BJS Academy is delighted to host the second edition of the textbook ‘basic concepts of fluid and electrolyte therapy’, by Lobo, Lewington and Allison.

The authors have kindly divided the book into four easily digestible sections, and then some multiple choice questions at the end. This is the third section.

Surgeons sometimes focus a little too much on the technical aspects of their work, but without a sound knowledge of fluid and electrolyte management, their efforts in the operating theatre may easily be undone.

All surgeons will benefit from reading this book and gaining an understanding of how best to optimise fluid management in their patients.

Jonothan Earnshaw

Director, BJS Academy

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The authors have made every effort to ensure that drug dosages in this book are in accordance with current recommendations and practice at the time of publication.

However, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions.

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PREFACE

The first edition of this book was published in 2013 with the aim of improving understanding and clinical practice in the field of fluid and electrolyte therapy. Studies at that time suggested that, even though fluid and electrolyte preparations are the most commonly prescribed medications in hospitals, management of fluid and electrolyte disorders was suboptimal, possibly due to inadequate teaching, causing avoidable morbidity and even mortality. It should not be forgotten that fluid therapy, like other forms of treatment, has the capacity to do harm as well as good unless administered with care and based on sound knowledge.

A second edition was felt appropriate in the light of further advances in knowledge and practice over the last 9 years. We have updated the book, adding new chapters, figures, tables and flow charts to help the reader. New chapters include Ageing and Fluid Balance, Chronic Kidney Disease, Fluid Overload and the De-escalation Phase, and Perioperative Fluid Therapy and Outcomes. We have also tried to maintain consistency with published national and international guidelines, where available. References have now been cited in the text. To limit the number of references, we have tried, as far as possible to cite important review articles from which original studies may be sourced. However, relevant original works have been referred to when appropriate. We have included multiple choice questions so that readers may test their knowledge after reading the book.

The subject of fluid balance in paediatrics is not addressed and this book should be regarded as relevant to adults only. It is still not our intention to write a comprehensive textbook dealing with complex problems, but to provide a basic hand-book for students, nurses, trainee doctors and other health care professionals to help them to understand and solve some of the most common practical problems they face in day to day hospital practice. We hope that it will also stimulate them to pursue the subject in greater detail with further reading and practical experience. In difficult cases, or where there is uncertainty, trainee health care professionals should never hesitate to ask for advice from senior and experienced colleagues.

Dileep N. Lobo

Andrew J. P. Lewington

Simon P. Allison

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Chapter 9:

OLIGURIA

INTRODUCTION

In health a normal diet generates about 600 mOsm/day of solute waste products that need to be excreted in the urine. With normal renal function and maximal antidiuretic hormone stimulation a minimum urine volume of 500 ml/day is required for this purpose (the volume obligatoire of Claude Bernard)^1,2. Oliguria is, therefore, defined as a urine output <0.5 ml/kg/h. However, it is important to determine whether it is physiological, i.e. a normal response to surgery/injury or pathological, e.g. secondary to hypovolaemia and/or sepsis, resulting in hypoperfusion of the kidneys and AKI (see chapter 10).

PHYSIOLOGICAL OLIGURIA

Oliguria, occurring soon after uncomplicated surgery, is usually part of the normal physiological response to injury (see Chapter 1), conserving salt and water in an attempt to maintain intravascular volume. Isolated oliguria in the first 48 hours after uncomplicated surgery, therefore, does not necessarily reflect intravascular hypovolaemia, although it may do so if confirmatory features are present, e.g. tachycardia, hypotension, low central venous pressure (CVP), decreased capillary refill, etc. (Table 9.1).

The key clinical question, therefore, is whether or not the oliguria is pathological, i.e. due to significant intravascular hypovolaemia requiring treatment. It is, therefore, essential that the patient’s volume status is assessed carefully (Table 9.1). Remember that serial changes give more information than single observations. Also remember the importance of charting data in a serial manner and in a way that is easily accessible to the clinician. In difficult cases, particularly intra-operatively, invasive monitoring may be required to guide optimal treatment⁷⁷.

Urine output should be interpreted in the light of these clinical signs and measurements before giving fluid treatment, which, in the absence of hypovolaemia, may not only be unnecessary, but also deleterious. Unnecessary fluid therapy not only expands the blood volume excessively but also over-expands the interstitial fluid volume, causing oedema and weight gain. The metabolic response to surgery further impairs the patient’s ability to excrete the additional saline load, making interstitial oedema worse and compromising organ function, increasing the risk of morbidity and mortality. Other consequences are dilution of the haematocrit and serum albumin concentration^50,51 (See Chapter 5).

OLIGURIA SECONDARY TO AKI

Although it is important not to give excess fluid, giving too little also has serious consequences⁶⁶. Failure to recognize and treat intravascular hypovolaemia (and pre-renal AKI) adequately may compromise organ perfusion and result in the development of intrinsic AKI. There is evidence that patients with oliguric AKI have more severe tubular damage and a worse outcome.

