Homeostasis and the kidney

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11 Homeostasis and the kidney

The kidney and urinary tract

The kidney is central to water, electrolyte, acid–base and calcium homeostasis, as well as having a crucial role in regulation of blood pressure, and via the action of erythropoietin, manufacture of red blood cells. Kidney function depends on an unimpeded blood supply, functioning renal parenchyma, and an unobstructed outflow of urine. Any of these may be affected by congenital malformation or inherited disease, inflammation or infection.

Examination

Most common renal problems produce few examination findings. Check the blood pressure and look for peripheral oedema. Interpretation of blood pressure values is aided by reference to published normal ranges for blood pressure. It is important to measure blood pressure, usually in the right arm, after a period of quiet rest, with the correct size cuff, and ideally to take repeated measures, as children are prone to ‘white-coat’ hypertension.

Palpate the kidneys and feel for tenderness in the loins. Inspect the back looking for a naevus that could overlie a spinal cord anomaly. Check the lower-limb reflexes. The external genitalia should be examined, but tact is needed and you may decide the examination should be deferred unless the history specifically suggests a genital problem. The examination is not complete without testing the urine with a multiple reagent stick (see Table 11.1).

Table 11.1 Significance of urine dipstick test results

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

Genitourinary defects

Congenital anomalies of the urinary tract

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).

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.

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:

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).

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).

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

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.

Glomerular disorders

Nephrotic syndrome

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

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).

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).

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:

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

Regulating calcium and bone metabolism

Hypocalcaemia

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.