Test	Significance
pH	Normal urine pH ranges from 5 to 7. Inappropriately alkaline urine is found in some infections, and in renal tubular acidosis
Protein	Proteinuria is seen in a range of renal diseases, and is the hallmark of nephrotic syndrome. The presence of proteinuria may be indicated by very frothy urine
Blood	See Box 11.1 for causes of haematuria
Nitrites and leucocytes	Nitrites are products of bacterial decomposition of urea and suggest urinary tract infection. Their presence may be suggested by the smell of ammonia. The findings of leucocytes in urine also suggests infection or inflammation
Glucose and ketones	Glycosuria indicates blood glucose levels above the renal threshold for glucose reabsorption. The presence of glycosuria and ketonuria together strongly suggests type 1 diabetes
Bilirubin and urobilinogen	Urobilinogen is responsible for the normal yellow colour of urine, but if detectable on a reagent strip implies enhanced red cell destruction, as in haemolytic anaemia, or impaired clearance in bile, most commonly due to hepatitis. The finding of bilirubin in urine suggests hepatocellular dysfunction or obstructive jaundice. Urobilinogen may be absent from urine in obstructive jaundice, although the urine is dark due to the presence of conjugated bilirubin

Investigations

Urine microscopy and culture

Isolation of a pure growth of an organism together with elevated leucocytes from a properly collected urine sample is essential for the diagnosis of urinary tract infection (UTI). Urine collection bags are unreliable and should not be used. A ‘clean catch’ urine sample, after cleaning of the perineum, is preferred. A catheter specimen should only be taken if antibiotics are to be commenced because of the risk of introducing infection. A suprapubic aspirate is rarely required, and should be performed under ultrasound guidance – a catheter specimen is preferable in the urgent situation. Failure to collect a urine sample will make it impossible to diagnose UTI and may commit the child to unnecessary and invasive investigations.

Urine microscopy is also useful in the confirmation of haematuria, and to look for the presence of granular casts, seen in glomerulonephritis.

Imaging the urinary tract

Ultrasound is the key first-line investigation in any disorder of the renal tract. It will demonstrate renal size, anatomical abnormalities, including scarring, reflux and hydronephrosis, and renal masses. Serial ultrasound measurements may be used to monitor renal growth and appearances of hydronephrosis.

A DMSA (dimercaptosuccinic acid) renogram is a static radionucleotide scan. It is the gold standard for detecting renal scars and enables comparison of renal function on the two sides.

A MAG3 scan is a dynamic renogram – the isotope can be seen to move through the kidney to the bladder and through voiding. It will distinguish urinary stasis and obstruction and also give information on reflux. This investigation requires control of voiding and thus is unsuitable in children who are not toilet-trained.

A micturating cystogram (MCUG) involves catheterization and radiographs as the child voids urine. It may be indicated after UTI in infancy to detect urethral valves in boys, and reflux in infants of either sex.

Genitourinary defects

Undescended testes

About 4% of newborn boys have an undescended testis (cryptorchidism). It is more common in premature infants. In the majority, the testes descend spontaneously by 3 months of age. By 6 months, there is little likelihood of the cryptorchid testis descending spontaneously, and orchidopexy is required to fix the testis in the scrotum. Laparoscopy may be necessary to locate abdominal testes, but in some cases the testis is simply absent as the result of intra-abdominal torsion or agenesis. If the testis cannot be located, renal ultrasound should be performed as there may be associated renal agenesis.

If both testes are undescended, intersex needs to be considered (see Chapter 12, p. 151).

There is an increased risk of malignancy in undescended testes, which persists even after orchidopexy.

Hypospadias

In hypospadias, the urethral meatus opens onto the ventral shaft of the penis or scrotum, or exceptionally, the perineum. In 60% the meatus is distal (glandular or coronal hypospadias) and in 15% proximal (perineoscrotal or perineal hypospadias), with the remainder affecting the penile shaft (subcoronal or mid-penile hypospadias). Hypospadias affects the urinary stream and may be associated with bowing of the erect penis, ‘chordee’, which will affect sexual function in later life. Proximal hypospadias may be associated with urinary tract abnormalities, and a micturating cystogram should be performed. Hypospadias with an undescended testis may be seen in intersex states (see Chapter 12, p. 151) and genetic sex determination should be performed. Surgical correction in infancy is straightforward. The parents should be advised not to have their son circumcised as the foreskin may be used as part of the surgical repair.

Inguinal hernia and hydrocele

Inguinal hernias and hydroceles arise from a patent processus vaginalis. The processus vaginalis is a pouch of peritoneum which accompanies the testis into the scrotum, and thereafter involutes. Before birth, peritoneal fluid enters the scrotum, resulting in a hydrocele. The great majority of hydroceles resolve spontaneously by 6 months but if the processus remains patent, surgery will be necessary. Inguinal hernias and hydroceles are especially common in premature infants. Presentation of hernias is usually with a variable groin swelling, particularly seen on crying or coughing, but complications include incarceration, strangulation and bowel infarction. Treatment is surgical.

