医科大学精品课件：16-Nephroticsyndrome-／11／25.ppt

1、,Glomerular disease, Nephrotic Syndrome,Jihong Yang MD,Overview,Definition of glomerular disease Definition nephrotic syndrome Pathology of primary nephrotic syndrome and clinical features Diagnosis and Differential diagnosis Complications Treatment of primary nephrotic syndrome Secondary nephrotic

2、syndrome -Diabetic nephropathy -Lupus nephritis -Renal Amyloidosis -HBV-associated nephropathy,Glomerular Disease,A heterogeneous group of disease, manifestating with hematuria, proteinuria, edema and hyperension , etc,Primary glomerular disease Secondary glomerular disease Genetic glomerular diseas

3、e,Divided by etiology:,The most common syndrome of kidney disease,Acute Nephritic syndrome Nephrotic syndrome Asymptomatic urinary abnormalities Acute renal failure or Rapidly progressive renal failure Chronic kidney disease(Table 1),(一)急性肾炎综合征 (二)肾病综合征 (三)无症状性尿检异常 (四)急性及急进性肾衰竭综合征 (五)慢性肾脏病(表1),2012

4、KDIGO指南更新再强调： 蛋白尿水平及GFR是评估CKD进展的重要指标,图注：绿色：低风险（如没有其他肾脏疾病的标志物）；黄色：中度增加风险； 桔色：高风险；红色：非常高风险,持续性蛋白尿诊断标准和范围,Kidney inter., Suppl. 2012; 2: 337414.,Pathophysiology: Proteinuria,Figure 3.,Three main mechanism of proteinuria,Glomerular (increase filtration) Tubular (decrease reabsorption) Overflow (marked o

5、verproduction of a particular protein,Nephrotic Syndrome,It is not a disease but a group of signs and symptoms presents with edema proteinuria usually 3.5g / 24hrs serum albumin 30g/L other features: hyperlipidaemia, and hypercoaguable state,Pathophysiology,PRIMARY NEPHROTIC SYNDROME,Minimal Change

6、Disease Mesanginal Proliferative Glomerulonephritis Focal Segmental Glomerulosclerosis Membranous Nephropathy Membranoproliferative Glomerulonephritis (MPGN),Normal glomerulus,Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the

7、thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke.,Light micrograph of an essentially n

8、ormal glomerulus in minimal change disease. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary walls is normal, and there is neither expansion nor hypercellularity in the mesangial areas in the central or stalk regions of the tuft

9、 (arrows). Courtesy of Helmut G Rennke.,Minimal change disease,Minimal change disease,Minimal change disease,Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigit

10、ating foot processes (arrow). The GBM is thin and no electron dense deposits are present. Two normal platelets are seen in the capillary lumen. Courtesy of Helmut Rennke, MD.,Normal glomerulus,Electron micrograph in minimal change disease showing a normal glomerular basement membrane (GBM), no immun

11、e deposits, and the characteristic widespread fusion of the epithelial cell foot processes (arrows). Courtesy of Helmut Rennke, MD.,Minimal change disease,Minimal Change Disease,Most frequent cause of nephrotic syndrome in children. generalized edema with normal renal function and selective proteinu

12、ria. Hematuria is absent and patients are normotensive. LM - Normal. IF - Negative. EM -foot process fusion. Responds readily to steroids, although relapses are common. The long term prognosis is excellent. Steroid resistant patients may progress to FSGS.,Membranous nephropathy,Most common cause in

13、adults. Especially elderly people. LM: glomerular basement membrane thickening with no cellular proliferation . IF:granular deposits of IgG and C3 along the basement membrane. EM: thickening of basement membrane and foot process fusion. The prognosis is variable. Spontaneous remissions occur in some

14、 cases whereas others progress slowly to chronic renal failure. Steroids and immune suppressive agents may be effective in retarding the progression to renal failure.,Immunofluorescence microscopy of MN (IgG),Membranous nephropathy,Light micrograph of membranous nephropathy, showing diffuse thickeni

15、ng of the glomerular basement membrane (long arrows) with essentially normal cellularity. Note how the thickness of the glomerular capillary walls is much greater than that of the adjacent tubular basement membranes (short arrow). There are also areas of mesangial expansion (asterisks). Immunofluore

16、scence microscopy (showing granular IgG deposition) and electron microscopy (showing subepithelial deposits) are generally required to confirm the diagnosis. Courtesy of Helmut Rennke, MD.,Complications,Infection Coagulation disorders Acute renal failure Protein malnutrition and dyslipidemia,The imp

17、airment of normal defense is not well understood;,Low levels of immunoglobulin G,Infection,Patients with the nephrotic syndrome are susceptible to infection, which was the leading cause of death in children with the nephrotic syndrome before antibiotics became available. Pneumonia,peritonitis were p

18、articularly common,Complications,decreased levels of antithrombin , plasminogen (urinary losses),hyperfibrinogenemia,increased platelet activation,10 to 40 percent of patients develop venous thromboemboli, particularly deep vein and renal vein thrombosis Renal vein thrombosis can present acutely or,