Once a diagnosis of AKI has been made, the underlying cause must be established (see Chapter 10). The most common causes are hypovolaemia and/or sepsis leading to hypoperfusion of the kidneys. Clinical examination must be performed to establish the patient’s volume status and the source of sepsis must be identified and treated promptly. If the patient is hypovolaemic, then appropriate fluid therapy must be given according to a documented management plan, which requires regular review and defined endpoints^78,79 (Fig. 9.1).

In a patient with hypovolaemia and oliguric AKI

• consider inserting a urinary catheter (not routine and may introduce infection) to aid with the assessment of volume status particularly if the patient is confused or incapacitated due to the severity of the acute illness
• resuscitate with IV fluids (fluid challenge)
  • stat fluid bolus of 500 ml (250 ml if in cardiac failure) of balanced crystalloid (0.9% saline if hyperkalaemic) or colloid
• assess clinical response to fluid in terms of
  • capillary refill time
  • pulse (reduction in pulse rate if tachycardic)
  • jugular venous pressure (rise in JVP)
  • blood pressure (rise in BP)
  • pulmonary oedema (if present stop iv fluids)
  • urine output
• if there is a clinical response to a fluid bolus, continue with replacement fluids and discuss further fluid therapy plans with a senior member of the team
• if there is no clinical response and no pulmonary oedema, administer a further 500 ml of crystalloid, reassess clinically and discuss with a senior member of the team. Remember to consider the possibility of postoperative bleeding as a cause for the hypovolaemia and failure to respond to a fluid challenge.
• if the patient has volume unresponsive oliguric AKI, continue with iv fluids cautiously, matching urine output and at the same time monitoring for signs of respiratory distress (rising respiratory rate, pulmonary oedema or falling oxygen saturations). Refer to the renal team.

Oliguric AKI secondary to hypovolaemia is either volume responsive or unresponsive. In patients who are fluid responsive, further fluid replacement can be prescribed as hourly fluid input equal to the previous hour’s output plus 30 ml, with continuous monitoring and frequent review. In some cases, despite apparently adequate intravascular volume replacement the patient remains oliguric and unresponsive to any further fluid challenge. At this point it is important to avoid precipitating pulmonary oedema and no further intravenous fluid should be administered. If the patient remains hypotensive, treatment with vasopressors should be considered and the advice of the critical care team sought. If the patient is haemodynamically stable but the AKI continues to progress, refer to the renal team.

In addition to the risk of pulmonary oedema, excessive fluid administration has been associated with a worse outcome. A number of studies in surgical patients have demonstrated that a fluid regimen that causes less than 2 kg weight gain, reduces the number of postoperative complications including anastomotic leak, sepsis, and bleeding requiring transfusion^9,57,65. On the other hand, a positive fluid balance greater than 2.5 kg is associated with increased morbidity^9,57,65.

DIURETICS

A common clinical question with oliguric AKI is whether the administration of loop diuretics (frusemide, bumetanide) improves renal recovery by increasing urine output. Studies have demonstrated that the use of high-dose loop diuretics to increase urine output in patients with established AKI does not decrease the need for renal replacement therapy or improve survival^80-82. However, they may have a short-term role in managing fluid overload and pulmonary oedema. In these patients, they may be used cautiously to try and establish a diuresis and treat the pulmonary oedema. If the patient fails to respond, referral to the renal team is recommended. It must be remembered that high doses of loop diuretics are not without side-effects and may cause permanent hearing loss.

Chapter 10:

ACUTE KIDNEY INJURY

INTRODUCTION

It is important to recognise AKI as a syndrome with many different causes. Failure to identify the cause may lead to misdiagnosis and a missed opportunity to initiate the most appropriate management plan. In many cases the patient will be hypovolaemic in the clinical setting of sepsis and there is, therefore, a need for careful assessment of volume status and the prescribing of intravenous fluids. Adequate initial fluid resuscitation needs to be balanced subsequently with appropriate de-escalation of fluid administration, particularly in patients with volume unresponsive oliguric AKI.

DEFINITION

AKI is a result of a rapid fall in glomerular filtration rate occurring over hours or days. The consequences include a failure to regulate fluid and electrolyte balance and a failure to excrete metabolic waste products and drugs^38,83.

AKI is diagnosed according to the kidney disease improving global outcomes (KDIGO) recommendations when one of the following criteria is met:

• Serum creatinine rises by ≥26 μmol/L within 48 hours or
• Serum creatinine rises ≥1.5 fold from a baseline value measured within the previous week or
• Urine output is <0.5 ml/kg/h for >6 consecutive hours

If serum creatinine concentration has not been measured in the previous week, use the most recent creatinine concentration measured within the last three months. AKI can be staged according to the criteria in Table 10.1.

Any patient who meets the criteria for AKI should have a thorough clinical evaluation, which includes an assessment of volume status, fluid balance and medication to identify any potential causes for the AKI. In the majority of cases, AKI may be reversible if the cause is identified and appropriate management implemented early enough.

