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Nephrotic syndrome final shivaom
Nephrotic syndrome is defined by heavy proteinuria, hypoalbuminemia, edema, and hyperlipidemia. It is caused by damage to the glomerular basement membrane that increases pore size and protein leakage. Loss of protein like albumin leads to edema as serum oncotic pressure decreases. Steroids are first line treatment but some patients are steroid resistant. Kidney biopsy guides treatment, which may include immunosuppressants for steroid resistant forms. Complications include infection, hypercoagulability, and renal failure.
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- 1. Nephrotic Syndrome A PRESENTATION BY:DR. SHIVAOM CHAURASIA 1ST YEAR RESIDENT DEPATMENT OF INTERNAL MEDICINE
- 3. Defination: The term“nephrotic syndrome” refers to a distinct constellation of clinical and laboratory features of renal disease . It is specifically defined by the presence of Proteinuria (>3.5g per day) Hypoalbuminaemia (< 3.5 g/dl) Generalized oedema Hyper lipidemia and thrombotic disease are also frequently observed
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- 5. PATHOPHYSIOLOGY PROTEINURIA Occurs becauseof structural damage to glomerular basement membrane which leads to increase in size and number of pores , allowing passage of more and larger molecules Electrical charge also involved in glomerular permeability destruction of fixed negatively charged components in glomerular disease is a key factor in genesis of heavy proteinuria
- 6. PATHOPHYSIOLOGY HYPOALBUMINAEMIA Urinary lossof 3.5 gram daily or more is required to cause hypoalbuminaemia Normal liver synthesis 10-12 g/day so how does daily protein loss of 3.5gm/day cause hypoalbuminaemia??? This can be explained by increased catabolism of of reabsorbed albumin in proximal tubules during the nephrotic symdrome even though actual albumin synthesis rate is increased . In addition , Dietary intake of protein increases albuminuria. So that the plasma albumin concentration tend to decrease during consumption of high protein diet.
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- 8. OEDEMA Patients withhypoalbuminemia have lower serum oncotic pressure, leading to the accumulation of fluid in the interstitial tissue around the body. Edema can affect many areas of the body, including: • Eyes: puffiness around the eyes, most prominent in the morning. • Legs: swelling in the legs and retains the indentation when pressure is applied to a small area (pitting edema). • Pleural cavity: effusion in the pleural cavity. • Peritoneal cavity: fluid in the cavity leading to ascitis Anasarca is the general term used to describe the accumulation of fluid throughout the body.
- 10. HYPERLIPIDAEMIA Increase in LDL,VLDL , IDL no change or decrease in HDL This results in increase LDL/HDL cholesterol ratio Hyperlipidaemia is the consequence of increased synthesis of lipoprotein (apoprotein b, C-III lipoprotein ) as a direct consequence of a low plasma albumin Reduced clearance of principal triglycerides bearing lipoprotein (chylomicrons and VLDL) in direct response to albuminuria.
- 12. GENETICS: Nephrin: Transmembraneprotein encoded by NPHS 1 on chromosome 19.(FINISH type congenital NS. Mutations in α-actinin-4, encoded by the gene ACTN4 on chromosome 19 and TRPC6 on chromosome 11, are associated with autosomal dominant forms of FSGS. Podicin: Encoded by NPHS 2 on chromosome 1. Autosomal recessive.
