Glomerulonephritis Lecture - RPGN by Dr. Hisham

‫بسم هللا الرحمن الرحيم‬ Glomerular Diseases BY Dr :- Hisham Mustafa Alomda Assistant Professor of Pediatrics , U of Gezira MD –Pediatric & child health, U of K ‫ادع إلي سبيل ربك بالحكمة والموعظة الحسنة‬ Kidney functions :- 1- Plays crucial role in keeping the blood clea...

‫بسم هللا الرحمن الرحيم‬ Glomerular Diseases BY Dr :- Hisham Mustafa Alomda Assistant Professor of Pediatrics , U of Gezira MD –Pediatric & child health, U of K ‫ادع إلي سبيل ربك بالحكمة والموعظة الحسنة‬ Kidney functions :- 1- Plays crucial role in keeping the blood clean and regulating the amount of fluid in the body. 2- Produce urine. 3- Removing of toxic materials --(uric acid- urea) 4- Regulate the blood pressure (renin -angiotensin system). 5- Regulate the body ( PH ) Acid base balance. 6- Processing of vitamin D ( bone mineralization). 7- Processing of Erythropoietin hormone (RBCs production in BM). Glomerulonephritis (Normal) Glomerulonephritis (Normal) Pathogenic mechanisms in renal disease : Glomerular :- 1-- Immunologic Many glomerular and a small number of tubulo-interstitial and vascular disorders are immunologically mediated. These may be the result either of antibody-mediated or cell- mediated processes. In most instances in humans, the immediate cause or antigenic stimulus for the immune reaction is not known. The detection of antibody-mediated damage in renal tissue depends on the use of immunofluorescence microscopy. Most glomerulopathies are immunologically mediated and are the result of antibody-induced injury. Combining with an extrinsic glomerular antigen, with immune complexes localizing or depositing in glomeruli. The antigens may be of endogenous or exogenous origin. Endogenous antigens occur in diseases such as SLE and include components of nuclei such as DNA, histones, etc. Exogenous antigens are usually of microorganism origin and include bacterial products, hepatitis B and C viral antigens, malarial antigen, etc. Circulating immune complexes are trapped or lodge in glomeruli in the mesangium and subendothelial aspects of capillary walls. Once immune complexes are deposited, complement is fixed and often leukocyte infiltration follows.The white blood cell accumulate in capillary lumina and infiltrate into the mesangium; in addition, intrinsic mesangial cells may divide and may also extend into peripheral capillary walls. Cell-mediated immune injury in human renal disease is evident in acute interstitial disorders such as drug-induced acute interstitial nephritis and certain forms of transplant rejection Complement components, especially C5b-C9, may have a large role in producing structural and functional damage, especially in glomeruli. Recent and continuing evidence has documented the important roles of cytokines especially IL-1 and TNF as well as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) in the genesis and progression of glomerular disease Nonimmunologic There are several important mechanisms that result in significant glomerular damage. Damage to glomerular visceral epithelial cells, from a wide variety of influences, causes cell swelling with loss of individual foot processes. Further damage results in vacuolization, accumulation of protein in lysosomes (protein reabsorption droplets), and detachment of cells from the basement membrane. Tubular and Interstitial Injury Pathogenic mechanisms in tubulo-interstitial injury include immunologic processes (antibody-mediated and cell-mediated immunity) with cytokine expression and release, and action of inflammatory mediators. Chronic changes (interstitial fibrosis and tubular atrophy) are also the result of cytokine (PDGF and TGF-β) and complement (C5) fibroblast chemo attraction and of interaction of fibroblasts with metalloproteinases and IL-1, TNF-α, and epidermal growth factor. Fibroblasts produce collagen types I, III, IV, V; tubular cells are capable of synthesizing types I and III collagens as well as type IV (basement membrane) collagen. Vasculature :- The kidneys are frequent targets of vascular injury because of their high blood flow (approximately 25% of cardiac output); furthermore, kidney function is critically dependent on blood pressure and flow and any interference may have profound effects. The major lesions affecting renal vasculature include (1) thrombosis and embolization; (2) fibrin deposition in the walls of arteries, arterioles, and glomerular capillaries; (3) inflammation and necrosis of vascular walls; and (4) arteriosclerosis.  