Management of Acute Renal Failure
Acute renal failure (ARF) is a rapid deterioration in renal function, leading to a fall in urine output (< 0.5 - 1.0 ml/kg/hr). In this oliguric state, the body is unable to excrete products of metabolism and a number of substances therefore accumulate. Plasma creatinine is used as a measure of glomerular filtration rate (GFR) and it is important to recognise that each doubling of plasma creatinine e.g. 50 to 100 mmol/l, reflects a halving of GFR. In practice, strict definitions regarding ARF are unnecessary, as the degree of disturbance will dictate the measures needed to maintain adequate fluid and electrolyte balance.
AETIOLOGY
The division of ARF in to prerenal, renal and postrenal causes remains a useful tool with respect to diagnosis and management. Table 1 shows the commoner causes of ARF in children. However, it should be recognised that there is often more than one insult e.g. dehydration plus a nephrotoxic drug.
Table 1. Causes of acute renal failure in childhood.
Prerenal Hypovolaemic shock Dehydration
Haemorrhage
Burns
Cardiac surgery
Cardiac failure
Birth asphyxia
Renal Haemolytic uraemic syndrome
Acute glomerulonephritis
Septicaemia
Nephrotoxic agents Drugs
Myoglobin
Tumour lysis syndrome
Interstitial nephritis
Postrenal Posterior urethral valves
Obstruction of a single kidney
Tumour
Children are particularly susceptible to prerenal failure. Normally the kidneys are able to maintain glomerular filtration in the face of a fall in arterial blood pressure, through a process of renal autoregulation. This is dependent on preglomerular vasodilation. The main reasons for impairment of this autoregulatory process in children are renal artery stenosis or ACE-inhibitor therapy. If the blood pressure continues to fall, these compensatory mechanisms fail and GFR falls.
Agents causing renal vasoconstriction can lead to renal failure, even in the presence of a normal blood pressure. These include a number of vasoactive agents used in paediatric intensive care, such as noradrenaline and high dose dopamine. Endotoxaemia may cause renal vasoconstriction, despite peripheral vasodilation.
It is important to recognise prerenal failure, as prompt administration of fluids may restore renal function, while excess fluid in the presence of established renal failure is hazardous. Management of such children, in the intensive care setting, can be aided by the monitoring of central venous pressure, as assessment of volume status is notoriously difficult in children. In the prerenal state tubular function should be intact and renal vasoconstriction causes sodium retention and a concentrated urine (see table 2). Administration of a limited fluid challenge should lead to a diuretic response.
Table
2. Indices aiding in the differentiation
of prerenal and renal failure.
|
|
Prerenal failure |
Renal failure |
Tubular function |
|
Urine [Na+] (mmol/l) |
<20 |
>40 |
Na+ retention |
|
Urine osmolality (mOsm/l) |
>500 |
<350-450 |
Urine concentration |
|
U Cr / P Cr |
> 40 |
<20 |
Urine concentration |
|
FE Na+ =
UNa+ x PCr PNa+ UCr |
<1% |
>3% |
Sodium retention and urine concentration |
Renal
One of the commonest causes of ARF in children is haemolytic uraemic syndrome, accounting for up to 30% of cases in some series. The clinical course is that of an episode of bloody diarrhoea followed by development of oliguric renal failure. It is linked to a verotoxin-producing strain of Escherishia coli (serotype O157:H7) and has been ascribed to ingestion of a number of food-stuffs, particularly poorly cooked beef. The histological finding is of capillary endothelial damage. As well as renal failure, other organs may be involved leading to hepatic, cardiac, CNS and pancreatic dysfunction.
"Acute tubular necrosis" is a term used to describe renal failure associated with a hypoxic / ischaemic insult to the kidney. However necrosis of tubular cells is rarely seen and a more accurate description is "tubular / obstructive" renal failure. A number of mechanisms are believed to underly this form of ARF:
Hypotension / Ischaemia. The renal medulla operates at a low pO2 and is susceptible to hypoxic injury. The tubular epithelium is metabolically active and hypoxia leads to depletion of cellular energy stores and depolarization of cell membranes. This results in leakage of calcium in to cells with activation of calcium-dependent proteases, lipases and endonucleases. There is also disruption of the cellular microfilament cytoskeleton and release of cytoplasmic vesicles in to the tubular lumen. Intercellular attachment is also compromised with detachment of cells from the basement membrane. Casts of cells and vesicles may then obstruct the tubular lumen and this leads to a rise in intratubular pressure. When this matches the glomerular filtration pressure, filtration ceases.