- 13. Classification of nephrotic syndrome: ETOLOGICAL CLASSIFICATION: Primary or Idiopathic NEPHROTIC syndrome: Disease limited to kidney Secondary NEPHROTIC syndrome: Other systems involved HISTOLOGICAL CLASISIFICATION: Minimal Change Disease Foal Segmental Glomerular sclerosis Membranous Nephropathy Membrano-Proliferative GlomeruloNephritis
- 14. Causes of Nephroticsyndrome: Primary causes: Minimal change disease (10-15% in adults and 70-90% in children Focal segmental glomerulosclerosis (15% in adult) Membranous glomerulopathy (30% in adults) Secondary causes: Diabetes mellitus Lupus erythematosus Amyloidosis Viral infections (Hep B, Hep C, HIV) Preeclampsia Drugs and toxins – mercury, snake venom, NSAIDs
- 16. NEPHROTIC SYNDROME: 1. MINIMALCHANGE DISEASE: nil lesion 70-90% of nephrotic syndrome in childhood 10-15% of nephrotic syndrome in adults On renal biopsy- No obvious glomerular lesion by light microscopy Immunofluorescence - no evidence of immune complex deposition diffuse effacement of epithelial cell foot processes on Selective proteinuria: principally contains albumin with minimal amounts of higher-molecular- weight proteins 30% children have spontaneous remission All children treated with steroids Non-responders are biopsied
- 17. 2. FOCAL SEGMENTALGLOMERULOSCLEROSIS: Most common cause of idiopathic nephrotic syndrome in adults 35% of all cases in United States and over 50% of cases among blacks On light microscopy, presence of segmental glomerular scars that involve some but not all glomeruli C/F: hematuria, hypertension and decreased renal function are more common, any level of proteinuria
- 18. 3. MEMBRANOUS NEPHROPATHY: Most common cause of primary nephrotic syndrome in adults Most often secondary disorder in children Uniform thickening of basement membrane along the peripheral capillary loops in light microscopy Diffuse granular deposits of IgG and C3 Electron dense sub-epithelial deposits Autoantibodies against Phopholipase A2 Receptors (PLA2R) may be present in most adults in idiopathic nephropathies
- 20. CLINICAL FEATURES OfNephrotic Syndrome:
- 21. CLINICAL FEATURES Inchildren the commonest form of N.S. is primary nephrotic syndrome Among these the MCNS is the most frequent Insidious onset of odema Mild fever and Cold Many children have recurrent episodes of such transient edema for many months. Physical examination Edema – The edema is initially noted around the eyes and in the lower extremities where it is pitting in nature, with time edema becomes generalized and may associate with weight gain and the development of ascites, pleural effusion and decreased urinal output Pallor White nails with red bands (leukonychia) Normal Blood Pressure No evidence of Renal failure
- 22. CBC Ureacreatinine and electrolytes Urine Examination Urine Culture and Sensitivity Serum Proteins Urinary Proteins Spot Urine Test Serum Cholesterol Testing for Hep B and C Complement system ANA, Anti double stranded DNA antibodies. Imaging USG abdomen X ray chest Genetic testing Renal biopsy INVESTIGATIONS:
- 23. Indications of renalbiopsy: Features s/o diagnosis other than MCD NS presenting in 1st year of life NS presenting after 6 years Failure to respond to adequate dose of steroid therapy in 28 days Relapsing Nephrotic Syndrome Development of steroid resistance Change in clinical course Patient with renal insufficiency and nephrotic syndrome Before starting immunosuppressive therapy
- 24. INTERPRETATIONS: Anemia ,raised urea creatinine, acidosis, hyperkalemia, hyperphosphatemia indicate Chronic renal disease. Raised Hb and haemetocrat indicates haemodilution reduced intravascular volume. Platelet is raised. Hyponatremia may be due to hyperlipidemia and due to water retention (pseudohyponatremia). Check liver enzymes for Hepatitis B and C
- 25. COMPLICATIONS DUE TO DISEASE: A.Loss of Proteins: Albumin Transferrin TMG Vitamin D Binding Globulin Immunoglobulin Coagulation factors Edema Anemia Biochemical hypothyroidism Hypocalcemia(Along with loss of 1,25 diOH chole calciferol) Infection Hypercoagulable State
- 26. C. Hypercoagulable State: dueto alteration in coagulation factors, associated infections, sepsis, Hypovolemia i) Renal Vein ii) Peripheral Vein Thrombosis iii) Cerebral Vein Thrombosis B. Infection: Loss of Immunoglobulin Depressed CMI Acute Chronic
