead of ATG (see below), together with CSA, mycophenolate and prednisone, for prevention of rejection. It has almost no side effects.
Daclizumab is a humanised antibody directed against the alpha chain of the IL-2 receptor. Adding this to CSA, AZA and prednisone therapy reduces acute allograft rejection. It has almost no side effects.

2. Polyclonal antibodies:

Antilymphocyte globulin (equine) is a horse-derived antilymphocyte antibody. A newer agent is a rabbit-derived antithymocyte globulin (ATG). ATG causes prolonged lymphocyte suppression. Side effects are allergic reactions, serum sickness, neutropenia, thrombocytopenia and increased propensity to infections. Fever, chills, arthralgia and dyspnoea can occur, but are decreased with pre-treatment with high-dose steroids, antihistamines and antipyretics. Both of these agents can be used in the treatment of rejection. ATG is also used to prevent rejection, especially in patients likely to suffer acute tubular necrosis (ATN) post-transplant, so that CSA or tacrolimus does not have to be started immediately (which would increase the risk of prolonged ATN).

Calcineurin inhibitors

1. Tacrolimus (TAC) is a fungus-derived macrolide, like CSA. It inhibits lymphokines derived from T-cells, including IL-2, IL-3, IL-4 and gamma interferon, and clonal expansion of helper and cytotoxic T-cells. Tacrolimus is effective in inducing graft tolerance. Its side effects are similar to those of CSA, including nephrotoxicity, neurotoxicity and infection, plus lymphoproliferative disease (more common than with CSA), but it does not cause the cosmetic side effects of hypertrichosis or gingival hyperplasia. It may induce diabetes mellitus. TAC was used in 6% of RTx in the USA in 1996; by 2006–07, it was used in 74%.

2. Cyclosporine A (CSA) is a fungus-derived cyclic peptide that blocks T-cell response. It binds to cellular proteins (cyclophilins), blocks IL-2 production and inhibits T-cell proliferation and differentiation. Side effects are nephrotoxicity, hypertension, hyperkalaemia, anaemia, hypertrichosis, gingival hyperplasia, susceptibility to infection and increased risk of malignancy. The newer microemulsion form of CSA has improved, more consistent absorption. If used during induction, it can be given intravenously by continuous infusion or 8-hourly. CSA has more rapid metabolism in children than adults, such that children have higher doses. The dose of CSA is lower when used with sirolimus, as the two drugs have a synergistic immunosuppressive effect. CSA previously used to be used in 82% of RTx in the USA in 1996, but its use declined to 8% by 2006–07, in the USA.

Management

The above agents can be divided into two groups:

• Induction therapy agents: biological (ATG, basiliximab, daclizumab).

• Maintenance therapy agents: steroids, calcineurin inhibitors (CSA, tacrolimus) and antiproliferative agents (AZA, MMF, sirolimus).

Prednisone, CSA, MMF and basiliximab are becoming the standard immunosuppressive agents. Quadruple regimens are preferred in many centres, especially in the USA. Candidates should be familiar with the side effects of the above treatments.

After transplantation, children usually remain in hospital for a week to 10 days, after which they are reviewed regularly (daily for the first month or so). Rejection episodes occur, but are relatively uncommon with the currently used group of immunosuppressant agents. Clinical features of rejection include tenderness over the graft and fever (although this sign is less useful in cyclosporine and tacrolimus-treated patients), and laboratory findings of a rising serum creatinine level and leukocytosis.

In most children now, rejection is suspected because of a rising creatinine and is confirmed on renal biopsy. High-dose intravenous steroids are usually effective, but antilymphocyte globulin may be required. Some units use cotrimoxazole prophylaxis against pneumocystis for 6 months. Most units now use valganciclovir, the prodrug of ganciclovir, as prophylaxis for CMV. If treatment of CMV is needed, then IV ganciclovir is given for 2 weeks. Prophylaxis against CMV disease is used in many units for 3 months in all renal transplants except donor CMV-negative to recipient CMV-negative. Others use it for donor CMV-positive to recipient CMV-negative or when giving ATG, where there is an increased risk of CMV disease. If treatment (as opposed to prophylaxis) for CMV is needed, then IV ganciclovir can be given for 2 weeks.

At each outpatient visit, check growth and blood pressure (hypertension can occur in up to 85% of transplant recipients), and look for signs of opportunistic infection and side effects of drugs (e.g. Cushing’s syndrome from steroids, hypertrichosis from CSA, pallor from AZA, abdominal pain and diarrhoea from mycophenolate mofetil). Check the skin and all lymph nodes (skin cancer and lymphomas can be seen in paediatric transplant recipients). Take blood to check renal function and for a full blood count). If the serum creatinine level is rising, think of the following possibilities: rejection, infection, obstructed blood supply to graft, or obstructed ureter or nephrotoxicity if taking tacrolimus or cyclosporin. It can be particularly difficult to decide between rejection and calcineurin inhibitor toxicity. Blood glucose should be checked when taking tacrolimus.

The main issues post-transplant can be divided into short term (at time of transplant and next few months), which comprise problems of rejection and infection, and long term, comprising decrease in renal function (50% renal survival at 15 years), malignancies (particularly lymphoma and skin cancer) and cardiovascular disease (long-term effects of left-ventricular hypertrophy, hypertension and hypercholesterolaemia lead to cardiovascular diseases [e.g. stroke, ischaemic heart disease] being more common).

Allograft loss

1. Chronic rejection (or chronic allograft nephropathy) is the most common cause: incomplete understanding of mechanism; presumed combination of immunological and non-immunological mechanisms, non-compliance, drug toxicity and recurrent disease; risk increased by multiple acute rejection episodes; late acute rejection. No effective therapies yet available.

2. Acute rejection (second most common cause). Complete rejection reversal can be achieved in around two thirds of patients, but reversal is less likely with an increased number of rejections, increased age of the recipient and late (over 12 months post-RTx rejection) rejection episodes.

3. Vascular thrombosis (third most common cause). The risks are decreased by use of calcineurin inhibitors or antilymphocyte antibody on day 0–1, and increased by peritoneal dialysis pre-RTx, cadaver donors under 5 years of age, recipients under 2 years of age or repeat RTx recipients.

4. Recurrent disease. See the list below. FSGS is a particular problem, and the most important, as most lose their grafts quickly. Children with FSGS are twice as likely as all other diagnostic groups (below) to have primary acute tubular necrosis (ATN) requiring dialysis post-RTx. If it does recur once, there is an 80% chance it will recur in any subsequent RTx.

Recurrence rates in transplants (histological recurrence)

1. Membranoproliferative glomerulonephritis (MPGN) type II: 100%.

2. Membranoproliferative glomerulonephritis (MPGN) type I: 70%.

3. Henoch–Schönlein purpura (HSP): 55–85%.

4. IgA nephropathy: 25–45%.

5. Focal segmental glomerular sclerosis (FSGS): 25–30%. FSGS is the most important, as most lose their grafts quickly, though some patients may respond to plasma exchange with or without rituximab.

