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1、1,Diabetic Nephropathy,2,Diabetic nephropathy is the leading cause of chronic renal failure in the industrialised world.It is also one of the most significant long-term complications in terms of morbidity and mortality for individual patients with diabetes.Diabetes is responsible for 30-40% of all e
2、nd-stage renal disease (ESRD) cases in the United States.Although both type 1 diabetes mellitus (insulin-dependent diabetes mellitus IDDM) and type 2 diabetes mellitus (noninsulin-dependent diabetes mellitus NIDDM) lead to ESRD, the great majority of patients are those with NIDDM.,3,The glomeruli an
3、d kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency, wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).,4,Signs and Symptoms Approximately 25% to 40% of patie
4、nts with DM 1 ultimately develop diabetic nephropathy (DN), which progresses through five predictable stages.,5,Stage 1 (very early diabetes)Increased demand upon the kidneys is indicated by an above-normal glomerular filtration rate (GFR). Hyperglycemia leads to increased kidney filtration (see lat
5、er) This is due to osmotic load and to toxic effects of high sugar levels on kidney cells Increased Glomerular Filtration Rate (GFR) with enlarged kidneys,6,Stage 2 (developing diabetes)Clinically silent phase with continued hyper filtration and hypertrophy The GFR remains elevated or has returned t
6、o normal, but glomerular damage has progressed to significant microalbuminuria (small but above-normal level of the protein albumin in the urine). Significant microalbuminuria will progress to end-stage renal disease (ESRD).Therefore, all diabetes patients should be screened for microalbuminuria on
7、a routine basis.,7,Stage 3 (overt, or dipstick-positive diabetes)Glomerular damage has progressed to clinical albuminuria.Basement membrane thickening due to AGEP The urine is “dipstick positive,“ containing more than 300 mg of albumin in a 24-hour period.Hypertension (high blood pressure) typically
8、 develops during stage 3.,8,Stage 4 (late-stage diabetes)Glomerular damage continues, with increasing amounts of protein albumin in the urine.The kidneys filtering ability has begun to decline steadily, and blood urea nitrogen (BUN) and creatinine (Cr) has begun to increase.The glomerular filtration
9、 rate (GFR) decreases about 10% annually. Almost all patients have hypertension at stage 4.,9,Stage 5 (end-stage renal disease, ESRD)GFR has fallen to 10 ml/min and renal replacement therapy (i.e., haemodialysis, peritoneal dialysis, kidney transplantation) is needed.,10,11,12,13,14,NORMAL GBM. LEFT
10、 - a single glomerulus. There are one million of these in each kidney. RIGHT - a close up of the GBM (G) around part of one tiny blood vessel in a glomerulus (red circle in left hand diagram),15,Glomerular Histology: The glomerular capillary wall is composed of an endothelial cell layer (blood side)
11、, a thick basement membrane, and epithelial cell layer (urine side).(i) Glomerular EndotheliumThe glomerular endothelium is fenestrated. The fenestrae (0.07 to 0.1 mm-micrometers- in maximal diameter) allow the passage of electrolytes, proteins, and globulin.However, platelets (3 mm), red cells (7 m
12、m) and neutrophils (15 mm) cant pass through the endothelial layer.,16,(ii) Glomerular Basement Membrane (GBM):The GBM is a tri-laminar structure, 0.3 microns in thickness, composed of collagen, proteoglycans and laminin.It is product of the fusion of the endothelial and epithelial basement laminae.
13、The dense central GBM area, or lamina densa, is due to the overlapping of the two laminae. Around 50% of the GBM is collagen IV.,17,The negative charge of the GBM has been attributed to the presence of the heparan sulphate proteoglycan (HSPG) called perlecan. These negatively charged molecules are g
14、eometrically arranged in clusters separated by about 0.003 m from each other. This anionic molecular sieve restricts the passage of molecules according to size and charge. Water, salts, glucose, amino acids and neutral, or cationic, molecules with radii less that 0.0035 m are filtered with relative
15、ease. The albumin molecule measures 0.0035 m and is negatively charged. Therefore its filtration is restricted.,18,Presence of protein in the urine is a sign that either the charge or the distance between the anionic clusters, or both, are pathologically altered.The presence of red cells in the glom
16、erular urine, is certain indication of GBM ruptures.Other classical constituents of the basement membrane are type IV collagen, laminin, and entactin.,19,Glomerular mesangium:The intra-capsular glomerular capillary network is kept together by the mesangium that is is composed of mesangial cells type
17、 I and II, and other tissue matrix.Mesangial type I cells are monocytes with phagocytic functions. These cells can extend cytoplasmic projections into the glomerular capillary.They also “clean“ the mesangium of materials that leak from the capillary lumen into the matrix. These cells are stimulated by cytokines to produce free radicals and cytotoxic peptides.,