- 27. D. Renal Failure: i)Chronic renal failure - as a part of disease process. – ii) Acute renal failure a) Hypovolemia induced ATN b) Septicemia leading to shock and ATN c) Septicemia causing bacteremia and AIN d) Other drugs causing AIN e) Bilateral renal vein thrombosis f) Crescentic GN on existing glomerular disease like FSGS, MGN and MPGN
- 28. E. Convulsions: i) Hypocalcemiadue to loss of Ca, 1, 25 di OH Cholecalciferol, Vit.D ii) Hypertension iii) Renal failure – uremic iv) Hyponatremia v) Cerebral Vein thrombosis
- 29. TREATMENT GENERAL MEASURES INITIAL TREATMENT Dietary sodium restriction Thiazide diuretics (eg bendroflumethiazide 5mg daily) Unresponsive patients may require furosemide 40-120 mg daily with addition of amiloride 5mg daily ,with serum potassium concentration monitored regularly patients are Hypovolaemic and moderate oedema may have to be accepted in order to avoid postural hypotension
- 30. NORMAL PROTEININTAKE is advisable . High protein diet (80-90grams protein daily) increases proteinuria can be harmful in long term . ALBUMIN INFUSION has transient effect Given only to patients who are diuretics resistant and those with oliguria and uraemia in absence of severe glomerular damage e.g. in minimal change nephropathy . Albumin infusion is combined with diuretic therapy and diuresis often continues with diuretic treatment alone
- 31. HYPERCOAGULABLE STATES Predisposes to venous thrombosis Due to loss of clotting factors (eg. Antithrombin) in urine and an increased production of fibrinogen Prolonged bed rest avoided In absence of any contraindication long term prophylactic anti coagulants If renal vein thrombosis occurs , permanent anticoagulation is required.
- 32. SEPSIS majorcause of death in nephrotic patients . Increased susceptibility to infection is partly due to loss of immunoglobulin in urine . Pneumococcal infection are common so pneumococcal vaccine should be given Early detection and aggressive treatment of infection , rather than long term antibiotics prophylaxis
- 33. LIPID ABNORMALITIES Are responsible for increase in the risk of cardiovascular disease in patients with proteinuria Treatment starts with HMG-CoA reductase inhibitor. Ace inhibitors and angiotensin II receptor antagonist Used for anti proteinuric properties in all types of GN Reduce proteinuria by lowering glomerular capillary filtration pressure Blood pressure and renal function should be monitored regularly
- 34. SPECIFIC MANAGEMENT AIM Reverse theabnormal protein leak Glomerular disease associated with nephrotic syndrome are divided into two disease a. With RBC cast ( active urinary sediments) b. Without RBC cast (bland urinary sediments)
- 36. MANAGEMENT OF NEPHROTIC SYNDROME: Atrial of corticosteroids is the first step in treatment of idiopathic nephrotic syndrome (INS) in which kidney biopsy is not initially indicated. • patients aged 1-8 years with normal kidney function • Normal kidney functions • No macroscopic gross hematuria • No symptoms of systemic disease. • Normal complement levels • Negative viral screen • No family history.
- 37. Following initial treatmentwith steroids for 12 weeks, the disease may take any of the following course: RESPONSE: protein free urine on 3 consecutive days within 7 days. RELAPSE: protein +ve urine on 3 consecutive days within one week with edema. FREQUENT RELAPSING NS: steroid sensitive nephrotic syndrome with 2 or more relapses in 6 months or more than 3 in one year. Infrequent relapses: Three or less relapses a year. Steroid resistance: Failure to achieve remission despite therapy with daily prednisolone at a dose of 2 mg/kg per day for 4 weeks. STEROID DEPENDANT: responder who relapses while steroid is being tapered or within 14 days of stopping steroid treatment. INITIAL NON RESPONDER: no response during initial 8 weeks of therapy. LATE NON RESPONDER: an initial steroid responder who fails to respond to 4 week treatment in relapse.
- 38. SSNS steroid sensitivenephrotic syndrome: Corticosteroids INDUCTION THERAPY: Exclude active infections and other contraindications to steroids Oral prednisolone 60mg/m2/ day…either single or divided doses for 4 weeks. 6 weeks therapy proves better . MAINTAINANCE THERAPY: Oral prednisolone at 40mg/m2/day single morning dose at alternate Days for 4-6 weeks. Longer duration of maintenance therapy results in fewer relapses.