Congenital anomalies of the urinary tract

Case 11.1

A baby with a congenital anomaly

Routine antenatal ultrasound scanning at 20 weeks’ gestation had shown bilateral renal pelvic dilatation in an apparently normal male infant. The dilatation persisted on a repeat scan at 32 weeks’ gestation. After birth, he was nursed with his nappy unfastened so that the urinary stream could be seen. His urinary stream was poor. He underwent ultrasound and MCUG to exclude obstruction of the urinary tract and was found to have severe bilateral hydronephrosis secondary to posterior urethral valves. He was catheterized to decompress the urinary tract and subsequently underwent surgery.

Congenital anomalies of the urinary tract may affect the kidney, urinary collecting system, bladder or urine outflow tract (as in Case 11.1).

Renal agenesis or dysplasia affecting both kidneys may produce antenatal oligohydramnios with lethal pulmonary hypoplasia (Potter’s syndrome) as fetal urine is essential for lung development. Unilateral agenesis or dysplasia may be associated with other congenital abnormalities such as contralateral vesico-ureteric reflux. The remaining kidney undergoes compensatory hypertrophy in post-natal life.

Abnormalities of the ureter include obstruction at the level of the renal pelvis (pelvi-ureteric junction obstruction) or bladder, normally due to a ureterocele – a cystic dilatation of the terminal ureter with a pinhole ureteral orifice. These result in proximal dilatation and predispose to infection and renal injury. Treatment is surgical. Occasionally, the ureter may be partially or completely duplicated. Typically, the ureter draining the upper pole inserts ectopically and is commonly obstructed, whereas the lower pole ureter inserts non-obliquely into the bladder, predisposing to reflux. In girls, an ectopic ureter commonly empties into the vagina leading to constant dribbling incontinence. In boys, the insertion is commonly into the prostatic utricle, seminal vesicle or vas deferens and thus leads to obstruction (see Figure 11.1).

Figure 11.1 Left pelvi-ureteric junction obstruction with resultant dilatation of the renal pelvis (hydronephrosis). The right kidney is duplex, with two pelvicalyceal systems, in this case, each supplied by its own ureter. The lower moiety of duplex systems is commonly affected by vesico-ureteric reflux (70%) due to its more lateral and less oblique course. The upper pole ureter is more susceptible to obstruction from a ureterocoele (ballooning of the distal ureter as it enters the bladder), producing vesico-ureteric junction obstruction, as in the illustration. The insertion of the upper pole ureter is usually inferior and medial to the normal position, and may be associated with dysplasia of the upper pole.

The most important congenital bladder abnormality is neuropathic bladder, in which the nerve supply to the bladder is defective, as occurs with spina bifida or spinal dysraphism. The bladder outlet fails to relax fully, leading to hydronephrosis and renal injury. Management is usually with intermittent self-catheterization.

Obstruction to the urethra occurs with posterior urethral valves in boys, in which the prostatic urethra is obstructed by abnormal tissue leaflets which impede renal flow, producing a variable degree of obstruction. The obstruction commonly results in renal injury with one-third of boys developing chronic kidney disease.

See Table 11.2 for congenital anomalies of the kidney and urinary tract.

Table 11.2 Congenital anomalies of the kidney and urinary tract

	Anomaly	Clinical consequence
Kidney	Agenesis ormulticystic dysplasia Infantile polycystickidney diseaseRenal ectopia andhorseshoe kidney	Bilateral: lethal pulmonary hypoplasia (Potter’s syndrome)Unilateral: associated congenital abnormalitiesChronic kidney disease Association with othercongenital anomalies
Ureter	Pelvi-ureteric junctionobstructionUreterocele Ectopic ureter Vesico-ureteric reflux Duplex ureter	Hydronephrosis Hydronephrosis and hydro-ureterHydronephrosis or dribbling incontinenceRisk of infection, renal scarringOften associated with a combination of reflux and obstruction
Bladder	Bladder or cloacalexstrophy Neuropathic bladder	Major reconstructive surgery requiredIncontinence, chronic kidney diseaseIncontinence, chronic kidney disease insufficiency
Urethra	Posterior urethralvalves (boys)	Chronic kidney disease, vesico-ureteric reflux

Urinary tract infection

The link between UTI and urinary symptoms is not always clear-cut. Even if the diagnosis seems clinically apparent (as in Case 11.2) the culture may be negative. In some cases the symptoms may be non-specific (irritability or failure-to-thrive) or severe enough, as in Case 11.3, to mimic septicaemia. Hyponatraemia due to renal salt loss may complicate urinary tract infection.

