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Nephrotic Syndrome

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Dr Chow Yok Wai

Dr Chow Yok Wai
Hospital Kuala Lumpur

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    Nephrotic Syndrome Nephrotic Syndrome Presentation Transcript

    • Complications of Nephrotic syndrome
    • Introduction
      • 3/100,000 (adults)
              • Llach, 1984 Postgraduate Medicine
      • Proteinuria >3.5g/24h
      • Lipiduria
      • Anasarca
      • Minimal change disease
      • Membranous GN
      • FSGS
    • Introduction
      • 1950’s- infection was commonest cause of death
      • Now  thromboembolic events
    • Complications nephrotic syndrome
      • selective loss of low molecular weight protein in the urine
      • overproduction of all hepatically synthesized proteins
      • accumulation of the higher molecular weight species
      • proteins smaller than 180–200 kDa show lower plasma concentrations, and above this size increased levels.
    •  
    • Nephrotic Oedema
      • EFP (effective filtration pressure)  ( P c − P i ) − (π c − π i )
      • Underfill theory
      • Overfill theory
    • Nephrotic Oedema- Underfill (classical) theory
      • Albuminuria not compensated by increased hepatic synthesis  reduction in COP  decrease in plasma volume  stimulate RAAS, sympathetic nervous system and supress atrial natriuretic peptide (ANP)  renal sodium and water retention
    • Nephrotic Oedema- Underfill (classical) theory
      • Elevated plasma renin, aldosterone
            • Rasher, Journal of Paeds, 1985
      • Non osmotic increase in production of ADH
      • Increase plasma and urinary cathecholamines
            • Usberti, KI, 1984
    • Nephrotic Oedema- Arguments against Underfill (classical) theory
      • However, reduction in blood/plasma volume not shown in all studies
            • Vande Walle, Lancet 1995
      • Renal sodium water retention found in many pt with mild reduction in serum albumin
            • Vande Walle, Lancet 1995
      • Natriuresis precedes increase in plasma albumin
            • Brown, Nephron, 1982
            • Koomans, Nephron, 1987
      • Correction of intravscular volume didn’t correct the natriuresis
            • Remuzzi, AJKD, 1993
    • Nephrotic Oedema- Overfill theory
      • Primary renal disturbance  sodium and water retention
    • Nephrotic Oedema- treatment
      • Low salt diet?
      • Diuretics
        • Many are diuretic resistance
          • Decrease delivery to tubules from reduced GFR
          • Low serum albumin promotes distribution of drug in extravascular space
          • IVI preferred as it prevents postdiuretic rebound sodium reabsorption
              • Kramer, Am J Med, 1999.
          • Bumetemide may be better as metabolised by liver
          • Metalazone- success in few studies
          • Spironolactone- if elevated aldosterone level
    • Nephrotic Oedema- treatment
      • IV salt free albumin
        • 100mls of 20%
        • Can lead to circulatory overload and hypertension if diuresis is not induced
        • Using it alone has little effect
              • Rabelink, KI, 1994
      • Diuretic vs Diuretic + IV albumin
        • No advantage in combination
              • Akcicek, BMJ, 1995
        • Beneficial
              • Fliser, KI, 1999
      • Suggest- EOD Diuretics+Albumin to allow re-equilibration of interstitial and plasma albumin. Up to 40L/2 weeks can be removed by this regime
    • Nephrotic Oedema- treatment
      • Gentle dialysis
          • HD
          • PD
            • Fauchald, Acta Medica Scandinavia, 1985
        • ? Albumin use + UF
    • Infection
    • Infections in nephrotic patients
      • important cause of deaths in children with NS even today: 6/10 deaths in 389 children with minimal change NS were from sepsis
          • International Study of Kidney Disease in Children 1984
      • higher in children treated with cytotoxic drugs than in those treated with prednisone alone
        • chlorambucil (6.5 per cent)
        • cyclophosphamide (1.5 per cent)
            • Latta, K., vom Schnakenburg, C., and Ehrich, J. H. H. (2001). A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatric Nephrology 16 , 271–282.
    • Primary peritonitis
      • particular feature of children with NS
      • older patients have been noted
              • Chuang, T. F. et al . (1999). Spontaneous bacterial peritonitis as the presenting feature in an adult with nephrotic syndrome. Nephrology, Dialysis, Transplantation 14 , 181–182.