In their laboratory reports the majority of biochemistry departments in England issue an AKI warning to primary and secondary care clinicians, based on rises in serum creatinine (Fig. 10.1). Some UK National Health Service (NHS) Trusts have developed AKI care bundles that are linked to AKI warning, prompting the clinician to review the patient and confirm a clinical diagnosis of AKI⁸⁴.

EPIDEMIOLOGY

AKI was previously ill-defined, with multiple definitions making it difficult to describe its epidemiology accurately. The new Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI has provided an opportunity to start to capture data about the incidence of AKI across the world^38,83. However, it is important to remember that the incidence of AKI will depend upon the available resources to measure serum creatinine in different healthcare systems. In high-income countries there is now an increasing amount of data on the incidence of AKI, based on serum creatinine measurements. Urine output is poorly measured within most healthcare systems and, therefore, reliable data on the incidence of AKI based on urine output are lacking. Analysis of large databases has estimated that 8-16% of all hospital admissions are associated with an episode of AKI⁸⁵. A further consideration is whether the AKI develops initially in the community (c-AKI) or occurs 24 hours after admission to hospital which is regarded as hospital acquired AKI (h-AKI).

AETIOLOGY OF ACUTE KIDNEY INJURY

If the criteria for diagnosing AKI have been satisfied, it is important to identify the underlying aetiology as this will determine the most appropriate therapy and influence whether early referral to the renal team is necessary. AKI can be considered as pre-renal, intrinsic and post-renal (Fig. 10.2). Pre-renal and post-renal AKI can both be considered as functional processes that may progress to structural injury to the parenchyma if not treated promptly.

The most common causes of AKI are:

• sepsis (50%)
• toxins (e.g. gentamicin, NSAIDs)
• hypovolaemia (e.g. blood loss, burns, vomiting and diarrhoea)
• hypotension (e.g. sepsis and continuation of diuretics/antihypertensive drugs)

The aetiology of AKI is commonly multifactorial and secondary to more than one of the above examples. Rarer causes (e.g. vasculitis, interstitial nephritis) must also be considered if the aetiology is not immediately apparent (Fig. 10.3). AKI is most commonly secondary to a combination of sepsis and hypovolaemia, resulting in hypoperfusion of the kidneys and initially pre-renal AKI. Failure to correct the hypoperfusion early may result in the development of acute tubular injury and intrinsic AKI, classically referred to as acute tubular necrosis (ATN).

RISK FACTORS FOR AKI

There are a number of risk factors for AKI, which may either be inherent to the patient or due to exposure to other causes (Tables 10.2 and 10.3).

CLINICAL FEATURES OF ACUTE KIDNEY INJURY

There should be a high index of suspicion for AKI, particularly in an acutely ill patient with known risk factors. Information about the patient’s previous kidney function (e.g. serum creatinine), particularly over the preceding 3 months, is a vital part of the evaluation. As in every other clinical condition, diagnosis is achieved by weighing all the evidence derived from a full history, examination and appropriate investigations86. Serial changes in clinical parameters are often more revealing than single measurements taken at any one time. AKI should be considered as part of the differential diagnosis in patients presenting with the clinical features described in Table 10.4.

AKI can be oliguric (<0.3 ml/kg/h) or non-oliguric. Pre-renal AKI (functional process) is associated with oliguria by virtue of the fact that there is reduced renal perfusion and intact renal tubules which endeavour to preserve salt and water. Patients with pre-renal AKI that evolves to intrinsic AKI (structural injury) or who experience direct tubular toxicity (e.g. from gentamicin or radiological contrast medium) may lose the ability to reabsorb fluid and are not therefore oliguric, maintaining a relatively normal urine output but with impaired concentration of solutes. These patients will require ongoing fluid therapy to maintain an optimal volume status adequate to excrete waste products. However, failure to establish adequate renal perfusion in these polyuric patients, who are evolving from pre-renal to intrinsic AKI, will ultimately result in oliguria. Careful and continued monitoring is, therefore, imperative.

INVESTIGATIONS

Urinalysis

• blood and/or protein suggest glomerular disease if infection is excluded

Blood biochemistry

• elevated urea and creatinine will trigger an assessment of whether AKI is present
• reduced eGFR will trigger an assessment of whether AKI is present, but eGFR is not used to define or stage AKI
• hypercalcaemia – may occur with widespread cancer in bone, multiple myeloma or hyperparathyroidism
• acidaemia – due to a failure to regenerate bicarbonate
• liver function tests – elevation may occur with hepato-renal failure

Haematology

• anaemia – may occur

Immunology

• myeloma screen (immunoglobulins, serum electrophoreseis, urine for Bence Jones protein)
• Anti Neutrophil Cytoplasmic Antibody (ANCA) – is associated with small vessel vasculitides
• Anti Nuclear Antigen (ANA) – is associated with lupus nephritis
• Complement – is associated with lupus nephritis

Imaging

• renal tract ultrasound scan (USS) to rule out obstruction if suspected. If there are no previous blood tests to confirm whether the patient has AKI or CKD, USS can also be used to assess kidney size. If one of the rarer forms of AKI suspected USS-guided kidney biopsy should be considered

Urinary electrolytes

The measurement of urinary electrolytes and osmolality has been proposed to distinguish pre-renal AKI from intrinsic AKI (Table 10.5). However, this assumption may be invalid, since if loop diuretics have been administered within the previous 12 hours or there is pre-existing CKD, the measurements of urinary sodium can be misleading in terms of staging the progression of AKI.

