Mcd 1
- 2. INTRODUCTION • Major cause of idiopathic nephrotic syndrome • Characterized by intense proteinuria leading to edema and intravascular volume depletion • In children >1 year of age, MCD is the most common cause of nephrotic syndrome, accounting for 70%–90% • In Adults-10%to15% • Around puberty, membranous nephropathy, become more frequent
- 4. Most children respond to steroid treatment, the disease is termed “Steroid-Sensitive Nephrotic Syndrome” 1 Lipoid Nephrosis-microscopic lipid droplets in urine and tubular cells 2
- 5. Epidemiology 10–50 cases per 1,00,000 children More common in Asia Male predominance (approximately 2:1) MCD is much less frequent in adults
- 7. Nephrotic Syndrome Edema Massive proteinuria (>40 mg/m2 per h in children, >3.5 g/d in adults) Hypoalbuminemia (<2.5 g/dl) Remission Resolution of edema Normalization of serum albumin (≥3.5 g/dl) Marked reduction in proteinuria Complete remission (<4 mg/m2 per h or negative dipstick in children, <0.3 g/d in adults) Partial remission (<2 g/1.73 m2 per d, decreased by 50% and serum albumin ≥2.5 g/dl in children, <3.5 g/d and decreased by 50% in adults)
- 8. Relapse Recurrence of massive proteinuria (>40 mg/m2 per h in children, >3.5 g/d in adults) Positive urine dipstick (≥3+ for 3 d or positive for 7 d, usually applicable to children) ±Edema Steroid-Sensitive Nephrotic Syndrome Response to PDN 60 mg/m2 per d within 4–6 wk ±MPD boluses in children Response to PDN 1 mg/kg per d or 2 mg/kg every other d, within 16 wk in adults
- 9. 50% of children achieve remission within 8 days of steroid treatment Most patients who are going to respond to steroids do so within 4 weeks. In contrast, in adults the median time to remission exceeds 2 months. In both populations, MCD has a high tendency to relapse Relapses tend to be more rapid in children
- 11. Infrequently Relapsing Nephrotic Syndrome <2 relapses per 6 mo (or <4 relapses per 12 mo) Frequently Relapsing Nephrotic Syndrome ≥2 relapses per 6 mo (or ≥4 relapses per 12 mo) Nonrelapsing Nephrotic Syndrome No relapses for >2 yr after the end of therapy for the first episode of nephrotic syndrome (applicable to children, not yet defined in adults)
- 12. Steroid-Dependent Nephrotic Syndrome Relapse during steroid therapy or within 15 d of discontinuation Steroid-Resistant Nephrotic Syndrome No response to PDN 60 mg/m2 per d within 4 wk ±MPD boluses in children No response to PDN 1 mg/kg per d or 2 mg/kg every other d, within 16 wk in adults Multidrug-Resistant Nephrotic Syndrome Poorly defined as absence of partial remission after 6 mo OR absence of complete remission after 2 yr Treatment often consists of MPD boluses + oral prednisone for 6 mo + CsA and, in some cases, rituximab. Other protocols are also used
- 13. RENAL BIOPSY INDICATION In adults early kidney biopsy is crucial The indications for renal biopsy in children are Onset, age <1 or >12 years Gross hematuria Low serum C3 Marked hypertension Renal failure without severe hypovolemia Positive history for secondary cause Steroid resistance or therapy with calcineurin inhibitors
- 14. PATHOLOGY • By LM, no glomerular lesions seen. • Sometimes- mild focal mesangial prominence not exceeding three or four cells per segment are seen. • Diffuse mesangial hypercellularity variant- presence of more than four mesangial cells per mesangial region affecting at least 80% of the glomeruli • Hematuria and hypertension
- 15. • Immunofluorescence is usually negative. • However, low-intensity mesangial IgM (sometimes accompanied by C3 or C1q) staining can be found • MCD is occasionally accompanied by glomerular IgA deposits- IgA nephropathy with MCD • Focal segmental distribution of IgM and C3 staining should strongly suggest FSGS • More than trace amounts of IgG and IgA suggest alternative diagnosis