6. Haemolytic uraemic syndrome (HUS): 12–25%. Most children with recurrent HUS associated with Factor H mutations lose their grafts with recurrent disease.

7. Systemic lupus erythematosis (SLE): 5–40%.

Histological recurrence does not correlate with clinical recurrence, the latter being much rarer. Recurrence can also occur in oxalosis, cystinosis (but no adverse effect on graft function) and congenital nephrotic syndrome.

Social problems

Although mentioned last, often these are the most important discussion points in the long case. Ensure that a full social history is taken, and that the social circumstances have at least been thought over before you confront the examiners. Knowing all the side effects of calcineurin inhibitors but not knowing if the family have their own transport or receive the Child Disability Allowance will cause you to fail the long case.

Schooling is a particular problem. ESRD patients go to school, but do not seem to learn as much as other children (poor self-esteem, depression) and tend to miss school for no good reason. How well the family copes is extremely important.

Compliance with medications is a real problem. A significant proportion (around 25%) of grafts lost from rejection are associated with non-compliance.

Minor issues

Congestive cardiac failure

This is usually related to fluid overload. Management includes normalising blood pressure, maintaining haemoglobin above 90 g/L, salt restriction, and cautious use of diuretics and dialysis. Cardiomyopathy is not uncommon and generally resolves post-transplant. It is related in part to nutrition.

Drugs

Many drugs require reduced dosage in CKD. It is impossible to remember them all, so it is safest to simply obtain a pharmacology book and look up any drug that is being considered. A brief list of commonly used drug groups that require decreased dosage in CKD is as follows:

• Aminoglycosides: in renal failure, gentamicin should not be given as a single daily dose. Dose reductions and/or increased intervals between doses are required. In haemodialysis patients, gentamicin is given post-dialysis.

• Some cephalosporins.

• Some penicillins.

• Sulphonamides.

• Digoxin.

• Thiazide diuretics.

• Paracetamol.

• Phenobarbitone.

Other issues

Genetic counselling

In children with hereditary nephropathies, genetic counselling is a very important and necessary component of the overall management.

Monitoring

The examiners may ask what follow-up you would recommend for your long-case subject. A brief checklist to consider is as follows:

1. Routine check of growth, blood pressure, oedema.

2. Electrolytes, bicarbonate, creatinine, urea, calcium, phosphate, alkaline phosphatase.

3. Haemoglobin, white cell count, platelet count.

4. Cholesterol, triglycerides, uric acid.

5. Bone X-rays—hips, knees, ankles, hands.

6. Chest X-ray.

7. Calculated GFR.

8. Follow-up by dietician, social worker, occupational therapist, especially for adolescent issues, and in younger children, development.

Nephrotic syndrome

There have been several advances in the understanding of the pathophysiology of nephrotic syndrome in recent years, following on from the discovery in 2006 that the cause of congenital nephrotic syndrome of the Finnish type (CNF1) is a mutation of a protein named nephrin, coded for by the gene NPHS. Nephrin is located within the visceral glomerular epithelium, at the slit diaphragms, which are membranes that bridge filtration pores between neighbouring podocytes. The slit diaphragm is attached to the cell cytoskeleton by adaptor proteins, including podocin and CD2AP. Podocytes are known to regulate integrity and survival of glomerular epithelial cells. It is now recognised that several diseases, both acquired and inherited, are due to defects in the slit diaphragm, which is essentially a multi-protein signalling complex. The phenotype focal segmental glomerulosclerosis (FSGS) can be caused by defects in the gene/proteins: NPHS2/podocin, located at the slit diaphragm; CD2AP/CD2AP, located near the slit diaphragm; TRPC6/TRPC6, located at the podocyte; ACTIN4/alpha actinin 4, located at the podocyte; and other genes located at the podocyte (WT1 [Wilms’ tumour suppressor gene], tRNA (leu), COQ2). Autosomal recessive nephrotic syndrome is an inherited form of FSGS due to mutations in the gene NPHS2 situated on chromosome 1q25–q31, which codes for podocin; it has early onset, minimal changes on early biopsy, FSGS on later biopsy, rapid progression to ESRD, but rare recurrence after RTx; it can present as familial FSGS with later onset, adolescent or adult. Podocin mutations occur in some 10–30% of sporadic steroid responsive nephrotic syndrome in some populations.

Children with nephrotic syndrome often appear in the examination. Those chosen as long-case subjects are unlikely to have uncomplicated idiopathic nephrotic syndrome (INS), but may present with therapeutic dilemmas, difficult-to-control disease or significant side effects from drug treatment.

Background information

Definition

Nephrotic syndrome (NS) is characterised by four components:

1. Proteinuria above 40 mg/m2/hour (or 1 g/kg/24 hour) or urinary protein ratio more than 200 mg/mmol creatinine.

2. Hypoalbuminaemia (serum albumin less than 25 g/L).

3. Hypercholesterolaemia (serum cholesterol over 200 mg/dL [5.17 mmol/L]) (not essential for diagnosis).

4. Oedema.

The primary abnormality is proteinuria. The other features are secondary to this. Other characteristic findings include the following:

• Hypocalcaemia (ionised fraction normal): below 2.25 mmol/L (9.0 mg/dL).

• Hyperkalaemia: over 5.0 mmol/L.

• Hyponatraemia: below 135 mmol/L.

• Hypercoagulability (decreased partial thromboplastin time [PTT]).

Aetiology

The most common cause of NS is INS. This was previously called minimal change nephrotic syndrome (MCNS), or minimal change disease (MCD). The name has been changed because it is now uncommon for children with NS to have renal biopsies. INS accounts for 80–90% of all forms of NS in childhood, with the remainder accounted for by other glomerulonephropathies and inherited renal diseases. INS is further subdivided into corticosteroid-sensitive INS (CSINS) and corticosteroid-resistant INS (CRINS).

Other important causes of NS are as follows:

1. Focal segmental glomerulosclerosis (FSGS). This is the most common progressive glomerular disease in children, and the second most common cause of ESRD (the most common cause being congenital renal anomalies). Several different genetic forms are known, some autosomal recessive (putative genes NPHS2, and WT1) and some autosomal dominant (putative genes TRP6, and ACTIN4). FSGS can be idiopathic (somes genes not discovered yet) or secondary to postinfectious glomerulonephritis, obstructive uropathy, reflux nephropathy or systemic diseases (e.g. sickle cell disease [SCD], systemic lupus erythematosis [SLE]).

2. Mesangial proliferative glomerulonephritis (MesPGN). This is usually idiopathic, but can be due to chronic infection (bacterial or viral), SCD, SLE, renal transplant or bone marrow transplant. Idiopathic forms of MesPGN may be associated with IgM or C1Q deposition on immunofluoresence, and are then referred to as IgM or C1Q nephropathy. It remains unclear whether MesPGN is a forerunner of FSGS in some patients.

