Nephrotic Syndrome (NS) Qiang Yao Renal Division, Renji Hospital Shanghai 2nd Medical Universigy Firstly, I have to apologize here that Prof. Qian could not come today, who is still in US. He is the vice president of Chinese Society of Nephrology and president of Shanghai Society of Nephrology. Maybe you will have some chances to listen to him later. OK, now let me introduce myself. I am Qiang Yao from Renal Division of Renji Hospital. I graduated from the same university with different name. What I am talking today is about one of the most common syndrome in Renal Disease, that is Nephrotic syndrome(肾病综合症).I hope my presentation today could help you comprehensive the kidney disease more and fit your interesting.

Introduction Etiology Pathophysiology Pathology and clinical feature Complications Diagnosis and differential diagnosis Treatment

Diagnosis: Proteinuria: >3.5g/d Hypoalbuminemia: SAlb <30g/L Edema; Hyperlipidemia. The nephrotic syndrome results from greater than 3.5g/d proteinuria and is characterized by edema, hyperlipidemia, hypoproteinemia and other metabolic disorders. We will explain these features one by one. We skip the proteinuria.

Hypoproteinemia Albumin Immunoglobulins Metal binding proteins Erythropoietin urinary loss Transferrin Complement deficiency Coagulation components Hypoalbuminemia is a cardinal feature of the NS. Please remember, serum albumin level are depressed not only as a consequence of loss in the urine but also because of an increased albumin catabolism. Although there is a correlation between the amount of proteinuria and the degree of hypoalbuminemia, some individuals have normal, or near normal, levels of albumin despite severe proteinuria. Prolonged and massive proteinuria may lead to malnutrition.

Hyperlipidemia Hypercholesterolemia Hypertriglyceridemia Low-density lipoproteins (LDL) Very low- density lipoproteins (VLDL) Hyperlipidemia is one of the sentinel features of the NS. Patients develop numerous alterations in lipid profiles including hypercholesterolemia and hypertriglyceridemia with increases in both LDL and VLDL

chemical composition of plasma lipoprotein (%) CM VLDL LDL HDL protein 2 10 20 45 lipide 98 90 80 55 triglyceride 88 55 8 10 phospholipid 6 20 24 22 cholesterol total 4 15 48 23 free 1 5 8 6 ester 3 10 40 17 lipide/protein 40~50 9 4 1~1.5 不同的脂蛋白因其组成（所含的脂类、蛋白质）以及密度的不同， 分为CM、 VLDL、 LDL、 HDL。

HL 和LpL来自同一家族，同样具有催化血浆中脂蛋白所含的甘油三脂水解，释放自由脂肪酸、甘油一脂和甘油二脂。尽管同源性，两者还是有不同：1）分布不同。HL 由肝细胞产生，附于肝细胞和肝内皮细胞上，LpL由脂肪细胞产生并局限在脂肪、肌肉和心肌层。2）LpL的活性需要ApoC-II，而HL不需要，因此HL可以水解不含ApoC-II的IDL和CM。3）HL可作为磷脂酶帮助HDL2转HDL3. 因此，两者的缺乏，可使甘油三脂、VLDL、IDL、 CM上升。 LCAT(卵磷脂胆固醇酰基转移酶)在HDL的成熟，即HDL2-HDL3的过程中，酯化胆固醇起到重要作用。在肾病综合症中，（尿中丢失和活性下降）蛋白尿-低蛋白血症，使蛋白结合的溶血卵磷脂减少，LCAT的作用减低。 ACAT(乙酰辅酶A胆固醇酰基转移酶)，催化细胞内胆固醇的酯化，并在几乎所有哺乳动物细胞内形成胆固醇酯。在肾病综合症中，ACAT2过度表达，可使胆固醇的酯化上升，降低局部胆固醇，从而，上调HMG-CoA还原酶，升高胆固醇合成，同时降低7a-羟化酶，使胆固醇分解代谢下降。 CETP(胆固醇酯化转移蛋白)，合成上升，催化富含胆固醇酯的HDL2和VLDL的残粒相互作用，生成LDL. Fig. 1.  Metabolism of liver derived lipoproteins. Very-low density lipoprotein (VLDL) is secreted by the liver and then hydrolyzed on the vascular endothelium by LPL. Lipoprotein lipase (LPL) is bound electrostatically to heparan sulfate and, in the presence of apolipoprotein C-II (apoC-II) hydrolyzes triglycerides (TG). LPL is important in binding of VLDL to the vascular endothelium and VLDL receptor. Surface constituents of VLDL, free cholesterol and phospholipids participate in the formation of nascent high density lipoprotein (HDL). Free cholesterol on the surface of nascent HDL is esterified by lecithin cholesterol acyltransferase (LCAT) to form cholesterol esters. These sink into the core as nascent HDL is converted to HDL3, and finally into cholesterol ester (CE) rich HDL2. The TG depleted VLDL remnant particle is released and then either taken up by liver directly via the remnant receptor, which recognizes apo E, or interacts with CE rich HDL2. In that interaction, catalyzed by cholesterol ester transfer protein (CETP), the CE rich core of HDL2 is exchanged for the TG rich core of the VLDL remnant, yielding a TG rich HDL molecule (not shown) and LDL, which is then taken up by the liver through the LDL receptor. HDL2 is processed by lipase to HDL3 to continue the cycle. LDL also may be synthesized directly, thorough pathways other than delipidation of VLDL. This is evident in some nephrotic patients. Synthesis of both LDL and Lp(a) are increased in nephrotic patients. Broken lines connote pathways believed to have increased synthesis in nephrotic patients