Case 11.2

A girl with urinary tract infection

Helen was a 3-year-old girl who presented with a 24-hour history of fever and vomiting. She had urinary frequency and cried on micturition. Her urine looked cloudy. She had achieved urinary continence for 2 years but had been getting spells of day- and night-time wetting for the previous 6 months. On examination she was flushed and lethargic with a high fever (39.5°C) and a tachycardia (110 beats per minutes).

Investigations showed a white blood cell count of 35 000, and a plasma sodium of 129 mmol/L. Urine showed blood, nitrites and leucocytes on dipstick testing, and organisms and white blood cells were seen on microscopy. A presumptive diagnosis of UTI was made and subsequently confirmed on urine culture.

Case 11.3

A baby with urinary tract infection

Harvey presented at the age of 9 weeks with high fever, irritability and diarrhoea. His general condition gave cause for concern so he underwent a number of investigations, including blood culture, lumbar puncture and, in view of his diarrhoea, catheterization to obtain a sterile urine sample prior to being commenced on high-dose intravenous antibiotics. Urine dipstick showed blood, leucocytes and nitrites, and Gram-negative cocci were seen on urine microscopy. Harvey remained ill with a high swinging fever and therefore had an urgent renal ultrasound. This showed the left kidney to be large and hyperechoic, suggesting pyelonephritis, associated with marked dilatation of the left renal pelvis with free reflux of urine visible on ultrasound. Harvey recovered after a 10-day course of antibiotics. A subsequent MCUG showed severe left vesico-ureteric reflux and a DMSA scan showed extensive scarring with the left kidney contributing 36% of renal function. A follow-up MAG3 scan at age 2 years showed a further decline in renal function with persistent left-sided reflux, despite apparently being free of infections, so he underwent a ‘Sting’ procedure in which an inert substance was injected into the ureteric orifice to abolish reflux during micturition.

UTI is very common in children, and affects 3–5% of girls and 1–2% of boys. In infancy, boys and girls are equally affected, but thereafter girls are much more commonly affected. The finding of UTI, especially in infancy, leads to a number of investigations, and it is essential to collect urine samples properly and to obtain repeat samples for confirmation prior to initiating therapy, if possible.

UTIs fall into three groups:

• Pyelonephritis

• Cystitis

• Asymptomatic bacteriuria.

The great majority of infections are due to ascending infection from faecal organisms, especially Escherichia coli, Klebsiella and Proteus. Pyelonephritis may occur secondarily to haematogenous spread, particularly in the neonatal period.

Pyelonephritis is characterized by malaise, fever, loin pain and vomiting. In infants, symptoms may be very non-specific, and a urine culture should be routinely obtained in any infant with unexplained fever. Pyelonephritis may lead to renal scarring, which, in turn, may lead to hypertension and chronic kidney disease. Scarring is most likely to accompany UTI in infancy. Infections after the age of 5 years are very unlikely to produce scarring if the kidneys were previously normal.

Cystitis is associated with bladder symptoms of urgency, frequency, dysuria, incontinence and abdominal pain, and is much more common in girls. It does not produce renal scarring. Cystitis is commonly associated with constipation.

Asymptomatic bacteriuria affects older girls and describes asymptomatic bacterial colonization of the bladder.

Investigation

The key objectives in investigating UTI are to determine the presence of congenital anomalies, scarring, or vesico-ureteric reflux. Ascending infection leading to pyelonephritis is more likely if there is vesico-ureteric reflux or anatomical abnormalities of the renal tract.

Anatomical abnormalities may predispose to pyelonephritis by producing stasis secondary to urinary obstruction, or by permitting reflux. Scarring may be visualized on ultrasound as obvious anatomical deformity or discrepancy in the size of the kidneys – normally length differs by less than 1 cm. More subtle scarring may be demonstrated by radio-isotope scanning with DMSA.

Vesico-ureteric reflux describes the backflow of urine from the bladder up the ureter due to a failure of the functional valve where the ureter penetrates the bladder wall. Reflux can be severe enough to distend the renal pelvis and produce backflow into the renal collecting ducts. It is a worrying finding in infants as it may be associated with renal scarring (see Figure 11.2).

Figure 11.2 Grades of vesico-ureteric reflux.

An MCUG is used in young children to determine the presence of reflux, whereas in older children MAG3 scanning is used. MCUG is often very distressing, and should not be used after infancy, with rare exceptions. It has the advantage of demonstrating abnormalities of the bladder or ureters such as the presence of bladder diverticula, ectopic ureters and duplex systems, not readily apparent by other imaging modalities. Antibiotic cover is required following MCUG to prevent ascending infection. MAG3 scanning is useful to differentiate reflux from obstruction and to determine the anatomical site of obstruction (see Figure 11.3).