- 16. By electron microscopy, Foot Process Effacement is the only morphologic feature of MCD
- 18. CLINICAL FEATURES • Edema- Periorbital ,scrotum or labia and of the lower extremities • Anasarca may develop with ascites and pleural and pericardial effusion • Severe infections such as Sepsis, Pneumonia, and Peritonitis Ig depletion and altered T cell function • Intravascular volume depletion and oliguria - AKI, which is more frequently seen in adults • Rarely, AKI with gross hematuria followed by anuria - secondary to bilateral renal vein thrombosis. • Gross hematuria is rare, occurring in 3% of patients
- 19. LAB VALUES • Urinalysis, with urinary dipstick showing 3+/4+ proteinuria • Nephrotic-range proteinuria • Urine proteins >40 mg/h per m2 or • Urine protein-to-creatinine ratio >200 mg/mmol in children and • Urine proteins >3.5 g/d in adults • Serum albumin<2 g/dl, with an increased α2-globulin and a reduced γ-globulin fraction • Reduced total serum calcium, with ionized calcium usually within the normal range • IgG is markedly decreased, IgA is slightly reduced, IgM is increased, and IgE is normal or increased
- 20. • Hyperlipidemia 1. Increased hepatic synthesis of cholesterol, triglycerides, and lipoproteins 2. Decreased activity of lipoprotein lipase which transforms VLDL to LDL 3. Decreased LDL receptor activity and 4. Increased urinary loss of HDL and proteins with anticoagulant properties, such as antithrombin III • Increase in circulating fibrinogen, factors V and VIII, and protein C, leading to a state of hypercoagulability • Increased risk of thrombosis, usually venous thrombosis (97% of patients)
- 21. Secondary causes of minimal change disease Allergy Pollen Dust Fungi Bee sting Cat fur Food allergens (cow’s milk, egg) Infections Viral Parasitic Mycoplasma pneumoniae
- 22. Malignancies Hodgkin disease Non-Hodgkin lymphoma Leukemia Multiple myeloma Thymoma Bronchogenic cancer Colon cancer Eosinophilic lymphoid granuloma (Kimura disease) Drugs Nonsteroidal anti-inflammatory drugs Salazopyrin D-penicillamine Mercury Gold Tiopronin Lithium Tyrosine-kinase inhibitors
- 23. Autoimmune disorders SLE Diabetes mellitus Myasthenia gravis Autoimmune pancreatitis Celiac disease Allogeneic stem cell transplantation Immunizations
- 24. PATHOGENESIS • Existence of a circulating mediator produced by abnormal T cells Shalhoub(1974) 1. Remission may follow measles infection, which causes cell-mediated immunosuppression 2. MCD may occur in Hodgkin disease, a lymphoid neoplasia; 3. MCD responds to drugs that suppress cell-mediated immunity; and 4. There is an absence of humoral (Ig and complement) deposition in glomeruli • T cell hybridoma lines produced from patients with MCD were able to induce foot process effacement and proteinuria in rats • Prevalence of circulating CD8+ T suppressor cells that aggravate renal damage in mouse models of nephrotic syndrome
- 25. • Prevalence of a type 2 T helper cell (Th2; IL4, IL5, IL9, IL10, and IL13) cytokine profile in patients • Association between MCD and atopy, as allergies are driven by Th2 responses. • Of all Th2 cytokines, IL13 overexpression has been shown to induce foot process effacement and proteinuria in rats
- 27. • Effectiveness of B cell depletion via Rituximab, an anti-CD20 monoclonal antibody, in different forms of nephrotic syndrome has suggested a role for B cells as drivers of disease 1. Total IgG and IgG subclasses display protracted alterations in nephrotic patients during remission; 2. MCD has been observed in diseases associated with monoclonal light chains, implicating altered Ig's in disease pathogenesis 3. Plasma soluble CD23, a classic parameter of B cell activation, is increased during relapse 4. Measles virus also has an inhibitory effect on Ig synthesis 5. The immunosuppressors employed in the treatment of MCD have an antiproliferative effect on B cells, as well as on T cells.