3. Membranous glomerulonephritis. This can be idiopathic, or due to SCD, SLE, drugs (e.g. non-steroidal anti-inflammatory drugs [NSAIDs], captopril), toxins (heavy metals) or infections (e.g. hepatitis B or C).

4. SLE. This can cause FSGS, MesPGN or membranous glomerulonephritis, but the typical histology is of a diffuse proliferative GN with typical immunofluorescent findings. Clinically, SLE is more likely to present with haematuria and acute nephritis, rather than a nephrotic syndrome.

These are the only diagnoses likely to come into the differential diagnosis of NS. Some textbooks give the impression that each type of glomerulonephritis has one particular type of presentation. Note that any clinical picture can be caused by any histological picture, which can have any clinical outcome.

Idiopathic nephrotic syndrome (minimal change disease)

INS tends to affect younger children (2–5 years), and more often boys (until puberty, then the sex incidence is equal). The proteinuria is due to changes in the integrity of the glomerular filtration barrier, which comprises three layers: fenestrated endothelium (cells have multiple openings (fenestrae), measuring 70–100 nm in diameter, which stop macromolecules passing from plasma into the renal tubule); the glomerular basement membrane (GBM) (contains negatively charged heparan sulfate proteoglycans, which block passage of anionic macromolecules, such as albumin); and the visceral epithelium, which is made up of podocytes and slit diaphragms. Filtration of albumin is limited by charge, whereas the filtration of IgG is not limited by charge, but by size, as circulating IgG is mainly neutral or cationic. INS occurs due to a defect in this electrostatic glomerular barrier (removal of anionic charge), although the cause of this defect remains unknown. INS characteristically shows fusion/effacement of epithelial foot processes on electron microscopy (although this is characteristic of all proteinuric states if ‘nephrotic’). INS is associated with loss in the urine of low molecular weight anionic proteins (e.g. albumin), but some higher molecular weight proteins such as IgG are also lost.

Clinically, hypertension and haematuria occur in 10% of children with INS, but are transitory. Most children with INS respond to corticosteroids (CSINS). Up to 80% of children have a frequently relapsing course (see below). Children may have one or more episodes per year for many years, and sometimes into adult life.

Other glomerulonephropathies

The other glomerulonephropathies tend to present in older children (6–15 years), with a variable sex ratio depending on the particular condition. Generally, in this group there tends to be a greater leakage through the glomerular filtration barrier, and higher molecular weight proteins may be lost. Clinically, haematuria is often present, and hypertension may also occur. If there is reduced renal function, then consideration of rarer causes of NS may be appropriate. Most of this group do not respond to steroids. In particular, FSGS is often the finding in a child who has CRINS.

Definitions used in INS

• Remission: urinary protein excretion less than 4 mg/m2/hour, or no trace of protein on urine dipstick, or protein/creatinine ratio below 0.02 g/mmol for three consecutive days.

• Relapse: recurrence of proteinuria as defined in definition of INS, or 2+ or more on dipstick for three consecutive days.

• Frequent relapsers: children with two or more relapses within the first 6 months of initial response, or more than four relapses in 12 months.

• Corticosteroid dependence: two consecutive relapses while on prednisone or within 2 weeks of ceasing prednisone.

• Corticosteroid resistance: failed response after 8 weeks of 2 mg/kg/day prednisone.

• Cyclosporine (CSA) dependent: relapses when CSA is tapered or stopped; it refers to the group of steroid-dependent children who achieve remission with CSA.

Differentiating between INS and other glomerulonephropathies

In practice, in children with uncomplicated NS, initial differentiation is not crucial, as they are all given a trial of steroids. Ultimate prognosis seems to depend on steroid response rather than selectivity of proteinuria or biopsy findings.

Complications of NS

Infection

Children with NS have increased susceptibility to infection with encapsulated bacteria (e.g. pneumococcus, Haemophilus, E. coli), including cellulitis, peritonitis and urinary tract infections. This is due to multiple factors, including urinary loss of immunoglobulin (IgG), loss of factors B and D of the alternate complement activation path, loss of transferrin, altered T-cell function, impaired ability to make antibodies, loss of opsonising factors (specifically, increases the risk to encapsulated organisms) plus the burden of steroid therapy or other immunosuppressive drugs, and mechanical factors such as oedema and ascites. Peritonitis occurs in 2–6% of patients. The risk is further increased by decreased mesenteric blood flow and increased coagulability (see below), with decreased flow and sludging causing microinfarction. In peritonitis, signs of peritoneal irritation are almost always present, and are not masked by steroid therapy. Other infections seen include septicaemia, meningitis, cellulitis and urinary tract infection. With pneumococcal polysaccharide vaccination becoming widespread, Streptococcus pneumonia is becoming less common and gram negative organisms, such as Escherichia coli and other coliforms, more common. Viral infections can include varicella, particularly in those receiving immunosuppressive therapy; again, increased uptake of varicella vaccine is making this less common.

Complications of treatment

Steroids often cause Cushingoid effects, but poor growth is the most serious complication. Medications used as steroid-sparing agents (cyclosporine [CSA], cyclophosphamide [CPA], chlorambucil [CAB], tacrolimus [TAC], levamisole [LVS], angiotensin-converting enzyme [ACE] inhibitors and mycophenolate mofetil) have significant potential side effects, which are discussed later under ‘Other agents’.

Oedema

For years, the theory has been that children with rapid onset of INS develop loss of oncotic pressure: fluid moves from the intravascular space to the interstitium, resulting in hypovolaemia. In these patients, infusion of albumin with administration of a loop diuretic (e.g. frusemide) has been given, leading to increased excretion of salt and water loss. However, plasma volume is decreased in children during the initial phase of a relapse. Children with chronic nephrotic syndrome, however, may have increased or normal plasma volume. In these patients, diuretics alone can be given (e.g. frusemide, together with spironolactone). Angiotensin-converting enzyme (ACE) inhibitors (e.g. enalapril) have been used in children with CRINS to reduce proteinuria, raise serum albumin and reduce oedema. It is now believed that rather than being due to the oncotic pressure theory, oedema is due to a primary defect in sodium excretion; also vasopressin excess occurs. Anasarca (generalised, massive oedema) can lead to the following: difficulty walking, from severe scrotal or vulval oedema; respiratory distress, from pleural effusions and/or severe ascites splinting the diaphragm; and tissue breakdown with cellulitis. This can be treated successfully with infusing salt-poor albumin followed by frusemide (see the later section on management).