- 39. Relapse therapy: For infrequent relapses steroid therapy may be resumed at 60mg/m2/day until proteinuria resolves Then switch to 40mg/m2/day for alternate days for 4 weeks. ALKYLATING AGENTS Cyclophospamide Chlorambucil Nitrogen mustard LEVAMISOLE CALCINEURINE INHIBITORS Cyclosporin Tacrolimus MYCOPHENOLATE MOFETIL TREATING FREQUENT RELAPSERS AND SDNS:
- 40. Steroid resistant nephrotic syndrome: Failure to achieve remission despite therapy with daily prednisolone at a dose of 2 mg/kg per day for 4 weeks is called steroid resistance. Incidence approximately 10-20%. Initial resistance: Lack of remission at the first episode. Late resistance: Steroid sensitive initially, but show steroid resistance during subsequent relapse. All children with steroid resistant nephrotic syndrome should under go renal biopsy.
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- 42. SRNS - Management All patients with SRNS should receive treatment with angiotensin converting enzyme inhibitors (e.g., Enalapril, Ramipril). These agents should be avoided if the estimated GFR is <30 ml / min/ 1.73 m^2 Angiotensin receptor blockers (e.g., Losartan,Valsartan) may be used in patients intolerant to ACE inhibitors, or as add-on therapy to achieve better antihypertensive and antiproteinuric effect. Dyslipidemia should be managed by HMG CoA reductase inhibitors (e.g. Atrovastatin 10- 20 mg daily).
- 43. DOSING AND REGIMENS: Cyclophosphamide (2–2.5 mg/kg daily) is given orally for 8-12 weeks. Steroids are usually overlapped with initiation of CYP then tapered Patients must have weekly CBC counts to monitor for leukopenia. Patients must also maintain adequate hydration and take CYP in the morning (not at bedtime) to limit the risk of hemorrhagic cystitis
- 44. FOCAL SEGMENTAL GLOMERULOSCLEROSIS Relatively common renal pattern of injury resulting from damage to podocytes Diagnosis requires kidney biopsy. Light microscopy shows sclerosis of portions (or segments) of some, but not all glomeruli (thus, focal and not diffuse disease). Electron microscopy shows fusion of epithelial foot processes as seen in minimal change disease. PREDNISOLONE 0.5-2 mg/kg per day is used in most patients and continued for 6 months before the patient is considered resistant to therapy Cyclosporin at doses to maintain serum levels at 150-300ng/ml may be effective in reducing or stopping urinary protein excretion . Relapse are common after stopping treatment . Cyclophosphamide , chlorambucil or azathoprin are used for second line therapy in adults . In patients with mesangial hyper cellularity Cyclophosphamide 1-1.5 mg/kg /day with 60mg of prednisolone and azathoprin can be used with maintenance therapy.
- 45. MEMBRANOUS GLOMERULOPATHY Membranousnephropathy is the most common cause of primary nephrotic syndrome in adults and often presents in the fifth and sixth decades. Patients may be asymptomatic or may have edema or frothy urine Venous thrombosis , such as un provoked DVT may be initial sign There may be symptoms or signs of underlying infection or neoplasm INVESTIGATIONS In light microscopy capillary wall thickness is increased When stained with silver methamine “spike and dome’’ pattern results from to excess GBM between the subepithelial deposits .
