+ Glomerulopathies: clinical syndromes November 6, 2015

+ Which patient is sicker? Se-creatinine 561 microm/l Previous measurement 576 microm/l Next measurement 542 microm/l Daily urine output: 1.4 l Se-potassium: 3.5 mmol/l pH: 7.28 Se-creatinine: 303 microm/l Previous measurement 576 microm/l Next measurement 581 microm/l Daily urine output: 150 ml Se-potassium: 6.3 mmol/l pH: 7.29

+ Which patient is sicker? Se-creatinine 561 microm/l Previous measurement 576 microm/l Next measurement 542 microm/l Daily urine output: 1.4 l Se-potassium: 3.5 mmol/l pH: 7.28 Se-creatinine: 303 microm/l Previous measurement 176 microm/l Next measurement 581 microm/l Daily urine output: 150 ml Se-potassium: 6.3 mmol/l pH: 7.29

+ Which patient is sicker? Se-creatinine 561 microm/l Previous measurement 576 microm/l Next measurement 542 microm/l Daily urine output: 1.4 l Se-potassium: 3.5 mmol/l pH: 7.28 Se-creatinine: 303 microm/l Previous measurement 176 microm/l Next measurement 581 microm/l Daily urine output: 150 ml Se-potassium: 6.3 mmol/l pH: 7.29

+ Which patient is sicker? Se-creatinine 561 microm/l Previous measurement 576 microm/l Next measurement 542 microm/l Daily urine output: 1.4 l Se-potassium: 3.5 mmol/l pH: 7.28 Se-creatinine: 303 microm/l Previous measurement 176 microm/l Next measurement 581 microm/l Daily urine output: 150 ml Se-potassium: 6.3 mmol/l pH: 7.29

+ General aspects for disease categories Kidney function Time course Urine volume Urine findings Histology Complaints Symptomes “Too many secrets”

+ Kidney function Simplest: eGFR CKD-EPI (age, gender) MDRD (age) Cockroft-Gault (age, gender, body weight) 24 h urine: creatinine clearance Isotope scintigraphy Cystatin C Inulin

+ Time: course of the disease Acute onset: days to hours Subacute: week-month Chronic: years

+ Urine output definition Oliguria<500 ml/day <17-21 ml/h < ml/kg/h <0.5 ml/kg/h Anuria<100 ml/day Polyuria>2.5-2 l/day

RIFLE Criteria

+ Urinanalysis findings NephroticNephritic* Protein over 3.5 g/24 hProtein less than 1.5 g/24 h Dysmorphic red blood cells = Acanthocytes Fatty castsRed cell casts White blood cells * If glomeruli affected diffusely heavy or nephrotic range proteinuria, hypalbuminaemia, edema, hypertension and renal insufficiency can also be observed.

+ Proteinuria Overflow: abnormal serum protein components Glomerular: abnormal glomerular structure Selective: minimal-change nephrotic syndrome Non-selective: glomerulonephritis, diabetic nephropathy Tubular: interstitial nephritis Hemodynamic: heart failure

+ Indication for kidney biopsy Diagnostic in cases with proteinuria greater than 2 g/day, hematuria, RBC casts Diagnostic in cases with renal failure and kidney size is normal and other approaches are non-conclusive Follow-up in diseases such as SLE, pulmonary-renal syndromes, paraproteinaemias

+ Approach to kidney patients Serum chemistry: Na, K, CN, Kreat, Mg, Ca, Phosph, uric acid, albumin GFR Urine dipstick 24-hour urine sample ESR, ANA, ANCA, anti-GBM, C3, cryoglobulins Hepatitis B, C, AST Serum and urine protein ELFO Imaging Renal biopsy

+ Classification of glomerulopathies Nephrotic syndrome – massive proteinuria (>3.5 g/day), hypoalbuminaemia, oedema, lipiduria and hyperlipidaemia. Acute glomerulonephritis (acute nephritic syndrome) – abrupt onset of glomerular haematuria (RBC casts or dysmorphic RBC), non-nephrotic range proteinuria, oedema, hypertension and transient renal impairment. Rapidly progressive glomerulonephritis – features of acute nephritis, focal necrosis with or without crescents and rapidly progressive renal failure over weeks. Asymptomatic haematuria, proteinuria or both. Chronic glomerulonephritis – Persistent proteinuria with or without haematuria and slowly progressive impairment of renal function

+ Thesaurus: Pathological terms Focal: some, but not all, glomeruli show the lesion Diffuse (global): most of the glomeruli (>75%) contain the lesion Segmental: only a part of the glomerulus is affected (most focal lesions are also segmental, e.g. focal segmental glomerulosclerosis) Proliferative: an increase in cell numbers due to hyperplasia of one or more of the resident glomerular cells with or without inflammation Membrane alterations: capillary wall thickening due to deposition of immune deposits or alterations in basement membrane Crescent formation: epithelial cell proliferation with mononuclear cell infiltration in Bowman’s space.

Dr. Járay Jen ő, dr. Hidvégi Márta MANET Nagygy ű lés, 2002

+ Playground: only two compartments

+ Sites of kidney injury and renal function

+ Features of glomerulopathies (GN) primarily an immunologically mediated injury to glomeruli, (renal interstitial damage is a regular accompaniment) the kidneys are involved symmetrically secondary mechanisms of glomerular injury come into play following an initial immune insult (such as fibrin deposition, platelet aggregation, neutrophil infiltration) renal lesions may be part of a generalized disease (e.g. systemic lupus erythematosus, SLE).