Mechanisms of Hyperlipidemia Increased hepatic synthesis of LDL, VLDL and lipoprotein (a) in response to hypoalbuminemia Urinary loss of HDL Enzymatic changes with abnormal lipid biosythesis and degradation 引起脂类代谢紊乱的原因在于蛋白尿而非低蛋白血症

Edema Lower colloid osmotic pressure? 15mmHg H2O

Edema Water and sodium retention? Does it related with renin-angiotensin-aldosterone system?

How many pathological types causes nephrotic syndrome?

Glomerular diseases that cause NS–-- Minimal Change Glomerulopathy Epidemiology: It is most common reason of NS in children, accounting for 80-90% of young patients with nephrotic syndrome , while only 20-25% in adults. There appears to be a male preponderance, especially in children, in whom the male- to- female ratio is 2~3 :1

Glomerular diseases that cause NS–-- Minimal Change Glomerulopathy Pathology No glomerular lesions by light microscopy No staining with antisera specific for immunoglobulins or complement components. Effacement of visceral epithelial cell foot processes

Glomerular diseases that cause NS–-- Minimal Change Glomerulopathy Clinical features: The cardinal clinical feature of minimal change glomerulopathy in children is the relatively abrupt onset of proteinuria and development of the NS. Hematuria, hypertension and impaired renal function are not common.

Glomerular diseases that cause NS–-- mesangial proliferative GN Epidemiology: It is a common reason of NS in our country, accounting for 30% of primary nephrotic syndrome, higher than those in western.

Glomerular diseases that cause NS–-- mesangial proliferative GN Pathology Diffuse proliferation of mesangial cells and ECM Positive staining with IgA, IgG, IgM or C3 in mesangial area Dense deposits in mesangial area

Glomerular diseases that cause NS–-- Mesangial Proliferative GN Clinical features: 50% has infection before onset of renal disease. Non-IgAN: 50% with NS, 70% with hematuria IgAN:15% with NS, almost all with hematuria

Glomerular diseases that cause NS–-- Mesangial Capilary Glomerulonephritis Epidemiology: It is accounting for 10% of nephrotic syndrome patients in our country .

Glomerular diseases that cause NS–-- Mesangial Capilary Glomerulonephritis Pathology Severe diffuse proliferation of mesangial cells and ECM, demonstrating doubling and more complex replication of glomerular basement membranes Peripheral granular to bandlike staining for C3 and IgG Dense deposits in mesangial subendothelial area

Almost all of patients with hematuria Glomerular diseases that cause NS–-- Mesangial Capilary Glomerulonephritis Clinic feature: 30% has infection before onset of renal disease (nephritic syndrome), half of them present as a nephrotic syndrome. Almost all of patients with hematuria Early onset of impairment of renal function, hypertension, anemia Progressive procedure (10 year renal survival rate was less than 65%)