PREVENTION OF ACUTE KIDNEY INJURY

Any patient admitted to hospital for major surgery or with acute illness⁸⁷ who has any of the risk factors for AKI (Tables 10.2 and 10.3) should

• have daily
  • clinical volume status assessment
  • assessment of the fluid prescription
  • fluid balance chart monitoring
  • weighing
• avoid nephrotoxic agents [e.g. non-steroidal anti-inflammatory drugs (NSAIDs), aminoglycosides]
• have other drugs (e.g. antihypertensive medications such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers) reviewed especially if they develop hypotension and/or sepsis. These should be withheld if clinically indicated
• have urea, creatinine and electrolytes checked daily until they regain health

Any inpatient with AKI or risk factors for AKI (Tables 10.2 and 10.3) who requires an iodinated contrast study should be considered for alternative imaging or a non-iodinated contrast scan. If an iodinated contrast study is required then the following recommendations should be followed

• highlight the risk to the radiologists
• stop nephrotoxic medication
• volume status assessment to determine whether intravenous volume expansion is required with 0.9% saline
• daily fluid balance chart
• daily weights
• urea, creatinine and electrolytes monitored for 3-5 days

MANAGEMENT OF ACUTE KIDNEY INJURY

Once a patient has developed AKI, treatment is initially supportive but ultimately dependent upon the underlying cause^86,88. Treatment involves the following:

• Identify and treat the underlying cause (not all AKI will be secondary to hypovolaemia and/or sepsis)
• Volume status assessment
  • If hypovolaemic
    • resuscitate with IV fluids
      • stat fluid bolus of 500 ml (250 ml if cardiac failure present) of crystalloidbalanced crystalloid preferred unless risk of hyperkalaemia is present, e.g. AKI secondary to rhabdomyolysis, when 0.9% saline preferredif 0.9% saline commenced switch to a balanced crystalloid
      consider urinary catheter (but risk of infection) to aid with the assessment of volume status
    • assess clinical response to fluid in terms of
      • capillary refill time
      • pulse (reduction in pulse if tachycardic)
      • jugular venous pressure (rise in JVP)

• blood pressure (rise in BP)
  • pulmonary oedema
  • urine output (increasing if oliguric)
  • if there is no clinical response and no pulmonary oedema administer further 500 ml of crystalloid, reassess clinically and discuss with a senior member of team
  • if there is a clinical response to a fluid bolus, continue with iv fluids and discuss further fluid therapy management plan with a senior member of team
• If the patient develops oliguric AKI (<0.3 ml/kg/24 h) despite adequate volume resuscitation, consider the patient as having volume unresponsive AKI and refer to the renal team. Further attempts at fluid resuscitation may result in pulmonary oedema.
• If the patient has volume unresponsive AKI continue with iv fluid cautiously, matching urine output and monitoring for signs of respiratory distress (rising respiratory rate, pulmonary oedema or falling oxygen saturations).
• Specific treatment of complications of AKI
  • Hyperkalaemia (see also Chapter 14) may be associated with
    • muscle weakness, palpitations, paraesthesiaECG changes: loss of P-waves, wide QRS complexes, peaked T waves
    It must be remembered that unless the cause of the AKI is treated, the measures described above are only temporary. Serum potassium concentrations will need to be monitored closely until recovery of sufficient kidney function to excrete potassium or institution of renal replacement therapy.Immediate treatment is required if
    • K+ >6.0 mmol/L and ECG changes are present orK+ >6.5 mmol/L with or without ECG changes
    Immediate treatment
    • iv 30 ml 10% calcium gluconate over 2-5 minutes (cautiously, as extravasation can cause tissue damage). This stabilises the myocardium rapidly, but has no effect on serum potassium concentration. Further doses may be required until a reduction in plasma potassium concentration is achieved. Onset of action 2-4 minutes. Duration of action 30-60 minutes.
    Further treatment
    • 10 U fast acting insulin (actrapid) added to 50 ml of 50% dextrose or 125 ml of 20% glucose infused iv over 20 minutes to increase cellular potassium uptake. Blood glucose must be monitored closely. Onset of action 15-30 minutes. Duration of action 4-6 hours.10-20 mg salbutamol nebuliser to stimulate cellular potassium uptake. Avoid in patients on beta blockers and/or who have a history of cardiac arrhythmias. Onset of action 30 minutes. Duration of action 2-4 hours.Medication review: stop any drugs that contain potassium or interfere with renal excretion of potassium (ACE inhibitors, angiotensin receptor blockers, beta-blockers, potassium sparing diuretics)Review potassium intake including intravenous fluids and enteral or parenteral feeds
  • Acidaemia
    • pH 7.2-7.4 – there is very little evidence to support correction with bicarbonate.
    • pH <7.2 – isotonic sodium bicarbonate 1.4% solution can be used in stable patients not imminently requiring renal replacement therapy. Bicarbonate therapy may worsen intracellular acidosis and