Thrombosis and embolism

NS can be associated with hypercoagulability, due to increase in plasma fibrinogen and clotting factors II, V, VII, VIII, IX, X and XIII (due to increased hepatic synthesis), decreased plasma antithrombin III and decreased protein S (latter two lost in urine), platelet abnormalities (thrombocytosis, increased aggregability), increased blood viscosity, decreased blood flow and hyperlipidaemia. In some cases of nephrotic syndrome due to SLE, the antiphospholipid syndrome has been implicated; this involves persistently raised antibodies against membrane anionic phospholipids (such as anticardiolipin antibody, and antiphosphatidylserine) or their associated plasma proteins (e.g. beta-2 glycoprotein I [apolipoprotein H]). This leads to increased risk of major vessel thrombosis, usually venous (risk around 2–5%). Most commonly, this involves renal veins or sagittal sinuses, but it can occur also in the deep vessels of the limbs, the pulmonary artery, the inferior vena cava, the femoral/iliac artery, the pulmonary venous system, the cerebral arteries, the meningeal arteries, the mesenteric veins and the hepatic veins. Thromboembolic complications include pulmonary embolism. Bilateral renal vein thrombosis can present with acute renal failure. Infants with congenital nephrotic syndrome are at particular risk of renal vein thrombosis. Thrombosis is more common in children with CRINS.

The likelihood of thrombosis is further increased by any coexisting illness leading to fluid loss, and by haemoconcentration, from vomiting or diarrhoea, from diuretic use, and from immobilisation and the presence of indwelling catheters. Irrespective of cause, the first line of treatment is low molecular weight heparin; if the thrombosis extends, then it may need thrombolytic drugs (e.g. tissue plasminogen activator)—it then may need warfarin until the nephrotic syndrome resolves. Aspirin therapy has been discussed, as it can prevent arterial thrombosis, but it cannot prevent venous thrombosis and thus its routine use is not recommended.

Hyperlipidaemia and cardiovascular disease risk

Hyperlipidaemia is reversed quite quickly in CSINS, in 4–6 weeks, and is not usually a clinical concern. Concerns for cardiovascular sequelae include exposure to corticosteroids, hypertension, hypercoagulability and anaemia (erythropoietin-responsive anaemia has been reported in NS). In children with unremitting NS, persistent hyperlipidaemia raises concerns, reflecting adult NS experience of increased risk of coronary heart disease, and the rare reports of myocardial infarction in children with NS. In adults, HMG-CoA-reductase inhibitors are used successfully to limit hyperlipidaemia and its complications. These drugs have been used in children, but adequate safety and efficacy data have yet to emerge.

Growth disturbance

This is noted particularly in congenital nephrotic syndrome, and is thought to be due to urinary loss of insulin-like growth factor (IGF) binding protein, decreasing the levels of IGF-I and IGF-II, and decreasing IGF-receptor mRNA. The use of recombinant human GH (rhGH) in treatment is as yet unproven. Growth disturbance can be compounded by use of corticosteroids. Children with CRINS unresponsive to other therapies may also grow poorly.

Hypocalcaemia

This is due to loss of vitamin D-binding protein in the urine. It can lead to bone demineralisation in the long term.

Hypothyroidism

Due to loss of thyroid binding protein in the urine, this is a common problem in children with congenital nephrotic syndrome.

Negative nitrogen balance

Loss of protein in urine, plus poor appetite, and nausea contribute to poor intake.

End-stage renal disease (ESRD)

Only a small minority of children presenting with NS develop ESRD. The group most likely to do so have steroid-resistant FSGS. Around 8–10% of this group will ultimately develop ESRD. Rarely, children who were initially steroid-responsive become steroid-resistant and progress to ESRD.

History

Presenting complaint

Reason for current admission.

Current symptoms

1. General health (e.g. anorexia, weight gain, lethargy, poor height gain).

2. Oedema (e.g. periorbital or ankle swelling, ascites).

3. Urinary (e.g. haematuria, oliguria, concentrated urine).

4. Other (e.g. infections, abdominal pain, hypertension).

Past history

Initial diagnosis (when, where, presenting symptoms, initial investigations, established aetiology, initial treatment), number of episodes per year (usual precipitants, usual treatment), number of hospitalisations, sequence of complications, management. Differentiate between congenital nephrotic syndrome (commences within the first 3 months of life) and patients with CRINS, who usually present later in life.

Management

Current diet, medications, management problems, present treatment in hospital, usual management at home, home urine testing, the sequence of prior drugs used, drug side effects (e.g. steroid effects), compliance, future treatment plans (e.g. introduction of cytotoxic drugs) and usual follow-up (by whom, where, how often).

Social history

Disease impact on child (e.g. amount of school missed, body image), impact on family (e.g. financial considerations, such as the cost of frequent hospitalisations), social supports.

Understanding of disease

By child and by parents.

Examination

See the short cases on oedema and renal examination in this chapter.

Management

Investigations

Any child with NS should probably have the following tests.

Urine

Urinalysis, including looking for cellular casts, which do not tend to occur in INS but may well occur in other glomerulonephropathies (note that hyaline or waxy casts are common in INS). Microscopic haematuria is usually transitory in steroid-sensitive NS, but may persist in steroid-resistant NS.

Blood

1. Urea, creatinine and electrolytes (renal function is usually normal in INS; may be abnormal in other glomerulonephropathies).

2. Albumin and total protein levels (to evaluate severity).

3. Serum complements C3 and C4 (low with MesPGN, SLE; normal in INS).

4. Full blood examination. The haemoglobin level is normal in INS. If anaemia is present, this suggests other diagnoses.

5. Hepatitis B and C serology (hepatitis B is associated with membranous nephritis; hepatitis C is associated with MesPGN).

Renal biopsy indications

Note that renal biopsy should be reserved for those with very atypical features. It is not a routine requirement. There is probably no indication for biopsy before commencing non-steroid agents if the child is completely responsive to prednisone (i.e. proteinuria absent for over 3 days).

Indications are as follows:

1. Age under 1 year.

2. Nephritic features (haematuria, hypertension), raised creatinine/renal impairment.

3. Persistent abnormal serum complement level (low C3).

4. Steroid resistance.

5. Older children, particularly among African Americans, where FSGS is more common.

Other tests

Another test that is often mentioned is the 24-hour urinary protein estimation. This is not very useful, as it is almost impossible to perform accurately and does not add to the diagnosis (although it may be useful in non-INS forms of NS or in non-nephrotic proteinuric states). Demonstration of steroid responsiveness may require the simpler test of the urinary protein:creatinine ratio (normal ratio less than 0.02 mg/micromol). Serum cholesterol and triglycerides are often requested, as is protein electrophoresis, but they do not aid diagnosis or management. Antinuclear antibody (screening for SLE) is not necessary in younger patients with uncomplicated NS.

Treatment

1. Corticosteroids

The mainstay of therapy remains steroids. Protocols vary between different units; it is wise to learn the regimen of your own teaching hospital. There is good data that, in the first episode of NS, when oral prednisone is given for 4–6 weeks and then on alternate days for 6–8 weeks or more (increase in benefit up to total course of prednisone of 7 months), fewer children relapse than those who are given ‘standard therapy’ of daily prednisone for 4 weeks (2 mg/kg/day or 60 mg/m2/day) and then alternate daily for 4 weeks. This standard therapy leads to remission within an average of 2 weeks in those with INS. There is good evidence that increasing the total dose of prednisone during the first episode and increasing duration results in fewer children relapsing by 12–24 months. Around 50–70% of children relapse after 8 weeks of therapy, with the relative risk of relapse falling by 13% for each month that the initial duration of therapy is extended beyond 8 weeks. In subsequent episodes, prednisone can be used until remission occurs for more than 3 days, and then alternate daily prednisone, considering other agents when the toxicity of the steroids exceeds the side effects of other agents. Most children will grow quite well on alternate-day steroids until they go into puberty, when growth slows.

