Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download อายุรศาสตร์โรคไต
Document related concepts
Transcript
อายุรศาสตร์โรคไต Nephrology GLOMERULAR DISEASES APPROACH TO THE PATIENTS WITH SUSPECTED OF GLOMERULAR DISEASES 2 Clinical presentations of glomerular diseases Differentiate between glomerular syndromes • Nephritic syndrome versus nephrotic syndrome • Proteinuria: varying in degree of proteinuria, more specific in proteinuria > 2 g/day Nephritic syndrome • Glomerular hematuria • Decreased GFR: oliguria, anuria, uremic symptoms • Salt and water retention: edema, hypertension Decreased of GFR: edema, oliguria, hypertension, azotemia Active urine sediments: dysmorphic RBC, RBC cast Subnephrotic-ranged proteinuria Nephrotic-ranged proteinuria Hyperlipidemia Nephrotic syndrome Hypoalbuminemia Edema Lipiduria: oval fat body, fatty cast • Asymptomatic versus symptomatic • Define onset of disease: history of urine volume and characters change, nocturia, edema, broad cast in urine (subacute to chronic onset), ultrasound kidney ‣ Acute onset: days to week ‣ Subacute onset: weeks to month ‣ Chronic onset: ≥ 3 months 3 Isomorphic RBC from light microscope Broad cast 4 Classify glomerular syndromes Evaluation of secondary causes of glomerular disease • Predict pathological findings by clinical manifestations • Asymptomatic urinary abnormalities ‣ Asymptomatic proteinuria Nephrotic features Nephritic features Minimal change disease (MCD) ++++ - Membranous nephropathy (MN) ++++ + Focal segmental glomerulosclerosis (FSGS) +++ ++ Fibrillary glomerulonephritis +++ ++ Mesangioproliferative glomerulonephritis ++ ++ Membranoproliferative glomerunephritis (MPGN) ++ +++ Proliferative glomerulonephritis ++ +++ Acute diffuse proliferative glomerulonephritis + ++++ Crescentic glomerulonephritis + ++++ ‣ Asymptomatic hematuria • Nephrotic syndrome • Acute glomerulonephritis (AGN): acute onset • Rapidly progressive glomerulonephritis (RPGN): subacute onset • Chronic glomerunephritis (CGN): chronic onset • Evaluation of secondary causes according to predicted pathological findings 5 Renal biopsy • Indication ‣ Significant proteinuria: urine protein > 1 g/day (or equivalent) ‣ Glomerular hematuria ‣ Unexplained renal impairment ‣ Renal manifestation of systemic disease • Contraindication Absolute contraindication Relative contraindication • Complication: incidence 3-9% (majority are minor complication), <7% of bleeding required intervention, > 90% occurs in 24 hours ‣ Gross hematuria ‣ Perinephric hematoma ‣ Arteriovenous fistula ‣ Sepsis Uncontrolled hypertension Bleeding diathesis Widespread cystic disease Renal malignancy Hydronephrosis Uncooperative patient Renal vein thrombosis Single kidney Antiplatelet or anticoagulant therapy Anatomic abnormalities Small kidneys Active urinary or skin sepsis Obesity ‣ Death: due to undiagnosed hematoma 0.2% • Prepare the patients for treatment: evaluation of occult infection (chest x-ray, dental examination, stool concentrate for parasite) • Select the treatment regimen according to type of glomerular disease 6 References • Emmett M, Fenves AZ, and Schwartz JC. Approach to the patient with kidney disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 844-867. • Salama AD, and Cook HT. The renal biopsy. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. P 1006-1016. 7 ASYMPTOMATIC PROTEINURIA 8 DEFINITION • Total protein excretion ‣ Normal < 150 mg/day ‣ Proteinuria ≥ 150 mg/day ‣ Nephrotic-ranged proteinuria mg/day > 3,500 • Albumin excretion ‣ Normal 2 – 30 mg/day ‣ Microalbuminuria 30 – 300 mg/day 9 Pathogenesis and etiologies • Overflow proteinuria ‣ Large amount of small molecular weight protein filter through normal glomerulus and exceeds the capacity of normal tubular cells for complete reabsorption ‣ Causes: monoclonal gammopthies (e.g. multiple myeloma), intravascular hemolysis (hemoglobinuria), rhabdomyolysis (myoglobinuria) • Tubular proteinuria ‣ Tubular cells injury results in increase secretion of Tamm-Horsfall protein, increase secretion of other brush border components, and decrease reabsorption of small molecular weight protein in urine - Infections: pyeolonephritis, tuberculosis - Metabolic: DM, hyperuricemia, uricosuria, hypercalcemia, hypercalciuria, hypokalemia, oxalosis, cystinosis - Immunologic: SjÖgrens’s syndrome, renal transplant rejection, drug hypersensitivity, sarcoidosis - Toxic: analgesic abuse, radiation nephritis, lithium, heavy metals (lead, cadmium, mercury), Balkan nephropathy, cyclosporine, cisplatin, aminoglycoside - Anatomic: obstruction, ureterovesical reflux, medullary sponge kidney - Miscellaneous: multiple myeloma, amyloidosis, sickle cell disease, medullary sponge kidney ‣ Urine protein usually < 2 g/day ‣ Urine albumin : β2 microglobulin ratio 10:1 ‣ Causes - Hereditary: polycystic kidney disease, medullary cystic disease 10 • Glomerular proteinuria ‣ Glomerular injuries result in loss charge- and/ or size-selectivity properties of glomerular basement membrane, and subsequently abnormally increase in clearance of urine protein ‣ Urine protein usually < 2 g/day ‣ Urine albumin : β2 microglobulin ratio > 1,000:1 ‣ Causes: primary and secondary glomerulonephritis and nephrotic syndrome (see in “Etiologies of nephrotic syndrome”), hereditary nephritis (Alport’s syndrome, thin basement membrane disease) • Benign orthostatic proteinuria ‣ Commonly found in tall adolescents ‣ Protenuria occurs only in the morning after ambulation, but not in the nighttime ‣ Urine protein < 1 g/day, and no any abnormal urine sediment ‣ Half of patients spontaneous recovery in 10 years, but small number progress to overt renal disease ‣ Functional and transient proteinuria ‣ Proteinuria which occurs associated with non-renal cause and disappear after resolution of disease process ‣ Heart failure, fever, or heavy exercise 11 Approach to the patients with asymptomatic proteinuria 12 Indications for renal biopsy • Urine protein > 2 g/day • Urine protein < 2 g/day with any of the followings: microscopic hematuria, hypertension, low serum complement, or family history of hereditary nephritis References • Kashif W, et al. Proteinuria: How to evaluate an important finding. Cleve Clin J Med 2003;70:535-547. • Adler SG and Kairley K. The patient with hematuria, proteinuria, or both, and abnormal findings on urinary microscopy. In: Schrier RW. editor. Manual of nephrology. 7th ed. Phiadephia: Lippincott Williams & Wilkins; 2009. P 122-139. 13 ASYMPTOMATIC HEMATURIA 14 DEFINITION AND ETIOLOGIES • Bed rest • Analgesics • Hydration: to increase urine flow rate to 2 – 3 L/ day • Avoid sports which at a risk of abdominal trauma: such as rugby, boxing 15 APPROACH TO THE PATIENTS WITH ASYMPTOMATIC HEMATURIA 16 17 Indications for renal biopsy • Impaired renal function • Urine protein > 2 g/day • Any of the followings: hypertension, low serum complement, or family history of hereditary nephritis References • Adler SG and Kairley K. The patient with hematuria, proteinuria, or both, and abnormal findings on urinary microscopy. In: Schrier RW. editor. Manual of nephrology. 7th ed. Phiadephia: Lippincott Williams & Wilkins; 2009. P 122-139. • Emmett M, Fenves AZ, and Schwartz JC. Approach to the patient with kidney disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 844-867. 18 NEPHRITIC SYNDROMES 19 DEFINITION • Inflammatory process occurred in glomeruli 20 ETIOLOGIES 21 Immune complex glomerulonephritis • Lupus nephritis (LN) • Post-infectious glomerulonephritis (PIGN) • IgA nephropathy (IgAN) and Henoch-SchÖnlein purpura (HSP) • Subacute bacterial endocarditis • Membranoproliferative glomerulonephritis (MPGN) • Cryoglobulinemia Anti-glomerular basement membrane Pauci-immune glomerulonephritis • ANCA-associated glomerulonephritis ‣ Granulomatosis with polyangitis (GPA) or Wegner’s granulomatosis ‣ Eosinophilic granulomatosis with polyangitis (EGPA) or Churg-Strauss syndrome ‣ Microscopic polyangiitis (MPA) ‣ Renal limited pauci-immune glomerulonephritis • Double positive disease (GBM) • Anti-GBM disease • Goodpasture’s syndrome 22 CLASSIFICATION • By onset of disease ‣ Acute glomerulonephritis (AGN) ‣ Rapidly progressive glomerulonephritis (RPGN) or crescentic glomerulonephritis ‣ Chronic glomerulonephritis (CGN) • By etiologies: see “Etiologies” 23 CLINICAL MANIFESTATIONS • Active urine sediment: dysmorphic RBCs, RBC casts, and often WBCs and WBC casts • Hematuria ‣ Sporadic, intermittent, or persistent hematuria ‣ Microscopic, or gross hematuria • Reduced GFR • Subnephrotic-ranged to nephrotic-ranged proteinuria • Variable degree of hypertension, oliguria, and edema 24 APPROACH TO THE PATIENTS WITH NEPHRITIC SYNDROME • Differentiate onset of disease ‣ AGN: most common and prototype is postinfectious GN ‣ RPGN: can caused by any disease in all three groups (immune complex GN, anti-GBM, and pauci-immune GN) ‣ CGN: can result from any diseases that causes nephritic or nephrotic syndrome • Differential diagnosis by using data from history taking and physical examination • (See “Approach to the patients suspected glomerular diseases”) • Investigations: depend on the differential diagnosis e.g. serum complement, ANA, ANCA, anti-GBM, HBsAg, anti-HCV, and renal biopsy 25 References • Emmett M, Fenves AZ, and Schwartz JC. Approach to the patient with kidney disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 844-867. 