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Nephrotic Syndrome

Nephrotic Syndrome. Outline. Definition Epidermiology Classification Ethiopathogenesis Pathophysiology Pathology/Histology. Clinical Features Lab. Investigations Treatment Complications Prognosis. Definition. N/ Synd is a Dz condition Xterized by: -Gross Proteinuria

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Nephrotic Syndrome

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  1. Nephrotic Syndrome

  2. Outline • Definition • Epidermiology • Classification • Ethiopathogenesis • Pathophysiology • Pathology/Histology • Clinical Features • Lab. Investigations • Treatment • Complications • Prognosis

  3. Definition N/Synd is a Dz condition Xterized by: -Gross Proteinuria -Hypoalbuminemia (2.5g/dl) -Hypercholesterolemia -Edema

  4. Nephrotic Range Proteinuria -24 hr. urine protein >50mg/kg -urine protein >40mg/m2/hr -Spot Upr/Ucr ratio >3 in a first morning sample - >3+ proteinuria on Dipstick (albustix)

  5. Epidermiology • 2/3 of N/S present b4 5yrs • Boys:Girls ratio 2:1, 1:1 by late adolescence • 90% of cases are Primary (not assoc.wt syst.dz. • 80-85% of prim. N/Synd are steroid sensitive or histologically minimal change type.

  6. classification • PRIMARY -steroid sensitive -steroid resistance • SECONDARY

  7. contd In 2ry N/Synd. Dz occurs as part of a systemic dz. e.g: Quartanmalaria,SLE,HSP,Chr. Hep.Binfection,PSGN

  8. Ethiopathogenesis (unsure) Hypothesis -Immune dysfxn of T lymphocytes >Unknown mediator> neutralizes anionic charge of Glom. Carpillary > inc. permb. To Albumin -A primary abnormality in the foot processes is also postulated. Mutations in podocyte proteins hvbn identified in many inherited N/Synd. Mut. In trans memb. Prot. Of the slit diahgram causes Finnish N/Synd.

  9. Pathology MCNS: Renal biopsy findings show: -No abnormality on light mcpy -Obliteration of foot processes on e-mcpy -Immunoflourescensemcpy: No deposition of Immune rxtants. In N/Synd due to SLE, immune comlex deposits in glom. + cellular proliferation is seen

  10. contd • Chr. Hep.Binfectn may cause membranous or membranoproliferative N/Synd

  11. Pathophysiology • Loss of charge selective barrier > loss of –vely charged mol like albumin that is normally repelled • It is postulated that infectious stim.> cytokines toxic to glom epith and Bm.> redctn in –ve charges and loss of albumin.

  12. Pathophysiology Hypoproteinemia: -Urinary prot. loss= abt 3-5g/day -Inc. catabolism of reabsorbed prot. By renal tube epith. Cells > amino acids= body pool Hypercholesterolaemia: -Reduced Albumin >gen. Inc hepatic prot. Synthesis > overprodctn of lipoprotein -Red. Actn of lipoprotein lipase > redcd transp. Of lipids to adipose tissue.

  13. contd Oedema: Hvyproteinuria > Alb (<2.5g/dl) >Red plasma OsmP > Fluid loss to interstitium > Oedema > Hypovolemia (dec. ECFvol) > RA/ADH system = salt & H20 retention. Thrombosis: Can occur in cerebral V or A,pulm, femoral vs. Inc. hepatic. Prot. Synth >inc level of clotting factors e.gI,II,VII,X,fibrinogen,protein C, prot.S

  14. contd • Inc spont. Platelet aggregatn in response to collagen & ADP. • Loss of anti thrombotic factors e.g anti thrombin III & plasminogen. • Inc haematocrit wt severe vol. contraction is a factor.