19、 much more commonly, in an indolent manner. The acute presentation includes flank pain, gross hematuria, and a decline in renal function. .,Thromboembolism,Hypercoagulability,Hypovolemia,Interstitial edema,Renal perfusion,Obstruction of tubular lumen,Renal vein thrombosis,Nonsteroidal antiinflammato

20、ry drugs And other drugs,Pre-renal,Renal failure,Acute Renal Failure,hypoalbuminemia,Malnutrition Retardation,negative nitrogen balance,hyperlipidemia,Urinary loss of hormones: vitamine D, T3 and T 4 Edema of the gastrointestinal tract: anorexia and vomit,Infection,Immunoglobin,Thrombosis and emboli

21、,Cardiovascular disease events,accelerated atherosclerosis,Protein malnutrition,Amyloidosis,Lupus nephritis,Diabetic nephropathy,Nephrotic syndrome associated malignance,Differential Diagnosis,Rest Dietary: sodium and water restriction (approximately 3 g/day) Diuretics Lower intraglomerular pressure

22、 Statin therapy do not recommend routine prophylactic anticoagulation.,General therapy (Nonimmunosuppressive therapies ),Treatment,Immunosuppressive therapy,Treatment,Glucocorticoids Other immunosuppressive agents Cyclophosphamide or cyclosporine A alone or in combination with prednison for relapsin

23、g, glucocorticoid-dependent disease or glucocorticoid-resist disease.,Daily oral prednisone (1 mg/kg per day to a maximum of 80 mg/day) A single dose upon awakening (usually betwee seven and nine AM) Some clinicians prefer alternate-day prednisone from the beginning to minimize the toxicity of long-

24、term daily prednisone, at an initial dose of 2 mg/kg every other day (to a maximum dose of 120 mg) Minimum of eight weeks, maximum duration is 16 weeks Slow tapering is performed both to sustain the remission and to avoid adrenal suppression,Glucocorticoid therapy,Response to Glucocorticoid therapy,

25、A complete remission is a reduction in proteinuria to 300 mg/day. A partial response is a reduction in proteinuria of 50 percent, with absolute values between 300 mg and 3.5 g/day. A relapse is return of proteinuria to approximately 3.5 gm/day in patients who had previously undergone a complete or p

26、artial remission. Glucocorticoid-dependence refers to relapse while requirement for continuation of steroids to maintain remission Glucocorticoid-resistance refers to little or no reduction in proteinuria after 16 weeks of adequate prednisone therapy.,Infectious disease :Heightened risk of typical i

27、nfections Opportunistic infections: Herpes zoster Endocrine: Diabetes mellitus Bone: Osteoporosis Gastrointestinal :Peptic ulcer disease, Pancreatitis,UGB Eye: Elevated intraocular pressure/glaucoma, Exophthalmos Cardiovascular: Hypertension Dermatologic and soft tissue:Skin thinning and purpura, Cu

28、shing appearance, Acne.,Major side effects associated with corticosteroid therapy,Cyclophosphamide （CTX） Azathioprine （AZA） Cyclosporine （CysA） Mycophenolate （MMF） Tacrolimus (FK506),Immunosuppressive agents,Not the first choise and dont use alone Frequently relapsing, glucocorticoid-dependent or gl

29、ucocorticoid-resist cases,Immunosuppressive agents,A 12-week course of 2 mg/kg per day of cyclophosphamide Cumulative dose of 168 mg/kg Neutropenia and infection Bone marrow suppression Gonadal toxicity a total dose greater than 200 to 300 mg/kg for CTX, Malignancy acute lymphoblastic leukemia. Alop

30、ecia and hemorrhagic cystitis Liver function injury. Others,cyclophosphamidemost commonly use,Alkylating agents,Cyclosporine at a dose of 3 to 5 mg/kg per day to maintain whole blood trough levels of 100 to 200 g/L at least six months Cyclosporine solution can be mixed with milk, chocolate milk, or

31、orange juice (but not grapefruit juice) at room temperature. Tacrolimus is 0.05 mg/kg per day to maintain whole blood trough levels between 3 and 5 g/L. The dose may be increased to achieve a higher trough level between 5 and 8 g/L, if there is no reduction in proteinuria by two months, providing th

32、e renal function has not worsened.,DOSAGE AND ADMINISTRATION Calcineurin inhibitors,Nephrotoxicity Neurotoxicity severe headache, visual abnormalities, and seizures Metabolic abnormalities Glucose intolerance Infections Bacterial, viral and fungal infections Risk of malignancy Other side effects Gas

33、trointestinal side effects include anorexia, nausea, vomiting, diarrhea and abdominal discomfort,Adverse effect associate with Calcineurin inhibitors,The target dosage of MMF is generally between 1.5 to 2 grams daily. Starting with lower doses at first (eg, 500 mg daily for several days) may improve