GN (Pathogenesis) Glomerulonephritis can be caused by various disorders, such as:- infections. inherited genetic disorder. or autoimmune disorders → deposition of Ag-Ab complexes. → cell mediated processes. → complement (components) deposition. → cytokines  GLOMERULONEPHRITIS PRESENTATIONS :- Urinary Abnormalities(proteinuria –haematuria ). Acute (Nephritic) (APSGN). Nephrotic Syndrome. Rapidly progressive glomerulonephritis (RPGN). Chronic Kidney Disease-(end stage renal disease)  GLOMERULONEPHRITIS Classifications:- Minimal Change Disease (MCD) Focal Segmental GN (FSGS) Proliferative – Diffuse --Focal – Mesangial – Membranoproliferative Membranous Rapidly Progressive GN (RPGN)  Classification of Glomerulonephritis Primary glomerulonephritis :- Membranous glomerulonephritis Membranoproliferative glomerulonephritis type I Membranoproliferative glomerulonephritis type II (dense deposit disease) IgA nephropathy Anti-GBM disease Idiopathic crescentic glomerulonephritis Secondary glomerulonephritis Poststreptococcal glomerulonephritis Henoch-Schonlein purpura Systemic lupus erythematosus Microscopic polyangiitis Wegener granulomatosus Cryoglobulinemia Rheumatic fever Acute post streptococcal glomerulonephritis: (APSGN) Nephritic syndrome.(Acute nephritis) Is a disorder of glomeruli (clusters of microscopic blood vessels in the kidneys with small pores through which blood is filtered). It is characterized by (edema), high blood pressure, and the presence of red blood cells in the urine (haematuria) ,, (+/-)oliguria and renal insufficiency. Etiology :- Acute glomerulonephritis that occurs after a streptococcal infection (post streptococcal glomerulonephritis) typically develops by certain strains(nephritogenic) of group A / B- hemolytic strep (serotype12-throat infection)& (49- skin infection). streptococcal antigen deposit in the affected glomeruli. Rarely, AGN can occur with chronic bacterial infections, such as subacute endocarditis, ventriculoatrial shunt infections, and deep- seated abscesses. Infections with other types of bacteria, such as staphylococcus and pneumococcus, viral infections, such as chickenpox , hepatitis B&C or HIV and parasitic infections, such as malaria, can also result in acute glomerulonephritis. Acute glomerulonephritis that results from any of these infections is called postinfectious glomerulonephritis. Noninfectious causes of acute glomerulonephritis include membranoproliferative glomerulonephritis, immunoglobulin A (IgA) nephropathy, thin basement membrane disease  Epidemiology :- AGN is still a major health concern in many geographic regions of the world. Because AGN follows upper respiratory or skin infection with group A β-hemolytic streptococcus in over 90% of cases, the term ‘acute post streptococcal glomerulonephritis’ (APSGN) is often used synonymously with AGN. APSGN associated with pharyngotonsillitis is more common in temperate climates, especially during winter, while impetigo- associated disease is more common in warm and humid climates during summer. Epidemic outbreaks of APSGN may occur under crowded and poor sanitary conditions. Pathology :- mesangial cell proliferation with an increase in mesangial matrix in some cases endothelial cells may proliferate and circulating polymporphonuclear cells, as well as monocytes and macrophages, may be present Kidneys appears enlarged , glomeruli enlarged and relatively bloodless (Bulky kidney). Pathogenesis :- Immune complex activation, ie (decreased C3 &C4).  When a renal biopsy is performed, it shows :-a diffuse endocapillary proliferative glomerulonephritis with numerous polynuclear cells and the presence of humps on the external side of the GBM.  Acute postinfectious glomerulonephritis. (A) Light micrograph showing a glomerulus in a patient with acute poststreptococcal glomerulonephritis.Glomerular capillaries are obliterated in many areas due to endothelial cell swelling. Numerous neutrophils are noted in the glomerulus. (B) Electron micrograph showing a large subepithelial deposit or ‘hump’ (arrow) in a patient with poststreptococcal GN. Frequency of APSGN :- 10 % of children with pharyngitis. 