Acute kidney injury (AKI) is a “must know” for medical school finals and for every competent doctor when starting their house jobs. The followed article is targeted at medical students and aims to recap key renal physiology; to appreciate ways in which AKI can be promptly recognized and effectively communicated amongst hospital staff. Finally, we attempt to explore the current recommendations with regards to the care of patients with AKI in clinical practice. 

Aims and outcomes

Authors assume students to be competent in the basic micro- and macro-scopic anatomy of the kidneys as well as their corresponding vascular supply and drainage.

The contents below does not cover every aspect of what students need to know to ace their undergraduate exams, but aims to consolidate their understanding of renal physiology, in particular the autoregulation of renal blood flow, counter-current multiplier and exchange that they may require when it comes to the appreciation of pathophysiology, classification and management of AKI.

Basic sciences

The kidneys generally receive 20-25% of the resting cardiac output via the right and left renal arteries.

In order to provide adequate perfusion to individual nephrons, the arteries then branch off into many smaller vessels – afferent arterioles, and finally form capillaries surrounding by glomeruli in the renal cortex (the outer aspect of the kidney). In most cases, the capillaries of each juxta-medullary nephron then reunite to form efferent arterioles which run down the renal medulla (the inner part of the kidney) as vasa recta; and finally empty into the renal veins (see illustration on the right).

A useful website with anatomy images can be accessed via:

Physiology of renal blood flow (RBF)

The amount of blood filtered by glomerulus per minute is known as glomerular filtration rate (GFR), and is determined by three limiting factors:

1. Cardiac output which determines the amount of blood flow down the renal arteries;

2. Autoregulation which sets the pressure gradient between the afferent and efferent arterioles; and

3. Size and charge of molecules that are going to be filtered through the nephrons


Autoregulation of RBF

The concept of autoregulation is slightly more complex than the other two and so is worth discussing further.

Autoregulation plays a crucial role in maintaining RBF. By two main mechanisms, ie.:

  • Myogenic control
  • Tubule-glomerular feedback

... autoregulation serves to regulate a constant, yet independent blood flow through the glomeruli over a wide range of perfusion pressure (mean arterial pressure from 90-200mmHg; N.B. some textbooks also quoted 75-170mmHg).

The ability for both afferent and efferent to contract is the key. 


Myogenic control:

The afferent and efferent arterioles are made of smooth muscles that can constrict or dilate in relation to RBF. If for instance the perfusion pressure to kidneys is too high, the afferent arterioles will constrict to increase vascular resistance to normalize RBF. Conversely, if the perfusion pressure is too low, the afferent arterioles will relax to keep RBF constant as the blood passes through the highly resistant efferent arterioles.


Tubule-glomerular feedback:

The appreciation of tubule-glomerular feedback requires firm knowledge of the “juxtaglomerular complex”, a group of structures formed by macula densa along the ascending loop of Henle; and that are in close proximity to the capillaries within the glomerulus.

Back to basic physiology, if the perfusion pressure of RBF is high, the glomerular filtration rate (GFR) and the passage of filtrates through the Bowman’s capsule will also be high. The increased concentration of sodium ions in the ascending loop of Henle will trigger macula densa to secret adenosine, an afferent constrictor to reduce GFR.

If however the pressure is low, the reduced amount of sodium and chloride ions that runs through the macula densa will trigger the renin-angiotensin-aldosterone (RAA) system. The role of angiotensin II is to cause generalized vasoconstriction so to increase systemic vascular resistance and blood pressure. “Renally speaking”, angiotensin II also mediates constriction of afferent and efferent arterioles (constriction: efferent > afferent) to lift GFR. Through its effect on the adrenal cortex, angiotensin II also stimulates the release of aldosterone which encourages sodium reabsorption in both the distal convoluted tubules (DCT) and collecting duct.


N.B. The control of RBF is also affected by substances such as nitric oxide and prostaglandin. Their exact mechanisms in relation to autoregulation are so far unknown, however it is still worth mentioning here for completion sake.