      • Onset- insidious
      • usually sudden
      • abdominal pain
      • diagnosis must be confirmed by direct microscopic examination of a Gram stain or an immunochemical search for bacterial antigens in ascitic fluid
      • Blood cultures are usually positive
      • Hypotension, shock, and even acute renal failure  DIVC
    • Primary peritonitis
      • Streptococcus pneumoniae (commonest)
        • Up to 50%
        • Penicillin-resistant strains of S. pneumoniae are now emerging
          • Giebink, G. S. (2001). The prevention of pneumococcal disease in children. New England Journal of Medicine 345 , 1177–1183.
      • β-haemolytic streptococci
      • Haemophilus
      • Gram-negative Gorensek et al . 1988 ).
    • Cellulitis
      • Spontaneous/ result of venepuncture
      • B-hemolytic strep
      • Gm –ve
      • Toxic, febrile, septic shock
      • Blood C+S usu +ve
    • Other infections
      • Viral infections  varicella, measles esp those with steroids/cytotoxics
      • Bacterium alkaligenes
      • Bacteroides
      • Aerobacter
      • Streptococcus viridans
      • Tuberculosis
    • Pathogenesis of infections
      • Physical factors
        • Fluid collection in cavities
        • Ruptures fragile skin
        • Dilution of local humoral defences by oedema
      • Immunological factors
        • Low IgG (but need to be <2g/L)
          • Tend to be chronic, staph, sinopulmonary site
    • Alternative complement pathway
      • spontaneous hydrolysis of C3
      • allows the binding of plasma protein Factor B
      • allows Factor D to cleave Factor B into Ba and Bb.
      • Bb- C3 convertase
      • consists of the activated B and D factors
    • Alternative complement pathway
      • stable after binding properdin
      • cleave multiple C3 proteins into C3a and C3b
    • Pathogenesis of infections
        • Factor B, Factor I
          • Alternative pathway of complement system
          • Approx 55kDa
          • Lost in urine
          • Imp in opsonization of encapsulated organisms eg strep pneumoniae
        • Transferrin
          • Essential for lymphocyte function
          • Carrier for zinc
          • Lost of Transferrin-Zinc  diminished production of Zn dependent thymic hormone thymulin
        • Reduced lymphocyte/polymorph function
    • Treatment
      • Induce remission ASAP
      • Pt with previous pneumococcal infection  prophylactic penicillin
      • Pneumococcal vaccine  start 14 days after discontinuing high dose steroids/cytotoxics
      • IV antibiotics- broad spectrum
      • Varicella zoster
        • Zoster Immune Globulin within 72h of contact
        • IV acyclovir
    • Thromboembolic complications
    • Thromboembolic complications
      • Arterial/venous circulation
        • 10% nephrotic adults
        • 50% nephrotic adults (subclinical)
        • 1.8% (paeds)
          • Higher levels of 92-macroglobulin (thrombin inhibitor)
        • Highest risk in adult Membranous nephropathy
      • What is the cause?
        • Abnormalities of coagulation
    • Commonest presentation
      • DVT +/- PE
      • Renal vein thrombosis
      • Hepatic vein thrombosis
      • Budd Chiari syndrome
      • Intracranial venous sinus thrombosis
    • Concentrations of proteins important in coagulation in the nephrotic syndrome in relation to molecular weight Reduced 54,000 α 1 -Antitrypsin Raised–normal 65,000 Protein C Normal–reduced 68,000 Antithrombin III Normal–reduced 70,000 α 2 -Antiplasmin Normal–reduced 75,000 Protein S Normal–reduced 81,000 Plasminogen Raised 840,000 α 1 -Macroglobulin Regulator proteins Normal–reduced 55,400 Factor IX Normal–reduced 56,000 Factor X Normal–reduced 72,000 Factor II (prothrombin) Normal–reduced 79,000 Factor XII Normal–reduced 160,000 Factor XI Raised–normal 200,000 Factor VII Raised 330,000 Factor I (fibrinogen) Raised 350,000 Factor V Raised 840,000 Von Willebrand factor Zymogens and cofactors Concentration in nephrotic plasma MW (Da) Protein
    • Physical Factors
      • Immobility
      • Haemoconcentration from hypovolaemia
      • Increase blood viscosity
        • Changes in red cell deformability
        • Increase fibrinogen
          •  favours margination of platlets and increased platlet aggregability
            • Zwaginga, J. J. et al . (1994). Thrombus formation and platelet vessel wall interaction in the nephrotic syndrome under flow conditions. Journal of Clinical Investigation 93 , 204–211.