25 % of children with impetigo. Familial incidence rate is 40% ,but no genetic marker. Morbidity and mortality :- Early death is extremely rare in children ie,penetrate the basement membrane and pass into tubules—Dark tae or cola like urine. Asymptomatic microscopic haematuria Gross haematuria may developed in 30%. Resolved within 3-6 months ,but may persist up to 18 months. EDEMA :- Periorbital increased at morning and decreased at daytime,(proteinuria can reach the nephrotic range). HYPERTENTION:- Occur in 60—80% of cases(salt &water retention)—it,s transient ie,returned to normal when GFR is corrected and loss of edema and normalized plasma volume. If HTN persist it indicates(either non APSGN or more chronic stage. OLIGURIA :- < 1ml/kg/hr infant. < 0.5 ml/kg/hr in a child. < 300 ml/m2/day in children. Occur in 10-50% of cases. It is transient and diuresis occur within 1-2wks(acute phase). If persist it indicates severe crescentic form. DD:- of APSGN :- Non SGN. Membranous GN. Lupus GN. IgA nephropathy. Investigations :- Urinalysis; (RBCs),with RBCs cast ,granular cast ,leukocyte , proteinuria (mild or severe—5-10% of APSGN have nephrotic range proteinuria which was disappear with in 6 months. Blood; anaemia , high WBCs.  Complement studies Low C3 complement is central in the diagnosis of APSGN. In some cases of APSGN, C3 complement returns to a normal level in less than 2 weeks, whereas C3 complement returns to normal by 8 weeks in all cases with this disorder. Persistence of low complement C3 beyond 8 weeks should indicate a diagnosis other than APSGN. Apart from APSGN, low complement C3 is also be seen in SLE and in MPGN. Complement C4 level is usually normal in APSGN, but can be slightly decreased in some cases.  A positive ASO titer is considered evidence supportive of recent streptococcal infection, but does not confirm the existence of glomerulonephritis. Anti-DNase B antibody titer is +ve following skin infection. Throat culture for group A β-hemolytic streptococcal infection should be obtained. Abd/ US. RFT & electrolytes. Atypical features requiring renal biopsy in early phase:- Anuria—normal C3—absence of latent period---rapidly deteriorating RFT---persistent high BP beyond 2 wks and continued decrease in GFR. In recovery phase :- Persistent microscopic haematuria >18 mo. Persistent albuminuria beyond 6 mo.  COMPLICATIONS OF ACUTE GLOMERULONEPHRITIS Hypertension :- Commonly related to fluid overload and / or alteration in vascular tone. Definitions:- Severe hypertension: BP exceeding 99th percentile for age, height percentile and gender. Hypertensive emergency:- rise in systolic and diastolic BP associated with end-organ injury to brain, heart + kidneys. Acute pulmonary oedema Congestive cardiac failure Hypertensive encephalopathy ,ARF, stroke, myocardial infarction. Acute renal failure uraemia Hyperkalemia (serum K-->6.0 mmol/l in neonates , and > 5.5mmol/l in children ,generally cardiac toxicity develops when plasma K+ >7mmol/l Regardless of degree of hyperkalemia , treatment should be initiated in anyone with ECG abnormalities ,, ( tall peaked T wave. prolonged PR interval. widened QRS complex. flattened P wave) TREATMENT:- No specific treatment is available in most cases of AGN and the treatment consists of supportive therapy only. Children without volume expansion, hypertension, electrolyte problems, or decreased kidney function need only close follow up. Patients who develop significant renal impairment or hyperkalemia or hypertension generally require hospitalization for monitoring and appropriate fluid and electrolyte management. Conservative treatments:- Restriction of physical activity is appropriate in the first few days. Fluid restriction →1 litre\day. low protein diet and sodium →2g\day may be necessary until kidney function recovers. Treatment of streptococcal infection:- Treat the family members and any closed contact personnel to prevent the spread of nephritogenic strains to others. Oral penicillin V →125-250-500mg \7-10days.max-14 day. Erythromycin in allergic patients. Skin hygiene. TRT of significant edema or high BP:- Loop or thiazide diuretic (1-2mg\kg)(increase urine output, improve CVS congestion and lowering the BP). If the BP is not controlled, give →Ca.channel blocker Nifedipine 0.2- 0.3mg/kg 3 times/day {max 3 mg/kg/day} , OR (Atenolol 1 – 2mg/kg once or twice /day. Caution