Counter current mechanisms

Though "counter currents" are being taught repeatedly throughout medical school, the concept of which still seem to be poorly understood by students. The following aims to refresh their memory and thereby, to bridge their understanding concerning the pathophysiology and management, in particular renal replacement therapies, in AKI. 

Key points to consider:

  • Counter current multiplier makes use of the loop of Henle to produce hyperosmolar fluid in the medullar interstitium
  • Counter current exchanger uses vasa recta to maintain hyperosmolarity created by the multipliers, to prevent the washout of solutes in the medullar interstitium; and to allow the reabsorption of water from the renal cortex.

Counter current multiplier

It is crucial to recap that the thin descending loop of Henle is permeable to water but not urea. This is to contrast that the thick ascending loop of Henle is permeable to urea but does not allow the passage of water.

A firm knowledge of the above would allow us to appreciate the mechanisms behind counter current multiplication.  As said before that it serves to concentrate isotonic fluid that are traveling down the proximal convoluted tubules, the impermeability of water together with, principally, the action of Na/K/2Cl symporter (a type of co-transporter) in the thick ascending loop of Henle helps to drive sodium, potassium and chloride ions out to the medullary interstitium. 

    Counter current exchange

    Vasa recta is the key in counter current exchange. In simple terms, the antegrade flow of blood through vasa recta is known to be againsting the forward flow of tubular fluid. Doing so would enable the uptake of abundant sodium and chloride ions from the distal end of the thick ascending loop of Henle; also subsequently the off-loading of these ions near the tip of the loop of Henle via simple diffusion.

    The increased osmolarity in the deep medulla as a result of the presence of abundant sodium, chloride and urea has thence caused the migration of water from the permeable descending loop of Henle to the upstream of vasa recta via osmosis. 

    Acute Kidney Injury (AKI)


    The "true epidemiology" of AKI has been impacted by the lack of a universal classification system in modern medical practice. However, a recent review article published on the Critical Care Research and Practice by Case and colleagues summarises that AKI:

    • has an incidence ranges from 20-50% in ICU and generally carries over 50% of mortality;
    • is more likely to occur in patients with sepsis;
    • is less likely to occur in electtive surgery except kidney transplants

    *Visit for further details


    AKI, like acute renal failure, is classified under the following three categories, i.e.

    • Pre-renal; 
    • Renal (intrinsic); and
    • Post-renal (obstructive)


      Pre-renal injury is triggered when RBF is depressed. While there is no pathophysiological change of glomerular and tubular function, pre-renal injury is often resolved by the correction of hypoperfusion to kidneys due to:

      • volume loss (e.g. polyuria/ vomiting/ diarrhoea/ haemorrhage/ burns/ third space losses); 
      • reduced cardiac output (e.g. heart failure/ valvular incompetence/ pulmonary embolism); 
      • systemic vasodilation (e.g. sepsis/ anaphylaxis/ anaesthesia/ drug overdose); and rarely 
      • excessive constrictions of the afferent arteriole (e.g. NSAID/ noradrenaline/ contrast medium/ hypercalcaemia/ hepatorenal syndrome)

      Renal injury occurs when the structural integrity of kidney is damaged. The aetiologies are often categorised as follows, but if the cause is not obvious or undetermined, it would be best to consult the nephrologists for advice:

      • vascular supply and/or drainage (e.g. atherosclerosis/ embolus/ thrombosis/ vasculitis)
      • glomerular (e.g. autoimmune/ vasculitis)
      • tubular (e.g. ischaemia/ cytotoxic)
      • interstitium (e.g. infections/ iatrogenic - drugs/ systemic diseases)

      Post-renal injury arises with obstruction anywhere down the length from urine tubules to the urethra. Generally speaking, the cause of obstruction includes but not exclusively:

      • stones or crystals (e.g. uric acids/ calcium salts/ myeloma chains)
      • masses (e.g. tumor from renal or extra-renal structures/ haematoma/ prostatic hypertrophy) 
      • others (e.g. strictures/ phymosis/ blocked urinary catheters/ increased intra-abdominal pressure)

        Clinical features

        The cardinal symptoms and signs for AKI is oliguria (urine output less < 400 mL/day) or anuria, from which fluid overloading and electrolyte imbalance may be manifested. The presence of haematuria, proteinuria, leukocytes; large, painless bladder on abdominal palpation; purpura, petechial rash, bleeding; or pericardial rub on auscultation may put one cause of AKI more likely than the other. 

