Ji Soo Kim (@KimneyJ), Wesley Hayes, Detlef Bockenhauer

Albert Einstein once said:

“The most beautiful thing we can experience is the mysterious. It is the source of all true art and science.”

Well reader, you’re in luck. Because over the next 5 days, I am taking you on a journey through the mysterious renal tubule, a work of true art and science. I will guide you through the normal, and then abnormal function of the renal tubule. But before the nitty-gritty physiology, let’s talk about how to identify and approach a suspected tubulopathy.

Introduction

Imagine you are a tubule. Blood just squeezed through the glomerulus and the filtrate is now on your turf. The glomerulus seems smug for keeping albumin in the blood. But you, the tubule, sigh because there are a lot of pieces to pick up after the glomerulus. Thanks a lot, lazy glomerulus.

When to suspect tubulopathy?

The tubules reabsorb 99% of the filtrate generated by the glomerulus. Therefore, the average adult can enjoy carrying on their normal daily lives excreting only 1-2 litres of urine, as opposed to a whopping 150 litres a day. By reabsorbing everything that the body needs and excreting only those excess substances that must be gotten rid of, the tubules maintain fluid and electrolyte homeostasis according to the body’s physiological needs.

Are you dry? Your tubules should say: “Ok, let’s concentrate the urine.” Did you just eat a potassium-rich banana cake drenched in chocolate sauce? Your tubules should go: “Woah, I don’t need all that potassium.”

The key pieces of information needed for assessment of tubular function are:

1. Physical examination
2. Blood and urine measurements.

The mindset in interpreting the data should be this: if I were a kidney, what would be the appropriate response to the current clinical situation? Are the findings in the urine consistent with this appropriate response? In that case there is no tubulopathy and the problem must be sought elsewhere.

However, if the urine findings are inappropriate, for instance, when you see a dehydrated child who is pouring out dilute urine when they should be conserving water, it’s time to wonder about their tubules. This article will guide you through how to recognise and approach a child with tubulopathy.

How do I approach tubulopathy?

Start from the beginning with history and clinical examination, thinking about what the child’s fluid and electrolyte status is and how you would expect the tubules to respond.

The History

• Antenatally has there been polyhydramnios? (i.e. producing excessive urine in the womb)
• Is there failure to thrive? (because the child was losing glucose/amino acids/electrolytes in the urine)
• Or signs of rickets? (from losing phosphate)
• Polyuria and polydipsia? (Is there a family history?)
• Constipation? (Because they are fluid deplete)
• Kidney stones or nephrocalcinosis?
• Medication history? (wait, are they on diuretics?)
• And actually, is this even tubulopathy? Is there a different explanation? (for example, electrolyte losses from diarrhoea)

The Examination

• What is their fluid status? Are they hypovolaemic, euvolaemic or hypervolaemic? A weight, especially in comparison to previous weights, is helpful here.
• What is their blood pressure; Low? Normal? High?
• Look for extrarenal manifestations that correlate with different tubulopathies

TOP TIPS

Sodium is the main osmotic constituent of extracellular fluid. Where Sodium goes, Water follows by osmosis.

The kidneys use sodium to regulate volume

Sodium losing disorders = lower blood pressure

Increased Sodium reabsorption = higher blood pressure

Once you suspect the tubules are not behaving ‘sensibly’, the next step behind diagnosing a tubulopathy is figuring out

1. What substance is the kidney leaking or retaining?
2. Where along the tubule is this happening?

To do so, we need to look at the urine, paired with the blood and your clinical assessment. There is no point looking at urine electrolytes in isolation, because you cannot make a judgment whether the tubules are ‘appropriately’ or ‘inappropriately’ conserving or wasting electrolytes and water! In the same line of thinking, it’s difficult to say “what is the normal range for urine electrolytes?”, because it all depends on CONTEXT.

Investigations

• Urine dip stick – is the pH high or low? Are we losing protein? Are we losing glucose in the urine in spite of normal blood glucose? Or phosphate, despite low blood levels?
• Blood gas – is there a metabolic alkalosis or acidosis? If there is acidosis, what is the anion gap?
• Blood and urine amino acids – if you suspect a proximal tubulopathy, it is worth seeing if ALL the amino acids are being wasted into the urine… or only a select few?
• Serum Bicarbonate
• Paired blood and urine  – Sodium, Potassium, Chloride, Magnesium, Phosphate, Calcium, Osmolality and Creatinine
• Kidney Ultrasound Scan – looking for nephrocalcinosis
• Do you need extrarenal investigations? Ophthalmology? Hearing assessment?

Useful Calculations

Anion Gap; assessing if there are ‘extra’ anions that are unaccounted for.

• Anion Gap = [Na + K] – [HCO3 + Cl]
• Normal anion gap 8-12 (think: bicarbonate is being lost via the GI tract or urine). As bicarbonate is lost typically as sodium bicarbonate, the anion gap is unchanged
• High anion gap (think: excess acids like lactate or ketones). Excess acids are buffered by bicarbonate, so only the bicarbonate value changes in the anion gap equation, leading to an increased gap.

Fractional Excretion of Sodium (FENa); this equation is used as sodium tends to be reabsorbed. FENa represents the percentage of sodium filtered through the glomerulus that is excreted in the urine.

• FENa (%) = 100 x [(Urine Na/Urine Creatinine) / (Plasma Na/Plasma Creatinine)]
• Remember to check the urine and plasma numbers are all in mmol/L (!) (e.g. serum creatinine would be reported in umol/L in the UK)
• In general, the amount of sodium in the diet represents approximately 1% of the filtered load of sodium. So, to maintain balance, the FENa is usually around 1%. But remember the top tip above: the kidneys use sodium to regulate volume. Thus, in hypovolaemia, the appropriate response is to conserve sodium (FENa<1%). Conversely with hypervolaemia, a FENa>1% is appropriate.

Transtubular Potassium Gradient (TTKG); this equation is used as potassium tends to be excreted. The TTKG is an index to gauge potassium secretion by the collecting duct.

• TTKG = (urine K/urine osmolality) / (plasma K/plasma osmolality)
• ‘Normal’ TTKG in children 4.1-10.5 (infants: 4.9-15.5)
• Always interpret ‘normal’ with CONTEXT because if the TTKG is high after a high potassium diet, the kidney is actually doing the ‘right thing’.
• Low TTKG = aldosterone deficiency or insensitivity (leading to hyperkalaemia)
• High TTKG = dietary excess of K (and therefore an appropriate response) or hyperaldosteronism (and inappropriately high losses of potassium)

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So that’s it. We’ve got our basic approach to a patient with a suspected tubulopathy. Tomorrow we’ll start our journey along the renal tubule, beginning with the proximal tubule. I’ll see you tomorrow.

Follow the yellow brick road…