The other use of steroids is for steroid-resistant NS, usually due to FSGS, using IV methylprednisolone. One regimen reported to be effective in observational studies was to give methylprednisolone starting at a dose of 30 mg/kg, three times a week for 2 weeks, then tapering gradually over 80 weeks with concurrent prednisolone on alternate days. While reported to provide remission rates of 60–70% by some researchers, others reported less satisfactory response rates. This regimen is very toxic (side effects: hypertension, delayed growth, cataracts, infections) and has largely been abandoned, though some clinicians may give methylprednisolone for three doses with cyclosporin in steroid-resistant NS.

2(a) Other agents for corticosteroid-sensitive idiopathic nephrotic syndrome (CSINS): additional options including cytotoxic drugs

The main agents that can claim success in NS (mnemonic CLAIM) are as follows:

C. Cyclophosphamide (CPA: 2 mg/kg/day for 8–12 weeks)/Chlorambucil (0.2 mg/kg/day day for 8 weeks)/Cyclosporine A (CSA: 2.5 mg/kg 12-hourly for 12–24 months)

L. Levamisole (2.5 mg/kg alternate daily for 12–24 months)

A. Angiotensin-converting enzyme (ACE) inhibitors

I. Immunisation with pneumococcal vaccine

M. Mycophenolate mofetil (25 mg/kg/day in divided doses for 12–24 months)

• CPA has significant side effects, short term (e.g. bone marrow suppression, risk of viral infections such as varicella, measles) and long term (e.g. gonadal toxicity and risk of carcinogenesis). However, it offers the chance of prolonged remission off therapy, with 36% of children with frequently relapsing CSINS remaining in remission at 5 years.

• CSA can cause nephrotoxicity, hypertension, gingival hyperplasia and hypertrichosis.

• CPA given for 8 weeks and CSA given for 6–9 months are equally effective in maintaining remission in randomised controlled trials while CSA is being given. However, the effect of CSA is not sustained, while that of CPA is.

• Levamisole causes enhanced cellular immune responses in certain conditions with depressed immune function. Levamisole may help to maintain remission in steroid-dependent INS, is well tolerated and has few side effects (neutropenia, rarely vasculitis, liver toxicity, convulsions), and these are all reversible on withdrawing the drug. It decreases the steroid requirement by 50%, and the relapse rate by 50%.

• ACE inhibitors reduce glomerular hyperfiltration. Also, from the ESCAPE trial (see the long case on CKD), it is now known that intensified blood pressure control (keeping blood pressure below the 50th centile) in children aged 3–18 with CKD, using high-dose ACE inhibition with ramipril at a fixed dose, delayed progression of kidney disease. Adverse effects include hypotension and cough.

• Immunisation as per schedule for pneumococcal vaccination of immunocompromised children: heptavalent conjugated pneumococcal vaccine (7vPCV) in children under 5, and polysaccharide pneumococcal vaccine (PPV23) in children 5 or older.

• Mycophenolate mofetil is used for steroid-sensitive NS, largely on the basis of observational data. A single underpowered RCT demonstrated no significant difference in efficacy between MMF and CSA, but there was considerable imprecision in the results. Its side effects include gastrointestinal effects (diarrhoea and abdominal pain), and haematological abnormalities, but its side effect profile is preferable to that of CSA.

Indications for commencing these agents include the following:

1. Failure to respond to steroids (depends on pathology—only CSA and ACE inhibitors have been shown to reduce proteinuria significantly in RCTs).

2. Unacceptable steroid side effects (e.g. reduced height gain).

3. Steroid-dependent NS (only if side effects are unacceptable).

4. Relapses with hypertension or thrombosis (only if frequent relapser or steroid dependent).

Poor compliance is not an indication, as monthly intravenous methylprednisolone can be given. One notable (relative) contraindication for the use of CPA is lack of varicella antibodies. While a patient is taking these drugs, the full blood count must be checked regularly, to detect development of marrow suppression (e.g. neutropenia).

2(b) Corticosteroid-resistant idiopathic nephrotic syndrome (CRINS)

In children who are steroid resistant the choices are different to the above. Agents that have been shown to be effective in RCTs are CSA, tacrolimus and ACE inhibitors. In RCTs, there was no significant difference in efficacy between cyclophosphamide and prednisone alone, so CPA is not recommended for CRINS. In observational studies, some children respond to mycophenolate or to rituximab (a chimeric anti-CD20 monoclonal antibody). Intravenous methylprednisolone is commonly used with a calcineurin inhibitor in an attempt to achieve complete or partial remission. Patients who fail to achieve complete or partial remission usually progress to ESRD. Thus it is important to try therapies to achieve complete or partial remission, but without excessive medication-related toxicity.

3 Antibiotics

Some units administer prophylactic daily penicillin, to avoid pneumococcal infection to children in relapse. However, other units feel that vaccination against pneumococcus is successful enough to not warrant penicillin, the use of which could increase the risk of infection with more serious organisms. Haemophilus can be a problem if children are not fully immunised. If a child with a relapse of nephrotic syndrome develops bacterial infection, most units now recommend broad cover for both gram-positive and gram-negative organisms, such as a third-generation cephalosporin (e.g. cefotaxime), which may cover penicillin-resistant pneumococcus, and coliforms, plus ampicillin to cover for Enterococcus.

4 Immunisations

Live viral vaccines should be avoided in patients taking high-dose corticosteroids or any immunosuppressive agents. Pneumococcal, Haemophilus and varicella vaccines are recommended, as above, because of the increased risk of infection with these pathogens.

5 Severe oedema (anasarca)

Children with INS with massive oedema (e.g. pleural effusions, ascites, scrotal or labial oedema) can receive intravenous concentrated (20%) albumin (1 g/kg infused over 4 hours) with intravenous frusemide (1 mg/kg) after the first hour of albumin. Note that albumin infusions can cause circulatory overload, hypertension and acute pulmonary oedema in patients with impaired renal function, or if INS is not the cause of the oedema. In the latter case, giving a diuretic may precipitate renal compromise. Albumin infusions should be used only when the child is very troubled by severe oedema symptomatically. They should not be used simply because albumin is very low, and should not be monitored by a rise in albumin.

6 Hypertension

A minority of children with NS will have hypertension. Agents of choice are ACE inhibitors or ARBs, as these delay deterioration in renal function that can occur with ongoing proteinuria in a minority of children with steroid-sensitive nephrotic syndrome, but in more children with steroid-resistant nephrotic syndrome.