Figure 11.3 Investigations in children with confirmed urinary tract infection. (a) Infants under 6 months; (b) children over 6 months.

Treatment

Treatment is directed to reducing the risk of renal injury. This requires prompt recognition and treatment of UTIs, with an appropriate antibiotic. High rates of resistance to trimethoprim and amoxicillin make these unsuitable choices, unless antibiotic susceptibility has been confirmed. Good first-line choices are co-amoxiclav or a cephalosporin such as cefalexin. Prophylaxis of UTI is no longer recommended. Urinary tract obstruction requires surgery. If vesico-ureteric reflux is severe, and renal function declines, then a ‘Sting’ procedure (as in Case 11.3) is usually performed, in which an inert substance, such as Deflux™), is injected just below the ureteral orifice. This usually alleviates reflux. If the Sting procedure fails, ureteric reimplantation may be effective. New scarring after the age of 2 years is uncommon and extremely rare after the age of 5 years.

Older girls with recurrent cystitis and/or bladder instability – voiding dysfunction – in which there may be dysuria, frequency, urgency and urge incontinence, are treated with antibiotics if appropriate. A regime of regular voiding, adequate fluid intake, good perineal hygiene and, if necessary, use of anticholinergic drugs such as oxybutynin or tolterodine, will assist in resolving symptoms. Concurrent constipation is common and should be treated, but may be exacerbated by use of anticholinergic medication. Very frequent infections may be ameliorated by antibiotic prophylaxis.

Haematuria

Often the clinical context will help in discovering the cause of haematuria. Otherwise the haematuria may be an isolated or chance finding (see Table 11.3).

Table 11.3 Causes of haematuria

Diagnosis	Other clinical features
Wilms’ tumour	Palpable abdominal mass
Acute glomerulonephritis	Oliguria, proteinuria, raised blood urea
Henoch–Schönlein purpura	Vasculitic non-blanching rash on legs, arthropathy, abdominal pain
Haemolytic-uraemic syndrome	Preceding gastroenteritis, haemolytic anaemia, renal failure
Pyelonephritis	Fever, rigors, back pain
Renal or ureteric calculi	Renal colic
Sickle-cell disease	Anaemia, painful crises
Subacute bacterial endocarditis	Congenital heart disease, fever, changing heart murmurs
Haemorrhagic cystitis	Heavy haematuria with dysuria
Urinary tract infection	Fever, dysuria, irritability

Incidental haematuria

Case 11.4

A boy with microscopic haematuria

Darren, a 9-year-old boy of Jamaican parents, was seen in the outpatient department with a history of enuresis. A routine urine dipstick test showed 3+ blood. This persisted on follow-up urine specimens. He had no abdominal pain, examination was normal and he was normotensive. The presence of red blood cells was confirmed by urine microscopy. Urine culture was negative and renal function was normal, with normal complement levels and a negative sickle screen. Renal ultrasound showed multiple renal cysts affecting both kidneys, confirming autosomal dominant polycystic kidney disease. His father, who was markedly hypertensive, was also found to be affected.

Polycystic kidney disease (PKD) has two forms – autosomal recessive or infantile, and autosomal dominant (as in Case 11.4). The infantile form may be detected by antenatal ultrasound. The kidneys are enlarged with innumerable cysts, and some degree of renal impairment is usually present at birth. Stage IV chronic kidney disease affects over 50% by the age of 10 years. Autosomal dominant PKD usually presents in adult life but presentation with frank or microscopic haematuria, UTI or hypertension may occur in affected children. Wilms’ tumour may present with haematuria (as in Case 7.14, Chapter 7), usually with a palpable flank mass.

Incidental microscopic haematuria also occurs with subclinical nephritis, Alport’s syndrome, renal calculi and IgA nephropathy.

Alport’s syndrome is an X-linked dominant condition causing glomerulonephritis starting in childhood, and deafness in later life.

IgA nephropathy causes brief bouts of haematuria (microscopic, or frank haematuria) usually precipitated by an upper respiratory tract infection. Some of these children will develop chronic kidney disease in adult life.

Urinary calculi are uncommon. They may complicate UTI, particularly if there is urinary stasis. The stones may remain in the kidney or enter the ureter with sometimes excruciating renal colic which radiates from loin to groin.

Management of haematuria

A clinical assessment and urinalysis will suggest the diagnosis in most cases. Haematuria should always be investigated with at least an ultrasound examination. Persistent haematuria may indicate the need for cystoscopy, particularly if symptomatic.

Children with persistent or recurrent microscopic haematuria (e.g. following Henoch–Schönlein purpura, or for suspected IgA nephropathy) require monitoring until resolution occurs, with periodic urinalysis and measurements of blood pressure and renal function.