26 NEPHROTIC SYNDROME (NS) 27 DEFINITION • Nephrotic-ranged proteinuria: urine protein > 3 – 3.5 g/day or equivalent • Hypoalbuminemia • Edema • Hperlipidemia 28 ETIOLOGIES 29 Secondary NS • Infections: HBV, HCV, HIV, tuberculosis, infective endocarditis, visceral abscess, shunt nephritis Secondary causes of NS MCD Hodgkin’s lymphoma, NSAIDs FSGS HIV, nephron loss, familial, obesity, hypertension, reflux nephropathy, heroin, analgesic nephropathy MN HBV, HCV, solid tumors, Dpenicillamine, NSAIDs, gold, SLE, non-Hodgkin’s lymphoma, amyloidosis MPGN Chronic infection (infective endocarditis, tuberculosis, HCV, HBV, visceral abscess, shunt nephritis), chronic inflammation (rheumatoid arthritis, SLE), light chain disease • Autoimmune diseases: SLE, rheumatoid arthritis, SjÖgren syndrome • Medications: NSAIDs, gold, D-penicillamine, heroin • Malignancies: hematologic malignancy (Hodgkon’s and non Hodgkin’s lymphoma, plasma cell dyscrasia), solid tumors • Metabolic abnormalities: DM, hypertension, obesity • Miscellaneous diseases: reflux nephropathy, analgesic, nephron loss, amyloidosis 30 Primary NS • Primary NS: diagnosis can be made after exclude secondary causes ‣ Minimal change disease (MCD) ‣ Focal segmental glomerulonephritis (FSGS) ‣ Membranous nephropathy (MN) ‣ Membranoproliferative glomerulonephritis (MPGN) ‣ IgM nephropathy (IgMN) 31 CLINICAL MANIFESTATIONS • Severity of diseases in primary NS are more severe than in secondary NS 32 Clinical manifestation of primary nephrotic syndrome Age Hypertension Hematuria Response to steroid therapy MCD Very young - - Good FSGS Young 1/3 of patients 2/3 of patients 1/3 response MN Aging 1/3 of patients 2/3 of patients None, but 1/3 of patients have spontaneous remission MPGN Young 1/3 of patients 80% of patients Poor IgMN Middle age 10% of patients <5% of patients 80% response 33 References • Emmett M, Fenves AZ, and Schwartz JC. Approach to the patient with kidney disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 844-867. 34 COMMON GLOMERULAR DISEASES 35 LUPUS NEPHRITIS 36 Epidemiology • Incidence 1.8 – 7.6 cases / 100,000 people, prevalence 40 – 200 cases / 100,000 people • Age of onset: peak 15 – 45 years, 85% are younger than 55 years • Female:male ratio 10:1 • More than 60% of adults with SLE have renal involvement • 50% of adults with SLE have renal involvement at presentation • Same incidence of renal involvement in male and female Pathogenesis • Genetic, environmental, immunoregulatory, hormonal, and epigenetic factors contribute sequentially or simultaneously on the immune system result in loss of self-tolerance and generation of autoantibodies, immune complexes, autoreactive or inflammatory T cells and cytokines which damage to various organ, including kidneys. 37 Classification International society of nephrology/renal pathology society (ISN/RPS) 2003 classification of LN Class I Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence Class II Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or electron microscopy, but not by light microscopy Class III Focal lupus nephritisa Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations Active lesions: focal proliferative lupus nephritis Class III (A) Active and chronic lesions: focal proliferative and sclerosing lupus nephritis Class III (A/C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis Class III (C) Class IV Diffuse lupus nephritisb Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental(IV-S) lupus nephritis when > 50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when >50% of the involved glomeruli have golbal lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation 38 Class IV-S (A) Class IV-G (A) Class IV-S (A/C) Class IV-S (C) Class IV-G (C) Class V Class VI Active lesions: diffuse segmental proliferative lupus nephritis Active lesions: diffuse global proliferative lupus nephritis Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis Membranous lupus nephritis Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed Class V lupus nephritis show advanced sclerosis Advanced sclerosis lupus nephritis >90% of glomeruli globally sclerosed without residual activity aIndicate the proportion of glomeruli with active and with sclerotic lesions. bIndicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions. 39 Abbreviated international society of nephrology/renal pathology society (ISN/RPS) 2003 classification of LN Class I Minimal mesangial lupus nephritis a Class II Mesangial proliferative lupus nephritis Indicate the proportion of glomeruli with active and with sclerotic lesions b Indicate Class III Focal lupus nephritisa the proportion of glomeruli with fibrinoid necrosis and cellular crescents c Class Class IV Class V Diffuse segmental (IV-S) or global (IV-G) lupus nephritisb Membranous lupus nephritisc V may occur in combination with class III or IV in which case both will be diagnosed Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions Class VI Advanced sclerosing lupus nephritis 40 Clinical manifestations Class I No clinical renal manifestation Class II Proteinuria: usually < 1 g/day, no hematuria, normal blood pressure, normal renal function Class III Hematuria, subnephrotic-ranged proteinuria, mild renal impairment, mild hypertension Class IV Hematuria, subnephrotic-ranged to nephrotic-ranged proteinuria, mild to severe renal impairment, mild to severe hypertension Class V Nephrotic syndrome, no hematuria, usually normal blood pressure, normal renal function Class VI Chronic kidney disease, depend of severity of disease 41 Investigations • Low complement in class IV, but variable in class V • Extra-renal manifestations as in the criteria for diagnosis Renal pathology Light microscope • see in classification Immunofluoresence • Immunofluoresence: positive staining in glomeruli, tubules, interstitium, and blood vessels ‣ Predominant IgG, with co-deposits of IgM and IgA in most specimens ‣ Presence of fibrin, fibrinogen, C3 and C1q staining are common Electron microscope • Class I and II: mesangial EDD • Class III, IV and V: subendothelial and subepithelial EDD • Tubulorecticular inclusions (TRIs): intracellular branching tubular structures, 24 nm in diameter located within dilated cisternae of the endoplasmic reticulum of glomerular nad vascular endothelial cells, can be found in patients with HIV infection, other viral infections, and who receive INF-α Diagnosis • Definite diagnostic tool for LN is renal biopsy • Presumptive diagnosis of LN can be done in the patients with renal manifestations who meet the criteria for diagnosis of SLE ‣ Full house staining: presence of IgG, IgM, IgA, C3 and C1q staining, highly suggestive of LN 42 Criteria for diagnosis SLE •SLICC ‣ SLICC (systemic lupus international collaborating clinics) criteria (2012) ➡ Diagnosis can be made if ➡ Presence of at least 4 of the followings, including at least one clinical criterion and one immunologic criterion, or ➡ Presence of biopsy-proven nephritis compatible with SLE, and presence of ANAs or antidsDNA antibodies Clinical criteria 1. Acute cutaneous lupus, including: • Lupus malar rash (do not count if malar discoid) • Bullous lupus • Toxic epidermal necrolysis variant of SLE • Maculopapular lupus rash • Photosensitivity lupus rash In the absence of dermatomyositis OR • subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias) 2. Chronic cutaneous lupus, including: • Classic discoid rash ‣ Localized (above the neck) ‣ Generalized (above and below the neck) • Hypertrophic (verrucous) lupus • Lupus panniculitis (profundus) • Mucosal lupus • Lupus erythematosus tumidus • Chillblains lupus • Discoid lupus/lichen plannus overlap 43 Clinical criteria Clinical criteria 3. Oral ulcers • Palate ‣ Buccal ‣ Tongue OR • Nalsal ulcers • in the absence of other causes, such as vasculitis, Behḉet’s disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, and acidic foods 6. Serositis • Typical pleurisy for more than 1 day OR pleural effusion OR pleural rub • Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day OR pericardial effusion OR pericardial rub OR pericarditis by EKG in the absence of other causes, such as infection, uremia, and Dressler’s pericarditis 4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs) in the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia 7. Renal Urine protein-to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 horurs OR red blood cell casts 5. Synovitis involving 2 or more joints, characterized by swelling or effusion OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness 44 Clinical criteria 8. Neurologic • Seizures • Psychosis • Mononeuritis multiplex in the absence of other