Endotoxin and cytokines. Septicaemia, particularly as a result of infection by meningococcus, often causes ARF. The aetiology is multifactorial and in addition to the effects of hypotension and ischaemia, endotoxin and accompanying circulating cytokines cause renal vasoconstriction. This occurs alongside dramatic systemic vasodilation. Endotoxin also appears to directly sensitize renal tubular tissue to ischaemic injury.
Oxidant injury. Reactive oxidant species may be released by both polymorphonuclear (PMN) cells as well as tubular cells themselves, under the stimulus of various cytokines (IL-1, TNF-a), which in turn are produced in response to circulating endotoxin. Up-regulation of cell adhesion molecules may promote this process. This has led to the demonstration of a partial protective effect of anti-PMN serum in an ischaemic mouse model and markedly increased tolerance to ischaemic ARF of an ICAM-1 deficient mouse.
Vasoconstrictors and nephrotoxic antibiotics. A range of exogenous and endogenous agents will promote the development of ARF by inducing renal vasoconstriction. In the intensive care setting vasoactive drugs are administered to support systemic blood pressure but their use must be balanced by concurrent renal vasoconstrictor actions. At the same time, there are raised circulating levels of endogenous vasoconstrictors such as noradrenaline, angiotensin II and endothelin. The effect of these agents will be enhanced by the injudicious use of nephrotoxic antibiotics.
Post renal causes of ARF are unusual in children. Boys with posterior urethral valves may present with ARF in the neonatal period. With routine antenatal screening, the majority of these children are identified prior to delivery. The main problem is salt and water wasting.
The other situation where obstruction may cause ARF is in children with a single kidney. This may suffer pelviureteric or vesicoureteric obstruction or obstruction from a calculus. Children with ARF, particularly when obstruction is a possibility, should therefore have an urgent ultrasound examination to exclude this correctable problem.
MANAGEMENT
The first and perhaps most important step in the management of ARF is its prompt recognition. Investigation will then be influenced by the mode of presentation and concurrent medical problems. The majority of children will not need renal replacement therapy (RRT) if attention is paid to maintaining organ perfusion and monitoring fluid and electrolyte balance. It is useful to contact the regional paediatric nephrology centre at an early stage to confirm treatment policy and arrange transfer if necessary.
Particular attention should be paid to:
Patients who are shocked or dehydrated need fluid resuscitation. This may be with crystalloid, but if colloid is required, despite recent concerns regarding albumin, there is continuing support for its use in the paediatric population1. Restoration of intravascular volume may re-establish urine output prior to the development of renal failure and a more prolonged period of oligo-anuria. Establishment of an adequate state of hydration removes the need for the kidneys to produce a concentrated urine, which is demanding of energy and oxygen. During this period of fluid resuscitation care must be taken to avoid fluid overload if ARF becomes established and urine does not flow. Once normal hydration is achieved, fluid balance is maintained by calculating fluid input equal to output (urine + other measurable losses) + insensible losses (300 - 400 ml/m2 per 24 hours). If urine output is insufficient to allow adequate fluid administration, dialysis is required.
Biochemical
features
Renal failure is characterised by the accumulation of a number of substances normally cleared by the kidney. The most important are potassium, hydrogen and phosphate ions.
Hyperkalaemia. Potassium should be omitted from any iv or oral fluids. Some drugs will promote hyperkalaemia e.g. potassium-sparing diuretics and ACE-inhibitors and these should also be stopped. Hyperkalaemia may cause cardiac arrhythmias and patients should be attached to a cardiac monitor. An algorithm for managing hyperkalaemia is shown in figure 1. It should be recognised that calcium resonium and dialysis are the only therapies which remove potassium from the body. Salbutamol, insulin and correction of acidosis shift potassium intracellularly.