Glomerular disorders

Nephrotic syndrome

Case 11.5

A boy with generalized oedema

Michael, a 5-year-old boy, was referred to hospital with facial oedema and abdominal distension. Symptoms had been emerging for 5 days but he did not feel particularly unwell. He had obvious facial and ankle oedema with ascites and enlargement of the scrotum. A urine dipstick showed heavy proteinuria, and his serum albumin was low (18 g/dL). Twenty-four hour urine protein excretion exceeded 40 mg/m².

Nephrotic syndrome describes the triad of oedema, proteinuria (>40 mg/m²/day) and hypoalbuminaemia (as in Case 11.5). Glomerular protein leak leads to loss of albumin and other plasma proteins. The low plasma oncotic pressure reduces capillary reabsorption of tissue fluid leading to oedema. Reduced plasma volume stimulates antidiuretic hormone (ADH) secretion and the renin–angiotensin system, producing sodium and water retention, compounding the pre-existing oedema.

Nephrotic syndrome is commoner in boys (male to female ratio 2:1), and about 85% of cases arise from minimal change glomerulonephritis. Most cases respond to high-dose prednisolone 60 mg/m²/day for 4–6 weeks, followed by a reducing course of steroids over 1–2 months.

The initial steroid treatment takes about 10 days to work. This can leave a child with uncomfortable and potentially dangerous oedema whilst waiting for a response. Fluid balance should be monitored. Both circulatory collapse and overload can complicate this condition. If the oedema becomes too uncomfortable, diuretics may be used. The effect can be potentiated by the combination of intravenous replacement albumin and diuretics, although this may precipitate pulmonary oedema.

The combination of ascites with loss of circulating immunoglobulins leaves the risk of acute pneumococcal peritonitis and prophylactic penicillin should be given. Thrombotic complications are rare – but do not forget the possibility of renal vein thrombosis if haematuria or renal failure supervenes.

Whilst some children have a single episode, some move on to chronic relapsing nephrotic syndrome when other immunosuppressants such as cyclophosphamide or ciclosporin may be used. Children who are not varicella immune should be immunized when remission is achieved. If a child who is not immune is exposed to varicella, they should receive zoster immune globulin and aciclovir, to reduce the risk of disseminated chicken pox, which may be fatal.

Nephritis

Case 11.6

A girl with oedema and cola-coloured urine

Casey, a 7-year-old girl, presented with malaise, headaches and abdominal pain with dark urine 2 weeks after a sore throat. On examination, she was hypertensive – 150/95 mmHg, miserable, and had a gallop rhythm and basal crepitations. Her urine was cola-coloured and strongly positive for blood and protein. Urine microscopy showed granular casts. Urea and creatinine were significantly elevated (urea 17.7 mmol/L, creatinine 242 μmol/L), but with normal electrolytes. Her C3 levels were depressed. She had an elevated DNase B antigen and ASO (anti-streptolysin O) titre, indicating recent streptococcal infection, confirming the diagnosis of post-streptococcal glomerulonephritis complicated by hypertensive heart failure.

Post-streptococcal glomerulonephritis is an immune-complex-mediated glomerulonephritis, which follows cutaneous or pharyngeal streptococcal infection (as in Case 11.6). It typically affects children aged 5–12 years. It is very common worldwide, but in developed countries it is less frequent and viral aetiology is as common as streptococcal disease. The severity of renal involvement determines prognosis, with presentations ranging from asymptomatic haematuria to acute renal failure. Greater degrees of renal impairment are associated with hypertension, which, if severe, may lead to hypertensive encephalopathy and heart failure.

Treatment is directed at eradicating streptococcal carriage and treating hypertension and oedema. Over 95% of children make a full recovery, although haematuria may persist for 1–2 years. If the symptoms do not remit, and haematuria and proteinuria persist, a renal biopsy should be performed to exclude other causes of nephritis such as membranous or membranoproliferative glomerulonephritis, sometimes secondary to connective tissue diseases, notably systemic lupus erythematosus (SLE).

Henoch–Schönlein purpura (see Chapter 6, p. 55) is associated with glomerulonephritis in 50% of cases. Children with this condition should have regular urine testing, and renal function and blood pressure checks until resolution. A minority of children develop aggressive glomerulonephritis with a mixed picture of nephritis and nephrotic syndrome, and usually progress to stage IV chronic kidney disease.

See Box 11.1 for the causes of glomerulonephritis.

Renal tubular disorders

Renal tubulo-interstitial disease may be conveniently divided into disorders of tubular function, such as renal tubular acidosis (usually inherited) or inflammatory diseases of the renal interstitium with sparing of glomeruli – interstitial nephritis. Interstitial nephritis may present acutely, with fever, urticaria and arthralgia, or with eosinophilia and renal impairment. Analgesics are an important cause. Chronic interstitial nephritis most usually occurs secondarily to chronic obstructive uropathy or vesico-ureteric reflux (see above).

