First, the boring bits: Kidneys (2 of them usually): Outer cortex and Inner medulla. They: Remove fluid; Remove electrolytes; Remove metabolic waste The mechanisms are tightly controlled in health to ensure homeostasis. Kidneys receive around 20% of cardiac output (400mls/100g/min): around 1 litre / min.
The functional renal unit-the nephron-starts with the Bowman’s capsule, where initial filtration occurs. There are 2 ‘types’ of nephron: The majority are cortical (or superficial), with a short loop of Henle Just over 10% are juxtamedullary, with loops of Henle descending into the outer medulla.
They have a massive ability to concentrate: they filter about 120mls per minute of glomerular filtrate, and from this, they produce around 1ml of urine per minute. There are 2 main processes: filtration and reabsorption. Filtration happens at the Bowman’s capsule, producing fluid having basically the same composition as plasma, without the plasma proteins. Reabsorption takes place in the rest of the nephron.
In the PCT, around 70% of the filtered Na is reabsorbed (by active transport mechanisms); Cl follows, and the osmotic gradient draws water out of the tubule. This results in a reduction in volume, with no change in osmolality.
In the Loop of Henle, active Na reabsorption happens only in the thick ascending portion of the loop. This area is not permeable to water, so the osmolality in the medullary interstitium rises (helped by a countercurrent multiplier system).
The descending limb can lose ions and water, so as it passes through the medulla, it is concentrated and reduced in volume. As fluid passes up the ascending limb, it actually becomes more DILUTE as Na is lost (finishing at 100 mOsmol/kg).
Most of the remaining Na is reabsorbed in the DCT, partially under the control of aldosterone.
Water is reabsorbed in the DCT and collecting duct, as it passes through the high osmolality of the medulla on the way to the renal pelvis. It’s here that the final concentrating of the urine occurs, depending on the osmolality generated in the medulla, and the degree of permeability of the collecting duct allowed by ADH.
The blood supply to the glomerulus (from the renal artery) is via afferent arterioles, with glomerular capillary drainage via efferent arterioles. The presence of these afferent and efferent arterioles means tight autoregulation of the blood flow across the glomerulus: if systemic arterial pressure falls, the afferents dilate, reducing renal vascular resistance, to limit the decrease in blood flow; filtration can therefore continue.
Blood flowing from the efferent arterioles then enters a second capillary system, surrounding the loop of Henle: the vasa recta. Now, the main reason some of the nephrons extend deep into the outer medulla is that this affords them excellent concentrating ability. The vasa recta allows a hypertonic medulla, but means this area is relatively hypoxic.
The main area in which concentrating takes place is the thick ascending limb of the loop of Henle, where active sodium reabsorption occurs, using the Na/K/ATPase pump. Fine, but this requires significant amounts of energy, as it’s an active process.
The arrangement of the vasa recta is something like this (slide): hairpin bend. While overall renal oxygen consumption is relatively low, in the outer medulla, where active sodium reabsorption tends to occur, oxygen extraction is very high. Blood leaving the vasa recta tends to be relatively hypoxic, and because the 2 limbs are so closely apposed, oxygen diffuses across the capillaries before they enter the medulla proper. This is the downside of a system designed to maintain a very concentrated interstitium to facilitate the reabsorption process. As a result, the part of the kidney with the highest oxygen usage is operating on the edge of aerobic metabolism, at around 2kPa.
I’ve mentioned that autoregulation aims to maintain glomerular perfusion; when the kidney is faced with reduced blood flow, such as when someone is hypotensive The first thing that happens is afferent dilation to maintain forward flow through the glomerulus. Renal blood flow redistributes from the cortex to preferentially maintain perfusion to the outer part of the medulla. This allows filtration to occur in the nephrons with the longest loops of Henle, maximizing the ability of the kidneys to concentrate urine, so minimizing fluid loss, while still excreting waste products.
A feedback mechanism (tubulo-glomerular feedback) kicks in when interstitial blood flow falls (because the maintenance of glomerular flow has meant efferent constriction now, as well as afferent). This mechanism lets the kidney reduce its oxygen requirement by reducing the volume of glomerular filtrate, and therefore the quantity of sodium needing reabsorbed. Blood flow to the medulla is maintained until the resistance to flow exceeds the input pressure. At this point, perfusion is lost.
Fine, so that’s all well and good, but what actually happens in the real world. Often, renal failure occurs as the effect of the body’s attempts at self preservation in the face of severe illness, often referred to as the Innocent bystander. The thing is, the outcome can be affected, either made worse or better, by our intervention.
Now, as an aside, what exactly is renal failure? It could be defined as the sudden (usually reversible) failure of kidneys to excrete nitrogenous and other waste products. The problem is that previously there were many definitions, leading to confusion. This has now been streamlined and clarified with the Acute Dialysis Quality Initiative producing the RIFLE criteria. ADQI was set up in 2000 to look critically at renal failure: the evidence for treatment, what needed further research, and how certain conditions should be managed. Thankfully, fairly early on, they realized that having come across over 30 definitions for acute renal failure, a major problem was the lack of any clear consensus definition. In 2004 they published their international consensus classification for acute kidney injury: RIFLE.