+ Cells involved in GNs

+ Link among syndrome and treatment MembranousProliferative Clinical syndromeNephrotic-syNephritic-sy TreatmentSteroidImmunosuppression

+ Nephrotic syndrome Heavy proteinuria Hypalbuminaemia Hypercholersterolaemia Edema Risk of thrombotic events

+ Minimal change nephritis Mainly childhood or young adults Nephrotic Secunder forms: lymphomas, Hodgkin’s disease EM: foot process fusion Steroids ESRD not typical

+ Focal segmental glomerulosclerosis Mainly adulthood Nephrotic Secunder forms: AIDS, SLE Remissions and relapses Steroids ESRD frequent (30-60%)

+ Membranosus nephropathy Any age Isolated proteinuria – nephrosis Secunder form: malignant diseases, SLE Prognostic factors determine outcome Remissions and relapses Steroid + cytotoxic treatment ESRD frequent (30-50%)

+ Poor prognostic factors in MN Age over 50 yrs Male gender Hypertension Reduced GFR Proteinuria greater than 10 g/day Interstitial fibrosis in Histology

+ Acute nephritic syndrome Haematuria (macroscopic or microscopic) – red-cell casts are typically seen on urine microscopy Proteinuria Hypertension Oedema (periorbital, leg or sacral) Temporarily oliguria and uraemia.

+ Post-streptococcal GN Kids Acute nephritic sy Streptococcal infection: throat, pyoderma AST increased Subepithelial hump deposits No specific therapy, anti-streptococcal antibiotics ESRD not likely

+ Membranoproliferative GN Young adults Various forms: Nephroso-nephritic, simple proteinuria, acute nephritis Secunder forms: Hepatitis B, C, SLE C3 level low Steroid+ cytotoxic drugs ESRD likely 30%

+ Rapidly progressive glomerulonephritis 50% decline in kidney function in 3 month Hematuria and casts Type I: anti GBM disease (type II hypersensitivity) Type II: immuncomplex disease (type III hypersensitivity) eg: SLE, Schonlein-Henoch purpura, SLE Type III: ANCA positive vasculitis, pauci-immune GN

+ Anti-GBM glomerulonephritis Above 50 yrs If lungs are involved Goodpasture’s sy Rapidly progressive GN C3 normal ANCA positivity Plasmapheresis ESRD frequent

+ ANCA-positive vasculitides Wegener’s granulomatosis, microscopic polyangiitis Churg–Strauss syndrome

+ ANCA positive (pauci-immun) GN Focal ( ≥50% normal glomeruli that are not affected by the disease process) Crescentic ( ≥50% of glomeruli with cellular crescents) Mixed (a heterogeneous glomerular phenotype wherein no glomerular feature predominates) Sclerotic (≥50% of glomeruli with global sclerosis).

+ IgA nephropathy Adult, male Mesangial IgA deposits Asymptomatic hematuria, but 10% nephrotic Secondary forms: hepatic cirrhosis, gluten sensitive enteropathy, dermatitis herpetiformis No optimal therapy: steroid, fish oil, ACEi ESRD possible in 20-30%

+ Lupus nephritis Class I – Minimal mesangial lupus nephritis (LN), with immune deposits but normal on light microscopy. Asymptomatic. Class II – Mesangial proliferative LN with mesangial hypercellularity and matrix expansion. Clinically, mild renal disease. Class III – Focal LN (involving <50% of glomeruli) with subdivisions for active or chronic lesions. Subepithelial deposits seen. Clinically have haematuria and proteinuria; 10–20% of all LN. Class IV – Diffuse LN (involving >50% of glomeruli) classified by the presence of segmental and global lesions as well as active and chronic lesions. Subendothelial deposits are present. Clinically, there is progression to the nephrotic syndrome, hypertension and renal insufficiency. Most common and most severe form of LN. Class V – Membranous LN affects 10–20% of patients. Can occur in combination with III or IV. Good prognosis. Class VI – Advanced sclerosing LN (≥90% globally sclerosed glomeruli without residual activity). This represents the advanced stages of the above, as well as healing. Immunosuppressive therapy is unlikely to help as it is ‘inactive’. Progressive CKD.

+ Therapeutical approaches Volume control: Appropriate circulating volume, no overload either RR control: hypertension, hypotension should be avoided Proteinuria: ACEi, ARB: maximal tolerable dose Hyperlipidaemia: statins Dietary: sufficient energy, protein restriction

+ Practical map Nephrotic syndrome MCD FSGS MN Rapidly progressive GN Anti-GBM GN Immuncomplex D ANCA-pos pauci immun GN Acute nephritic syndrome Poststreptococcal GN MPGN Isolated hematuria IgA Chronic kidney diease

+ Bigger resolution for advanced adverturers AGENephroticMild nephriticSevere nephritic <15MCD, FSGS, MesaProlG Postinfect, IgAN, HSP Postinfect, MembranoprolGN 15-40FSGS, MCD, MN, DN IgAN, thin basal membrane D, LN, MesaProlG Postinfect, LN, RPGN, IgAN, MembranoprolGN >40FSGS, MN, DN, MCD, IgAN IgANRPGN, vasculitis, IgAN MCD: minimal change, FSGS: focal segmental glomerulosclerosis, MesaProl: mesangioproliferative GN, MN: Membranosus nephropathy, DN: Diabetic nephropathy, IgAN: IgA nephropathy, Postinfect: postinfectious nephropathy, HSP: Henoch-Schonlein purpura,