Renal Physiology VII Flashcards by Joel Glotfelty

Since the ability of the liver to respond to insulin is impaired, hepatic gluconeogenesis is upregulated, setting in motion a viscious cycle of

Hyperglycemia and hyperinsulinemia

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Obesity is defined as a body mass index (BMI) of

Greater than 30kg.m^2

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The deposition of fat in the regions of the hip and buttocks is not strongly correlated with

Metabolic disease

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Whereas accumulation of visceral fat is linked with a syndrome that is described as

Type 2 DM

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The distribution of fat around the abdominal wall and visceral mesenteric location

Android obesity

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On the other hand, the presence of subcutaneous abdominal fat has less of an association with

Insulin resistance

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Correlated with the development of hypertension and dyslipidemia, among other risk factors for cardiovascular disease

Android obesity

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The android obesity phenotype results in an abnormally increased

Waist-to-hip tatio (greater than 0.9 in males and 0.85 in females)

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Has a gene expression pattern that makes it distinct from other fat stores

Visceral fat

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Mutations and/or abnormal expression/activity of adipokines (e.g., adiponectin and leptin), cytokines (e.g., tumor necrosis factor-a, TNFa), and FFA which are produced by visceral fat have the ability to alter both

Glucose metabolism and Insulin sensitivity

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Each increae sensitivity to insulin

Leptin and adiponectin

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Has been shown to impede insulin dependent glucose metabolism

TNFa

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Impede both insulin secretion and insulin-directed glucose uptake in peripheral tissues

FFAs

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FFAs stimulate dipocytes to secrete

TNFa

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TNFa in turn exerts positive feedback on

FFA secretion

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In response to insulin resistance, visceral fat undergoes

Lipolysis

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The lypolysis that visceral fat undergoes results in increased levels of

Tryglycerides and small and dense LDL (the really bad kind of LDL) and decreased HDL

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Visceral fat thus increases

CV risk

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It is therefore important to realize that visceral abdominal fat is very active in terms of its production of a cohort of factors which

Impede insulin secretion and impair insulin-dependent glucose uptake

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The ideal goals for preventing the progression of IGT to Type 2 DM

Weight loss and exercise

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A biguanide that impairs hepatic gluconeogenisis and intestinal glucose absorption, and enhances peripheral glucose uptake

Metformin

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An insulin sensitizer

Thiazolideniones (pioglitazone)

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Insulin secretagogues that promote endogenous insulin production

Sulfonylureas

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Injectables or insulin pump that can replace pancreatic and islet cells

Insulin replacement

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Impedes glucose reabsorption from forming urine

SGLT2 inhibitors

Impede the degradation of glucagon-like peptide 1 (GLP-1)

DPP-4 inhibitors

Promotes insulin secretion and inhibits glucagon secretion

GLP-1

The renal system is an important contributer to

Glucose counter regulation

What do the kidneys use for gluconeogenesis?

1. ) LActate (predominant) 2. ) Glutamine 3. ) Glycerol

Under conditions of prolonged fasting, hypoglycemia, and acidosis, the kindeys can account for what percentage of gluconeogenesis?

As much as 20%

Glucagon, glucocorticoids, and norepinephrine/epinephrine all stimulate

Renal gluconeogenesis

Following hepatic failure, the kidneys can partially compensate for

Impaired gluconeogenesis

Renal glucose uptake is regulated by

Insulin

The kidneys also metabolize insulin in order to lower

Plasma insulin levels

This partially explains the hypoglycemia that is often observed as a result of

Renal failure

Within the nephron, glucose is freely filtered and reabsorbed with reabsorption being approximately equal to

Filtration

Reabsorbs essentially ALL of the filtered glucose

The proximal tubule

The reabsorption of glucose by the proximal tubule is mediated by the regional expression of : 1. ) Apical? 2. ) Basolateral?

1. ) SGLT1 and SGLT2 | 2. ) GLUT1 and GLUT2

An Na+-glucose cotransporter that is driven by Na+ gradients established by the Na+/K+ ATPase

SGLT

Functions via facilitated diffusion

GLUT

The threshold for spillover of glucose into the excreted urine is approximately

180 mg/dL plasma

1dL =

100 mL

Physiologic glucose levels are between

65 (fasting) to 120 (post prandial)

In the diabetic, failure of the insulin system results in impaired

Cellular glucose uptake

This results in a marked increase in

Serum glucose

As a result, the filtered load of glucose goes through the roof. When the reabsorptive machinery within the tubule becomes saturated (180 mg/dL) the result is

Glucosuria

The primary diagnosis for approximately 30-40% of end stage renal diseases (ESRD)

Diabetes melitus

Approximately 1/3 of patients with diabetes develop

Microalbuminuria (elevated urine albumin)

This process of microalbuminuria often precurses

Proteinuria (macroalbuminuria), diabetic neuropathy, and renal fucntion loss

Proteinuria due to a loss in glomerular function

Glomerular proteinuria

Determined by the following: the mean transcapillary | hydraulic pressure difference, glomerular surface area, and the size- and charge-selectivity of the glomerular membrane

Glomerular proteinuria

How much albumin per day is typically filtered and completely reabsorbed by the glomeruli?