7 Diet

No added salt. No fluid restriction, except when very oedematous and diuretics are required. High biological value protein. Dietary and fluid restrictions are generally not required in children in remission. However, they should maintain an adequate calcium and vitamin D intake. Since obesity is a common side effect of steroid therapy, families should be encouraged to put in place a healthy eating regimen, with adequate exercise to prevent excessive weight gain.

8 In-hospital management

When these children are admitted, important observations include fluid balance chart, twice-daily weight and 4-hourly temperature, pulse, respirations and blood pressure.

9 Activity

There is no need for bed rest or any restriction of activity.

10 Prognosis

The best prognostic indicator in NS is steroid sensitivity. Of children with CSINS, 60–80% will relapse; and 60% of them have five or more relapses. Most children ultimately ‘lose’ the nephrotic syndrome towards adolescence (non-relapse rate 84% at 10 years). There are fewer relapsers if children are aged over 4 at presentation (remission occurs within 7–9 weeks of the start of corticosteroid treatment) and no microhaematuria. In children with steroid-resistant FSGS, many progress to ESRD if they do not achieve complete or partial remission with non-corticosteroid therapies and ultimately need renal transplantation. FSGS recurs in around 25% of renal allografts. For children with familial forms of NS, immunosuppressive treatment is less likely to be effective, transplantation is the definitive treatment and the original disease rarely recurs in the graft. However, sometimes children develop an immunologically based nephrotic syndrome (e.g. development of antibody to nephrin in congenital nephrotic syndrome) in the transplanted kidney.

Short Cases

Renal examination

A short-case approach to a renal examination is useful both in the long-case setting, for cases with chronic kidney disease (CKD), and in the short-case setting for children with haematuria, proteinuria or other symptoms referable to the urinary tract.

Start by introducing yourself, and try to gain an impression of the patient’s mental status (for encephalopathy, due to uraemia, or depression, due to chronic illness); note the child’s age to assess any delay in pubertal development.

Stand back and observe whether the child looks sick or well. Look at the growth parameters and percentile charts, and note the nutritional status (visually scan for muscle bulk and subcutaneous fat) and pubertal status (Tanner staging). Note any dysmorphic features (several malformation syndromes involve the genitourinary system). Look for any evidence of rickets (CKD) or hemihypertrophy (association with Wilms’ tumour).

Look at the skin, for sallow complexion (CKD), pallor (anaemia of CKD or haemolytic uraemic syndrome [HUS]), and periorbital or peripheral oedema. Also note any jaundice (hepatorenal syndrome), bruising (CKD), uraemic ‘frost’ (CKD) or scratch marks (pruritis with CKD), although it is unlikely that patients who are that sick would participate in the examination. Note any hirsutism (steroids), hypertrichosis/gum hypertrophy (cyclosporine [CSA]) or Cushingoid features (steroids for transplant or nephrotic syndrome). There may be other peripheral signs, such as nearby bags of peritoneal dialysis fluid (CKD), and a visible peritoneal dialysis catheter (CKD), arteriovenous fistula, subclavian or jugular venous catheter. Look for evidence of previous dialysis access (particularly in renal transplant patients); in the neck for subclavian or internal jugular dialysis catheters, in the arms for previous fistulae and in the abdomen for previous peritoneal dialysis catheters (both the incision and exit sites of the catheter). Also look for scars of previous or current transplants. Most transplants are in the right or left iliac fossae and are easily palpated beneath a ‘hockey stick’ scar. However, in small children there may be a central abdominal incision and the kidney may be palpated bimanually, usually to the left of the scar.

After initial inspection, a systematic examination can be performed, starting with the hands, followed by checking the blood pressure, and then examining in turn the head and neck, chest and abdomen, and finally the gait and lower limbs. This suggested order is outlined in Figure 12.1. Details of findings sought at each step are outlined in Table 12.1.

image

FIGURE 12.1 Renal examination

Table 12.1 Additional information: details of possible findings on renal examination

Head and neck
Face

• Malar flush (SLE)

• Hirsute (Cushing, CSA)

• Periorbital oedema (nephrosis)

• Hearing aid (Alport’s syndrome, aminoglycoside toxicity)

Eyes

• Aniridia (Wilms’ tumour)

• Anaemia (CKD, HUS)

• Jaundice (hepatorenal syndrome)

• Band keratopathy (hypercalcaemia)

• Cataract (steroids)

• Uraemic retinopathy (CKD)

• Retinitis pigmentosa (nephronophthisis)

Hearing: impaired (e.g. aminoglycosides, Alport’s syndrome) Mouth

• Dry (hydration)

• Uraemic breath (CKD)

Neck

• Jugular venous pressure raised (cardiac failure with CKD); measure at 45 degrees

• Cervical adenopathy (e.g. CMV, lymphoma, if immunosuppressed)

Chest Anterior aspect Rib rosary (CKD) Examine praecordium for:

• Cardiomegaly (fluid overload, CKD cardiomyopathy)

• Murmurs (anaemia)

• Pericarditis (CKD)

• Cardiac failure (fluid overload)

Posterior aspect Sacral oedema (nephrosis) Examine lung fields for pleural effusion (nephrosis) and pulmonary oedema (fluid overload) Abdomen Inspection CAPD catheter Other intervention, often related to congenital anomalies

• Ureterostomy

• Vesicostomy

• lleal conduit

• Colostomy/ileostomy (e.g. related to imperforate anus)

• Nephrostomy or pyelostomy (e.g. related to sacral agenesis)

Scars (e.g. transplant [current or previous renal transplant has central abdominal scar in younger children, and scar in either iliac fossa for older children], CAPD) Swelling (ascites due to CAPD fluid, or nephrosis) Prune belly appearance (triad syndrome) Tanner staging (delay with CKD) Palpation: •Abdominal wall musculature (lacking in triad syndrome) •Tenderness (peritonitis) •Kidneys (e.g. enlarged with polycystic disease, hydronephrosis) •Transplanted kidney (also measure, note consistency, tenderness) •Lymph nodes (enlarged with CMV or lymphoma, from immunosuppression) Genitalia

• Tanner stage of testes (delay with CKD)

• Cryptorchidism (e.g. triad syndrome)

Percussion: bladder (for urine retention) Auscultate: •Renal arteries (renal artery stenosis) •Transplanted kidney (arterial stenosis) Lower limbs and gait Inspection

• Muscle bulk (poor in CKD)

• Flaring at ankles (CKD bone disease)

Palpation: ankle oedema (nephrosis, cardiac failure) Stand and re-inspect: valgus deformity at knees (CKD bone disease) Gait

• Foot slapping (peripheral neuropathy with CKD)

• Limp (slipped femoral epiphysis from CKD)

Squat: proximal weakness (CKD, steroids) Return to bed:

• Reflexes (decreased with peripheral neuropathy of CKD)

• Hip movement (slipped femoral epiphysis from CKD)

CAPD = continuous ambulatory peritoneal dialysis; CMV = cytomegalovirus; CKD = chronic kidney disease; CSA = cyclosporine; HUS = haemolytic uraemic syndrome; SLE = systemic lupus erythematosus.