known causes such as primary vasculitis • Peripheral or cranial neuropathy in the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus • Acute confusional state in the absence of other causes, including toxic/metabolic, uremia, drugs 9. Hemolytic anemia Clinical criteria 10. Leukopemia (< 4,000/mm3 at least once) in the absence of other known causes such as Felty’s syndrome, drugs, and portal hypertension OR Lymphopenia (< 1,000/mm3 at least once) in the absence of other known causes such as corticosteroids, drugs, and infection 11. Thrombocytopenia (< 100,000/mm3 at least once) in the absence of other known causes such as drugs, portal hypertension, and thrombotic thrombocytopenic purpura 45 Immunologic criteria Immunologic criteria 1. Immunologic criteria 5. Low complement • Low C3 • Low C4 • Low CH50 2. Anti-dsDNA antibody level above laboratory reference range (or > 2-fold the reference range if tested by ELISA) 3. Anti-Sm: presence of antibody to Sm nuclear antigen 6. Direct Coombs’ test in the absence of hemolytic anemia 4. Antiphospholipid antibody positivity as determined by any of the following: • Positive test result for lupus anticoagulant • False-positive test result for rapid plasma regain • Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM) • Positive test result for anti-β2-glycoprotein I (IgA, IgG, or IgM) 46 ACR (American college of rheumatology) criteria (1997) 4 of the 11 criteria are needed for the diagnosis Criterion Definition Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions Skin rash as a result of unusual Photosensitivity reaction to sunlight, by patient history or physician observation Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician Nonerosive arthritis Involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion Criterion Definition Pleuritis or pericarditis 1. Pleuritis – convincing history of pleuritic pain or rubbing heard by physician or evidence of pleural effusion, or 2. Pericarditis – documented by EKG or rub or evidence of pericardial effusion Renal disorder 1. Persistent proteinuria > 0.5 g/ day or more than 3+ if quantitation not performed, or 2. Cellular casts – may be red cell, hemoglobin, granular, tubular, or mixed 47 Criterion Definition Neurologic disorder 1. Seizures – in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance, or 2. Psychosis – in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance Hematologic disorder 1. Hemolytic anemia – with recticulocytosis, or 2. Leukepenia < 4,000/mm3 on ≥2 occasions, or 3. Lymphopenia <1,500/mm3 on ≥2 occasions, or 4. Thrombocytopenia <100,000/ mm3 in the absence of offending drugs Criterion Definition 1. Anti-DNA: antibody to native DNA in abnormal titer, or 2. Anti-Sm: presence of antibody to Sm nuclear antigen, or 3. Positive finding of antiphospholipid antibodies on: 3.1 an abnormal serum level of IgG Immunologic or IgM anticardiolipin antibodies, disorder 3.2 a positive test result for lupus anticoagulant using a standard method, or 3.3 a false positive test result for at least 6 months confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test Antinuclear antibodies An abnormal titer of antinuclear antibody by immunofluoresence or an equivalent assay at any point in time and in the absence of drugs 48 Treatment Specific treatment • Specific treatment • Class I: treat extrarenal manifestations • Class II: treat extrarenal manifestations ‣ In case of proteinuria > 3 g/day, treat as MCD • Class III and IV ‣ Initial therapy - Calcineurin inhibitors (CNIs): alternative therapy for patients who intolerance to azathioprine or MMF • Class V ‣ In case of persistent nephrotic-ranged proteinuria: corticosteroid plus cyclophosphamide, or CNIs, or MMF, or azathioprine • Class VI: treat extrarenal manifestations • Hydroxychloroquine: maximum dosage 6 – 6.5 mg/kg/day, in all LN patients unless contraindicate - Corticosteroid plus cyclophosphamide or MMF - In case of worsening LN during first 3 months of treatment, change to alternative treatment, or repeat renal biopsy to guide the treatment ‣ Maintenance therapy: continue after complete remission for at least 1 year before tapering the dosage - Corticosteroid ≤ 10 mg/d plus azathioprine 1.5 -2.5 mg/kg/day or MMF 1 – 2 g/day 49 Other circumstances • Relapse disease ‣ Resume the effective initial therapy, or ‣ High cumulative dosage of cyclophosphamide, change to non-cyclophosphamidebased regimen ‣ In case of antiphospholipid antibody syndrome (APS) involve kidney, treat the patients with anticoagulants with target INR 2 – 3 ‣ In case of thrombotic thrombocytopenic purpura (TTP), treat the patients with plasma exchange • Pregnancy ‣ In case of possible histologic class of LN has changed, repeat renal biopsy ‣ Delay pregnancy until achieve complete remission ‣ Evaluation for the precipitating factors: poor drug compliance, infections, pregnancy, or drugs (estrogen-containing oral contraceptive pills) ‣ Mode of contraception: condom • Resistant disease ‣ Repeat renal biopsy to distinguish active disease from scarring ‣ In case of active disease, treat the patients with alternative regimen ‣ In case of failed treatment ≥ 2 initial regimens, consider treatment with rituximab, or IV immunoglobulin (IVIG), or CNIs • SLE with thrombotic microangiopathy (TMA) ‣ Administration of low-dose aspirin during pregnancy to decrease risk of fetal loss ‣ Do not use cyclophosphamide, MMF, ACEI and ARB ‣ Switch MMF to azathioprine during the pregnancy ‣ In case of relapse disease during pregnancy, treat the patients with corticosteroid and/or azathioprine depend on disease severity ‣ In case of receiving corticosteroid and azathioprine, continue same dosage for at least 3 months after delivery 50 Side effect of treatment • Corticosteroid ‣ Hyperglycemia, hypertension, hyperlipidemia, atherosclerosis, adrenal insufficiency ‣ Cushingoid appearance, abnormal hair growth, weigt gain, growth retardation ‣ Peptic ulcer, pancreatitis ‣ Posterior subcapsular cataract, glaucoma ‣ Psychosis, sleeplessness, pseudotumor cerebri ‣ Proximal muscle weakness, osteoporosis, AVN ‣ Infections, panniculitis, spontaneous tendon rupture ‣ Birth defect: 1/1,000 of cleft lip/palate ‣ Increase risk of infertility if cumulative dosage ≥ 250 mg/kg (if BW 50 kg = 12.5 g) ‣ Hemorrhagic cystitis • Azathioprine ‣ Bone marrow suppression ‣ Hepatitis ‣ DO NOT concomitantly use with allopurinol, unless severe bone marrow suppression ‣ Increase risk of malignancy if cumulative dosage > 600 g • MMF ‣ Bone marrow suppression ‣ GI side effect: nausea, vomiting, diarrhea ‣ Pneuonitis • Cyclophosphamide ‣ Bone marrow suppression: nadir at 2 weeks ‣ Increase risk of malignancy if cumulative dosage ≥ 36 g 51 Prognosis • Progress to ESRD 5 - 50% • Class I and II: excellent prognosis • Class IV: least favorable prognosis ‣ Patient survival: 10 years – 100%, 20 years – 85% ‣ No doubling serum creatinine: 10 years – 85%, 20 years – 72% • Class V: natural history is less clear 52 References • Appel GB, Radhakrishnan J, and D’Agati VD. Secondary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1192-1277. • Weening JJ, et al. The classification of glomerunephritis in systemic lupus erythematosus revisited. J Am Soc Neprhol 2004;15:241-250. • Petri M, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-2686. • Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997;40:1725. • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274. • Ponticell C. Glucocorticoids and immunomodulating agents. In: Ponticelli C, and Glassock RJ. Editor. Treatment of Primary Glomerulonephritis. 2nd ed. New York: Oxford University Press Inc.; 2009. P 47-126. 53 POST-INFECTIOUS GLOMERULONEPHRITIS (PIGN) 54 Definition • An immunologic response of the kidney that occurs following a non-renal infection Related terms • Bright disease • Streptococcus-related glomerulonephritis • Post-streptococcal glomerulonephritis Epidemiology • Incidence and prevalence are lower in developed countries • Incidence 0.6 – 39.24 and prevalence 0.02 – 10.14 cases / 100,000 population • Median age of onset 36 – 58 years • High prevalence in DM, alcoholism • 30 – 50% associated with gram negative bacilli infection 55 Pathogenesis • Remains unknown, believed to be the deposition of immune complex within glomerular tuft • Nephritogenic antigens ‣ SpeB (Streptococcal cationic proteinase exotoxin B) or NSAP (neprhitis-strain-associated protein) or NPBP (nephritis plasmin-binding protein) ‣ GADPH (Streptococcal gluceraldehyde phosphate dehydrogenase) or NAPIr (nephritis-associated plasmin receptor) The nephritogenic antigens are normally unable to penetrate through the GBM because of having similar negative charge. These antigens interact with plasmin and activate procollagenase and matrix metalloproteinase (MMP) result in degradation and reducing the negative charge of the GBM. These antigens and immune complexes are now able to pass through the GBM and deposit at subepithelial area to form hump-liked EDD result in foot processes effacement and proteinuria. 