FRCA Notes

Renal Glucose Handling

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Glucose is freely filtered at the glomerulus and, in health, almost entirely reabsorbed in the proximal convoluted tubule (PCT)
Reabsorption is a saturable, carrier-mediated process, so glucose appears in the urine once plasma glucose exceeds the renal threshold
This mechanism is the target of SGLT2 inhibitors

Glucose is small (molecular weight 180Da) and not protein-bound, so is freely filtered
The filtered load is directly proportional to plasma glucose concentration:

Filtered load = GFR × plasma glucose concentration
E.g. 180L/day × 5mmol/L = 900mmol/day
900mmol × 180g/mol ÷ 1000 = ~160g of glucose filtered each day

Virtually all of this is reabsorbed, so normal urine is glucose-free

Apical membrane

Glucose is reabsorbed by secondary active transport, coupled to Na⁺ moving down its concentration gradient
The gradient is maintained by the basolateral Na⁺/K⁺-ATPase

	SGLT2	SGLT1
Location	Early PCT	Late PCT (also small intestine)
Na⁺:glucose stoichiometry	1:1	2:1
Affinity / capacity	Low affinity, high capacity	High affinity, low capacity
Proportion of glucose reabsorbed	~90%	~10%

Basolateral membrane

Glucose leaves the tubular cell down its concentration gradient into the interstitium by facilitated diffusion
This occurs via GLUT2 (early PCT) and GLUT1 (late PCT)

SGLT2 inhibition

Blocking SGLT2 causes loss of several grams of glucose (and the associated Na⁺) in the urine each day
Only ~50% of filtered glucose is excreted, as SGLT1 in the S3 segment upregulates and compensates

Reabsorption increases linearly with filtered load until the carriers start to saturate
Renal threshold: the plasma glucose at which glucose first appears in the urine, ~10-11mmol/L
Transport maximum (T_max): the maximal rate of tubular glucose reabsorption, ~1.5-2mmol/min (~300-375mg/min)
Once T_max is reached, reabsorption plateaus and any further filtered glucose is excreted

Splay

Glucose appears in the urine at a plasma concentration below that predicted from T_max, so the titration curve is rounded rather than sharply angled
This is because:

Nephrons are heterogeneous, with differing filtration rates and reabsorptive capacities, so some saturate before others
Carrier binding is not infinitely avid, so some glucose escapes reabsorption before full saturation

Glucose titration curve

Plotting filtered load, reabsorption and excretion against plasma glucose gives three lines:

Filtered load: a straight line through the origin
Reabsorption: follows the filtered load, then curves (splay) and plateaus at T_max
Excretion: zero until the renal threshold, then rises in parallel with filtered load

Glucose titration curve showing filtered, reabsorbed and excreted glucose against plasma glucose concentration

Adapted from Physics, Pharmacology and Physiology for Anaesthetists: Key Concepts for the FRCA

Glycosuria occurs once the renal threshold is exceeded
Above T_max, excretion rises linearly in parallel with filtered load
Glucose in the tubular fluid holds water osmotically, causing an osmotic diuresis with loss of water and electrolytes

This explains the polyuria, polydipsia and dehydration of uncontrolled diabetes and DKA

Glycosuria without hyperglycaemia

Pregnancy: ↑ GFR raises the filtered load, and the renal threshold falls
SGLT2 inhibitor therapy
Familial renal glycosuria (SGLT2 gene mutations)
Proximal tubular dysfunction e.g. Fanconi syndrome, heavy metal toxicity

Altered threshold in diabetes

In poorly controlled diabetes, SGLT2 expression increases, raising T_max
This maladaptive response increases glucose reabsorption and worsens hyperglycaemia
Conversely, the renal threshold may be raised in the elderly and in diabetic nephropathy, so glycosuria is an unreliable marker of hyperglycaemia