The urinalysis may be requested at any stage (e.g. before laying hands on the patient), but it must not be forgotten.

Hypertension

This is an infrequent case, and as such often ‘stumps’ the candidate. The lead-in can take several forms; for example, ‘This child has hypertension; examine her/examine her for complications/examine her for the cause’. The approach given here includes both causes and complications, and may need modification depending on the introduction. It is essentially an extended cardiovascular examination. Likely cases would be renal artery stenosis with bruits, NF-1, or infantile polycystic kidneys with large kidneys, liver, portal hypertension and previous portosystemic shunts. Remember that the vast majority of young children with chronic hypertension have a renal cause for their hypertension. The most common are reflux nephropathy (usually proteinuria) and renal artery stenosis (usually bruits).

Begin by introducing yourself to the child and asking his or her name, age and school grade, noting any irritability (hypertensive encephalopathy), dysphasia (intracerebral bleeding) or difficulty hearing your speech (deafness with Alport’s syndrome, or with congenital rubella). Any suggestion of developmental delay should be further assessed (previous cerebrovascular accident or congenital rubella).

Commence the general inspection with assessment of the growth parameters. Children with chronic kidney disease (CKD), syndromal diagnoses (e.g. Turner syndrome) or other systemic disease, such as neurofibromatosis type 1 (NF-1) or Cushing’s syndrome, are often short. Children with congenital rubella (and associated renal artery stenosis) and some with NF-1 may have small head circumferences, whereas others with NF-1 may have large head circumferences. NF-1 is associated with renal artery stenosis, phaeochromocytoma, coarctation of the aorta and neuroblastoma, all of which can cause hypertension. Weight is important in Cushing’s syndrome. Truncal obesity with buffalo hump, loss of supraclavicular hollow and striae suggest this diagnosis.

While inspecting for growth parameters, note any asymmetry of limb size (hemihypertrophy with Wilms’ tumour) or posture (hemiplegia from intracerebral bleed), and look for obvious scoliosis (NF-1).

Note any syndromal features (e.g. webbed neck in Turner syndrome) and, in infants, the typical ‘ex-premmie’ appearance of the neonatal intensive-care graduate (umbilical arterial catheterisation leading to renal arterial thrombosis).

Look at the skin for pallor or sallow appearance (CKD), purpura (Henoch–Schönlein purpura, haemolytic uraemic syndrome, CKD), plethora (Cushing’s syndrome), flushing and sweating (phaeochromocytoma), hirsutism (congenital adrenal hyperplasia [CAH], Cushing’s syndrome), hyperpigmentation (CAH), café-au-lait spots or freckling (NF-1), or depigmented macules (tuberous sclerosis with renal angiomyolipomata).

Note the facial characteristics. In particular, look for the moon face, hirsutism and acne of Cushing’s syndrome, the heliotrope rash of dermatomyositis, the butterfly rash of SLE, the periorbital oedema of nephrotic syndrome and, in girls, the syndromal findings of Turner syndrome (e.g. webbed neck, low hairline). Also note any asymmetry, either of facial movement—especially smiling (seventh cranial nerve palsy)—or facial structure (hemihypertrophy associated with Wilms’ tumour).

After inspection, take the blood pressure (BP) reading yourself, in both arms. Make sure you use the right cuff size and the correct technique. The recommended cuff bladder width is 40% of the circumference of the midpoint of the upper limb, midway between the olecranon and the acromion. The cuff bladder must cover at least 80% of the circumference of the arm. The BP should be measured with the cubital fossa at the level of the heart, the arm being supported, with the stethoscope placed over the brachial arterial pulse, medial and proximal to the cubital fossa, inferior to the lower edge of the cuff. Note that current normative BP tables include height percentiles, age and gender, as BP depends on all these variables. A taller child will have a slightly higher BP than a shorter child of the same sex and age. Reference to the appropriate tables is essential. Note also that the fifth Korotkoff sound is used to define diastolic BP.

A rough rule of thumb is that an adult-sized cuff is appropriate in a normal-sized 6-year-old or older child. A thigh cuff can be used in large obese teenagers. Take particular note of the size (width) of the cuff supplied and, if it is too small, request a more appropriate cuff size. Question the values given if these were obtained with the same incorrectly sized cuff.

Note that most children and adolescents with BP levels at or above the 95th centile for their age and sex are overweight. Body size is the most important determinant of BP in childhood and adolescence. If the child has both diastolic and systolic BP above the 95th centile, there will be an underlying cause, usually renal disease. In children under 12 months of age, systolic BP is used to define hypertension.

Request the values for the lower limbs, or measure these yourself (make sure that you have practised this, as the exam is not the best place to start).

The remainder of the examination can commence at the hands, as in a standard cardiovascular examination; in particular, feeling the radial and femoral pulses simultaneously, looking for coarctation, as evidenced by diminished strength of femoral pulsation. Then, work up to the neck, for jugular venous pressure and carotid pulses. The examination of vision, fundoscopy and hearing are best left until after abdominal examination, but scanning the face and head for signs such as conjunctival pallor is valid at this stage. After this, examine the heart, lungs and back. When examining the abdomen, it may be worth checking with the examiners that there is no contraindication to deep palpation, particularly if there is flushing or sweating, as palpation of a phaeochromocytoma can cause an acute hypertensive crisis. This need not be asked if the signs clearly suggest another diagnosis, such as renal disease (this is only a theoretical consideration, as it is very unlikely that a patient with this tumour would be in the examination, but it is a point worth noting in practice). Next, check the vision and hearing, and then the gait.

The urinalysis is an essential part of the examination of the hypertensive child. It is valid to request the result of this before anything else, as it may direct the examination (and renal causes are by far the commonest) and will also prevent it being overlooked and the case consequently being failed.

The relevant findings sought at each point are listed in Table 12.2, and the suggested order of approach is outlined in Figure 12.2.