        There are incidences when AKI is resulted from polyuria or dehydration, the clinical presentation for these cohort will surely differ. 


        Having appreciated the huge array of causes that may precipitate AKI, clinicians from the Renal Association in March 2011 have recommended that "all patients presenting with AKI should have appropriate baseline investigations performed which should include a urinalysis and a renal tract ultrasound within 24 hours (if renal tract obstruction is suspected)

        The baseline investigations that they suggested include:

        • FBC;
        • U&E;
        • Urinalysis ± microscopy;
        • Urine and blood cultures if infection is suspected

        Where indicated, nephrologists and/or urologists should be involved and further investigations should thence be instigated. Depending on the clinical picture, the tests that they may request include:

        • Renal immunology;
        • Urinary electrolytes and osmolality;
        • ECG;
        • Chest x-ray;
        • Abdominal x-ray;
        • Renal tract ultrasound, with or without kidney biopsy


        Indicator(s) of renal dysfunction

        The two most common serum indicators of renal dysfunction are urea (U) and creatinine (Cr). 

        Our knowledge in biochemistry tells us the following:

        Urea is a waste product from liver. It is freely filtered through the glomeruli but also reabsorbed from the PCT and the lower portion of collecting duct. While it is a product of protein metabolism, it is fair to say that its concentration in plasma will be co-influenced by protein absorption and catabolism in the body; also the degree of reabsorption in the kidney in response to dehydration. 

        Creatinine is a by-product of muscle metabolism. It is freely filtered through the glomeruli but is unusual to be reabsorbed from tubular fluid. Factors such as age, body mass index, drugs and organ failure are known to upset muscle metabolism and to cause Cr to vary in individuals. However, having had balanced the pros and cons between the two, Cr is still considered as superior for routine use. 


          There is no universal classification for AKI.

          A system that author finds helpful, also a method that has been prospectively trialed in multiple studies, is the RIFLE score. It is a mnemonic for Risk, Injury, Failure, Loss and End-stage renal disease, and is based on the deterioration of GFR and urine output of patients. 


          The care of AKI patients should be shared between the multi-disciplinary team which may consist of nephrologists and/or urologists. When care has to be escalated, members of the critical care outreach service and/or intensivists should also be alerted.

          With regards to management, the practice guideline published by the Real Association in 2011 highlights that clinicians should focus on "optimisation of haemodynamic status by appropriate fluid therapy, administration of vasopressors and/or inotropes and treatment of any underlying sepsis." When indicated, nephrotoxic medications should also be stopped to avoid iatrogenic AKI.


          Fluid therapy

          Evidence for the best timing and agent to replace volume in AKI is awaiting. However, the consensus to treat hypovolaemia is by delivering repeated, small volume (often 250mL) of intravenous fluids via rapid infusion and to titrate therapy according to patient response.

          The trend measurements of central venous pressure (CVP) and hourly urinary outputs are useful to prevent fluid overloading associated with fluid therapies. Additionally, serial measurements of blood gas components - lactate and base excesses, via arterial access can give clinicians a valuable indicator of tissue hypoperfusion, hence to guide more effective strategies in fluid administration.

          The discussion of which fluid (i.e. crystalloid vs colloids) to give has been on-going for sometime. Though robust and statistical correlations are lacking, the larger molecular size of hydroxy ethyl starch and its associated risk of causing AKI in septic patients has somewhat limited the use of colloids in practice. 