Acidosis. Human metabolism produces ~ 1 mmol/kg/day of H+ and this is excreted in the urine in a number of buffered forms. Renal failure is accompanied by a fall in plasma bicarbonate, which may initially be compensated for by lowering pCO2 through an increased respiratory rate. However, eventually plasma pH will start to fall, with a detrimental effect on organ function. This may be treated with sodium bicarbonate (half correction = 0.15 x Wt. (kg) x Base deficit (mmol/l)). However, repeated use of sodium bicarbonate will lead to the development of hypernatraemia, preventing further administration. Uncontrolled acidosis is an indication for dialysis.
When correcting acidosis secondary to renal failure a potential problem is hypocalcaemia. Serum calcium levels may already be low and as plasma pH rises there is a fall in ionised calcium levels, which may become symptomatic.
Hyperphosphataemia will develop in renal failure and is accompanied by a fall in serum calcium. This is not usually an acute problem, although patients with ARF who are eating should be on a low phosphate diet and calcium carbonate as a phosphate binder. Hypocalcaemia should not be treated unless symptomatic, until phosphate levels have been reduced.
There is continuing debate as to the merits of vasoactive agents and diuretics in the amelioration and prevention of ARF. Of these perhaps the most widely used is dopamine. Two dopamine-specific receptors have been identified. Dopamine-1 (D1) receptors are located on vascular smooth muscle cells. Dopamine-2 (D2) receptors are found predominantly on presynaptic terminals of post-ganglionic sympathetic nerves. Stimulation of D2 receptors results in decreased noradrenaline release and passive vasodilation. Both receptors are found in the kidney. Dopamine can also stimulate peripheral a and cardiac b1 adrenoreceptors. The benefits to renal function have been attributed to use of dopamine at relatively low dosage. Doses of 0.5 - 1.0 mg/kg/min primarily activates D1 and D2 receptors resulting in vasodilation while doses of 2 - 3 mg/kg/min causes stimulation of b1 receptors, increasing cardiac output. These two actions will support renal blood flow and GFR. Higher doses lead to stimulation of a1 and a2 receptors and a predominantly vasoconstrictor action.
There is little good controlled data on the efficacy of dopamine in ARF, particularly in children. However evidence suggests that dopamine does not have a significant effect on the outcome of ARF2. A number of studies have combined dopamine with frusemide and shown an improvement in azotaemia and shortening of the duration of ARF.
Frusemide inhibits metabolically demanding chloride-pumps in the thick ascending limb of the loop of Henle. It may therefore reduce oxygen requirements in the renal medulla, where oxygen delivery is precarious. Experience suggests that it is helpful to give frusemide when intravascular volume is replete and urine is still being produced. The frusemide should be administered as an infusion rather than boluses, as toxicity is reduced and the dose response improved3. The dose can be 0.1 - 4 mg/kg/hr, higher doses being needed in renal failure. Once anuria is established, further frusemide is of no benefit.
Calcium-channel blockers are now widely used to improve renal function post-transplantation and a possible benefit in ARF has been proposed. The effect in transplant patients is likely to be related to its ability to counter the renal vasoconstrictor effect of cyclosporine. A beneficial effect of verapamil plus frusemide was noted in a study of 6 patients with established ARF secondary to malaria or leptospirosis comparing them with 6 patients given iv frusemide alone4. Recovery of GFR was faster in the verapamil group. The same workers have also shown a benefit of another calcium-channel blocker, gallopamil in a mixed group of ARF patients.
Atrial natruretic peptides (ANP) have given promising results in experimental models of ARF and may be of value in improving renal function and decreasing the need for dialysis in established ARF. However a recent multicentre study involving 504 critically ill adults with ARF failed to improve the overall rate of dialysis-free survival. It did improve dialysis-free survival in patients with oliguria, but appeared to worsen it in patients without oliguria who had acute tubular necrosis5.
Hypertension when seen in ARF is invariably due to fluid overload. This situation is typically seen in acute post infectious nephritis and while acute control of blood pressure may be achieved using a vasodilator such as nifedipine, correction of the salt and water overload should be obtained using iv frusemide. If the patient is anuric, fluid removal will require dialysis.
