Biochem Flashcards
Key enzymes located in renal medulla
Hexokinase
Phosphofructokinase
Pyruvate kinase
Key gluconeogenic enzymes found in renal cortex
Pyruvate carboxylase
Phosphoenolpyruvate (PEP) carboxykinase
Fructose-1,6, -biphosphate
Glucose-6-phosphate
Energy requirment for renal medulla and end product? ONLY part of kidney that has all enzymes for gluconeogenesis
Glucose
Lactate (not CO2 and water)
Proximal tubule
Insulin and glucagon in kidney
Insulin: suppress glucose release
Glucagon: no effect on kidney
Kidney in contrast to liver because glucose release is increased after glucose ingestion
Metabolic fate of glucose in medulla? Cortex?
Medulla: obligate user of glucose (anaerobic) for energy (lactate end product)
Cortex: uses very little glucose, relies mainly on beta-oxidation of FFAs
Major energy requiring process in kidney is glucose reabsorption from glomerular filtrate in PCT
Filtered glucose is reabsorbed via
Two sodium dependent glucose co-transporters (SGLTs)
SGLT2: reabsorbes 90% glucose, low affinity-high capacity, in S1 segment. Associated with GLUT2
SGLT1: 10% glucose, high affinity-low capacity, located in S3, associated with GLUT1. TYPE 2 DIABETES MELITUS RE-ABSORPTIVE CAPACITY OF SGLT1 INCREASES BY 20%
Familial renal glucosuria (FRG)
Detectable amounts of urinary glucose at normal blood glucose concentrations
due to SLC52A (codes for SGLT2) mutation
mild glucosuria: heterozygous mutation
severe: homozygous or compound heterozygous
Glucose-galactose malabsorption syndrome (GGM)
Severe osmotic diarrhea, dehydration, and shock soon after glucose or galactose introduced into diet after birth
Mild glucosuria
due to SLC51A1 (encodes SGLT1) mutation
Autosomal recessive
Fanconi syndrome (aka De Toni-Fanconi syndrome)
Glucosuria in the setting of global impairment of proximal tubular function (also causes hypophosphatemia, hypouricemia, renal tubular acidosis and aminoaciduria)
presents with polyuria, polydipsia, dehydration, fever, bone deformities and fucked up growth
2 degree to inherited defects (see slides)
Cytinosis
Fanconi-Bickel syndrome (FBS)
presents at 3-10 months with combination of hepatomegaly (due to glycogen accumulation), Fanconi-type nephraopathy with severe renal glucosuria, hypoglycemia in the fasted state, and glucose/galactose intolerance in the fed state, and glucose/galactose intolerance in the fed state
due to mutations in the GLUT2 gene (autosomal-recessive). Expressed in both hepatocytes and at basolateral membrane of proximal tubules
Once in the kidneys glutamine is taken up and metabolized to
Ammonium ion (NH4+): acid-base balance, increased glutamine uptake in acidosis (metabolic and respiratory), results in compensatory increase of NH4+ excretion in urine
Alpha-ketogluterate, used for: glucose production, oxidized CO2 (TCA cycle), converted to alanine (via tranaminase)
Renal mucin
Mucin 1: encoded by MUC1 gene, heavily glycosylated protein located on apical surface of tubular cells, provides protective covering to lumina in the kidney, has signal transduction functions
Autosomal dominant tubulointerstitial kidney disease (ADTKD)
Bland urinary sediment with minimal blood and protein
Pathological changes: tubular and interstitial fibrosis, slowly progressive CKD
Caused by MUC1 frameshift mutation (also caused by mutations in the uromodulin gene), mutant protein aggregates and deposits in tubular cells (conformational disease)
Blood urea nitrogen (BUN)
Cleared by kidneys
PROS: well-established, measured cheaply & easily
Routinely measured in serum (enzyme/oxidation reaction assay)
CONS: levels affected by non-renal influences (protein intake, dehydration, liver function, GI bleeding, steroid use)
Assay often underestimates renal function due to interfering chromogens
Creatinine
Cleared by kidneys
PROS: well-established; measured cheaply and easily.
Measured in serum & urine: jaffe rate, high performance liquid chromatography (most sensitive, unaffected by chromogens)
Serum level used to estimate GFR
CONS: levels affected by non-renal influence, lacks sensitivity when renal impairment mild
Cystatin C
Cysteine protease inhibitor produced by uncleared cells/released into blood
Reabsorbed & catabolized by kidney tubules
PROS: recently emerged and reliable, serum level measured by immunonephelometry or ELISA
CONS: affected by steroid use or thyroid dysfunction
Uric acid
End product of purine catabolism; excreted by kidneys
circulating levels increase during renal impairment in CKD: predicts greater risk of end-stage renal disease
Kidney injury molecule-1 (KIM-1)
Transmembrane protein expressed on the luminal surface of injured proximal tubules
increased urine levels with tubulointerstitial damage correlate with increased renal expression
Neutrophil gelatinase associated lipocalin (NGAL)
Iron-transporting protein almost entirely reabsorbed by tubules in the normal kidney
Very good marker of acute kidney injury (indicates defects in proximal tubular reabsorption and in the distal nephron)
Bio markers of renal oxidative stress
OS evident in patients with moderate to severe CKD
Advanced glucagon end products (AGEs): irreversibly cross-linked derivatives of sugar/macromolecule complexes, increased formation during OS, accumulate in blood of diabetic and uremic patients
Pentosidine: serum and urine levels detected by HPLC or ELISA, predicts development of diabetic nephropathy
Biomarkers of renal fibrosis
TGF-beta1 & connective tissue growth factor: promote renal fibrosis, increase urine levels with progressing CKD
TGF-beta-inducible gene H3 (Big-H3), levels 1000X greater than TGF-beta1 in diabetes
Plasminogen activator inhibitor-1: levels correlate with renal injury and fibrosis in diabetic nephropathy and progressive chronic glomeruclonephritis
Collagen type IV: major component of kidney ECM (increases with progression of renal fibrosis), increased urine levels elevated in IgA nephropathy and diabetic nephropathy
IgG renal biomarker
Fractional excretion predicts progression of primary focal segmental glomerulosclerosis (FSGS) and its response to treatment
IgA
Urine levels can indicate renal damage severity in IgA nephropathy and correlate with proteinuria, serum creatinine and glomerulosclerosis in this disease
IgM
Urine levels strong predictor of disease progression for anti-nuclear cytoplasmic antibody-associated vasculitis
Interleukin-18
Pro-inflammatory agent produced by leukocytes, vessel, kidney tubules
Increased production by tubules during acute renal injury
Increased urine levels sensitive and specific marker of acute tubular necrosis (ATN) and delayed graft function in post-ischemic kidney
Monocyte chemoattractant protein-1 (MCP-1) or aka CC-chemokine ligand 2
Attracts monocytes and macrophages
Urine levels correlate with interstitial macrophage accumulation in lupus nephritis and diabetic nephropathy
Interferon-inducible protein 10 (IP-10) aka CxCL10
Attracts activated T cells
Urine levels increase in diabetic nephropathy and renal allograft rejection
CXC-chemokine ligand 16 (CXCL16)
Attracts activated T cells
Urine levels correlate with T-cell accumulation in acute and chronic renal diseases
Urine levels increase in lupus nephritis or renal allograft rejection