Case 11.7

An infant with failure-to-thrive and glycosuria

Irfan, a 14-month-old male infant of Turkish parents, was referred with severe failure-to-thrive. His weight was far below the 0.4th centile. His length was also below the 0.4th centile and his head circumference was on the 2nd centile. His parents reported that he always seemed thirsty, but preferred water to milk. He vomited frequently. He also appeared to dislike light. A urine dipstick showed 1+ glycosuria. Preliminary investigations showed hypophosphataemia with markedly elevated alkaline phosphatase suggestive of rickets, coupled with a metabolic acidosis, but a normal anion gap (Na – [HCO₃ + Cl] < 12). His urine was inappropriately alkaline, given his underlying metabolic acidosis, indicating renal tubular acidosis. A urine amino acid profile showed generalized aminoaciduria.

The boy in Case 11.7 has generalized proximal tubular dysfunction – known as renal Fanconi syndrome. Measurement of leucocyte cystine content confirmed cystinosis as the cause. In cystinosis, cystine accumulates in lysosomes and causes progressive renal tubular dysfunction, culminating in renal failure. Cystine accumulation in the cornea causes photophobia. Hypothyroidism, central nervous system (CNS) abnormalities and myopathy occur in later life.

Renal tubular dysfunction may be specific, when just one element of tubular function is impaired, or part of a generalized disorder – renal Fanconi syndrome – of which cystinosis is the commonest cause (see Box 11.2).

Water homeostasis

Water homeostasis is achieved using the twin controls, thirst and antidiuretic hormone (ADH, also known as vasopressin). ADH is secreted from the posterior pituitary in response to increasing plasma osmolality. It acts by increasing the permeability of the collecting ducts and allowing the urine to become more concentrated as it flows through the hyperosmolar regions of the renal medulla. ADH is regulated by plasma osmolality and plasma volume. Plasma osmolality is exquisitely regulated by hypothalamic osmoreceptors, and ADH secretion is completely inhibited at plasma osmolalities below 282 mOsmol/kg. In contrast, low-pressure baroreceptors, which detect volume depletion, in the heart, pulmonary vessels and great veins stimulate ADH secretion only when volume depletion is significant (>8–10% dehydration or volume loss, such as haemorrhage). The latter mechanism stimulates ADH secretion regardless of osmolality. Sodium balance is regulated in the renal tubules by aldosterone produced in the adrenal gland under the control of the renin–angiotensin system. The juxtaglomerular apparatus within the kidney senses sodium concentration and renal blood flow. Low sodium or impaired perfusion leads to secretion of renin, which cleaves the plasma protein angiotensinogen to angiotensin I. This is converted, in the pulmonary vasculature and elsewhere, to angiotensin II. Angiotensin II stimulates thirst, and aldosterone and ADH secretion, in addition to direct pressor effects on the vasculature. These mechanisms stimulate sodium and water retention and increase blood pressure, thus restoring water and sodium balance. Hyperkalaemia also stimulates aldosterone production directly. Drugs that act on the renin–angiotensin system, such as angiotensin- converting enzyme (ACE) inhibitors, are very useful for regulation of blood pressure and volume overload states such as cardiac failure.

This complex control system is tested by various pathologies that may overwhelm the capacity of the kidney to maintain homeostasis. Fluid-losing conditions such as gastroenteritis may result in water loss or as salt loss. A mixed picture of water and salt loss may occur.

If homeostasis is overwhelmed this may result in hypernatraemic or hyponatraemic dehydration (see Chapter 13, p. 166).

Primary failure of the control systems is less common but includes inappropriate ADH secretion, diabetes insipidus and aldosterone deficiency (see Chapter 12).

Syndrome of inappropriate ADH secretion

Inappropriate ADH secretion occurs in certain pathological states, notably the post-operative period, chest infections and CNS disorders. The hallmark is a low sodium with oliguria. Rarely, mainly in the intensive care situation, cerebral salt-wasting may occur. In this condition, sodium depletion leads to hyponatraemia, but oliguria is not usually present, unless there is coexisting volume depletion.

Treatment of the syndrome of inappropriate ADH secretion is with volume restriction and diuretics if necessary. Tolvaptan, an ADH receptor antagonist (not licensed for children), may be appropriate in the intensive care situation. Cerebral salt-wasting requires cautious sodium replacement, with close monitoring of urine output, weight and cardiovascular parameters.