Glomerular diseases that cause NS–-- Membranous Glomerulopathy Epidemilology Idiopathic membranous glomerulopathy is the most common cause for nephrotic syndrome in adults

Glomerular diseases that cause NS–-- Membranous Glomerulopathy Pathology Subepithelial immune complex; projections of basement membrane; deposits surrounded by basement membrane; thickened basement membrane IgG and C3 positive staining in capillary

Glomerular diseases that cause NS–-- Membranous Glomerulopathy Clinic feature: 80% with NS 5-10 years later, renal function declined Renal vein thrombosis is not uncommon (4-52%)

Glomerular diseases that cause NS–-- Focal Segmental Glomerulosclerosis Epidemilology Over the past two decades, there has been an increased incidence of FSGS, accounting for 10% in our country. Some cases developed from minimal changes GN.

Glomerular diseases that cause NS–-- Focal Segmental Glomerulosclerosis Pathology It is characterized by focal and segmental glomerular sclerosis Nonsclerotic glomeruli and segments usually have no staining for immunoglobulins or complement.

Glomerular diseases that cause NS–-- Focal Segmental Glomerulosclerosis Clinic feature: NS With hematuria Hypertension and renal function declining are common

Diagnosis Diagnosis: NS? Primary or secondary? Complications?

Differential diagnosis Primary Secondary children minimal change allergic purpura nephritis Teenager mesangial proliferative FSGS nephritis Middle age mesengial capillary SLE LN old age membranous myeloma, amyloidosis nephropathy

Complications Infection malnutrition loss of immunoglobulins corticosteroids Thrombosis coagulation, coricosteroids, PLT activity

Complications Acute renal failure( ARF) Hypoalbuminemia Hypovolemia pre-renal azotemia Dyslipidemia

Treatment Support care Rest in bed; limitation of protein intake(0.8-1.0g/kg/d); limitation of salt intake (<3g/d) Diuretic therapy Diminishing proteinuria: ACEI and ARB

Treatment Corticosteroid therapy (onset): Inhibition of inflammation and immune response Corticosteroid therapy (onset): for children: prednisone 60mg/m2/d for adult: prednisone 1mg/kg/d (<80mg/d) 4-6 weeks later , complete remission of proteinturia occurs, the dosage then decreased (10% every 1-2 weeks). Be careful for the side effects of corticosteroid therapy

Patterns of response of cordicosteroids Prognosis: Primary responder, no relapse (steroid sensitive) Primary responder with only one relapse in the first 6 mo after an initial response Initial steroid response with two or more relapses within 6 mo (frequent relapse) Initial steroid-induced remission with relapses during tapering of corticosteroid, or within 2 wk after their withdrawal (steroid dependent) Steroid-induced remission, but no response to a subsequent relapse No response to treatment (steroid resistant)

Treatment Cytotoxic drugs with corticosteroid: Cyclosporine (for steroid dependent or steroid resistant) Cyclophosphamide (CTX): p.o. or intravenously Side effects: liver injury, inhibition of bone marrow, etc. Cyclosporine (for those failed responsing to combination of steroid and cytotoxic drugs) Dose: 5mg/kg/d, bid, p.o. Side effects: renal and liver toxic injury, expensive, etc.

Treatment Mycophenolate mofetil, MMF (for steroid dependent or steroid resistant) Dose:1.5-2g/d, bid, p.o. for 3-6 months, maintaining 0.5 year

Treatment Minimal changes: sensitive to steroids; single drug; reuse when relapse; combined with cytotoxic drugs when resistant or dependent on steroids Membranous GN: combine steroid with cytotoxic drugs or cyclosporin; avoid using drugs when Scr>354umol/L; for the patients with risks for progressing, otherwise, investigate 6 months (antihypertensive).

Treatment FSGS: sensitive to steroids in 30-50% of patients; slow response to therapy; steroids therapy (onset) for 3-4 months; if not response until 6 month (resistant), then try cyclosporine. Mesangial proliferative GN: no evidence show that adults will response to steroids; aspirin

Treatment Treatment for complications Infection Thrombosis ARF（HD; cordicosteroids, diuresis, SB） dyslipidemia