56 Infections associated with PIGN • Infectious syndromes ‣ Skin and throat infections (S. pyogenes, S. equi, S. constellatus) ‣ Bacterial endocarditis (S. aureus, S. viridans) ‣ Pneumonia (S. pneumoniae, M. pneumoniae) ‣ Visceral abscesses (dental abscess, deepseated abscesses, osteomyelitis) ‣ Shunt nephritis (S. epidermidis, Propionivacterium) • Specific bacterial diseases ‣ Gram positive bacteria: streptococci, staphylococci, pneumococci, enterococci, L. monocytogenes • Fungal infections ‣ C. albicans, H. capsulatum, C. immitis • Viruses ‣ DNA viruses: HBV, VZV, EBV, cytomegalovirus, parvovirus B19, adenovirus ‣ RNA viruses: HIV, coxsackievirus, echovirus, HAV, dengue virus, HCV, mumps virus, measles virus, hantavirus, rotavirus • Parasitic infections ‣ P. falciparum, P. malariae ‣ S. hematobium, S. mansoni ‣ T. gondii, W. bancrofti, T. spiralis, E. granulosus, E. histolytica • Others ‣ Gram negative cocci: Meningococcus, N. gonorrhea ‣ oTuberculosis and nontuberculous mycobacterium ‣ Gram negative coccobacilli: Hemophilus ‣ T. pallidum, L. interrogans, C. burnetii, M. pneumonia, C. pneumoniae ‣ Gram negative bacilli: Salmonella Klebsiella, Seratia, Yersinia, Proteus, Pseudomonas ‣ Others: Legionellosis, brucellosis, bartonellosis 57 Clinical manifestations • There are 3 major patterns of clinical manifestations ‣ Acute nephritc syndrome - Prototype of PIGN - Common after Streptococcal infection - Some patients had anuria and nephrotic-range proteinuria ‣ Rapidly progressive glomerulonephritis - Rare - Crescent formation in glomeruli - Associated with aging, S. aureus, gram negative bacilli, Mycoplasma and M. leprae infection - Subclinical disease was 4 – 19 times more common than classic PIGN • Gross hematuria is possible • Hypertension: 75% of patients • Edema: 90% of patients • Prior infection before onset of disease: pharyngitis 10 days (7 – 21 days), skin infection 14 – 21 days • Site of infection: upper respiratory tract 0 – 67%, skin 6 – 28%, teeth and oral mucosa 0 – 23%, heart 0 – 20%, urinary tract 0 – 15%, osteomyelitis 0 – 10% • Some different manifestations between age group - In case of crescent formation less than 50%, recovery of renal function are likely ‣ Subclinical glomerulonephritis - Low-graded proteinuria (< 1 g/day), pyuria, microscopic hematuria 58 GBM Fibrocellular Cresent Parietal Epithelial Cell Endothelial Cell Bowman Capsule Podocyte Mesangial Cell Crescent formation Bowman Space Normal glomerulus 59 Investigations • Hematuria: 2/3 had microscopic hematuria, gross hematuria is possible • Proteinuria: 80% had subnephrotic-ranged proteinuria, 20% had nephrotic-ranged proteinuria Children Adult Elderly Hematuria 97- 100% 86% 100% Gross hematuria 30% NA NA Proteinuria 47 – 80% 56 – 99% 92% Nephrotic syndrome 4% 20 – 32% 20% Renal failure 25 – 40% 38 – 51% 72 – 83% Hypertension 50 – 60% 63 – 89% 81 – 86% Heart failure < 5% 46% 43% • Declined GFR in 60% of patients age of 55 years or more • Throat swab culture: can be found ¼ of group A Streptococci infected patients • Transient RTA type 4 • Antibodies for detection of recent Streptococcal infection 60 ‣ ASO (Anti-streptolysis O): found in 2/3 in patients with URI, and 1/3 in patients with impetigo ‣ Antideoxyribonuclease B (anti-DNaseB), antihyaluronidase (anti-Hase): associated with impetigo ‣ Antistreptokinase, anti-nicotinamide adenine dinucleotidase ‣ Streptozyme test combines several antistreptococcal antibody assays: screening test • Low C3 and CH50, but normal C4 level 61 Renal pathology Light microscope: diffuse endocapillary prolifGarland Starry sky Mesangial pattern pattern pattern (Capillary (diffuse wall pattern) pattern) eration, mesangial hypercellularity, PMN infiltration, some had crescent formation Immunofluoresence • Positive IgG, C3 staining, occasionally IgM and rare for IgA • 3 patterns of staining which associated with clinical manifestation patterns Electron microscope: Acute nephritic syndrome X RPGN electron dense deposit (EDD) at subepithelial area (subepithelial hump), some had EDD at subendothelial and intramembranous area Subclinical GN X X X X 62 Treatment • Specific treatment ‣ None for glomerulonephritis ‣ Treatment of underlying infectious diseases ‣ Steroid therapy is controversial - RPGN and/or high percentage of crescent and severe interstitial lesion: short course of high-dose intravenous steroid, follows by 1 - 2 months with prednisolone - In patients with S. aureus, Brucellosis and Schistosomiasis infection, glomerulonephritis can progress in spite of eradicate of the organism. Treatment with corticosteroids or cytotoxic agents might have a role in this circumstance. • Supportive treatment ‣ BP control ‣ Restrict protein intake ‣ Correct electrolytes and acid-base disturbances ‣ RRT if indicated Prognosis • Resolve of clinical manifestations ‣ Edema and hypertension in 1 – 2 weeks: occurs after dieresis ‣ Normal complement level in 8 weeks ‣ No hematuria and proteinuria in months to year • Complete remission: children almost 100%, adults about 60% • Hypertesion with urinary abnormalities 5 – 60%, CKD 0 – 49%, ESRD 4 – 34% • Mortality 0 – 36% • More unfavorable prognosis in aging patients ‣ Volume control: diuretic ‣ Restrict salt intake 63 References • Nasr SH, Radhakrishnan J and D’Agati VD. Bacterial infection-related glomerulonephritis in adults. Kidney Int 2013;83:792-803. • Kanjanabuch T, Kittikowit W and Eiam-ong S. An update on acute postinfectious glomerulonephritis worldwide. Nat Rev Nephrol 2009;5:259-69. • Ponticell C, and Moroni G. Acute post-infectious glomerulonephritis. In: Ponticelli C, and Glassock RJ. Editor. Treatment of Primary Glomerulonephritis. 2nd ed. New York: Oxford University Press Inc.; 2009. P 153178. • Nachman PH, Jennete C, and Falk RJ. Primary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1100-1191. • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274. 64 IgA NEPHROPATHY (IgAN) 65 Definition • Predominance of IgA deposits, either alone or with IgG, IgM, or both in the glomerular mesangium Epidemiology • Most common primary glomerular disease ‣ Hit 3: Formation of pathogenic circulating immune complexes from autoantigen (galactose-deficient IgA) and O-glycanspecific antibodies ‣ Hit 4: Deposition of pathogenic immune complexes in the mesangium, activation of mesangial cells, and induction of glomerular injury • Occurs in all age groups • Most common at age of 10 – 20 years, 80% of patients are age of 16 – 35 years at the time of biopsy • More common in males than females: male / female ratio 2:1 to 6:1 Pathogenesis • Multi-hit mechanism ‣ Hit 1: Increased circulating galactosedeficient (at hinge region of heavy chain) IgA1 ‣ Hit 2: Production of anti-glycan antibodies that recognize galactose deficient IgA1 66 Etiologies • Primary IgAN • Secondary IgAN: associate with ‣ Rheumatologic disorders: HenochSchÖnlein purpura, seronegative spondyloarthropathy, ankylosing spondylitis, Reiter’s syndrome, Berger’s disease Classification • Oxford classification: is a pathological classification using 4 scoring system ‣ M: mesangial score; ≤ 0.5 (M0) or > 0.5 (M1) ‣ E: Endocapillary hypercellularity; absent (E0) or present (E1) ‣ Infections: HIV infection, toxoplasmosis, leprosy ‣ S: segmental glomerulosclerosis; absent (S0) or present (S1) ‣ GI disorders: liver disease, alcoholic cirrhosis, celiac disease, Crohn’s disease, gluten-sensitive enteropathy ‣ T: Tubular atrophy; atrophy/interstitial fibrosis ≤25% (T0), 26 – 50% (T1) or >50% (T2) ‣ Neoplasm: mycosis fungoides, lung cancer, mucin-secreting carcinoma ‣ Hematologic disorders: cyclic neurtopenia, immunothrombocytopenia (ITP), ‣ Others: scleritis, Sicca syndrome, mastitis, pulmonary hermosiderosis, dermatitis herpitiformis • Familial IgAN 67 Clinical manifestations There are 4 patterns of clinical manifestations • Asymptomatic hematuria and/or proteinuria: 50 – 61% • Nephrotic syndrome : 0 – 13%, found in 2 patterns of renal pathology ‣ Mesangial IgA deposit with extensive foot process effacement (coexisting IgAN and MCD) ‣ Isolated microscopic hematuria 27 – 36% - Hematuria: may presence or absence ‣ Microscopic hematuria with proteinuria 16 – 17% - Good response to steroid as in MCD, and excellent prognosis • AKI or RPGN: 25 – 29% ‣ AKI: ATN - Occured after gross hematuria, due to obstruction of RBC casts or Hb degradation product toxicity - Duration 5 – 7 days - Could be spontaneous recovery to need RRT ‣ RPGN or crescentic IgAN - Turn to ESRD 50% and 80% at 1 and 5 years, respectively - In case of there are cellular crescent > 10 – 20%, immunosuppressive may be beneficial ‣ Mesangial expansion - Microscopic hematuria - Progress to CKD • CKD or ESRD Hematuria: could be asymptomatic hematuria to gross hematuria • 40 -50% had gross hematuria without dysuria, and tend to occur close to upper respiratory tract infection, so called “synpharyngitis” or “synpharyngitic nephritis” • 30 – 40% had microscopic hematuria • Intermittent macroscopic hematuria occurred in 25% of patients 68 