34、 patients gastrointestinal tolerance of MMF Adverse effect: Bone marrow suppression: cytopenias , require regular monitoring Gastrointestinal nearly 75 percent initially had gastrointestinal (GI) symptoms, including nausea, diarrhea, and abdominal cramping. These symptoms were tolerated better with

35、time,Mycophenolate mofetil: (MMF),Treated with heparin followed by warfarin The goal INR is 1.5 to 2.0 Duration of anticoagulation Warfarin therapy is given for a minimum of 6 to 12 months. As long as the patient remains nephrotic.,Serum albumin below 2.0 g/dL (20 g/L),Optimal therapy of hypercoagul

36、ability,Lotension,Losartan,Vasartan ,etc lower intraglomerular pressure, reduction in protein excretion, slow the rate of disease progression. It is not dependant to the antihypertensive effect. It is positively related to the dose of drug.,ACEI and ARB,Acute renal failure Hyperkalemia Notices: Hypo

37、volummia, use NSAID together,Side effects,Clinical Features and Pathology of Primary Nephrotic Syndrome,20 percent of cases of steroid-resistant NS are due to mutations of the NPHS1,NPHS2, WT1 gene. In patients with steroid-resistant NS due to gene mutation, we do not recommend immunosuppressive the

38、rapy Optimal treatment of SRNS not due to a genetic disorder is unknown, A combination of cyclosporine and prednisone is recommended,. Alternatively, cyclophosphamide, and tacrolimus have also been used.,Hot points 1: About FSGS,Secondary Glomerular Disease -Secondary nephrotic syndrome,Why talk abo

39、ut diabetic nephropathy?,Most common single cause ESRD in the US, Europe, and Japan 17 million diabetics in the US 20-30% diabetics (both type I and type II) develop diabetic nephropathy 40% ESRD in US related to diabetic nephropathy,Definition,A microvascular complication of diabetes marked by albu

40、minuria, elevated blood pressure, and a deteriorating course from normal renal function to ESRD.,Clinical features,Gradually progressive proteinuria Microalbuminuria is first clue Bland urine sediment no RBCs, casts, etc Gradually decreasing GFR Patients asymptomatic, but develop worsening hypertens

41、ion,Nature course,How to distinguish from another kidney disease,Likely diabetes: Macroalbuminuria Microalbuminuria, and Presence of diabetic retinopathy Type 1 diabetes for at least 10 years No active urinary sediment,Likely another cause of CKD: Absence of retinopathy Rapidly decreasing GFR hematu

42、ria Refractory hypertension Signs or sx of other systemic disease,Treatment,Early screening Tight glycemic control HTN management Use ACEI as first line, if not tolerated, use ARB. Use the maximum dose as tolerated,Lupus nephritis,Systemic lupus erythematosus (SLE)is a multisystem, autoimmune ds. wi

43、th antibodies directed against a wide variety of cellular components Lupus nephritis is one of the most serious manifestations of (SLE).,Frequency, race,sex and age,The prevalence of SLE is 1 case per 2000 in the general population. SLE is more common in black people, Hispanic people and Asian than

44、in white people. lupus nephritis more common in females and typically occurs in patients aged 20-40 years; clinical renal disease with a worse prognosis is more common in males with SLE.,Clinical features,Various organ systems are effected, like skin, joints, serous membranes, heart, neurologic, blo

45、od and the kidneys. Rash, oral or nasal ulcers, synovitis, fatigue, fever, arthritis, serositis, edema, etc.,Clinical signs,Laboratory Studies,Tests of SLE disease activity Disease activity: ANA, anti-dsDNA, C3, C4, and CH50 , ESR or CRP. Creatine,urea,urialysis Renal biopsy is useful in determining

46、 prognosis and treatment. IF: Full house.,Lupus Nephritis,Pathology of lupus nephritis,Amyloidosis,Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils that injure tissue.,Amyloidosis,AL amyloid (primary amyloid) associated with plasma cell disorders, m

47、ostly overt myeloma AA amyloid (secondary amyloid) is an acute phase reactant associated with chronic inflammatory diseases like tuberculosis, osteomyelitis, rheumatoid arthritis and bronchiectasis More common in elderly The amyloid is an eosinophilic extracellular substance, Congo red stain positiv

48、e and blue-green birefringence.,Amyloidosis,A range of clinical presentations with renal, heart, gastrointestine, local deposition and other problems Renal failure and nephrotic range proteinuria are the most common renal presentation Abnormal elevating of Monoclonal Ig in blood and light chains (Be

49、nce Jones) in urine in AL amyloid. Related renal disorders include light chain deposit disease, fibrillary GN and immunotactoid GN Prognosis for is poor.,Monoclonal pattern SPEP,Urinary monoclonal protein,Panel B: A dense, localized band (red asterisk) representing a monoclonal protein of gamma mobility is seen on serum protein electrophoresis on agarose gel (anode on left). Panel A: Densitometer tracing of these findings reveals a tall, narrow-based peak (red asterisk) of gamma mobility and a