    • Alterations in zymogen (enzyme precursors) and cofactors
      • Increase  VWF, fibrinogen, FV, X, VII
      • Fibrinogen and FVII – independent variables predicting vascular disease
            • Cameron, J. S. (1984). Thromboembolic complications of the nephrotic syndrome. Advances in Nephrology 13 , 75–114.
    • Alterations in fibrinolytic, regulator proteins and platlet function
      • Low antithrombin III
      • Low plasminogens
      • Low functional Protein S +/- C
      • Hyperaggregability of platlets
      • Increased TxA2
      • LDL enhance platlet aggre via adenylate cyclase
      • LDL inhibits prostacyclin on endothelial cells
      • HDL has opposite effect from LDL
    • Alterations in fibrinolytic, regulator proteins and platlet function
      • LDL is enriched with lysolecithin
        • Toxic to endothelial cells
          • Reduce NO production
            • Diminished platlet adhesion
      • Hyperaggregability to ristocetin
        • ? d/t increased vWF
        • ?altered charge on platlets
      • Impaired response to endothelium dependent vasodilatation
    • Summary :-
      • Loss of antithrombin III
      • Loss of Protein S
      • Increase Fibrinogen
      • Platlets hyperactive d/t increase responsiveness to ADP
              • Llach , Postgraduate Medicine, 1984
              • Vigano D’Angelo, Annals of Int Med, 1987
    • Role of drugs
      • Steroids
        • Increases some zymogens
        • Decrease PT, PTT
        • Anta Warfarin effect
        • But increase ATIII and inhibit platlet aggregation at high doses
      • Diuretics
        • Increases blood viscosity (d/t increase fibrinogen)
            • Lilova, M. I., Velkovski, I. G., and Topalov, I. B. (2000). Thromboembolic complications in children with nephrotic syndrome in Bulgaria. Pediatric Nephrology 15 , 74–78.
    • Peripheral venous thrombosis and PE
      • DVT
        • 3-12%
        • 25% by doppler USG
      • PE
        • 0-15%
        • 9-12% via V/Q scan
        • Mortality:-
          • Hemodynamically stable  8.1%
          • Cardiogenic shock  25%
          • Need CPR  65%
        • Recurrence: 28% (diagnosed via V/Q)
      • Other venous thrombi
        • Renal vein thrombosis
        • Subclavian, axillary, jugular, iliac, portal, splenic, hepatic, mesenteric vein thrombosis
        • Sagittal sinus thrombosis
            • Cameron et al 1984, 1988
    • Arterial Thrombosis
      • Less common than venous thrombosis
      • Occurred in almost every artery
      • Some multiple arterial thrombi
      • Some combined arterial and venous thrombosis
      • Commonest  femoral artery
    • Renal Vein Thrombosis
      • 4-8% in membranous nephropathy
            • Cameron et al 1988
      • Up to 50% via venography
            • Llach, F. (1985). Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome (Nephrology Forum). Kidney International 28 , 429–439.
      • 13-18%
            • Rostoker, G. et al . (1992). Asymptomatic renal-vein thrombosis in adult nephrotic syndrome. Ultrasonography and urinary fibrin–fibrinogen degradation products: a prospective study. European Journal of Medicine 1 , 19–22.
      • Men more affected
      • 35% have PE as well
            • Cameron et al 1988
    • Renal Vein Thrombosis
      • Loin pain
      • Hematuria
      • Renal enlargement
      • Pain and swelling in ipsilateral testicle in male
      • Deterioration of renal function
      • Lower limb oedema if vena cava involved
    • Renal Vein Thrombosis- Prognosis
      • Unknown
        • As most are anticoagulated
      • Impaired renal function is poor prognostic sign
    • Treatment/prevention of thromboembolic events
      • Paucity of RCTs
      • Only 1 study looking into prophylactic LMWH for TEE in NS
              • Rostoker, Nephron, 1995
      • No known standard protocol for :-
        • Duration of anticoagulation
        • Intensity of anticoagulation
        • Type of anticoagulation
      • Expert opinion mainly (no evidence)
    • Prevention
      • Mobilize patient
      • Avoid sepsis
      • Treat sepsis
      • Avoid dehydration
      • Judicious use of diuretics
      • Minimize haemoconcentration
      • Heparin acts mainly via activation of AT III (decrease concentration in nephrotics)
        • May need higher dose
      • Heparin binds to α 2-macroglobulin and endothelial cell surface  may enhance platlet aggregation
      • Warfarin  bound to albumin.