Proteinuria: could be asymptomatic proteinuria to nephrotic-ranged proteinuria • Most common: subnephrotic-ranged proteinuria Edema, hypertension Renal pathology • Light microscope: focal or diffuse mesangial matrix expansion and hypercellularity, focal glomerular sclerosis Azotemia: could be AKI, RPGN, CKD, ESRD ‣ Crescent formation may be found in severe IgA nephropathy Systemic symptoms: some had abdominal pain or flank pain ‣ Some patients had endocapillary proliferation Investigations • UA: dysmorphic RBC, proteinuria • Normal complement level • Serum galactose-deficient IgA1 level, IgG specific for galactose-deficient IgA, urine immune complex with galactose-deficient IgA1 • Immunofluoresence: positive stain dominant IgA or codominant for IgA with IgG and IgM, positive stain for C3, rare for C1q • Electromicrocope: mesangial electron dense deposit (EDD), minority subendothelial and/or subepithelial EDD, foot process effacement • IgA / C3 level > 4 – 4.5 69 Treatment Specific treatment • Corticosteroid therapy: ‣ Use in patients with GFR > 50 ml/min/1.73 m2 who had persistent proteinuria ≥ 1 g/day, despite 3 – 6 months of optimized supportive care - Prednisolone: 6-month course ➡ 1.0 mg/kg/d x 2 months, then ➡ 0.8 mg/kg/d x 1 month, then ➡ 0.6 mg/kg/d x 1 month, then ‣ Similar regimen to the treatment of ANCAassociated GN (see “ANCA-associated glomerulonephritis (ANCA-associated GN)”) • Fish oil therapy ‣ Use in patients with GFR > 50 ml/min/1.73 m2 who had persistent proteinuria ≥ 1 g/day, despite 3 – 6 months of optimized supportive care - Fish-oil supplement 6 g oral bid (1.87 g of eicosapentaenoic acid and 1.36 g of docosahexaenoic acid) x 2 years • Mycophenolate mofetil (MMF), antiplatelet therapy, and tosillectomy: not recommend ➡ 0.4 mg/kg/d x 1 month, then ➡ 0.2 mg/kg/d x 1 month, then off ‣ Use in patients with coexisting IgAN and MCD - Similar regimen to the treatment of MCD (see “Minimal change disease (MCD)”) • Cyclophosphamide and azathioprine therapy: ‣ Use in patients with crescentic IgAN (crescent > 50% of glomeruli) and RPGN 70 71 Supportive treatment • Control BP: target BP depend on degree of proteinuria ‣ Proteinuria < 1 g/day: < 130/80 mmHg ‣ Proteinuria > 1 g/day: < 125/75 mmHg • ACEI and/or ARB therapy in patients with proteinuria ≥ 0.5 g/d, with up-titrating as far as tolerated to achieve proteinuria < 1 g/day • Avoid dihydropyridine calcium channel blockers if possible • As in general CKD treatment (see “Chronic kidney disease (CKD)”) Prognosis • Poor prognostic factors ‣ Clinical factors: severe proteinuria, hypertension, elevated serum creatinine, male, absence of any history of recurrent macroscopic hematuria, older age at presentation, marked erythrocyturia ‣ Histologic factors: widespread global and/ or segmental glomerulosclerosis, marked tubulointerstitial fibrosis, marked extracapillary proliferation, marked arteriolar hyalinosis, extension of IgA deposits into the walls of peripheral capillary loops • Serum creatinine ‣ 1.7 mg/dL - Proteinuria <1 g/day: turn to ESRD 13.4% at 7 years - Proteinuria ≥1 g/day: turn to ESRD 78.7% at 7 years ‣ > 3 mg/dL: all patients turn to ESRD, so called “point of no return” 72 References • Nachman PH, Jennete C, and Falk RJ. Primary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1100-1191. • Wyatt RJ, and Julian BA. IgA nephropathy. N Engl J Med 2013;368:2402-2414. • Suzuki H, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol 2011;22:1795-1803. • Kang SH, et al. The Oxford classification as a predictor of prognosis in patients with IgA nephropathy. Nephrol Dial Transplant 2011;0:1-7. • Ishiguro C, et al. Serum IgA/C3 ratio may predict diagnosis and prognostic grading in patients with IgA nephropathy. Nephron 2002;91:755-758. erulonephritis. Kidney Inter., Suppl. 2012;2:139-274. • Floege J, and Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol 2011;22:1785-1794. • Manno C, et al. Randomized controlled clinical trial of corticosteroid plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant 2009;24:3694-3701. • Donadio JV, et al. A controlled trial of fish oil in IgA nephropathy. N Engl J Med 1994;331:1194-1199. • D’Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Neprhol 2004;24:179-196. • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glom- 73 ANCA-ASSOCIATED GLOMERULONEPHRITIS (ANCA-ASSOCIATED GN) 74 Definition • Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles, and small arteries), associated with myeloperoxidase (MPO) ANCA (anti-neutrophil cytoplasmic antibodies) or proteinase 3 (PR3) ANCA. Not all patients have ANCA Related terms • Pauci-immune glomerulonephritis Epidemiology • Incidence 3.9 cases / 1,000,000 people • Renal-limited ANCA-associated vasculitis 23 – 25% • ANCA-negative pauci-immune GN 27 – 38% 75 Pathogenesis • Anti-anti-complementary PR3 ‣ The sense strand of PR3 gene encodes sense PR3, and the anti-sense strand encodes complementary PR3 (cPR3). ‣ Subsequently, the immune system responses against cPR3 by developing anticPR3 antibody. ‣ The immune system, again, responses against anti-cPR3 antibody and develops anti-anti-cPR3, which is PR3-ANCA because the epitope of anti-cPR3 was resembled to sense PR3. • ANCAs bind to endothelial cells and membrane-bound PR3/MPO on neutrophils, results in inflammation of vascular endothelial cells, called vasculitis. • Dysregulation of immune system result in further worsening inflammatory response. 76 77 Etiologies • Genetics factors ‣ GPA: HLA-DPB1*0401, SERPINA1, PRTN3 ‣ MPA: HLA-DQ ‣ Others: PTPN22, CTLA4 • Environment factors ‣ Air pollutants: silica ‣ Infection: S. aureus, E. coli ‣ Medications: propylthiouracil, cocaine Classification • 4 types of ANCA-associated vasculitis (AAV) ‣ Granulomatous with polyangiitis (GPA) or Wegener’s granulomatosis ‣ Eosinophilic granulomatosis with polyangiitis (EGPA) or Churg-Strauss syndrome ‣ Microscopic polyangiitis (MPA) ‣ Renal limited AAV or idiopathic necrotizing crescentic GN or renal-limited pauciimmune GN Clinical manifestations • Renal manifestations: RPGN • Extra-renal manifestations: can be found in others, not renal-limited ANCA-vasculitis Criteria for diagnosis At least 2 of the 4 criteria, as followings • Nasal or oral inflammation (oral ulcers or bloody nasal drainage) Granulomatous • Abnormal chest radiograph (nodules, with fixed infiltrates, cavities) polyangiitis • Urinary sediment (> 5 RBC/HPF or (GPA) or RBC casts) Wegener’s granulomatosis • Granulomatous inflammation on biopsy (in wall of artery or arteriole, perivascular, or extravascular) Eosinophilic granulomatosis with polyangiitis (EGPA) or Churg-Strauss syndrome At least 4 of the 6 criteria, as followings • Asthma • Eosinophilia >10% • Neuropathy, mono or poly • Pulmonary infiltrates, non-fixed • Paranasal abnormality • Extravascular eosinophils 78 Investigations • Urinalysis: telescopic urine sediments (can be found in other causes of RPGN) which composed of ‣ Dysmorphic RBCs or RBC cast ‣ Oval fat bodies ‣ Broad casts • Normal complement level • P-ANCA (anti-MPO antibodies) and C-ANCA (anti-PR3 antibodies): positive 62 – 73% • HNE-ANCA (Human neutrophil elastaseANCA): associated with drug-induced AAV • Anti-LAMP-2 antibody (anti-lysosomal membrane protein-2 antibody): controversial 79 Renal pathology Treatment Light microscope: crescent formation, fibrinoid necrosis, karryorhectic nuclei • 2 phases of treatment • EGPA: presence of eosinophils in interstitium, tubule • Unable to differentiate between GPA and MPA Immunofloresence: no staining, or minimal of IgG or IgM Electromicroscope: no EDD, or minimal EDD ‣ Initial treatment ๏ Cyclophosphamide - Intravenous 15 mg/kg every 2 weeks for two cycles the every 3 weeks till remission for 3 months, or - Oral 2 mg/kg/day till remission, then 1.5 mg/kg/day for 3 months Plus prednisolone 1 mg/kg/day, and decrease dosage to 10 mg/day ๏ Rituximab and corticosteroid: alternative treatment in - Patients without severe disease - Contraindicated to cyclophosphamide ๏ Plasmapheresis: additional treatment in patients with - Dialysis dependent - Rapidly increasing serum creatinine 80 - Diffuse pulmonary hemorrhage - Overlap with anti-GBM (glomerular basement membrane) GN ๏ Discontinue cyclophosphamide therapy who require dialysis after 3 months of treatment and do not have extra-renal manifestation of disease ‣ Maintenance therapy: in patients who achieved remission, continue treatment for at least 18 months with prednisolone 10 mg/d with ๏ Azathioprine 1 – 2 mg/kg/day oral ๏ MMF up to 1 g po bid: alternative in patients who - Allergic to azathioprine ๏ Etanercept: not use • Relapse disease ‣ In severe case, use similar regimen to initial treatment ‣ In non-severe case, increasing dose, or reinstituting, or add other immunosuppressive drugs • Resistant disease ‣ Addition of rituximab ‣ Immunoglobulin iv (IVIG) or plasmapheresis: alternative treatment • Transplantation • After complete extra-renal remission for 12 months, not including positive ANCA - Intolerance to azathioprine ๏ Methotrexate 0.3 mg/kg/week, up to 25 mg/ week: alternative in patients who intolerance to azathioprine and MMF, and have eGFR ≥ 60 ml/min/1.73m2 ๏ Trimethoprim-sulfamethoxazole: adjunctive treatment in patients with upper respiratory tract disease 81 Prognosis • Histopathological classification of ANCAassociated GN Class • Renal survival (no development of ESRD) rate according to histopathological classification Inclusion criteria Class Focal ≥ 50% normal glomeruli Crescentic ≥ 50% glomeruli with cellular crescents Mixed Sclerotic < 50% normal, < 50% crescentic, <50% globally sclerotic glomeruli ≥ 50% globally sclerotic glomeruli 1-year renal 5-year renal 7-year renal survival survival survival Focal 93% 93% ≈ 93% Crescentic 84% 76% ≈ 70% Mixed 69% 61% ≈ 50% Sclerotic 50% 50% 25% • 82 References • Jennette JC, et al. 2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65:pp 1-11. • Wilde B, et al. New pathophysiological insights and treatment of ANCA-associated vasculitis. Kidney Int 2011;79:599-612. • Furuta S, and Jayne DRW. Antineutrophil cytoplasm antibody-associated vasculitis: recent developments. Kidney Int 2013;84:224-249. • Appel GB, Radhakrishnan J, and D’Agati VD. Secondary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1192-1277. • Leavitt RY, et al. The American college of the rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33:1101-1107. • Masi AT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33:1094-1100. • Kain R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 2008;14:1088-1096. • Roth AJ, et al. Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis. J Am Soc Nephrol 2012;23:545-555. • Kain R, et al. High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibodyassociated vasculitis. J Am Soc Nephrol 2012;23:556-566. • Slot MC, et al. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: A long-term followup study. Arthritis Rheum 2005;53:108-113. 83 • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274. • Berden AE, et al. Histopathological classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 2010;21:1-9. 84 MINIMAL CHANGE DISEASE (MCD) 85 Related terms • Lipoid nephrosis • Minimal change glomerulopathy Epidemiology ‣ Drugs: NSAIDs, gold, lithium, interferon, ampicillin, rifampin, trimethadione, tiopronin ‣ Tumors: Hodgkin’s disease, lymphoma, leukemia, solid tumors • 10 – 15% of primary glomerular syndrome in adults ‣ Allergies: food, dust, bee stings, pollen, poison ivy, poison oak, dermatitis herpitiformis • 70 - 90% of nephrotic syndrome in children under age of 10 year, and 50% of older children ‣ Others: SLE, following hematopoietic cell transplantation • Male : female ratio 2:1 – 3:1 Pathogenesis • Remains unclear • Most likely a consequence of abnormal regulation of T cells Etiologies and classification • Primary MCD Clinical manifestations • Abrupt onset of nephrotic syndrome • Hematuria is distinctive unusual • Hypertension is uncommon, but can be found in aging patient • AKI can be found in adults with MCD, but the true cause remains uncertain and probably multifactorial • Secondary MCD ‣ Infections: virus, parasite 86 Investigations • Severe proteinuria • 15% of patients have microscopic hematuria • Serum albumin concentration is generally less than 2 g/dL • Renal function is usually preserved, but can deteriorate in some adult patients The diagrams show A) normal glomerular capillary loop and Renal pathology Light microscope: normal, or minimal focal segmental mesangial prominence Immunofloresence: no staining, or low level of mesangial staining of IgM, or C3 Electromicroscope: podocyte foot process effacement, microvillous transformation B) capillary loop in MCD. The latter shows epithelial (podocyte) foot process effacement (arrow), and microvillous transformation. 87 Treatment • Frequent relapse and steroid-dependent MCD • Initial episode ‣ Corticosteroid: ๏ Prednisolone - 1 mg/kg/day (maximum 80 mg/day), or - 2 mg/kg every other days (maximum 120 mg/day) ๏ Maintain high-dose of prednisolone for - Minimum for 4 weeks, if achieve complete remission ‣ Then, tapered slowly over 6 months - Maximum for 16 weeks, if not achieve complete remission ‣ Cyclophosphamide oral: in case of intolerate, or contraindicate to corticosteroid ‣ Calcineurin inhibitor: in case of intolerate, or contraindicate to corticosteroid • Infrequent relapse disease: similar regimen to the treatment of initial episode ‣ Cyclophosphamide 2 – 2.5 mg/kg/day oral for 8 weeks ‣ Cyclosporine 3 – 5 mg/kg/day or tacrolimus 0.05 – 0.1 mg/kg/day oral for 1 – 2 years: in patients who ๏ Relapse during cyclocphosphamide therpy, or ๏ Wish to preserve their fertility ‣ MMF 500 – 1,000 mg twice daily for 1 – 2 years: in patients who intolerant to corticosteroid, cyclophosphamide, and calcineurin inhibitors (cyclosporine, or tacrolimus) • Steroid-resistant MCD ‣ Re-evaluate other causes of nephrotic syndrome, especially FSGS • Statin: not be used in initial episode of MCD • ACEI or ARB: not be used in normotensive patients Prognosis • Good long-term prognosis 88 References • Nachman PH, Jennete C, and Falk RJ. Primary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1100-1191. • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274. 89 FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) 90 Definition • Histological pattern of glomerular injuries, segmental obliteration of glomerular capillaries by extracellular matrix Related terms • Progressive lipoid nephrosis • Focal glomerular scleroses • Epidemiology • Epidemiology Incidence 0.84 – 21 cases / 1,000,000 people • 0 – 67% of primary glomerular diseases • Most common primary glomerular disease causing ESRD in US Pathogenesis • Circulating permeability factors: alters the podocytes’ structure and increase proteinuria ‣ Serum soluble urokinase receptor (suPAR): found 2/3 of patients with primary FSGS ‣ Cardiotrophin-like cytokine 1 (CLC-1) ‣ |Integrin-linked kinase (ILK) Etiologies Primary FSGS Secondary FSGS • Familial or genetic: mutation in specific genes ‣ Slit diaphragm protein: nephrin (NPHS1), podocin (NPHS2), CD2-associated protein (CD2AP) ‣ Cell membrane-associated proteins: transient receptor potential cation channel 6 (TRPC6), protein tyrosine phosphatase receptor type O (PTPRO), laminin-β2 (LAMB2), β4-integrin (ITGB4), tetraspanin CD151 (CD151) ‣ Cytosolic or cytoskeletal proteins: α-actinin-4 (ACTN4), phospholipase Cε1 (PLCE1), my91 osin heavy chain 9 (MYH9), inverted formin 2 (INF2), myosin 1E (MYO1E) ‣ Nuclear proteins: wilms tumor 1 (WT1), SMARCA-like protein (SMARCAL1) ‣ Mitochondrial components: tRNAleu (mtDNAA3243G), parahydroxybenzoatepolyprenyltransferase (COQ2), coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) ‣ Lysosomal protein: lysosomal integral membrane protein type 2 (SCARB2) ‣ Unknown cellular location: apolipoprotein L1 (APOL1) • Viral-associated: HIV type 1, parvovirus B19, simian virus 40, cytomegalovirus, EBV • Drug-induced: heroin, IFN-α, IFN-β, IFN-γ, lithium, pamidronate, sirolimus, calcineurin-inhibitor nephrotoxicity, anabolic steroids vanced renal disease with reduced functioning nephrons ‣ Initially normal renal mass: hypertension, acute or chronic vaso-occlusive processes (atheroembolization, thrombotic microangiopathy, renal artery stenosis), elevated bodymass index (obesity, increased lean body mass [e.g. bodybuilding]), cyanotic heart disease, sickle cell anemia Classification • Not otherwise specified (NOS) • Perihilar • Cellular • Tip • Collapse • Adaptive ‣ Reduced renal mass: oligomeganephronia, very low birth weight, unilateral renal agenesis, renal dysplasia, reflux nephropathy, sequel to cortical necrosis, surgical renal ablation, renal allograft, aging kidney, any ad92 Histological variants of FSGS Subtypes Defining features Associations NOS ≥ 1 glomerulus with segmental increases in matrix obliteraign the capillary lumina There may be segmental glomerular capillary wall collapse without overlying podocyte hyperplasia Exclude perihilar, cellular, tip, and collapsing variants Most common subtype Primary or secondary (including genetic forms and other diverse secondary causes) Other variants can evolve into FSGS (NOS) over time May present with the nephrotic syndrome or subnephrotic-ranged proteinuria Common in adaptive FSGS Predisposition for vascular ≥ 1 glomerulus with perihilar hyalinosis, pole is probably due to with or without sclerosis normally increased filtration > 50% of glomeruli with segmental pressures at the proximal lesions must have perihilar sclerosis and/ afferent end of glomerular or hyalinosis capillary bed, which are Exclude cellular, tip, and collapsing heightened under conditions variants of compensatory demand and vasodilatation of the afferent arteriole In adaptive FSGS, patients are more likely to present with subnephrotic-ranged proteinuria and normal serum albumin level Perihilar Clinical features 93 Subtypes Cellular Tip Defining features Associations ≥ 1 glomerulus with segmental endocapillary hypercellularity occluding Usually primary, but