  15. infections • Due to redctn in IgG and factor B due to urinary losses • Impaired lymphocyte fxn • Steroids and immunosuppressive Rx inc risk of infection

  16. Clinical features • History: Early morning puffiness of eyelids Slowly progressing gen. edema Dec urine output Hx may suggest complications e.gperitonitis,thrombosis,symptoms of intravacular depletion. Hx may exclude diff. Diagse.gpharyngitis and skin infection =PSGN,Erythematous skin rash,athralgia/arthritis =HSP,SLE Hx to exclude CCF & liver pathology both causes of edema. Age of onset may suggst MCNS or Atypical N/S +vefhx of NS may suggest familial NS of FSGS type

  17. Physical Examination • Extent of Edema • Search for complications of Dz or Rx + effusions, Tender jtswellings,Hepatosplenonomegaly may suggest vacsulitis,CVA etc • BP • Wt. • Abd girth to monitor progress

  18. Lab Investigations • Urinalysis=Neph. Range proteinuria • Up to 25% have mcpichaematuria • Casts= hyaline, granular & few wbc casts occas. • Presence of RBC casts and sig amt of RBC suggest secondary cause. • CBC,SEUC,C3,ASO titre,Albumin&cholesterol diff NS from other causes of edema.

  19. contd • Low C3 suggests APGN,MPGN & SLE • ANA screens and other collagen vascular dz. • + HepBsAg suggests MN or MPGN • Cxray= not routine >pleural effusion • Abd U/S > renal sz to r/o Hivan-renomegaly or CRF-shrunken kidneys.

  20. Treatment (symptomatic/supportive) Indications for admission -Anarsacacompromizingmovt or resp. -Unstable vital signs Fever U.O < 1ml/kg/hr= oliguria Severe haemoconc. i.ePcv>48% Presence of life threatening complications

  21. contd • Stict input/output fluid chart • BP monitoring • Daily weighing • Daily abd. Girth measurement • Daily urinalysis • Mantoux testing bcos of impending steroid Rx to prevent disseminated TB. • Parental Education

  22. . • Diet: No added salt diet : only in severly edematous. • Fluid may be restricted along wt Na in some cases of edema(inensible loss + previous days output) • Normal protein diet. High protein intake May cause hyperfilteration injury to kidneys. • Activity: No restriction on activity except if BP is raised in rare occ.

  23. Diuretics • NB: not all NS pts require diuretics • Used in mod. to severe edema or oliguria in euvolemic or hypervolemic pts (n. carp refill, no orthostatic hypotension, good vol. pulse) • Frusemide 1-2mg/kg per dose p.o/i.v • Spironolactone + for k+ sparing effect • Thiazide 1-2mg/kg/day+ frusemide or Metazolone 0.5mg/kg/day are beneficial in pts refractory to frusemide alone

  24. contd • I.V 25% albumin is useful in pts with refractory edema,markedasciteswch impairs pulmfxn, peripheral oedema with skin breakdown, labial/severe scrotal edema. • Dose 1gm/kg max 25gm.Give over 2hrs +I.V frusemide after. Can rpt albumin after12hrs. If no change in U.O consider ARF.

  25. Specific Rx • Goal is to induce and maintain remission from active NS while minimizing S/e of drugs Corticosteroid >90% of MCNS are steroid sensitive. Rx any systemic infectn b4 starting steroids. 50% & 90% of MCNS achieve remission in 2wks & 4wks respectively

  26. Corticosteroids • 60mg/m2/day or 2mg/kg/day oral prednis’one Max. dose of 60mg /day given in 2-3 divided doses x 6wks, followed by 40mg/m2/d or 1.5mg/kg/d oral pred. x 6wks. At the end of 6wks prednisolone is stopped and pt monitored on out pt basis afterwards 2wkly for signs of relapse.

  27. Response to steroid Rx. • Remission: Negative trace, or + proteinuria x 3 consecutive EMU samples. • Relapse: Urine Albustix 2+ or more for 3 consecutive EMU samples,may be assoc wt edema. • Frequent relapse: relapse 2 or more times in the first 6mths after presentatn or 4 or more times in any 12mths period

  28. Steroid dependent: relapse while on steroid Rx or when u taper steroids or within 14 days of stopping steroids. • Steroid resistant: Failure of proteinuria to resolve after 4-6wks of 60mg/m2/day of steroid Rx. Some authors use 8wks i.e 4wks dly & 4wks alt die prednisolone.