should be exercised with the use of ACEI or angiotensin receptor blockers because of the risk of hyperkalemia or renal failure. Hypertensive emergency :- Parentral anti hypertensive :- Hydralazine 0.1 – 0.8 mg/kg/dose {max 3.5 mg/kg/day} iv infusion over 5—20 minutes , every 4 – 6 hrs , every 20mg reconstituted with 1ml water for injection, then dilute with Na Cl 0.9% Or Ringer lactate. Sodium nitroprusside (0.53-0.10 µg/kg/min IV) max. dose 8µg /kg/min ,in continuous infusion. Diazoxide. Management of complications :- HYPERKALAEMIA:- # Dietary K restriction # potassium exchange resin, sodium polystyrene sulfonate (Kayexalate) (Resonium) 1g/kg orally or rectally 4 times/day. Calcium polystyrene sulphonate (Calcium Resonium) 0.25g/kg orally. Life-threatening hyperkalemia should be treated as an emergency using:- Emergency drugs:- Ca gluconate 10% (0.5-1ml/kg iv over 5-15 mins ,(dilution 1:1) immediate onset of action. Na bicarbonate 4.2% 1 mmol/kg iv over 10--30 mins. Salbutamol-iv or nebulised 0.5—1 ml in 2 ml NaCl ,{onset of action 30 mins}. Dextrose 50%(1 ml/kg with iv soluble insulin 0.1 u/kg over 15-- 30 min ,{onset of action 30 mins}. Rare cases of severe or symptomatic hyperkalemia should be treated with dialysis UREMIA Protein restriction Dialysis Hemodialysis or continuous veno-venous haemofiltration may be necessary in severe cases with uremia, especially if diuretic unresponsive anuria or oliguria is present. Prognosis:- APSGN resolves completely in most cases, more than 95% , especially in children. Acute phase resolve within 2 mo , but urinary abnormalities persist for more than 1 yr. In 1% of children and 10% of adults who have acute glomerulonephritis, it evolves into rapidly progressive glomerulonephritis, in which most of the glomeruli are destroyed, resulting in kidney failure.  Follow up :- Inpatients → renal charts. Outpatients :- BP→ monthly for 6 months then every 6 months. RFT →creatinine every 3 months for one year. Check C3. Urine check →RBCs & protein every 3-6 months. THANK YOU Minimal Change Disease (MCD) Features Mainly in children Present with – Proteinuria & usually nephrotic syndrome – Urine sediment usually clear Normal renal function Normal BP  Minimal Change Disease (MCD) Natural history Benign: No kidney Failure Complications –  tendency to thrombosis –  susceptibility to infection – Hyperlipidaemia  Minimal Change Disease (MCD) Treatment Steroids – 1 mg/kg for 3-4 months Relapse – Frequent: Cyclophosphamide Focal Segmental GN (FSGS)  Focal Segmental GN (FSGS) Features Children affected more than adults Present with – Proteinuria & usually nephrotic syndrome – Urine sediment usually clear Can progress to CKD ± HTN  Histological Variants Collapsing Tip lesion Perihilar Cellular Collapsing Tip Lesion  Focal Segmental GN (FSGS) Treatment Steroids – 1 mg/kg for about 6 months Response – Some patients may not respond → CKD  Proliferative (Diffuse) Post Infectious – Post Streptococcal – Other infections: Bacterial, Viral Connective tissue Diseases  Proliferative (Diffuse) Histology Affects most glomeruli (> 50%) Global: All the glomerulus tuft affected Infiltration with inflammatory cells Swollen Endothelial cells Proliferative (Diffuse) Features Usually follows throat or URTI Acute presentation – Haematuria Macroscopic (tea-like) – Oliguria – Oedema HTN Nephritic/Nephrotic ± Abnormal renal function  Proliferative (Diffuse) Investigations Antistreptolysin O Titre (ASOT) Renal function Serum Albumin Urine – Haematuria (dysmorphic RBCs) – Proteinuria (24-hours protein) – Casts DysmorphicRBCs Cellular Casts Granular Casts  Proliferative (Diffuse) Course Usually benign < 98 % recover Some may persist Or progress Treat features  Proliferative (Focal) < 50% of glomeruli involved Usually Secondary – Connective tissue diseases – Infections Course: follows underlying disease  Mesangioproliferative GN (IgA) Commonest worldwide Proliferation – Mesangial Matrix – Mesangial Cells Mesangioproliferative GN (IgA) Features Urine – Haematuria: microscopic or macroscopic – Proteinuria: mild or nephrotic range Nephrotic Syndrome HTN 30% may progress to ESRD  Mesangioproliferative GN (IgA) Treatment ACEI Manifestations: HTN, hyperlipidaemia Steroids Other immunosuppressives  Membranoproliferative GN (MPGN) (mesangiocapillary) 1ry or 2ry Types 1) Sub endothelial (immune