Diabetic Nephropathyx

Diabetic Nephropathy Glomerular Pathology: LM • Nodular intercapillary lesions (Kimmelstiel-Wilson Nodules) o Micro-aneurysmal dilation of capillary loop with mesangiolysis o 10-50% of biopsies o Seen in other forms of CKD: amyloidosis, MPGN • Diffuse glomerular lesions o More frequently seen in T1DM >10 years o Mesangial expansion o Correlated with worsening renal function • GBM thickening: 3x normal range • Hyaline material replaces vascular structures in both AA and EA • Podocytopathy o ↑Foot process width o ↓Foot process number o Proteinuria Pathogenesis Haemodynamic Changes: Glomerular Hyperfiltration • Dilation of AA o Insulin-like growth factor (IGF-1): stimulates cell growth and proliferation, inhibits apoptosis o ANP (↑Na  ↑Blood volume  ↑ANP release) o Early glycation products o Intracellular sorbitol o ↑tubular Na Hyperfiltration occurs as a result of: • Intraglomerular hypertension  ↑GFR • Glomerular hypertrophy Advanced Glycation End Products • Excess glucose + free amino acids  AGEs • This can occur in circulation or with tissue proteins • This non-enzymatic process initially forms o Early glycation products (reversible) o Advanced glycation end products (irreversible) • AGEs accumulate in tissues and contribute to renal and microvascular complications • ↑AGEs in diabetics but ↑↑↑ AGEs in diabetics with renal insufficiency because AGEs are usually secreted in the urine • ↑AGEs in tissues leads to crosslinking with collagen  renal complications 𝐾1 𝐾2 𝐾𝑛 Intermediate 𝐾𝑧 Glucose + Protein ↔ Schiff Base ↔ Amadori Product → Glycosylation → AGE Product • K1: hours • K2: days • Kn: weeks AGE Mechanisms • Accumulation of ages in ECM cause collagen crosslinking  ↓Vessel elasticity • Binding of AGEs to AGE receptors (RAGEs) on different cell types and activation of key cell signalling pathways such as NFκB activation with subsequent modulation of gene expression of inflammatory cytokines HbA1C • Glycated Hb • RBCs are freely permeable to glucose • Rate of Hb glycation is proportional to blood glucose concentration • Indicated blood glucose levels over lifespan of RBC (120 days) Risk Factors for Diabetic Nephropathy • Genetic susceptibility o Likelihood of developing diabetic nephropathy is increase in patients with diabetic siblings or parents with diabetic nephropathy • Blood pressure o ↑Na and water reabsorption via increased glucose reabsorption in PCT o DM  vascular stiffness due to ↑protein glycation and later atheromatous disease • Race o ↑incidence and severity in blacks, Mexicans, PimaIndians with T2DM • Obesity o High BMI has a strong link to ↑risk of CKD and DM • Diabetic control o Glycaemic variability: the effects of fluctuations in glucose levels is implicated in endothelial damage and atherosclerotic plaque formation • Smoking o ↑Albuminuria and risk of ESKD • Contraceptives • GFR • Age Inflammation and Cytokines • Hyperglycaemia stimulates: o ↑VEGF (Vascular Endothelial Growth Factor) expression VEGF is a mediator of endothelial injury in diabetics  VEGF blockade improves albuminuria o ↑TGF-β (Transforming Growth Factor β) expression   In glomeruli and matrix proteins Contribute to both cellular hypertrophy and enhanced collagen synthesis o ↓Renal BMP-7 (Bone Morphogenic Protein 7) expression   Counteracts profibrogenic actions of TGF-β Proteinuria The earliest sign of diabetic nephropathy is moderately increased albuminuria • Urine dipstick is not sensitive (positive for 300-500mg/day) • Specific albumin assay more specific o Normal albumin excretion: <30mg/day (mcg/min) o Moderate/microalbuminuria: 30-300mg/day (20-200mcg/min) o Severe/macroalbuminuria: >300mg/day (>200mcg/min) • Urine albumin to creatinine ratio is an untimed sample o 3.434mg/mmol of creatinine suggests albumin excretion is 30300mg/day Proteinuria • Glomerular capillary walls limit filtration via size and charge selectivity • ↑number of large pores (limits size selectivity) • ↓Heparin sulphate (major component of charge barrier) Rate of Decline in GFR (mL/min/year) Type I Type II Normoalbuminuria 1.2-3.6 0.96 Microalbuminuria 1.2-3.6 2.4 Overt nephropathy 9.6-12.0 5.4-7.2 1. Microalbuminuria. Kidney function normal. Glomerular hyperfiltration and eGFR rise 2. Proteinu ria increases over 10-15 years, nephrotic syndrome may develop 3. Renal function deteriorates. 5-10 years later, kidneys are almost unable to remove waste 4. ESKD. Toxic levels of waste in blood. Prevention and Treatment Glycaemic Control • Intensive insulin therapy • Can partially reverse glomerular hypertrophy and hyperfiltration • Can delay progression of albumin excretion • Can stabilise or decrease protein excretion in patients with albuminuria (2 years of normoglycaemia needed) • Restoration of euglycaemia with pancreas transplantation in T1DM patients prevents recurrent nephropathy in renal allograft Preservation of Renal Function • ACE-inhibitor actions: o ↓Systemic BP o EE vasodilation  ↓Intraglomerular pressure o ↓TGF-β expression o Improves nephrin o ↓Podocyturia • CARI guidelines o Lower systolic BP minimizes the risk of progression to ESRD, especially with proteinuria. (Level II evidence) A target BP of < 125/75 mmHg (or mean BP < 92 mmHg) if proteinuria > 1gm/24 hours, may be beneficial. (Level II evidence) o A target BP of < 130/80 mmHg (or mean BP < 97 mmHg) if proteinuria is o 0.25 – 1g/24 h, may be beneficial. (Level II evidence) o Target BP should be < 130/85 mmHg (or mean BP < 100 mmHg) if proteinuria < 0.25 g/24 hours. (Level II evidence) However, there may be other potential benefits of achieving lower BP than a mean of 100 mmHg with respect to reduced cardiovascular risk.” Reduction of Proteinuria • ↓Intraglomerular pressure needed • ACE-Is and ARBs used • Salt restriction and diuretics enhance effects of RAAS blockade  Avoid high protein diet Risk Factor Reduction • Weight reduction • Lipid reduction (to reduce atherosclerosis and glomerular sclerosis) • Smoking cessation