  29. Treatment of relapse • In children with relapse: Daily pred.60mg/m2 until pt. achieves remission, followed by 4wks of 40mg/m2 alt.die pred. • In freq. relapsers after we achieve remission we ct 60mg/m2/d alt die which is tapererd over several wks to the min dose that maintains remission for abt 12months.

  30. Rx of relapse contd • Levamisole: Also an anti helminthic is an immunomodulator used in freq. relapers wt steroid sens. N/S. First we achieve remission then change to alt.die steroids then we stat. levam. 2-2.5mg/kg alt die on days steroid is not given x 6mths.Tx can ct x1-2yrs.Steroid should reduce to 0.25mg/kg by 1yr. • Levam. Is used for steroid sparing effect not for remission induction.

  31. Rx of relapse contd • Cyclophosphamide: Where alt.die steroid with or without levam. Fails to maintain remission nxt step is use of cyclophosphasmide 2mg/kg/d x12weeks not exeeding total dose of 168mg/kg/course. Toxicity viz:Bmsuppression,inc risk of infectn,alopecia,haemorrhagiccystitis,gonadaltoxicity.Small risk of 2ry malig.NB @ 2m/kg/d risk of infertility does not appear to be inc.

  32. Rx contd • Chlorambucil, another alkylating agent is an alternative to cyclophosphamide. Repeat courses of both agents are usually not given. • Cyclosporin A: At a dose of 6mg/kg/d.It can be used when a child ct to be steroid dependent even after a course of c’phamde. • S/E include:hirsutism,gingival hyperplasia, wch regress when Rx is stopped.HTN & hypomagnesemia are known s/e.Long use can be nephrotoxic.Follow up renal biopsy indicated after 1yr to check for renal toxicity.

  33. Indications for renal biopsy in N/S • Steroid resistance • Before cytotoxic Rx • N/S in extremes of age i.e <6/12 or >8yrs • N/S assoc with persistent ARF • Nephritic onset of N/S • N/S assoc wt systemic features e.g recurrent jaundice, hepatosplenomegaly,arthritis,serositis.

  34. Prognosis • MCNS is essentially benign: approx.1/3 relapse once, another 1/3 have occassional, the remaining 1/3 bcome steroid dependent. • In many cases the relapses eventually cease. Many retain norm. renal fxn. • Most of the steroid resist. End in renal failure needing dialysis • Death usually results from: iatrogenic hypovolemia, sepsis and thrombosis.

  35. Complications of N/S Usually multifactorial: Drug related Toxicity- Steroids,cyclophospamide, Frusemide,spironolactone etc. -Due to

  36. Complications of N/S Usually multifactorial: Drug related Toxicity- Steroids,cyclophospamide, Frusemide,spironolactone etc. -Due to Disease-Infections,Thrombosis,Anaemia,ARF,Shock etc.

  37. Secondary N/S • This is thot to be the most common variety in the tropics. QMNS was thot to constitute up to 80% of N/S in some areas. • Causes include: G/nephritis, quartan malaria, schistosomiasis, syphilis, hydatiddz, Hep.B, Toxoplasmosis and varicella. Less common causes include: DM, SLE, anaphylactic purpura,renal vein thrombosis, heavy metals.Sickle cell anaemia,sarcoidosis.

  38. Quartan malaria N/S • MCNS • Temperate region • Idiopathic • Peak age, 2-5yrs • Haematuria-rare • Protein selectivity-nearly always. index.<0.1 • Steroid response-good • S/e/u/c may be temp raised but later normalize • Histology: min. change on light mcpy.fusion of epith foot processes-e mcpy • QMNS • Tropics • Quartan malaria • Peak age,5-8yrs • Rare • Poor selectivity-index >2 • steroid response-Poor • S/e/u/c persistently raised • Definite,gross pathologic features wt thickened carpillary walls leading to eventual glom. Sclerosis.

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