also lumina, with or without foam cells and seen in secondary FSGS karyorrhexis Least common variant Exclude tip, and collapsing variants ≥ 1 segmental lesion involving the tip domain (outer 25% of tuft next to origin of proximal tubule) The tubular pole must be indentified in the defining lesion The lesion must have either and adhesion or confluence of podocytes with parietal or tubular cells at the tubular lumen or neck The tip lesion may be cellular or sclerosis Exclude collapsing, and perihilar variants Clinical features Usually present with nephrotic syndrome Usually presents with Usually primary abrupt onset of Probably mediated by nephrotic syndrome physicl stresses on the More common in white paratubular segment owing race to the convergence of Best prognosis, high protein-rich filtrate on the rate response to tubular pole, causing shear gllucocorticoid stress and possible Lowest risk of prolapse progression 94 Subtypes Defining features Associations Primary or secondary to Viruses: HIV-1, parvovirus B19, simian virus 40, EBV, CMV, hemophagocytic syndrome ≥ 1 glomerulus with segmental or global Drugs: pamidronate and Collapsing collapse and overlying podocyte interferon hypertrophy and hyperplasia Vaso-occlusive disease: atheroemboli, calcineurin inhibitor nephrotoxicity, and chronic allograft nephropathy Clinical features Most aggressive variant Severe nephrotic syndrome More common in black race Worst prognosis, poor response to glucocorticoid Rapid course tot renal failure 95 Clinical manifestations • Depend on histopathological variants (see “Histological variants of FSGS”) Renal pathology Adequate sampling: ≥ 25 glomeruli, and include juxtamedullary glomeruli ‣ Proteinuria: subnephrotic-ranged proteinuria to nephrotic-ranged proteinuria Light microscope: depend on histopathological variants (see “Histological variants of FSGS”) ‣ Normal renal function to rapid declined of renal function Immunofloresence: IgM, C3, granular pattern Investigations Electromicroscope: tubulorecticular inclusion (TRI) in HIV-associated nephropathy (HIVAN) • Evaluation of the secondary causes 96 Treatment • Corticosteroid: in primary nephrotic syndrome ‣ Prednisolone 1 mg/kg/day (maximum 80 mg) or 2 mg/kg/day every other days (maximum 120 mg) ๏ Duration of high-dose corticosteroid - Minimum 4 weeks - Maximum: up to 16 weeks, or as tolerated, or until complete remission, whichever earlier ๏ After complete remission, slowly tapered off in 6 months • Calcineurin inhibitors (CNI): alternative for patients intolerance to, or contraindicated to high-dose corticosteroid • Relapse disease: treat as relapse MCD • Steroid-resistant FSGS ‣ Cyclosporine 3 -5 mg/mg/day bid for at least 4 – 6 months ๏ In case of partial or complete remission, continue cyclosporine treatment for at least 12 months, followed by slowly taper off ‣ Combination of MMF with high-dose dexamethasone, in patients who intolerate to cyclosporine 97 Prognosis Variants 1-year renal survival 3-year renal survival Tip 88% 76% Perihilar 89% 75% NOS 86% 65% Cellular 83% NA Collapsing 74% 33% Overall 86% 67% 98 References • Nachman PH, Jennete C, and Falk RJ. Primary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1100-1191. • Wei C, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011;17:952-960. • McCarthy ET, et al. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2010;5:2115-2121. • Hattori M, et al. Increase of integrin-linked kinase activity in cultured podocytes upon stimulation with plasma form patients with recurrecnt FSGS. Am J transplant 2008;8:1550-1556. • D’Agati, et al. Focal segmental glomerulosclerosis. N Engl J Med 2011;365:2398-2411. • D’Agati, et al. Pathological classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 2004;43:368-382. • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274. • Thomas DB, et al. Clinical and pathological characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney Int 2006;69:920-926. 99 MEMBRANOUS NEPHROPATHY (MN) 100 Related terms • Membranous glomerulopathy Epidemiology • 25% of nephrotic syndrome in adults, most common • Male : female ratio 2:1 Pathogenesis of primary MN • Possible from circulating anti-M-type phospholipase A2 receptor (PLA2R) autoantibodies which most are IgG4 subclass ‣ Sensitivity 75%, and specificity 100% Etiologies and classification • Primary MN • Secondary MN ‣ Autoimmune disease: SLE, autoimmune thyroiditis ‣ Infections: HBV, HCV, malaria ‣ Drugs: D-penicillamine, gold ‣ Malignancies: colon cancer, lung cancer, prostate cancer Clinical manifestations • Malignancy in MN ‣ 25% of patients have negative test on anti-PLA2R, might be possibly caused by unknown antigens ‣ In patients older than 60 years, MN associate with malignancy in 20 – 30% of patients ‣ PLA2R-Ag-Ab immune complexes deposit at subepithelial area, subsequently complement pathway is activated, results in podocyte injuries and proteinuria ‣ Usually asymptomatic ‣ Median time from diagnosis of MN to diagnosis of cancer is 60 months ‣ Risk factors: older age, and smoking ‣ Remission of malignancy is associated with reduction in proteinuria 101 Investigations • Proteinuria: most nephrotic-ranged proteinuria, 10 – 20% subnephrotic-ranged proteinuria • Microscopic hematuria: 1/3 of patients • Hypertension: 2/3 of patients Renal pathology • Light microscope: • Immunofloresence: positive staining of IgG and C3 in granular pattern • Electromicroscope: subepitheial immune complex deposits, podocyte foot process effacement, microvillous transformation 102 Pathological staging • Stage I: small EDD at subepithelial area • Stage II: projections of basement membrane material around the subepithelial deposits, appears as a “spike formation” • Stage III: new basement membrane material surrounds the EDD, appears as intramembranous EDD • Stage IV: loss of EDD, results in irregular electro-lucent zones within irregularly thickened basement membrane Stage I Stage II Stage III Stage IV 103 Treatment of primary MN • Evaluation for secondary causes of MN • Immunosuppressive therapy should be started only in patients with NS with one of the followings ‣ Urine protein > 4 g/day, and remains over 50% of the baseline value, and does not progressive decline during antihypertensive and antiproteinuria therapy during an observation period of at least 6 months ‣ Presence of severe, disabling, or life-threatening symptoms related with NS ‣ Rising of serum creatinine ≥ 30% within 6 – 12 months from the time of diagnosis and eGFR > 25 – 30 ml/min/1.73 m2 and this change is not explained by superimposed complications • Initial therapy ‣ 6-month course of alternating monthly cycles of ๏ Corticosteroids IV and oral Plus Alkylating agents oral - Prefer cyclophosphamide rather than chlorambucil ๏ In case of unable to achieve complete remission after completion of this regimen, considered as a treatment failure if - Presence of deterioration of kidney function, severe, disabling, or potentially life-threatening symptoms related to NS - Unless, after conservative treatment for at least 6 months 104 - Repeat kidney biopsy if the patients have rapid deteriorate of kidney function (double of serum creatinine over 1 – 2 months) without massive proteinuria (> 15 g/day) ‣ Continuous daily (noncyclical) use of oral alkylating agents may also effective, but my be at a greater risk of toxicity, particularly when administered for > 6 months ‣ Not use monotherapy regimen with neither corticosteroid nor MMF • Alternative therapy ‣ Cyclosporine or tacrolimus for 6 months, if the patients are contraindicated, or choose to not use cyclical regimen ๏ Monitor drug level during the initial treatment, and whenever unexplained rising in serum creatinine > 20% during the treatment ๏ Gradually decrease the dosage of CNIs every 1 – 2 months to 50% of initial dosage, and continue for at least 12 months ๏ Discontinue, if unable to achieve complete or partial remission after 6 months of treatment • Resistant to initial therapy ‣ Patients who resistant to cyclical regimen, should switch to CNI-based regimen ‣ Patients who resistant to CNI-based regimen, should switch to cyclical regimen • Relapse disease ‣ Reinstitution of the same therapy that results in initial remission ๏ Cyclical regimen can be repeat only once 105 • Prophylactic anticoagulant (warfarin) should be considered in patients with MN and nephrotic syndrome with serum albumin < 2.5 g/dL and additional risks for thrombosis Prognosis • Complete spontaneous remission: 25 - 50% at 5 years • Progressive renal impairment: 30% at 8 years, and 62% in patients who had nephrotic-ranged proteinuria at presentation • Renal survival: 86% at 5 years, 65% at 10 years, and 59% at 15 years • ESRD: 35% at 10 years 106 References • Nachman PH, Jennete C, and Falk RJ. Primary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1100-1191. • Beck LH, and Salant DJ. Membranous nephropathy: recent travels and new road ahead. Kidney int 2010;77:765-770. • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter., Suppl. 