        • Dosing problem
    • Should we anticoagulate asymptomatic DVT?
      • Yes
      • Heparin UF/LMWH, Warfarin
      • INR 2-4
      • When to stop anticoagulation?
        • Min 3 months
        • 6 months
        • When stopping, ensure no edema, serum albumin > 25g/l
    • Prophylactic anticoagulation in nephrotic patients?
      • Yes esp if membranous nephropathy
            • Bellomo and Atkins, Nephron, 1993
            • Sarasin and Schifferli, KI, 1994
      • Standard anticoagulants
      • Low dose aspirin
      • Dipyridamole
            • Andrassy, 1980
    • Lipid abnormalities
    • Hyperlipidaemia
      • Commonest complication
      • 90% of pt with nephrotic range proteinuria
      • Contributes to atherosclerosis and progression of renal damage
            • Samuelsson, NDT, 1997
      • Correlates inversely with serum albumin
      • Independent of cause of nephrosis
    • Hyperlipidaemia
      • Increase VLDL, IDL, LDL (esp smaller and denser), Tg
      • HDL usually normal (decrease in HDL-2, increase in HDL-3)
      • Increase in Lp(a) (strong predictor of vascular events in general pop)
    • Hyperlipidaemia- Pathogenesis
      • Reduced oncotic pressure or albumin concentration  increase transcription of liver regulated proteins
      • Infusion of IV albumin reduces cholesterol levels
            • Appel, NEJM, 1985
      • Result of increase synthesis and decreased catabolism of lipoprotein
      • Impaired conversion of VLDL to LDL
      • Increased hepatic LDL secretion
      • Increase Lp(a) production by liver
      • Impaired HDL maturation
      • Decrease receptor mediated clearance of circulating VLDL
    • Hyperlipidaemia- Pathogenesis
      • Increase synthesis and reduce degradation of Tg
      • Loss of ApoC-II in urine
    • Hyperlipidaemia- consequences
      • Nephrotics
        • 5.5 fold MI
        • 2.8 fold coronary death
              • Ordonez, KI, 1993
        • No difference from controls
              • Wass, Lancet, 1979
      • Duration of hyperlipidaemia is most critical
      • Highest risk in patients with unremitting proteinuria
      • A/W glomerular and interstitial renal disease in animal studies. Never proven in humans
    • Hyperlipidaemia- treatment
      • Controversial
      • Most extrapolated from general population
      • Increase in premature atherosclerosis and MI in nephrotics
            • Niaudet, Paediatric nephrology, 1992
      • Independent risk factor for atherosclerotic disease
            • Radhakrishnan, AJKD, 1993
      • May promote progression of renal disease
            • Falk, 2001
    • Hyperlipidaemia- treatment
      • Reduce proteinuria
      • Statins
      • Nicotinic acid
      • Bile acid resins (cholestyramine, colestipol)
      • Lipopheresis
        • No effect on protein excretion and serum albumin levels
    • Acute Renal Failure in Nephrotic Syndrome, Hein, NDT 2001
      • Rapid progression of original glomerular disease
      • Renal vein thrombosis
      • Allergic interstitial nephritis
        • Diuretics
        • Antibiotics
        • NSAIDS
        • Foscarnet
        • Interferon alpha
      • Sepsis
      • ATN
      • Tubular obstruction from proteinuria (protein cast)
    • Acute Renal Failure in Nephrotic Syndrome- Pathology
      • 85%- MCD
      • 60%  ATN findings
      • 40%  interstitial oedema
      • ARF group also have more arteriolosclerosis (intimal hyperplasia amd hyalinosis)
    • Acute Renal Failure in Nephrotic Syndrome
      • Elderly
      • Hypertensive
      • Severe proteinuria
      • Very low albumin
      • 2/3  male
      • Most have severe oedema
      • Time between onset of NS and ARF is 4 weeks
      • Recovery usually over 7 weeks
            • Smith, AJKD, 1992
      • Children and young adults  progression can be early with fast occurrence and resolution
      • Protracted ARF needing dialysis less commonly occur in children
    • Others
      • Loss of metal binding proteins
        • Serum iron/ transferrin
        • Caeruloplasmin
        • Zinc
      • Loss of vitamins and hormones
        • Vit D binding protein
        • Thyroid binding globulin
        • Cortisol binding protein
        • Erythropoietin
    •