Diabetes Mellitus: Large volume of glucose-containing urine

Why is there glucose in the urine?

Why is urine volume increased?

Consider the following case:

Blood volume decreases, so we retain more water (i.e., what we discussed during the previous class)

But that would cause dilution of the body fluids …

Proximal Tubule

65%

Distal Tubule

3-5%

Loop of Henle

25-30%

Collecting T

ubule

1-3%

Glomerulus

Filter ~ 1 lb of Na daily

Tubular reabsorption of Na

Proximal Tubule Sodium ReabsorptionProximal Tubule

Epithelial Cell

ATP

Tubular Lumen

(urine)

Capillary Lumen (blood)

2K+

3 Na+

Na+

H+

H+

H2ONa+

3 HCO3-

OH-

CO2

Na+

glucoseamino acidsPO4

2-

Loop of Henle Sodium Reabsorption – thick ascending limb

Ascending Thick Limb of the Loop of Henle Epithelial Cell

ATP

Tubular Lumen

(urine)

Capillary Lumen (blood)

2K+

3 Na+

Na+

K+

ROMK

channel

K+

K+ recycling

Na+ Ca+2 Mg+2 Paracellular Pathway

+-

2 Cl-

Cl-

Flatman (2008) Curr Opin Nephrol Hypertens 17: 186-192

Bartter’s syndrome: hypotension with salt wasting and hypokalemia as a result of loss of Na reabsorption in the thick ascending limb

Point: if there are abnormalities in the various transport processes involved in Na+ reabsorption, there are serious consequences in terms of volume and osmotic regulation.

Ascending limb of the loop of Henle

ATP

Tubular Lumen

(urine)

2K+

3 Na+

Na+

Cl-

Cl-

Distal Tubule Sodium Reabsorption

Capillary Lumen (blood)

K+

Distal Tubule Epithelial Cell

Gitelman’s disease: a mutation in the Na, Cl cotransporter; results in sodium wasting and hypotension

ATP2K+

3 Na+Na+

Capillary Lumen (blood)

K+

Collecting Tubule

Tubular Lumen

(urine)

K+

+-

Collecting Tubule Epithelial Cell

Principal Cell

Regulation of Tubular Na+ Transport

• Hormones regulate the extracellular fluid volume by altering renal Na+ excretion

• Hormones that enhance tubular Na+ reabsorption – angiotensin II– arginine vasopressin– Aldosterone

• Hormones that inhibit tubular Na+ reabsorption– atrial natriuretic peptide– natriuretic factors

• Ouabain• Ouabain analogs

Silverthorn Figure 19-12

Actions of Aldosterone (the simple version)

Model for the early transcriptional action of aldosterone on ENaC function. The ubiquitin ligase Nedd4-2 that tonically inhibits ENaC surface expression is highlighted in red, and red dashed arrows indicate pathways downregulating ENaC that are antagonized by aldosterone. Blue boxes represent the regulatory proteins implicated in the early aldosterone action that are rapidly induced via activated MR. The blue lines terminated by a dash indicate at what level these regulatory proteins interfere with ENaC inhibition.

Verrey et al. Kidney International (2008) 73: 691-696

The key point of the next few slides is that the actions of aldosterone and the regulation of Na+ transport are quite complex, and abnormalities in these regulatory processes can result in diseases.

Figure 1. Regulation of ENaC activity in the distal nephron Left-hand panel: Segments of the distal nephron including the distal convoluted tubule (DCT; dark grey), connecting tubule (CNT; black), cortical collecting duct (CCD; light grey) and medullary collecting duct (MCD; white) are shown. The juxtamedullary nephrons have a long connecting tubule. Right-hand panel: Schematic of the principal cell of the connecting tubule or cortical collecting duct. Aldosterone (Aldo) binds mineralocorticoid receptor (MR) in the nucleus to stimulate expression of several genes: some important examples are shown. Aldosterone may also have non-genomic effects in the cortical collecting duct/connecting tubule (not shown). Nedd4 and Nedd4-2 promote endocytosis and ubiquitination of epithelial sodium channel (ENaC). Serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates ENaC via inhibition of Nedd4-2 and possibly by a direct mechanism. Furin and channel-activating protease (CAP) proteins activate ENaC by proteolysis. Ub(n) is a polyubiquitin moiety and ER is the endoplasmic reticulum. From:   Thomas: Curr Opin Nephrol Hypertens, Volume 13(5).September 2004.541-548