deliver excessive sodium load. In the presence of hypocalcaemia, bicarbonate can cause a further reduction in calcium and provoke convulsions. Bicarbonate should only be used when the serum calcium concentration is known, and near normal and after obtaining senior medical advice. Renal replacement therapy will be required if the patient is hypervolaemic and/or refractory to medical treatment

• Pulmonary oedema
  • sit the patient up and provide supplementary oxygen (up to 60%) via a Venturi face mask. A nonrebreathing mask (15 L/min O₂) may be required if severe pulmonary oedema is present.buccal glyceryl trinitrate 2-5 mg works rapidly and can be repeated as frequently as required. If intolerable headache or hypotension develop, both resolve rapidly after removing the tablet from the mouth.iv glyceryl trinitrate 50 mg in 50 ml 0.9% sodium chloride. Commence at 2 ml/h and titrate up to 20 ml/h maintaining systolic BP >95 mmHg.iv frusemide can be tried if the patient is haemodynamically stable and adequately intravascularly filled. The dose is dependent on the severity of AKI. Frusemide 160 mg (slow infusion over 1 hour) may be required for severe AKI (stage 3) (Table 10.5).if the patient is in extremis with or without mechanical ventilation institute renal replacement therapyuraemic encephalopathy
    • renal replacement therapy
  • uraemic pericarditis
    • renal replacement therapy

MEDICATION MANAGEMENT

In patients with AKI it is important to identify medications that are normally metabolised and/or excreted by the kidneys, and either avoid or make appropriate dose adjustments. Common examples include:

• penicillins
• cephalosporins
• vancomycin
• morphine (metabolites will accumulate)
• fractionated heparin

If the patient is hypotensive there should be a low threshold for withholding antihypertensive therapy, since these drugs only exacerbate renal hypoperfusion. Common examples include:

• angiotensin-converting enzyme inhibitors
• angiotensin receptor blockers
• diuretics

Nephrotoxic medications should be avoided if possible (unless life-saving) and include:

• non-steroidal anti-inflammatory drugs (NSAIDs)
• gentamicin
• amphotericin

AKI CARE BUNDLES

A number of NHS Trusts have developed AKI care bundles, which prompt the clinician to initiate early patient management⁸⁹. One example is the STOP AKI care bundle (Fig. 10.4), which focuses on treating sepsis promptly, optimising blood pressure, optimising volume status, avoiding toxins and preventing harm to the patient. It is essential to identify the underlying cause to provide the definitive treatment.

REFERRAL TO RENAL TEAM

• NOT all patients diagnosed with AKI need to be referred
• Prior to referral the following should be performed
  • a thorough clinical history and examination (including fluid balance assessment)
  • initial investigations (as recommended in Table 10.5)
  • initial supportive management (as recommended above)
• Early renal referral is recommended in the following patients
  • AKI stage 3 (serum creatinine ≥3 × baseline value) (Table 10.2)
  • persistent oliguria and/or rising serum creatinine despite supportive therapy
  • complications refractory to medical treatment
    • hyperkalaemia (serum K+ >6 mmol/L)
    • pulmonary oedema
    • acidaemia (pH <7.15)
    • uraemic encephalopathy
    • uraemic pericarditis

• suspicion of rarer renal disease
  • absence of defined cause, e.g. sepsis or hypovolaemia
  • systemic features e.g. rash, uveitis, joint pains, blood and protein on urinalysis
  • hypercalcaemia and paraprotein
  • bloody diarrhoea, haemolysis and low platelets
  • poisoning suspected
    • ethylene glycol
    • methanol
    • lithium

RECOVERY

The first signs of recovery from oliguric AKI may be an increase in urine output followed by a reduction in the incremental daily rise in serum creatinine followed by a plateau and an ultimate fall in the creatinine concentration.

Recovery from AKI can result in a polyuric state in some patients with the production of large urine volumes until the capacity of the renal tubule to concentrate urine returns. There must, therefore, be continuing careful attention to the patient’s volume status and fluid requirements.

During this polyuric recovery phase, patients can be at risk of developing a free water deficit, manifest as hypernatraemia, which requires an increased intake of water (intravenous 5% dextrose if unable to drink). Failure to address the free water deficit promptly will not only slow renal recovery but will also put the patient at risk of the neurological complications of hypernatraemia. Another potential complication is the development of hypokalaemia, which requires appropriate therapy due to the risk of cardiac arrythmias and ileus. A balanced crystalloid containing potassium is recommended in this clinical context. Additional potassium supplementation may also be necessary.