We now have standardized definitions based on either GFR criteria (change in GFR or change in Creatinine) or urinary output criteria: the Urinary output was included to improve sensitivity, and increase awareness of the potential reversibility in the early stages. There are 3 grades of injury severity:RiskInjuryFailure With 2 outcome classes:LossEnd stage kidney disease Note that RIFLE “F” is present if the rise in creatinine is less than x3, as long as the new creatinine is over 4mg/dl (eqv to 350micromols/l), with a rise of at least 40micromols/l. These criteria have been studied subsequently in differing environments, including medical intensive care, cardiothoracic surgery, trauma, and found reliable, easy to use and repeatable.There is a continuum here, from reversible oliguria, to established disease. This is why identifying problems earlier and treating the cause, may help prevent development of established renal failure.
What causes acute renal failure? The most important question to be answered is: is the renal impairment caused by a pathological process outside or within the kidney? Often, renal failure is the result of several insults. Paper in Critical Care Medicine 2001 (Bellomo), looking at the epidemiology, management, and outcome of severe ARF of critical illness in Australia. They found the most common reasons for patients developing ARF were Ischaemia/hypotension Severe sepsis/septic shock Acute lung disease (usu. Pneumonia) Myocardial pump failure Rhabdomyolysis Nephrotoxic drugs
Patients with certain pre-morbid conditions Have an impaired ability to compensate and therefore are more vulnerable to insults
In ICU, many patients already have these problems, compounded by a bucketload of medications… Such that the background of limited reserve, along with Hypovolaemia Hypotension Sepsis Loss of autoregulation Drugs Some specific toxins Can all lead to ischaemia of the outer medulla with death of the proximal and thick ascending limb tubular cells, resulting in established ARF.
Before I go on to what we can do about this, I want to ask: does it really matter? After all, if someone’s kidneys fail, can’t we just stick them on a washing machine and that’s that? Well, and probably fairly obviously if I’m asking the question, That’s not just the end of it!
There’s lots of evidence out there that it’s not just a bit of an inconvenience, but the development of ARF can significantly affect outcome. Certainly, in general, people don’t die OF renal failure, but 1996: Levy et al JAMA Looked at almost 200 patients with renal failure due to contrast nephropathy, and compared them to a group with the same severity of illness but no renal failure. They felt renal failure contributed a x6.5 risk of death with similar severity scoring. Several studies in post-cardiac surgery patients, showing that development of renal failure elevates risk of death. Large multi-centre study in Critical Care Medicine 2002 looking at ICU patients: almost 900 with ARF out of 17000. Of patients with similar disease severity, those with renal failure had a mortality almost twice that of those with no renal failure.
I’m not going into the details of all of this, and while remembering that a lot of the detail of managing a patient in ICU means walking a line between support for ALL their organ systems, which does sometimes mean allowing renal function to suffer to allow other systems to recover. The point is that renal failure is not benign. So, if we can prevent it, surely we should try??
Renal Physiology and Failure
CT1 Education Series (Intro)
• Renal blood supply
– Glomerular filtration is not energy-intensive
– Most energy (and O2) use in the kidney is for
Na/K/ATPase active pumps: Na reabsorption
• Mainly in thick ascending limb of LoH
• Blood flow to nephron
– Hairpin-bend arrangement
– Highest O2 consumption in outer medulla
• Blood leaving capillary bed hypoxic
• O2 tends to leave capillaries on entering to diffuse across (close apposition)
– Medulla therefore hypoxic
• Of most concern in outer medulla
– Highest energy consumption in area with relative hypoxia
• Glomerular filtration hydrostatic pressure initially maintained:
afferents dilate (flow remains)
• Blood flow still relatively maintained to outer medulla
– Allows concentration to continue
• Feedback mechanism reduces glomerular filtration
– Reduces energy expenditure by medulla
– Reduces Na loss
Glomerular blood flow
• If autoregulation fails…
– Flow becomes pressure
– Filtration therefore falls…
– And if GFR falls, then less
can be excreted.
– Renal failure often the effect of distant
– “Innocent bystander”
– Early intervention can reduce likelihood
• What is it?
– Sudden (usually) reversible failure of kidneys to
excrete nitrogenous and other waste
– Multiple definitions
– Now: ADQI
• Review evidence
• Set research agenda
• Make management recommendations
In acute renal failure, and use of renal replacement
• Does renal failure matter?
– Acceptable casualty??
– Another organ failure??
• Renal failure is an independent risk
factor for mortality
– Levy et al (1996): similar illness severity
with renal failure-up to x6.5 risk of death
– CCMed (2002): similar disease severity
and renal failure x2 mortality of those
without renal failure
– Optimal support for all organ systems
– Overall patient support
Means kidneys sometimes do suffer
Remember this is not benign!
• PCT: Na-H exchange
• Catalysed by Carbonic Anhydrase
• DCT/CD: H loss independent of Na in
– ATP driven proton pump
• Stimulated by aldosterone
• Maximum gradient against which
transport mechanisms can secrete
corresponds to urine pH 4.5
• Buffers allow more H secretion
H2CO3 (C. Anhydrase: PCT only)
(DCT / CD)
+ NH3 NH4
(PCT and DCT)
• Carbonic anhydrase is in PCT
– Allows formation of CO2 and H2O in tubular
• CO2 diffuses across membranes, becoming
available to form H2CO3
• Since most of H+
removed from tubule, pH of
fluid changes little
• Alcohol: inhibits vasopressin
• Caffeine: inhibits vasopressin
• CA inhibitors: decrease H secretion; resultant rise in
Na and K loss
• Metolazone, thiazides: Inhibit Na-Cl cotransport in
• Loops: inhibit Na-K-2Cl cotransporter in medullary
thick ascending LoH
• K-sparing naturietics: inhibit Na-K exchange in CD by