ENaC

Ubiquitin Ligase

Ubiquitin

Internalization and Degradation

N C

PY

Ubiquitin Ligase

WW DomainsC2Nedd4

N C

PY

N C

PY

Ubiquitination

X

X X

Liddle’s mutations disrupt the interaction between Nedd4 and ENaC

Mutations or Truncations β or γ subunit

Liddle’s syndrome is an autosomal dominant form of salt sensitive hypertension

Expression of major sodium and potassium transport proteins in the distal nephron, including WNK kinases and associated regulatory proteins.

Hoorn E J et al. JASN 2011;22:605-614

So, Aldosterone is important, but what controls aldosterone secretion?

Silverthorn Figure 19-13

AngII is the major stimulus of aldosterone secretion

renin secreting cells of the juxtaglomerular apparatus

Factors controlling renin secretion

Schematic depiction of the renin–angiotensin system components 2013

Carey R. Hypertension 2013;62:818-822

Decarboxylation of asp to ala in position 1

Only in tissue

Point here: there is a lot more going on with the renin-angiotensin system than just the classical stuff represented by the blue line in the figure.

Germann figure 20.18

Silverthorn 19-15

Atrial Natriuretic Hormone

Fig. 1. Effects of increased renal sympathetic nerve activity (RSNA) on the 3 renal neuroeffectors: the juxtaglomerular granular cells (JGCC) with increased renin secretion rate (RSR) via stimulation of 1-adrenoceptors (AR), the renal tubular epithelial cells (T) with increased renal tubular sodium reabsorption and decreased urinary sodium excretion (UNaV) via stimulation of 1B-AR, and the renal vasculature (V) with decreased renal blood flow (RBF) via stimulation of 1A-AR.

G.F. DiBona

Sympathetic influences on renal function

A quick word about ‘salt appetite’

At least in some species, Na+ deficit elicits the motivation for salt seeking and increased salt intake

Weinberger M H Hypertension 1996;27:481-490(based on data from Luft et al., 1979)

Copyright © American Heart Association

Percentage change in mean arterial pressure in normotensive subjects receiving incremental increases in sodium.

Issue of salt sensitivity of blood pressure, and dietary recommendations

Percentage change in mean arterial pressure in normotensive subjects receiving incremental increases in sodium.

Weinberger M H Hypertension 1996;27:481-490(based on data from Luft et al., 1979)

Copyright © American Heart Association

Current recommended

Current US average

Typical range for assessing salt sensitivity of BP

Low salt: 20 mmol/day (460 mg)High salt: 240 mmol/day (5520 mg)

Flow chart of responses to severe dehydration:

Silverthorn Figure 19-17

Figure 29-1 Normal potassium intake, distribution of potassium in the body fluids, and potassium output from the body.

Now switching to K+

Figure 29-2 Renal tubular sites of potassium reabsorption and secretion. Potassium is reabsorbed in the proximal tubule and in the ascending loop of Henle, so that only about 8 per cent of the filtered load is delivered to the distal tubule. Secretion of potassium into the late distal tubules and collecting ducts adds to the amount delivered, so that the daily excretion is about 12 per cent of the potassium filtered at the glomerular capillaries. The percentages indicate how much of the filtered load is reabsorbed or secreted into the different tubular segments.

Figure 29-3 Mechanisms of potassium secretion and sodium reabsorption by the principal cells of the late distal and collecting tubules.

ROMK

Figure 29-4 Effect of plasma aldosterone concentration (red line) and extracellular potassium ion concentration (black line) on the rate of urinary potassium excretion. These factors stimulate potassium secretion by the principal cells of the cortical collecting tubules. (Drawn from data in Young DB, Paulsen AW: Interrelated effects of aldosterone and plasma potassium on potassium excretion. Am J Physiol 244:F28, 1983.)

