Renal Physiology VII Flashcards
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
Obesity is defined as a body mass index (BMI) of
Greater than 30kg.m^2
The deposition of fat in the regions of the hip and buttocks is not strongly correlated with
Metabolic disease
Whereas accumulation of visceral fat is linked with a syndrome that is described as
Type 2 DM
The distribution of fat around the abdominal wall and visceral mesenteric location
Android obesity
On the other hand, the presence of subcutaneous abdominal fat has less of an association with
Insulin resistance
Correlated with the development of hypertension and dyslipidemia, among other risk factors for cardiovascular disease
Android obesity
The android obesity phenotype results in an abnormally increased
Waist-to-hip tatio (greater than 0.9 in males and 0.85 in females)
Has a gene expression pattern that makes it distinct from other fat stores
Visceral fat
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
Each increae sensitivity to insulin
Leptin and adiponectin
Has been shown to impede insulin dependent glucose metabolism
TNFa
Impede both insulin secretion and insulin-directed glucose uptake in peripheral tissues
FFAs
FFAs stimulate dipocytes to secrete
TNFa
TNFa in turn exerts positive feedback on
FFA secretion
In response to insulin resistance, visceral fat undergoes
Lipolysis
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
Visceral fat thus increases
CV risk
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
The ideal goals for preventing the progression of IGT to Type 2 DM
Weight loss and exercise
A biguanide that impairs hepatic gluconeogenisis and intestinal glucose absorption, and enhances peripheral glucose uptake
Metformin
An insulin sensitizer
Thiazolideniones (pioglitazone)
Insulin secretagogues that promote endogenous insulin production
Sulfonylureas
Injectables or insulin pump that can replace pancreatic and islet cells
Insulin replacement
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?
- ) LActate (predominant)
- ) Glutamine
- ) 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 :
- ) Apical?
- ) Basolateral?
- ) 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?
- ) Supranormal GFR (hyperfiltration)
2. ) Microalbuminuria
What three things induce unfavorable glomerular remodeling?
- ) Hypertension
- ) Hyperlipidemia
- ) 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