- 46. There isno consensus on therapy but in general , patient with moderate to heavy proteinuria are treated Oral high does corticosteroids and azathioprine are not associated with any significant benefit Alkylating agents , cyclophosphamide and chlorambucil , both are effective in management of severe or prolonged nephrosis , renal insufficiency and hypertension Chlorambucil (0.2 mg/kg/day in months 2, 4 , 6 alternating with oral prednisolone 0.4mg/kg/day in month 1 ,3,5)
- 47. Cyclosporin andmycophenolate with oral steroids may become agent of choice Anti CD-20 antibodies ( rituximab , which ablates B lymphocytes) Improves renal function , reduce proteinuria and increases serum albumin No significant adverse effects have been shown
- 48. AMYLOIDOSIS Caused byextracellular deposition of abnormally folded protein There are several different protein that have the potential to form amyloid fibrils Most common is AL amyloid , due to plasma cell dyscrasia, in which the protein is monoclonal Ig light chain Secondary amyloidosis is due to deposition of amyloid A protein (AA) Serum urine and protein electrophoresis is screening test Amyloid affected kidneys are enlarged (>10cm) Glomeruli are filled with amorphous deposits Treatment that reduce production of the amyloidogenic protein can improve organ function and surrounding vival in immunoglobin light chain related amyloidosis and hereditary transthyretin associated amyloidosis In AA amyloidosis , production of serum amyloid A can sometimes be decreased by treatment of underlying inflammatory condition but can not be completely suppressed .
- 49. DIABETIC NEPHROPATHY LIFESTYLE CHANGES ACE inhibitors and Angiotensin II receptor antagonist , regardless of blood pressure elevation Works best in patient with high sodium intake in there diet Who respond poorly to ACE inhibitor and ARB therapy
- 50. Other therapy: Pneumococcal vaccines to all the patients. Diuretic therapy for symptomatic edema. with furosamide 2mg/kg/day. Anasarca with low intravascular volume ,albumin infusion, slow 1mg/ kg/day can be considered. Diet: Salt restriction is important to reduce edema. Start with salt free diet in the presence of edema and then slowly add salt. Water: Along with salt restriction water restriction is necessary to prevent dilutional hyponatremia. In mild edema intake is restricted to the urine output. In moderate edema intake is restricted to insensible water loss. In massive edema fluid intake is restricted to milk only equivalent to insensible water loss.
- 51. POTASSIUM: Serumpotassium abnormalities are infrequent in NS without renal failure Hypokalemia is the consequence of indiscriminate diuretics. Add oral potassium in the presence of excessive tiredness or muscle weakness Periodic serum potassium level estimation will be useful PROTEIN: Normal protein diet is advised. In case of malnutrition increased protein is recommended CALORIES: In the acute phase of Nephrotic Syndrome nutritional intake is reduced. In malnutrition caloric supplementation is necessary. LIPID: HDL levels are elevated in MCNS. Abnormal coagulability and glomerulus necrosis are consequence of lipid abnormalities. Weight control is essential. Diet should contain cholesterol less than 250 mg/day
- 52. CALCIUM: Secondaryto hypoalbuminemia there is low ionic calcium, which is responsible for cramps and tetany. Hence calcium intake of 800 mg/day either by diet or tablet with Vit.D is necessary. IRON & ZINC: Iron supplementation is necessary in microcytic hypochromic anemia. Rarely Zinc may be needed in the presence of deficiency symptoms.
- 53. HOME MONITORING: Home monitoring of urine protein and fluid status is important. Patient should be trained to monitor first morning urine by dipstick. Record of daily weight , urine protein and steroid dose should be kept in log book. Any increase in urine protein or daily weight should be reported as early as possible.
- 54. Prevention: Yearly influenzavaccination is recommended to prevent serious illness in the immunocompromised patient, as well as to prevent this possible trigger of relapse. Pneumococcal vaccination should be administered to all patients with INS to reduce the risk of pneumococcal infection. Vaccination should be repeated every 5 years while the patient continues to have relapses. Routine childhood vaccines with live virus strains are contraindicated in patients taking steroids and until off steroid treatment for a minimum of 1 month. Because of the high risk of varicella infection in the immunocompromised patient, in the nonimmune patient, post exposure prophylaxis with varicella-zoster immune globulin is recommended. Patient with varicella zoster infection should be treated with acyclovir and carefully monitored Routine, non live viral vaccines should be administered according to their recommended schedules
- 55. Reference 1. Current medicaldiagnosis & treatment 2. Kumar and clark’s clinical medicine 3.Harrison’sPrinciples_of_Internal_Medicine,Twentieth_Edition(Vol.1_&_Vol.2
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