1g albumin

Microalbuminuria in diabetics is predictive of a high probability of

Cardiovascular morbidity and mortality as well as progressive renal disease

Functions as an antigen which causes immune and cellular responses within the nephron -the form of albumin in diabetics

Glycated albumin (glycosylated albumin)

Causes the generation of reactive oxygen species which can chelate proteins and cause other damage to the glomerular embrane

Glycated albumin

In the face of the assault by glycated albumin, the glomerular membrane loses

Size and charge selectivity

Induce the 1) overloading of tubule intracellular lysosomes, 2) local production of inflammatory cytokines, and 3) increased synthesis of extracellular matrix proteins within the tubular tissues

Elevated concentrations of urinary proteins

Collectively this leads to

Glomerulosclerosis, fibrosis, and renal failure

During the early stages of diabetes, the glomerulus and tubular epithelium can -correlated with thickening of cellular basement membranes

Hypertrophy

This condition of glomerular hypertrophy is commonly accompanied by what 2 things?

1. ) Supranormal GFR (hyperfiltration) | 2. ) Microalbuminuria

What three things induce unfavorable glomerular remodeling?

1. ) Hypertension 2. ) Hyperlipidemia 3. ) Hyperglycemia

Excess glucose in the glomerular filtrate (due to hyperglycemia) induces a significant upregulation in the expression of

Proximal tubule SGLT2

Upregulation in the expression of proximal tubule SGLT2 enables increased proximal Na+ reabsorption, resulting in decreased Na+ delivery to the

Macula Densa

The TGF mechanism is thus tricked into perceiving this as low perfusion and responds in kind with the secretion of

Vasodilators

The vasodilators secreted by the TGF result in dilation of the

Afferent arteriole

Afferent dilation results in

Increased glomerular pressure and hyperfiltration

In addition, experimental evidence shows that inadequate glycemic regulation and diabetic hypertension collectively tax the vascular endothelium by

Pressure-induced capillary stretch

This causes increased vascular permeability and leads to

Glomerular injury

These conditions collectively support an amplifying cycle of increased reabsorption by the proximal tubule and its stimulatory effect on

GFR

From the vascular side, the diabetic kidney may receive aberrant signals regarding

ECF volume

These miscued feedback loops can then induce an inappropriate response within the renal microvasculature that leads to a cycle of osmotic imbalances and increased tubule reabsorption, which once again

Stimulates GFR

So-called tubular events can result in altered GFR due to disruptions in the

TGF mechanism

These disrupted TGF mechanisms are at the root of a cascade of problems that disrupt the reabsorptive capacity of tubules upstream from the

Macula densa (so-called primary tubule events)

Over time, glomerular basement membrane thickening, hypertrophy, podocyte injury/loss, and glomerulosclerosis develop, leading to

Decreased GFR

The final common pathway to ESRD is the diabetic kidneys formation of

Tubulointerstitial fibrosis

Unchecked extracellular glucose assaults

Renal interstitial and tubule cells

This overwhelming glucose load stimulates the

RAS

Promotes the release of intrarenal fibrogenic cytokines, chemokines, chemotactic factors, cell adhesion molecules, and growth factors; while inhibiting the production of antifibrogenic factors

RAS

Collectively, this milieu facilitates the formation of glomerulosclerosis and may promote epithelial-to-mesenchymal cell transitions that lead to

Tubulointersitital Fibrosis

Has been shown to induce phosphorylation of insulin receptor substrate-1 (IRS-1)

An-II

This phosphorylation event blocks insulin from using IRS-1, which induces a state of

Insulin resistance

In addition, upregulated RAS activity can impair the expression of

Nephrin

A transmembrane protein that aids in restricting protein filtration across the glomerulus -present within the slit diaphragms of glomerular podocytes

Nephrin

Thus, in the face of a sustained RAS challenge, nephrin content is compromised, resulting in a

Leaky glomerulus

Recall, AII stimulates aldosterone secretion. Elevated aldosterone means increased Na+ retention, Na+ retention means increased H2O retention, and H2O retention means elevated BP and the propensity for

Diabetic hypertension

Have been shown to reduce proteinuria and slow the progression of diabetic neuropathies in some diabetic patients

Treatment with renin and ACE inhibitors and ARBs

Furthermore, in certain patients with diabetic neuropathies, treatment with renin and ACE inhibitors and ARBs togehter provides a greater renoprotective effect than

Treatment with just one

Hyperglycemia can induce -will make diabetic ketoacidosis more complicated

Hyperosmolality

Hyperosmolality will induce osmotic diuresis, resulting in a continuous siphoning off of

Intracellular K+

This siphoning of intracellular K+ an result in

Hyperkalemia

Furthermore, hyperkalemia with volume depletion (i.e. due to the osmotic diuresis) will stimulate -will exacerbate the loss in total body K+

Aldosterone secretion

It is not unusual for the DKA patient at the time of presentation to have eu- or hyperkalemia in the face of

Depleted total body K+

What is the key component in the treatment of DKA?

Insulin therapy

Remember that the most sensitive response to insulin is not cellular glucose uptake, but rather

Cellular K+ uptake

Plasma K+ levels generally fall with

Insulin therapy

The majority of Ca2+ and phosphorus that is reabsorbed is reabsorbed in the

Proximal tubule

Coupled to Na+ reabsorption within the proximal tubule and is also orchestrated by parathyroid hormone (PTH) and diuretics elsewhere in the nephron

The regulation of Ca2+ and PO4 reabsorption

Changes in serum calcium content signal the parathyroid glands to

Increase PTH secretion when Ca2+ is low and vice versa

Kidney tubular cells contain specific enzymes which hydroxylate 25-hydroxy vitamin D (calcidiol) to form

1, 25-dihydroxyl vitamin D (Calcitriol)

The formation of calcitriol is primarily stimulated by

PTH and hypophosphatemia

Renal Physiology VII Flashcards

(100 cards)