Nutrition
Uraemia will be exacerbated by poor nutritional intake. However studies have not shown any benefit from aggressive nutritional therapy in ARF. In oliguric patients, enteral nutrition is more effective than parenteral forms, because of volume constraints. This restriction is overcome by the introduction of RRT. It is important to customise nutritional support to the metabolic and biochemical needs of the individual patient.
Drugs
Doses of drugs excreted by the kidneys must be adjusted to take in to account loss of renal function. If this is not done, toxic levels of such drugs will accumulate and this may have a further adverse effect on the kidneys.
In recent years more sophisticated RRT techniques have developed, particularly in adult intensive care, which have been adapted by paediatric units. This gives greater opportunity for tailoring treatment to the individual patient. However we are handicapped by the lack of data on the efficacy of different therapies, particularly in children.
Peritoneal dialysis (PD) is still the most popular dialysis option in children. It is simple and relatively inexpensive, providing adequate removal of fluid and solute.
An increasingly popular form of RRT is haemofiltration, particularly continuous veno-venous haemofiltration (CVVH). It has the advantage over intermittent haemodialysis, of bringing about a gradual correction of fluid and electrolytes and is particularly useful in haemodynamically unstable patients. Fluid removal is more predictable than with PD. However the need for systemic anticoagulation in an extracorporeal circuit and the reliance on specialist equipment and nursing staff, may restrict its use.
OUTCOME
This is dependent on the underlying cause. When ARF is associated with multi-organ failure mortality rates remain high, quoted at up to 73%, despite advances in intensive care and RRT. In these patients the development of ARF is, in itself, a marker of a poor prognosis. Children with isolated renal failure have a much better outlook. Children with typical HUS have a low mortality in developed countries, although long term effects on renal function and blood pressure are increasingly recognised.
FUTURE
DEVELOPMENTS
Prevention of ARF is the sensible goal. However fluid resuscitation of hypovolaemic patients is the only therapy of proven benefit in preventing the development of ARF. Use of dopamine, frusemide or ANP may have a role in individual patients but their routine use cannot be recommended.
Experimental models of ARF continue to hint at possible therapies. An example is the use of peptide growth factors to enhance renal recovery. A number of growth factors have been identified in models of ARF in rats and their administration has been found to accelerate the recovery of renal function and normal histology. One of these, insulin-like growth factor I (IGF-I) has been used in humans at risk of developing ARF following surgery. There were no adverse effects and the patients receiving IGF-I post-operatively had a 33% reduction in the incidence of renal dysfunction6.
SUMMARY
Managing a child with ARF requires careful attention to fluid and electrolyte balance and supportive care to allow time for renal function to recover. In this way dialysis is usually avoided and outcome, at least from isolated ARF, is good. Failure to recognise the need to match fluid input to output can have serious consequences, be it fluid overload and pulmonary oedema during the oliguric phase or dehydration during the polyuric recovery phase of ARF. Similar care must be taken with electrolyte administration.
REFERENCES
1. Pollard AJ, Britto J, Nadel S, DeMunter C, Habibi P, Levin M. Emergency management of meningococcal disease. Arch Dis Child 1999; 80: 290-296.
2. Chertow GM, Sayegh MH, Allgren RL, Lazarus JM. Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure? Auriculin Anaritide Acute Renal Failure Study Group. Am J Med 1996; 101: 49-53.
3.
4. Lumlertgul D, Hutdagoon P, Sirivanichai C. Beneficial effect of intrarenal verapamil in human, acute renal failure. Renal Failure 1989-90; 11: 201-208.
5. Allgren RL, Marbury TC, Rahman SN et al. Anaritide in acute tubular necrosis. N Eng J Med 1997; 336: 828-834.
6. Franklin SC, Moulton M, Sicard G, Hammerman MR, Miller SB. Insulin-like growth factor I preserves renal function postoperatively. Am J Physiol 272; F257-F259.
KEY POINTS
· Early recognition of ARF is important
· The only proven preventitive measure is correction of dehydration / hypovolaemia
· Treatment of ARF is primarily supportive, with careful attention to fluid and electrolyte balance
· Dialysis is indicated for management of fluid overload, hyperkalaemia and acidosis