FOLLOW UP

AKI is a recognised antecedent for CKD and patients therefore require follow up. The discharge summary to primary care should include:

• the cause of AKI
• risk factors for AKI
• medications stopped and when to be re-started
• kidney function on discharge
• longer-term monitoring requirements, e.g. blood pressure, U&Es, urinary protein

Patients with an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 should be referred to the renal team for follow-up.

OUTCOMES FROM ACUTE KIDNEY INJURY

AKI is associated with worse patient outcomes^90-92 including increased

• length of stay
• mortality
• risk of chronic kidney disease (CKD)
• cost (£1 billion/year in the UK)

Chapter 11:

CHRONIC KIDNEY DISEASE

INTRODUCTION

There are many causes of CKD, which leads to irreversible loss of kidney function over a period of months to years. The incidence of CKD has increased by 89% over the last 3 decades⁹³. The predominant reason for this is an increase in the number of cases secondary to diabetes mellitus and glomerulonephritis, with fewer cases due to hypertension.

DEFINITION OF CHRONIC KIDNEY DISEASE

CKD is defined by an eGFR less than 60 ml/min/1.73m², by the presence of markers of kidney damage (structural or albuminuria), or both, for at least 3 months. The term CKD now replaces the term chronic renal failure and is categorised into 5 stages using the eGFR expressed as ml/min/1.73 m² (Fig. 11.1).

The eGFR is an estimate of the GFR and can be calculated simply, using either the MDRD (Modification of Disease in Renal Disease)⁵⁴ or the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation⁹⁴ based on age, sex and serum creatinine. The CKD-EPI equation has been reported to perform better and with less bias than the MDRD equation, especially in patients with higher GFR. The calculated eGFR needs to be interpreted with caution when tested in different hospitals as the value is dependent upon which equation each laboratory uses.

More information on eGFR and the MDRD and CKD-EPI equation⁹⁴ can be found at www.mdrd.com along with an eGFR calculator.

By definition, the diagnosis of CKD requires two serum creatinine values measured at least 90 days apart. Previous blood tests are, therefore, necessary to ascertain if someone has CKD.

EPIDEMIOLOGY OF CHRONIC KIDNEY DISEASE

The incidence and prevalence of CKD, which increases with age⁹⁵ varies according to ethnicity, social class and country. The prevalence is reported to be about 11% in high-income countries and is rising worldwide, representing a significant burden on healthcare resources.

AETIOLOGY OF CHRONIC KIDNEY DISEASE

There are many causes of CKD, but the most common are diabetes, glomerulonephritis and hypertension. Diabetes accounts for 30-50% of all causes of CKD.

• Disease
  • Diabetes mellitus
  • Hypertension
  • Congenital and inherited disease
    • Autosomal dominant polycystic kidney disease
    • Alport Syndrome
  • Glomerular disease
    • Primary disease, e.g. membranous nephropathy
    • Secondary disease, e.g. lupus nephritis
  • Vascular disease
    • Renovascular disease
  • Tubulo-interstitial disease
    • Infection
    • Drugs, e.g. proton pump inhibitors
  • Acute kidney injury – even patients with recovery of kidney function after AKI are at high risk of CKD92
  • Urinary tract obstruction
    • Renal stone disease
    • Prostatic disease
• Environmental Factors
  • Outdoor and agricultural work and lack of shade are associated with a rapid fall in eGFR⁹⁶

CLINICAL FEATURES OF CHRONIC KIDNEY DISEASE

CKD can develop insidiously, without apparent symptoms or signs until an advanced stage (eGFR <15 ml/min/1.73m²).

The symptoms may include:

• Nausea
• Lethargy
• Shortness of breath (anaemia, acidaemia, pulmonary oedema)
• Insomnia
• Nocturia (decreased ability to concentrate urine)
• Pruritis (uraemia, hyperphosphataemia)
• Paraesthesia
• Restless legs
• Muscle weakness
• Bone pain (metabolic bone disease)
• Ankle oedema (salt and water retention)

The clinical signs may include:

• Pallor (anaemia)
• Excoriation (pruritus)
• Hypertension (salt and water retention)
• Pericardial friction rub (uraemia)
• Pulmonary oedema (salt and water retention)
• Peripheral oedema (salt and water retention)

INVESTIGATIONS

Urinalysis

• blood and/or protein suggest glomerular disease if urine culture is negative (Fig. 11.2)

Biochemistry

• elevated urea and creatinine and reduced eGFR
• hyperkalaemia – can occur due to failure to excrete potassium
• acidaemia – can occur due to failure to regenerate bicarbonate
• hypocalcaemia – occurs in advanced CKD due to decreased production of activated Vitamin D
• hyperphosphataemia – occurs in advanced CKD due to decreased urinary excretion

Haematology

• anaemia – occurs in advanced CKD due to decreased secretion of erythropoietin
• platelet dysfunction and easy bruising – effect of uraemia