Polyuria

Damage to the hypothalamus or pituitary caused by tumours, trauma or infection may prevent release of ADH, causing diabetes insipidus. This leads to the production of large volumes of dilute urine. Congenital diabetes insipidus may also occur, usually in boys due to defective V2 ADH receptors (the X-linked disorder, nephrogenic diabetes insipidus).

Diabetes insipidus must be distinguished from habitual or psychogenic polydipsia, which is much commoner. Some toddlers appreciate the comfort of having some juice to hand and may consume several litres each day. They can usually be discouraged by offering smaller volumes and increasing dilutions. Habitual drinkers will seldom drink water. If simple measures to restrict fluid intake are ineffective, habit polydipsia and diabetes insipidus may be distinguished by a water-deprivation test. This may rapidly result in severe dehydration in diabetes insipidus so must be carefully managed in hospital. Children with habit polydipsia will produce concentrated urine within a few hours. Children with ADH deficiency continue to pass large volumes of dilute urine and rapidly lose weight. The water deprivation test is onerous, and potentially hazardous, and should be carried out under the supervision of a paediatric endocrinologist.

Kidney failure

Introduction

In renal failure of whatever cause, there is a progressive breakdown of renal homeostatic mechanisms. In acute renal failure, the progression is rapid, with the principal clinical manifestations being oliguria, hypertension and oedema. This is accompanied by elevated urea and creatinine and derangement of electrolyte, calcium and acid–base balance with resulting hyperkalaemia, hypocalcaemia and acidosis. Acute renal failure may be temporary, depending on the cause, or may progress to chronic kidney disease. In chronic kidney disease, the same derangements occur progressively as renal function declines from early chronic kidney disease to stage IV chronic kidney disease, requiring renal replacement therapy (dialysis or transplantation). Failure to eliminate toxins may result in uraemic encephalopathy, which may be compounded by hypertension, acidosis and electrolyte imbalance.

Chronic kidney disease is also associated with:

• Anaemia from chronic disease and erythropoietin deficiency

• Growth failure from several causes

• Renal bone disease from hyperparathyroidism secondary to chronic hypocalcaemia and hyperphosphataemia

• Uraemic toxins leading to impaired cellular immunity

• Bleeding and easy bruising secondary to impaired platelet function.

See Table 11.4 for the causes of acute and chronic kidney disease.

Table 11.4 Causes of acute and chronic kidney disease

	Acute	Chronic
Prerenal	Shock, e.g. haemorrhage dehydration, burns, sepsis
Renal	Glomerulonephritis Haemolytic-uraemic syndrome Renal vein thrombosis Liver failure (hepatorenal syndrome)	Congenital cystic or dysplastic diseases, e.g. medullary cystic kidney Chronic reflux nephropathy Glomerulonephritis Metabolic disease, e.g. cystinosis
Post-renal	Acute urinary tract obstruction	Posterior urethral valves Bilateral pelvi-ureteric or vesico-ureteric obstruction Renal calculi Neurogenic bladder, e.g. spina bifida

Management of renal failure

Treatment is directed at alleviating the cause, if possible, and to mitigating the consequences of loss of renal function.

In acute renal failure, it is essential to determine whether it is of renal or prerenal origin. This may be apparent from the clinical situation. Useful clues may be obtained from the composition of urine. In prerenal failure, oliguria is associated with the passage of concentrated urine (osmolality >500 mOsmol/kg) with little sodium (<20 mmol/L), whereas intrinsic renal failure is suggested by the passage of dilute urine (osmolality <350 mOsmol/kg) with high sodium concentration (>40 mmol/L). In prerenal uraemia, cautious volume loading coupled with a diuretic may prevent progression to acute tubular necrosis.

Obstructive renal failure usually responds well to relief of the obstruction, e.g. catheterization in the child with a neurogenic bladder or percutaneous nephrostomy in a child with pelvi-ureteric junction obstruction.

See Table 11.5 for the treatment of renal failure.

Table 11.5 Treatment of renal failure

Problem	Treatment
Hyperkalaemia	Calcium polystyrene sulphonate enemas
	Intravenous or inhaled salbutamol
	Intravenous calcium gluconate
	Insulin and glucose infusion
	Dialysis
Hypertension and/or oedema	Loop diuretics, e.g. furosemide
	ACE inhibitor Calcium-channel blocker Beta-blocker
Acidosis	Sodium citrate or bicarbonate
Hypocalcaemia	Phosphate binders, e.g. calcium carbonate
	Parenteral calcium for severe hypocalcaemia
	1α vitamin D, calcium supplements
Hyponatraemia	Sodium supplements
Anaemia	Blood transfusion
	B₁₂ and folate supplementation
	Erythropoietin
Growth failure/failure-to-thrive	Optimal nutrition
	Treatment of anaemia and acidosis
	Growth hormone
	Renal transplantation
Uraemic encephalopathy	Treatment of hypertension
	Correction of metabolic abnormalities
	Renal transplantation

Dialysis and transplantation

Dialysis allows correction of metabolic abnormalities by allowing plasma to equilibrate with an appropriately constituted dialysate across a permeable membrane. This may be achieved through haemodialysis, or by using the patient’s peritoneum as a dialysis membrane via peritoneal dialysis. Peritoneal dialysis takes longer, and is less efficient, so it must be performed daily, but can be done at home, whereas haemodialysis, usually done in hospital, is done three times weekly.