          Pharmacological agents

          The Renal Association recommends no specific pharmacological therapy to treat AKI. However, the two important drugs to discuss here are loop diuretics and dopamine. 

          A recap of renal physiology reminds us about the action of Na/K/2Cl symporters on the thick ascending loop of Henle. By achieving temporary blockade of the pump, literatures propose that loop diuretics could reduce workload, and thus ischaemic changes of the kidneys. Through retaining tubular fluid, it also encourages diuresis to enable better control of fluid and electrolyte balance. Care however should be taken not to over-correct as high doses of loop diuretics are nephro- and ototoxic.

          Dopamine, a precursor of adrenaline and noradrenaline, is a powerful inotrope that works on alpha, beta and non-selectively on dopamine receptors. At low doses (<5 mg/kg/min) it exerts a dose-dependent effect to increase RBF (N.B. NOT renal perfusion). There however are no conveniencing evidence to show that low dose dopamine as being renal protective. The risks of cardiac arrhythmia and mesenteric ischaemia associated with higher doses have made the routine use of dopamine debatable.


            Renal Replacement Therapy (RRT)

            Statistics shows that about 3-5% of patients with severe AKI require RRT. According to the Intensive Care Society Standards and Recommendations for RRT in 2009, the indications for RRT in association with AKI include one or a combination of the following:

            • Severe hyperkalaemia (K > 6.5 with no or minimal improvements despite medical therapy);
            • Severe metabolic acidosis (pH < 7.1);
            • Rapidly rising urea and creatinine (values no absolute);
            • Refractory fluid overloading despite diuretics (worse when pulmonary function is compromised);
            • Ureaemia with complications (e.g. encephalitis, pericarditis, bleeding, nausea, puritis etc);
            • Anuria/oliguria (urine output < 200ml/12hrs)

            Without diving into details, RRTs in critical care are generally classified by the:

            • Duration of action (intermittent versus continuous); and
            • Mechanisms of the elimination of solutes in blood (convection/filtration versus diffusion/dialysis)

            The most routinely used RRT in ICU is continuous venous-to-venous haemofiltration (CVVH; uses convection). Some ICUs, however, might supplement it with haemodialysis to maximize efficiency, hence the name of Continuous Venous Venous HaemoDiafiltration (CVVHD; uses convection and diffusion). Merit students should be able to draw, compare and contrast CVVH and CVVHD using three physics principles, i.e. convection, diffusion and the counter current mechanisms. The two scehmatics in the following may aid discussion of CVVH/CVVHD during exams.

            Schematics comparing CVVH and CVVHD


            Life-threatening complications

            • Severe hyperkalaemia
            • Severe metabolic acidosis
            • Fluid overloading which may be refractory to diuretics
            • Major uraemic bleeding

            Prognosis and discharge planning

            Being able to formulate a clear plan for discharge is paramount. Descriptive statistics indicates that 15-32% of survivors are dependent on RRT at hospital discharge. Therefore, regular follow-ups and/or surveillance for chronic kidney disease by the nephrologists will be appropriate. 

            Furthermore, medication review by expert clinicians is another crucial task to complete prior to patient discharge. It is hoped that by adjusting and/or eliminating the list of medications of patients could prevent the recurrence of AKI from iatrogenic cause.

            References and suggested readings

            1. C Battle. Perioperative renal dysfunction. Anaesthesia Tutorial of the Week. Accessed June 2013. Available from:

            2. B T Workeneh. Aetiology - Acute Kidney Injury. MedScape. Accessed June 2013. Available from:

            3. J Griffiths. Current concepts of ARF on the ICU. FRCA. Accessed June 2013. Available from:

            4. A Lewington, S Kanagasundaram. Acute Kidney Injury. The Fifth Edition of the Clinical Practice Guidelines

            5. Standards and Recommendationsfor the Provision of RenalReplacement Therapy on IntensiveCare Units in the United Kingdom. The Intensive Care Society. Accessed June 2013. Available from:


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