Immunology

• myeloma screen (immunoglobulins, serum electrophoreseis, urine for Bence Jones protein. Suspect if hypercalcaemia present)

Imaging

• CXR – interstitial fluid with salt and water retention
• renal tract ultrasound scan (USS) to assess kidney size (small scarred kidneys are consistent with CKD)

ECG

• Voltage criteria for left ventricular hypertrophy with long standing hypertension
• Peaked T waves, loss of P waves, widened QRS complex occur in hyperkalaemia

MANAGEMENT

Management of CKD should aim to slow disease progression and treat metabolic complications⁹⁷. Patients with CKD are more likely to be hypertensive because of their kidney disease, resulting in more rapid progression of the disease. Serum cholesterol concentrations must be closely monitored and treated.

Treatment

• Stop smoking
• Weight loss/increased exercise
• Blood Pressure
  • In CKD aim for <140/90 mmHg
  • In CKD and diabetes and/or albumin:creatinine ratio (ACR) ≥70 mg/mmol aim for <130/80 mmHg
  • Medication
    • Angiotensin converting enzyme inhibitor (ACEi)
      • Ramipril
      Diuretic
      • Thiazide (not effective if eGFR <15 ml/min/1.73m²)
    • Calcium channel blocker
      • Amlodipine
• Fluid balance (salt and water retention)
  • No robust evidence that reduced salt intake can prevent CKD or its progression⁹⁸
  • Loop diuretics e.g. frusemide
• Hypercholesterolaemia
  • Statins

Treatment of complications

• Hyperkalaemia
  • reduce dietary intake
  • correct acidaemia
  • potassium binding resins
• Acidaemia
  • sodium bicarbonate tablets
• Metabolic bone disease
  • phosphate binders (these are tablets taken with meals that bind to phosphate from food in the gut and allow it to be excreted and not absorbed)
  • vitamin D analogues
• Anaemia
  • replete iron stores
  • subcutaneous erythropoietin therapy
• Pruritus
  • antihistamines

Specific therapy

Tolvaptan has been demonstrated to slow the decline in eGFR compared with placebo in patients with later stage autosomal dominant polycystic kidney disease⁹⁹.

Those patients who develop end stage kidney disease may choose to have renal replacement in the form of dialysis (haemodialysis/peritoneal dialysis) or kidney transplantation. Patients who do not wish to have dialysis are offered conservative care aimed at symptom control.

Intravenous fluid and electrolyte therapy in patients with CKD

Patients with progressive late stage CKD have reduced sodium filtration, suppression of fluid reabsorption, and ultimately volume overload. They are also at higher risk of hypertension, left ventricular hypertrophy, cardiac failure and oedema, and are likely to be on a number of medications including ACE inhibitors and diuretics. Patients with CKD require higher doses of loop diuretics to enable the drug to be transported across the tubule and reach the active site on the ascending limb of Henle. Such patients have less reserve kidney function and are at increased risk of electrolyte complications, e.g. hyponatraemia, and hypo- or hyperkalaemia.

Patients with CKD are also at increased risk of AKI, and those with CKD Stage 4 and 5 on diuretics and ACE inhibitors who develop AKI are at higher risk of hyperkalaemia. If the cause of AKI is hypovolaemia and hypotension, then these drugs (diuretics and ACE inhibitors) need to be withheld. Clinical signs need to be interpreted carefully in patients with previous advanced CKD who develop AKI as they may have pre-existing peripheral oedema even in the presence of acute hypovolaemia.

Intravenous fluid resuscitation should be carefully monitored, recognising that baseline kidney function will not be normal. Excessive fluid resuscitation and failure to de-escalate the fluids appropriately will result in volume overload. Potassium containing fluids should be used with caution as the patient may already have an excess potassium load and be at a higher risk of hyperkalaemia.

OUTCOMES

The majority of patients with CKD do not progress to advanced stages of CKD because they die earlier from cardiovascular disease. However, the burden of CKD is substantial and, according to the WHO global health estimates, is responsible for 1.5% of deaths worldwide, being ranked 14^th in the list of leading causes of death at 12.2 deaths per 100,000 people, a rate which is predicted to rise to 14 deaths per 100,000 people by 2030. A retrospective cohort study of patients with severe CKD demonstrated that, over a five-year period of follow up, 53% of patients died, with 24% having had a cardiovascular event¹⁰⁰.

Chapter 12:

FLUID OVERLOAD AND THE DE-ESCALATION PHASE

INTRODUCTION

Acutely ill patients requiring fluid resuscitation to restore haemodynamic stability invariably develop some degree of positive salt and water balance causing tissue oedema. Such overload may be a necessary price to pay for adequate resuscitation and survival. This is a particular problem in patients who go on to develop oliguric AKI as the kidneys are unable to excrete the excess salt and water load until recovery of renal function.