Dialysis is necessary in acute renal failure if there is severe volume overload with hypertension refractory to diuretics, severe hyperkalaemia, acidosis or hypocalcaemia, or inexorable progression of the underlying renal failure.

In the child with stage IV chronic kidney disease, it is preferable to proceed to renal transplantation to avoid the necessity for dialysis as this gives a much better quality of life, with the least disruption to the child’s life.

Gastroenteritis and renal failure

Case 11.8

A girl with acute renal failure

Katie, a 3-year-old girl, presented with a 12-hour history of severe gastroenteritis. She was pale and febrile, with abdominal pain, severe vomiting and bloody diarrhoea. Initial investigations showed severe anaemia and thrombocytopenia with a coagulopathy and markedly elevated urea and creatinine with hyperkalaemia, confirming haemolytic-uraemic syndrome. Stool cultures subsequently grew Escherichia coli O157:H7. Katie quickly deteriorated and was transferred to a specialist renal unit for dialysis. She recovered after 24 days of intensive care, but unfortunately her renal failure did not improve and she remained dialysis-dependent. Katie was one of six children and four adults who were infected following ingestion of contaminated hamburgers from a local fast-food restaurant.

Haemolytic-uraemic syndrome

Haemolytic-uraemic syndrome (HUS) is the commonest cause of acute renal failure in children. Eighty per cent of cases result from infection with Shiga-toxin-producing Escherichia coli O157:H7 (as in Case 11.8). The infection results from contact with infected domestic animals or ingestion of under-cooked or contaminated meat. The toxin induces widespread endothelial injury with resultant haemolytic anaemia with platelet consumption and renal failure. One in ten children with HUS die, and a further 10% develop stage IV chronic kidney disease.

Regulating calcium and bone metabolism

Introduction

Ionized calcium is very tightly maintained within the normal range by parathyroid hormone (PTH). PTH mobilizes calcium from bone, and activates 1α-hydroxylase in the kidney, thus facilitating production of 1,25-dihydroxycholecalciferol, the active form of vitamin D. Vitamin D increases calcium and phosphate absorption by the small intestine and the kidney. Vitamin D is essential for bone turnover and remodelling.

Hypocalcaemia

Case 11.9

A baby with low blood calcium

A baby born at 32 weeks’ gestation and small for gestational age was very irritable on the second day of life and had a brief seizure. The blood glucose was normal (4.2 mmol/L) but the serum calcium was only 1.32 mmol/L.

Acute hypocalcaemia leads to neuromuscular excitability, which may manifest with seizures (as in Case 11.9), tetany and laryngeal spasm. Chronic hypocalcaemia leads to psychomotor retardation, sometimes with raised intracranial pressure, cataracts and photophobia. Low calcium may occur due to deficiency (hypoparathyroidism) or end-organ resistance to PTH (pseudohypoparathyroidism), or due to vitamin D deficiency. Low magnesium commonly accompanies hypocalcaemia.

In the sick neonate, transient hypoparathyroidism may lead to severe hypocalcaemia, as in Case 11.9. This may also be observed in infants born to mothers with hyperparathyroidism, due to suppression of fetal PTH secretion by maternal hypercalcaemia. Hypoplasia of the parathyroid glands occurs to a variable extent in Di George syndrome (see Chapter 18, p. 272), although in most infants hypocalcaemia is transient. In pseudohypoparathyroidism the PTH receptor is defective. It is associated with a characteristic appearance and mental retardation in some cases. Hypoparathyroidism also occurs as an autoimmune disease, classically in association with chronic mucocutaneous candidiasis and adrenal insufficiency, and other autoimmune disorders, and is inherited in an autosomal dominant manner (polyglandular endocrinopathy).

Vitamin D deficiency sufficient to cause hypocalcaemia and rickets is rare. In the UK, it is most commonly seen in children from ethnic minorities with restricted diets. Renal tubular loss of calcium may occur in renal Fanconi syndrome (see below). Chronic renal failure leads to progressive impairment of vitamin D activation, and may lead to hypocalcaemia.

Acute treatment of hypocalcaemia for tetany or seizures is with intravenous calcium and, if appropriate, magnesium. Hypoparathyroidism is most conveniently treated with supraphysiological doses of vitamin D, adjusted according to the serum calcium.