Table 12.2 Additional information: details of procedure and possible findings in the hypertension short case

Introduction
Irritability (encephalopathy)
Dysphasia (CVA)
Hearing impairment (Alport, congenital rubella, aminoglycoside toxicity)
General inspection
Parameters

• Height (short with CKD, Cushing, NF-1, congenital rubella; with CAH, tall early, short later)

• Weight (obese with Cushing)

• Head circumference

• Percentiles

Request urinalysis (protein, blood, casts, specific gravity) Pubertal status

• Advanced (CAH)

• Delayed (Turner)

Posture: hemiplegia (CVA) Symmetry: hemihypertrophy (Wilms’ tumour) Scoliosis: NF-1, spina bifida Skin

• Pallor (CKD, HUS)

• Purpura (HSP, HUS, CKD)

• Plethora (Cushing)

• Flushing, sweating (phaeochromocytoma)

• Pigmentation (CAH)

• Café-au-lait spots (NF-1)

• Axillary freckling (NF-1)

• Depigmented macules (TS with renal involvement)

Facial characteristics

• Moon face (Cushing)

• Acne, hirsutism (Cushing, CAH)

• Butterfly rash (SLE)

• Periorbital oedema (nephrotic syndrome)

• Findings of Turner syndrome (webbed neck, low hairline)

• Asymmetrical smile (seventh cranial nerve lesion)

• Hemihypertrophy (Wilms’ tumour)

• ‘Ex-premmie’ appearance (UAC causing renal artery thrombosis)

Wears glasses (Alport, medullary cystic disease, congenital rubella, NF-1) Wears hearing aid (Alport, congenital rubella, aminoglycoside toxicity) Tachypnoea (pleural effusion with nephrotic syndrome, BPD in ex-premmies, LVF secondary to hypertension) Head This is best examined after chest and abdomen, unless obvious clues on inspection Face: as under ‘General inspection’, above Eyes

• Conjunctival pallor (CKD)

• Cataracts (Cushing, congenital rubella)

• Leave testing vision and fundoscopy until later

Ears

• Low set or hypoplastic (congenital renal dysplasia)

• Hearing can be left until later

Facial nerve palsy due to hypertension Chest Full praecordial examination for sequelae of hypertension

• Palpate for heaving apex, cardiomegaly

• Listen for: loud S2 (aortic); prominent S3 or S4; systolic murmur (coarctation)

Lung fields

• Percuss for hyperinflation (ex-premmie infants with BPD), pleural effusion (nephrotic syndrome)

• Listen for radiation of murmurs (coarctation), crackles (LVF).

Back Inspection

• Midline scars (spina bifida)

• Sacral agenesis (renal anomalies)

• Buffalo hump (Cushing)

• Scoliosis (NF-1): get child to bend forward to check this

Palpation

• Sacral oedema (renal disease, CCF)

• Spinal tenderness (Cushing)

• Renal angle tenderness (nephritis)

Auscultation for renal arterial bruits (renal artery stenosis) Abdomen Inspect Anteriorly

• Distension (ascites with renal disease)

• Dialysis catheter (CKD)

• Striae (Cushing)

• Scar of renal transplant

• Tanner staging (CAH)

Posteriorly

• Midline scar (repaired myelomeningocoele)

• Sacral agenesis (associated renal anomalies)

• Buttock purpura (HSP)

Palpate Kidneys

• Bilateral enlargement (polycystic disease, hydronephrosis)

• Unilateral enlargement (polycystic disease, Wilms’ tumour, hydronephrosis, dysplastic kidneys, renal vein thrombosis, trauma)

• Tenderness (glomerulonephritis, pyelonephritis)

Suprarenal areas: mass (neuroblastoma) Liver and spleen: enlarged (connective tissue diseases, congenital hepatic fibrosis associated with polycystic kidneys) Bladder (after micturition): enlarged (posterior urethral valves, neurogenic bladder, obstructive uropathy) Percuss For ascites (nephrotic syndrome); over any masses to determine whether retroperitoneal Auscultate Bruits (renal arterial in renal artery stenosis, abdominal coarctation) Vision and hearing Visual acuity decreased in Alport, congenital rubella Visual fields: hemianopia (intracranial bleed), constricted peripheral fields (medullary cystic disease) Fundoscopy

• Papilloedema (raised ICP)

• Hypertensive retinopathy

• Perimacular degeneration (Alport)

• Retinitis pigmentosa (medullary cystic disease [nephronophthisis])

Hearing

• Loss with Alport, aminoglycoside toxicity

• Do Rinne and Weber tests to confirm sensorineural loss

BPD = bronchopulmonary dysplasia; CAH = congenital adrenal hyperplasia; CCF = congestive cardiac failure; CVA = cerebrovascular accident; HSP = Henoch–Schönlein purpura; HUS = haemolytic uraemic syndrome; ICP = intracranial pressure; LVF = left ventricular failure; NF-1 = neurofibromatosis type 1; SLE = systemic lupus erythematosus; TS = tuberous sclerosis; UAC = umbilical artery catheterisation.

image

FIGURE 12.2 Hypertension

Oedema

This short case is not infrequent and requires a rapid assessment of several major systems to determine the aetiology. Oedema can have the following causes:

1. Renal; for example, nephrotic syndrome or chronic kidney disease (CKD).

2. Liver; for example, chronic liver disease (CLD).

3. Cardiac; for example, congestive cardiac failure (CCF).

4. Bowel; for example, protein-losing enteropathies, including inflammatory bowel disease (IBD) and cystic fibrosis (CF).

5. Nutrition; for example, protein calorie malnutrition (PCM).

6. Local causes; for example, lymphadenopathy causing leg oedema.

Each of these conditions deserves initial consideration.

This is one case where it is reasonable to request the urinalysis and blood pressure results before beginning to examine the patient, as these may well direct the candidate along a renal path (see the short case on renal examination in this chapter). If the urinalysis and blood pressure are unhelpful (i.e. normal), then a careful appraisal is necessary to detect other groups of causes.

A suggested way to approach this case is first to assess the extent of the oedema, and then to look for the cause.

Begin by asking the child to stand up (in underwear only) and inspect for periorbital oedema, findings of CKD (e.g. sallow complexion, pallor, skeletal changes of renal osteodystrophy), CLD (e.g. jaundice, spider naevi) and CCF (e.g. raised jugular venous pressure), Cushingoid features of steroid-treated glomerulonephritis (especially idiopathic nephrotic syndrome [INS]), and nutrition and abdominal swelling from ascites. Also inspect from the side for ascites and kyphoscoliosis (osteodystrophy) and from the back for scoliosis (osteodystrophy) and buttock rash (Henoch–Schönlein purpura).

Next, demonstrate the distribution of the oedema. This can be done starting at the feet and working up (child lying down initially), or by starting at the head and working down (child standing up). The following abnormal signs should be sought:

1. Ankle oedema: press over the anterior tibiae for one minute (remember: one finger, one spot, one minute).

2. Ascites: shifting dullness, fluid thrill.

3. Sacral oedema: press over sacrum for one minute.

4. Pleural effusion: percuss the posterior chest wall.

5. Periorbital oedema: inspect.

Note that the time that you spend palpating for oedema can give you the opportunity to re-inspect the child and comment on whether there are any (previously overlooked) signs of CKD (e.g. transplant scar), CLD (clubbing, leuconychia, palmar erythema, caput medusae) or bowel disease (e.g. clubbing, erythema nodosum, joint swelling with IBD).

After demonstrating the extent of the oedema, proceed to examine for the aetiology. A suggested order is as follows: hands, blood pressure (if not yet requested), face, chest, abdomen and urinalysis (again, if not already requested). Figure 12.3 outlines the findings sought at each stage of the examination procedure.

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FIGURE 12.3 Oedema

At the completion of the case, summarise succinctly, give a brief differential diagnosis and suggest which investigations you think are appropriate.

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