deposits are in the sub endothelial space) 2) Dense Deposits Disease (Dense deposits within the mesangium) 3) Mixture of 1 & 2 (diffused deposits) Causes of MPGN Hepatitis C (70-90%). Bacterial endocarditis. Chronic Hepatitis B. Collagen vascular disease (SLE-Sjogren Synd Malignancy (CLL—Non Hodgkin Lymphoma) Clinical Presentation Microscopic hematuria. Non nephrotic proteinuria (35%) Nephrotic syndrome (35%) Chronic progressive GN (20%) RPGN(10%) Systemic hypertension Diagnoses Renal biopsy is the standard. Other useful tests:- Low C3—C4 ELISA for HCV—HBV ANA—Anti DNA RFT Urinanalysis Treatment Supportive treatment to :- Control the BP,(Antihypertensive) Reduce proteinuria ,(Antiproteinuric therapy ,, eg ACE inhibitors) Special situations:- Non nephrotic +normal RFT = Follow up every 3 months. Nephrotic or impaired RFT → Prednisone 2—2.5 mg/kg on alternate days for 2 yrs ,, then tapering for 3-7 yrs. Interferon alpha ,(HCV-associated MPGN) MPGN type 1 MPGN type 2  Membranous GN Diffuse thickening of the basement membrane Usually affects most glomeruli Immunoglobulins deposited in the BM  Membranous GN Causes Primary Secondary – Connective tissue diseases – Infections: HBV, HCV, Schistosomiasis, Malaria – Malignancy: Lymphomas, bronchial  Membranous GN Features Urine: Proteinuria (nephrotic range) Nephrotic Syndrome HTN Abnormal renal function  Membranous GN Course – 25-50% resolve spontaneously – 25% persist – 25% progress to ESRD Treatment Features: HTN, NS Specific – Steroids + immunosuppressants  Rapidly Progressive GN (RPGN) Definition This group of disorders causes microscopic damage to the glomeruli and progress rapidly. Sometimes they are caused by an infection or other treatable disorder. deterioration over days, wks, months Causes Any type can → RPGN With other diseases e.g. collagen vascular Idiopathic  RPGN (Types) 1) Anti-GBM Disease (Goodpasture’s D) – 10-40% ANCA +ve 2) Immune complex – Antistreptococal, IGA, SLE, Mixed cryog 3) Pauci-immune (necrotizing with few ID) – WG, Microscopic Polyangiitis, CSS, Renal-limited – Mostly ANCA +ve, some ANCA -ve 4) Double A/B positive RPGN (Type 1 & 3)  ANCA Detection – Indirect Immunofluorescence Assay > sensitive – ELISA > specific Types Cytoplasmic C-ANCA – Proteinase 3 (PR3) Perinuclear P-ANCA – Myeloperoxidase (MPO) C-ANCA P-ANCA  ANCA (Associations) C-ANCA PR3: WG 80-90% P-ANCA Microscopic Polyangiitis (MPA) 70% Churg-Strauss Synd (CSS) 50% (75% MPO) Renal-limited Vasculitis Majority +ve 75%MPO Anti-GBM Disease 10-40% Rheumatic diseases: RA, SLE, Sjogren’s Synd Drug-induced ANCA-Associated Vasculitis – Thiouracil , penicillamine , allopurinol , procainamide.  Rapidly Progressive GN (RPGN) Crescentic GN Features Acute course – Usually severe oliguria – Fluid retention – HTN – Features of diffuse proliferative – Early abnormality of renal funciton  Rapidly Progressive GN (RPGN) Crescentic GN Treatment Aggressive – High dose steroids – Other immunosuppressant – Plasmapheresis – Dialysis and kidney transplantation  For RPGN drugs to suppress the immune system are started promptly. High doses of corticosteroids are usually given intravenously for about a week(methyl prednisolone), followed by a variable period of time when they are taken by mouth. Cyclophosphamide as an immunosuppressant, may also be given. In addition, plasmapheresis is sometimes used to remove antibodies from the blood. The sooner treatment occurs, the less likely are kidney failure and the need for dialysis. Kidney transplantation is sometimes considered for people who develop chronic kidney failure, but rapidly progressive glomerulonephritis may recur in the transplanted kidney. ACEI and angiotensin II receptor blockers (ARBs) either alone or in combination often slow progression of chronic glomerulonephritis. Taking drugs to reduce high blood pressure and reducing sodium intake are considered beneficial. Restricting the amount of protein in the diet is modestly helpful in reducing the rate of kidney deterioration. End-stage kidney failure can be treated with dialysis or a kidney transplant. Prognosis :- The prognosis is poor. At least 80% of people develop end-stage kidney failure within 6 months without treatment. The prognosis is better for people younger than 60 years or if an underlying disorder causing the glomerulonephritis responds to treatment. THANK YOU