- 28. • Evidence against a direct role of B cells in MCD pathogenesis 1. No Ig deposition on renal biopsy. 2. In vitro, rituximab has been proven to bind directly to podocyte SMPDL3b 3. Rituximab antiproteinuric effect may be independent of B cell depletion 4. Moreover, after rituximab infusion, some patients maintain prolonged remission despite reconstitution of B cells 5. the reconstitution of memory B cells predicts relapse Targeting B cells may affect costimulatory pathways involved in T cell activation, and this may well be one of the mechanisms involved
- 29. • Potential target of T cells on the Podocyte is CD80(B7–1) • T cell costimulatory molecule expressed on antigen- presenting cells and B cells • Which has been found in the urine of patients with MCD during disease relapse • Recently, however, the presence of CD80 on human podocytes during renal disease, including MCD and FSGS, has been excluded • The efficacy of recombinant CTLA4-Ig (Abatacept and Belatacept, which downregulate CD80) in reducing proteinuria was not confirmed by studies
- 30. • A plasma protein that binds sialoglycoproteins in podocytes, • Leading to proteinuria and foot process effacement in rats and cytoskeletal rearrangement in human cultured podocytes Hemopexin, • Overexpressing c-mip in podocytes develop heavy proteinuria without any inflammatory lesions or cell infiltration. • It interferes with podocyte signaling, • Cytoskeletal disorganization and foot processes effacement c-mip • Induce proteinuria, foot process effacement, and dyslipidemia Angiopoietin- like 4
- 31. TREATMENT • Acute management, • Salt and fluid intake restriction • Steroid treatment with prednisone or prednisolone are the primary drugs used at disease onset
- 32. KDIGO 2012-CHILDREN • 60 mg/m2 per d (or 2 mg/kg per d), 4–6 wk • 40 mg/m2 every other d (or 1.5 mg/kg every other d), 2–5 mo, taper • Minimum duration 12 wk PDN at onset • 60 mg/m2 per d (or 2 mg/kg per d) until 3 d after remission • 40 mg/m2 every other d (or 1.5 mg/kg every other d), 4 wk PDN in relapse (first relapses)
- 33. • 60 mg/m2 per d (or 2 mg/kg per d) until 3 d after remission • 40 mg/m2 every other d (or 1.5 mg/kg every other d) • Taper over ≥3 mo Long-term PDN (FRNS or SDNS) • CPA 8–12 wk • Chlorambucil 8 wk • Lev>1 yr • CsA/TAC>1 yr • MMF>1 yr • Rituximab Steroid- sparing agents (FRNS or SDNS)
- 34. Levamisole, • An immunostimulatory drug with an anthelmintic effect in animals, • Is reported to increase time to relapse in frequently relapsing NS compared with prednisone alone Calcineurin Inhibitor • cyclosporin A (CsA) tacrolimus; TAC) • Blocks the activation of T cells, modifying the immune response. • CsA is easier to handle (no need for frequent check of the blood count and no gonadal toxicity) • Led to a preference for CsA, especially in steroid-dependent NS. • Tacrolimus - prefered in adolescents, especially girls, as it does not induce hypertrichosis or gingival hypertrophy
- 35. Mycophenolate mofetil (MMF) • It has an antiproliferative effect on both B and T cells. • The main advantage of MMF compared with CsA is that it is not nephrotoxic. • This has made it the first choice in treating steroid-dependent NS Rituximab • It is a chimeric monoclonal antibody • It binds to the CD20 antigen expressed on B cells, thus inducing B cell depletion. • Rituximab reduces drug dependency, allowing interruption of all therapy, though often only temporarily, • Serious side effects: fulminant myocarditis, pulmonary fibrosis, fatal Pneumocystis jirovecii infections, severe ulcerative colitis, and severe allergic reactions Humanized anti-CD20 monoclonal antibody, Ofatumumab
- 36. Steroid-Resistant Forms • Steroid resistance is declared after 4 weeks of treatment. • Genetic screening for genetic forms of nephrotic syndrome and • Performing a renal biopsy, • Three intravenous methylprednisolone boluses followed by the introduction of a calcineurin inhibitor, most frequently CsA, • Oral prednisone is usually reduced to alternate days and gradually tapered until discontinuation within 6 months
- 37. ADULTS First Episode of Nephrotic Syndrome PDN 1 mg/kg per d or 2 mg/kg every other d (maximum 80 mg/d or 120 mg every other d) for 4–16 wk (evidence level 2C) Taper slowly over a total period of up to 6 mo after achieving remissionb (evidence level 2D) Infrequent relapses PDN 1 mg/kg per d or 2 mg/kg every other d (maximum 80 mg/d or 120 mg every other d) for 4–16 wk (evidence level 2C) Taper slowly over a total period of up to 6 mo after achieving remissionb (evidence level 2D)
- 38. Frequent relapses and steroid dependency CPA 2–2.5 mg/kg per d for 8 wk (single course) (evidence level 2C) If relapse occurs despite CPA or to preserve fertility: CsA 3–5 mg/kg per d in two divided doses for 1–2 yr (evidence level 2C) Or TAC 0.05–0.1 mg/kg per d in two divided doses until 3 mo after remission, then tapered to the minimum efficient dose for 1–2 yr (evidence level 2C) If intolerant to PDN, CPA, and CsA or TAC: MMF 500–1000 mg twice daily for 1–2 yr (evidence level 2D)
- 39. Outcome In children, • After remission of the first episode of nephrosis, about 30% do not suffer relapses for 18–24 months, • 20%–30% progress to infrequent relapses • The remaining 40%–50%, more frequently children <5 years of age, will have a frequently relapsing or steroid-dependent course • Initially steroid-sensitive disease will develop secondary steroid resistance. • This clinical feature is highly predictive of post-transplant recurrence In adults, relapses are frequent, occurring in about 56%–76% of patients
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