Often the patient has sepsis or an inflammatory state which causes increased vascular permeability and leakage of fluid into the interstitial space. This necessitates the administration of even more fluid to maintain the intravascular volume, cardiac output and tissue oxygen delivery²⁰ (see Chapter 1). It has been shown, for example, that during the first 48 hours of resuscitation of a patient with sepsis, total body water may increase by up to 12.5 L, an excess which may take up to 3 weeks to excrete¹⁰¹. It is, therefore, important to recognise when patients have been resuscitated adequately, and their condition has been optimised and stabilised (Fig. 12.1). At this stage, fluid intake should be reduced to that which meets maintenance or replacement requirements (see Chapter 7). Failure to de-escalate fluid therapy at this stage may result in continued and unnecessary positive salt and water balance.

All patients receiving resuscitation fluids should be monitored with fluid balance charts, regular clinical assessment for signs of volume overload and, if possible, by regular weighing. Healthcare professionals should be alert to any early signs indicating the development of oliguric AKI and should recognise when this has become unresponsive to fluid administration – the point when the patient has been adequately resuscitated but remains oliguric⁸⁸. If haemodynamic stability has been achieved, fluid administration should be curtailed to reduce the risk of pulmonary oedema, a common iatrogenic consequence of overzealous fluid resuscitation. On the other hand, if the patient remains haemodynamically unstable, the use of vasopressors should be considered rather than continuing fluid resuscitation.

DE-ESCALATION PHASE

The period of clearance of excess salt and water acquired during resuscitation, optimisation and stabilisation is described as the de-escalation phase^102,103 (Fig. 12.1).

During the de-escalation phase the aim should be to prevent further unnecessary salt and water overload and to promote excretion of the accumulated excess, with the aim, as far as possible, of restoring organ function and normal fluid balance. Oral intake should be started as soon as possible. It is only too easy to overload patients with intravenous salt and water, whereas it is difficult to do so by the oral route. Salt and water intake, by whatever route, should be limited to that which meets maintenance requirements and replaces any additional losses, e.g. from intestinal fistulae or gastric aspiration. One of the major causes of unnecessary fluid overload is a failure to make a timely adjustment of the fluid prescription from resuscitation to maintenance mode. During the de-escalation phase, prescription of fluids should allow a small negative balance each day, as the patient’s ability to excrete a salt and water load returns (the sodium and water diuresis phase of injury¹⁸). The rate at which this transition can be achieved may vary from patient to patient according to the natural history and severity of their particular illness. This process requires careful monitoring to strike a balance between getting rid of the interstitial fluid overload and avoiding depletion of intravascular volume¹⁰⁴.

The natural excretion of salt and water by the kidneys is dependent on underlying kidney function and the stage of recovery from acute illness. Persistent sepsis and/or hypovolaemia delays the recovery from AKI and the ability to excrete salt and water.

THERAPEUTIC OPTIONS IN THE DE-ESCALATION PHASE

The therapeutic options, apart from allowing a gradual drift into negative fluid balance, as described above, include the use of loop diuretics or ultrafiltration using renal replacement therapy.

Prior to deciding on the most appropriate therapeutic approach to a particular patient, a full clinical evaluation of volume status including an assessment of fluid balance is necessary. Loop diuretics, it must be remembered, act on the ascending limb of Henle to prevent the reabsorption of sodium, potassium, chloride and water. It, therefore, means that there must be sufficient renal blood flow and perfusion for the diuretics to be delivered to their point of action. In the presence of intravascular hypovolaemia, the kidneys are relatively unresponsive to diuretics which are, therefore, inappropriate and possibly harmful under these conditions. It is recommended that diuretics should only be used in patients who are both adequately intravascularly filled and haemodynamically stable. The assessment of the response requires daily clinical examination of volume status with review of the urea and electrolytes, urine output and daily weighing. There is no evidence to support the use of diuretics to treat AKI per se and this should not be encouraged. However, in the presence of both severe fluid overload and AKI, a trial of diuretics may be warranted^105,106. Patients who fail to recover kidney function and yet remain severely volume overloaded despite the use of diuretics will need referral to the renal team for a further evaluation of the cause of the AKI and consideration of renal replacement therapy (RRT) to remove excess fluid and electrolytes¹⁰⁷. Treatment with diuretics also runs the risk of hypernatraemia with a true water deficit, and a failure to recover kidney function. There must, therefore, be careful daily review of the patient’s fluid and electrolyte status to assess the response to the continued administration of diuretics.

CRITICALLY ILL PATIENTS

Volume overload in the critically ill patient can be difficult to quantify precisely and has been strongly associated with adverse outcomes. Critically ill patients who have received large volumes of fluid in the resuscitation phase may still require vasopressor support. In those requiring RRT, usually for the correction of acid-base and electrolyte abnormalities secondary to AKI, there is an opportunity, as the haemodynamic status improves, to increase the volume of fluid removal by RRT¹⁰⁷. Care must be taken to do this without causing intravascular hypovolaemia and a relapse into haemodynamic instability¹⁰⁸.