Figure 29-5 Effect of extracellular fluid potassium ion concentration on plasma aldosterone concentration. Note that small changes in potassium concentration cause large changes in aldosterone concentration.

Figure 29-8 Effect of large changes in potassium intake on extracellular fluid potassium concentration under normal conditions (red line) and after the aldosterone feedback had been blocked (blue line). Note that after blockade of the aldosterone system, regulation of potassium concentration was greatly impaired. (Courtesy Dr. David B. Young.)

Figure 29-9 Effect of high sodium intake on renal excretion of potassium. Note that a high-sodium diet decreases plasma aldosterone, which tends to decrease potassium secretion by the cortical collecting tubules. However, the high-sodium diet simultaneously increases fluid delivery to the cortical collecting duct, which tends to increase potassium secretion. The opposing effects of a high-sodium diet counterbalance each other, so that there is little change in potassium excretion.

Model of the “aldosterone paradox.” Two pathophysiological settings are depicted: hypovolemia (left) and hyperkalemia (right).

Hoorn E J et al. JASN 2011;22:605-614

The key point to take away from this is that the overall effect on Na+ reabsorption versus K+ secretion in the nephron is dependent upon whether the increase in aldosterone occurs with or without an increase in AngII.

A word about Ca++ homeostasis

Regulation of parathyroid hormone secretion by Ca++

Point: PTH secretion is directly sensitive to changes in blood Ca++

Diuretic Drugs: (see table 31-1 in Guyton)

•Osmotic diuretics (e.g., mannitol)

•Loop diuretics (e.g., furosemide)

•Thiazide diuretics (e.g., hydrochlorothiazide)

•Aldosterone antagonists (e.g., spironolactone)

•Drugs that block Na channels in the collecting ducts (e.g., amiloride)

•Carbonic anhydrase inhibitors (e.g., acetazolamide)

(notice that ADH antagonists are not on the list. Why?)

Is coffee a diuretic?

TBW measured by dilution of D2O(Caffeine intake ~ 300 mg/day)

In higher doses, caffeine is a diuretic; its action is mostly on the proximal tubule to reduce Na+ reabosorpton

Journal of Pharmacology and Experimental Therapeutics 313: 403-409, 2005

A1 knockout mice

Caffeine dose: 45 mg/kg oral ~5-7 cups of coffee per day

And to put this back into physiology, the adenosine A1 receptors are required for the signaling of tubuloglomerular feedback!

Macula densa

J. Schnermann and J.P Briggs

Mahfoud F et al. Circulation. 2011;123:1940-1946

Copyright © American Heart Association, Inc. All rights reserved.

Effect of Renal Sympathetic Denervation on Glucose Metabolism in Patients With Resistant Hypertension Clinical Perspective

Felix Mahfoud, Markus Schlaich, Ingrid Kindermann, Christian Ukena, Bodo Cremers, Mathias C. Brandt, Uta C. Hoppe, Oliver Vonend, Lars C. Rump, Paul A. Sobotka, Henry

Krum, Murray Esler, and Michael Böhm

Effects of increased sympathetic activity on peripheral circulation and organs.

Böhm M et al. Circulation Research. 2014;115:400-409

Copyright © American Heart Association, Inc. All rights reserved.

(NPN = nonprotein nitrogen)

Effects on plasma constituents of shutting down the kidneys

ConstituentNormal Plasma

Dialyzing Fluid

Uremic Plasma

Electrolytes (mEq/L)

  Na+ 142 133 142

  K+ 5 1.0 7

  Ca++ 3 3.0 2

  Mg++ 1.5 1.5 1.5

  Cl- 107 105 107

  HCO3- 24 35.7 14

  Lactate- 1.2 1.2 1.2

  HPO4= 3 0 9

  Urate- 0.3 0 2

  Sulfate= 0.5 0 3

Nonelectrolytes

  Glucose 100 125 100

  Urea 26 0 200

  Creatinine 1 0 6

Table 31-7. Comparison of Dialyzing Fluid with Normal and Uremic Plasma

Renal Dialysis