2012;2:139-274 107 ACUTE KIDNEY INJURY (AKI) DEFINITION • Increase in serum creatinine ≥ 0.3 mg/ dL within 48 hours; or • Increase in serum creatinine ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or • Urine volume < 0.5 ml/kg/hour for 6 hours 109 STAGING Stage Serum creatinine Urine output 1 1.5 – 1.9 times baseline; or ≥ 0.3 mg/dL increase < 0.5 ml/hg/hour for 6-12 hours 2 2.0 – 2.9 times baseline < 0.5 ml/hg/hour for ≥ 12 hours 3 3.0 times baseline; or Increase in serum creatinine to ≥4.0 mg/dL; or Initiation or renal replacement therapy; or In patients < 1 years, decrease in eGFR to < 35 ml/min/1.73 m2 < 0.5 ml/hg/hour for ≥ 24 hours; or Anuria for ≥ 12 hours 110 ETIOLOGIES 111 Pre-renal AKI Pre-renal AKI: decreased renal blood flow • Decrease intravascular fluid volume ‣ Renal loss: diuretic, renal salt wasting, primary adrenal insufficiency ‣ Extra-renal loss - GI loss: vomiting, diarrhea, fistula, GI bleeding, NG suction - Peritoneal cavity: ascites in cirrhosis, pancreatitis, peritonitis - Insensible loss: burn, sweating - Fluid leakage: hypoalbuminemia (serum albumin <2 g/dL), cirrhosis, nephrotic syndrome - Others: external or occult bleeding, shock • Heart failure • Peripheral vasodilatation: sepsis, adrenal insufficiency, vasodilators, hypoxia, hypercarbia • Obstruction of renal artery ‣ Mechanical obstruction: stenosis, thrombosis, emboli, surgery ‣ Vasculitis: Polyarteritis nodosa, Takayasu arteritis ‣ Vasoconstriction: sepsis, NSAIDs, hepatorenal syndrome 112 Intrinsic renal AKI • Vascular causes: malignant hypertension, TTP, HUS, DIC, sclerodermal renal crisis • Glomerular causes (acute glomerulonephritis; AGN): post-infectious glomerulonephritis, IgA nephropathy • Interstitial causes (acute interstitial nephritis; AIN) ‣ Drugs - Common causes: penicillin, NSAIDs use Post-renal AKI • Occurs in ‣ Lower urinary tract obstruction ‣ Upper urinary tract obstruction: bilateral obstruction, unilateral obstruction in solitary functioning kidney • Nephrolithiasis, retroperitoneal fibrosis, CA bladder, CA cervix, neurogenic bladder, urethral stenosis, urethral stone, obstructed Foley catheter - Uncommon causes: quinolone, leukemia, lymphoma, sarcoidosis ‣ Infections: various organisms • Tubular causes (acute tubular necrosis; ATN) ‣ Ischemic ATN: prolong pre-renal AKI ‣ Nephrotoxic ATN: aminoglycosides, colistin, vancomycin, NSAIDs, radiocontrast agents ‣ Intratubular obstruction: tumor lysis syndrome, cast nephropathy, rhabdomyolysis, crystals (methotrexate, acyclovir, indinavir) 113 APPROACH TO THE PATIENTS WITH AKI 114 Differentiate between AKI and progression of CKD • Differentiate between AKI and progression of CKD: onset of renal disease ‣ History of nocturia, history of intermittent edema, change of urine volume ‣ Investigations: small size kidneys (< 9 cm in length), anemia of renal disease Using data from history taking and physical examination to determine the most possible causes of AKI • Using data from history taking and physical examination to determine the most possible causes of AKI ‣ Pre-renal AKI: vomiting, diarrhea, bleeding, diuretic, vasodilator use, underlying diseases (nephrotic syndrome, cirrhosis), hypotension, orthostatic hypotension, low JVP - In patients with heart failure: orthopnea, PND, chest pain, edema, high JVP ‣ Post-renal AKI: passing stone, underlying diseases (CA bladder, CA prostate, CA cervix, BPH, neurogenic bladder), positive bimanual palpation and/or full bladder ‣ Intrinsic AKI; vascular causes: severe hypertension, diarrhea, fever, alteration of consciousness, underlying disease (scleroderma, atrial fibrillation, hypercoagulable state) ‣ AGN: hematuria, history of infection (see Postinfectious glomerulonephritis (PIGN) and IgA nephropathy (IgAN), hypertension, edema, high JVP ‣ AIN: penicillin, NSAIDs, quinolone use, leukemia, lymphoma, sarcoidosis, infection, arthralgia, rash ‣ ATN: prolong pre-renal AKI, red-brown urine (rhabdomyolysis), hematologic malignancy, aminoglycosides, colistin, vancomycin, NSAIDs, radiocontrast agents, methotrexate, acyclovir, indinavir 115 Urine examination • Urinary indices to differentiate between pre-renal AKI and intrinsic AKI ‣ AIN: presence of WBC in urine, without bacteriuria, eosinophiluria by Hansel stain ‣ ATN: muddy brown cast ‣ AGN: dysmorphic RBCs, RBC cast, glomerular proteinuria Ultrasound Urinary indices Parameters Pre-renal Intrinsic renal AKI AKI uNa (mEq/L) <20 > 40 Urine specific gravity > 1.020 ≤ 1.010 Urine osmolality (mOsm/kgH₂O) > 500 < 350 sUrea / sCr > 20 10 - 15 Fractional excretion of Na (FE Na) [ (uNa/sNa) / (uCr/sCr) ] x 100% < 1% >2% Fractional excretion of urea (FE urea) [ (uUrea/sUrea) / (uCr/sCr) ] x 100% < 30% > 50% • Post-renal AKI: bilateral hydronephrosis, hydroureter Renal biopsy sCr: serum creatinine, sNa: serum sodium, sUrea: serum urea or BUN, uCr: urine creatinine, uNa: urine sodium, uUrea: urine urea 116 Limitation in interpretation of urinary indices • Urine specific gravity: false high in proteinuria, glucosuria, mannitol, colloidal fluid use • sUrea/sCr: false low in rhabdomyolysis, malnutrition • uNa and FE Na: false high in diuretic use, CKD, non-reabsorbable solute excretion (bicarbonate, glucose, mannitol) • FE Na and FE urea: false low in contrast-induced nephropathy, acute myeloma kidney, acute urate nephropathy, hepatorenal syndrome, NSAIDs, sclerodermal renal crisis, TTP, sepsis, acute glomerulonephritis, early obstructive nephropathy, 10-15% of non-oliguric ATN 117 TREATMENT 118 Treatment Specific treatment • Correct the causes of AKI Supportive treatment • Diet requirement ‣ Fluid requirement (in case of patients in euvolemic status) = urine output + insensible loss (in general 500 – 800 ml/d) • Discontinue all nephrotoxic agent when possible ‣ Energy requirement 20 – 30 kcal/kg/day • Avoid all nephrotoxic agent if possible. In case of therapeutic alternatives are not available ‣ Protein ‣ Aminoglycoside: prefer single dose daily, rather than multiple-dose daily treatment and monitor drug level if possible ‣ Amphotericin B: prefer lipid formulation, rather than conventional formulation • Ensure volume status and perfusion pressure • Avoid hyperglycemia: keep plasma glucose 110149 mg/dL in critically ill patients - Noncatabolic AKI without dialysis: 0.8 – 1.0 g/kg/day - AKI with dialysis: 1.0 – 1.5 g/kg/day, and up to maximum of 1.7 g/kg/day in patients on CRRT (continuous renal replacement therapy) and in hypercatabolic patients ‣ Sodium restriction in case of hypervolemia ‣ Potassium restriction for prevention of hyperkalemia 119 • Furosemide may be beneficial in switch the hypervolemic patients with oliguric AKI and to non-oliguric AKI, but not enhancing kidney function recovery Indications for initiate renal replacement therapy • Adjust the drug dosage: eGFR of the patients with AKI are presumed to be less than 10 ml/min/1.73 m2 • Not using dopamine, fenoldopam, atrial natriuretic peptide (ANP), and recombinant human IGF-1 (rh IGF-1) to treat AKI • Monitor serum creatinine, urine output Biochemical indications • Correct electrolytes and acid-base abnormalities: hyperkalemia, metabolic acidosis, hypocalcemia • If indicated, initiate renal replacement therapy (RRT) ‣ Modalities of RRT: intermittent hemodialysis (IHD), SLEDD (sustained low efficacy daily dialysis), CRRT (continuous renal replacement therapy), PD (peritoneal dialysis) ‣ Adjust the drug dosage according to modalities of RRT Clinical indications Refractory hyperkalemia > 6.5 mEq/L Refractory metabolic acidosis pH < 7.15 Refractory other electrolyte abnormalities: hyponatremia, hypernatremia, or hypercalcemia BUN > 80 mg/dL Tumor lysis syndrome with hyperuricemia and hyperphosphatemia Refractory volume overload End organ involvement: pericarditis, encephalopathy, neuropathy, myopathy, uremic bleeding Severe poisoning or drug overdose Creation of intravascular space for plasma and other blood product infusions and nutrition AKI with multiple organ failure Severe hypothermia or hyperthermia • Discontinue RRT when it is no longer required 120 Advantages and disadvantages of different RRT modalities in AKI Modality Use in hemodynamically unstable patients Solute clearance Volume control Anticoagulant PD Yes Moderate Moderate No IHD No High Moderate Possible without SLEDD Possible High Good Possible without CRRT Yes Moderate / High Good Possible without CRRT: continuous renal replacement therapy, IHD: intermittent hemodialysis, PD: peritoneal dialysis, SLEDD: sustained low efficacy daily dialysis 121 The video was taken on the 81-year-old male with AKI due to septic shock. His serum BUN was more than 100 mg/dL and he became uremic encephalopathy. The physical examination showed positive frog legs sign. He was resuscitated and underwent hemodialysis. 122 The video was taken on the 81-year-old male with AKI due to septic shock. The video was taken 8 days later when his serum BUN was 94 mg/dL. The physical examination showed positive flapping tremor sign. 123 CHRONIC KIDNEY DISEASE (CKD) DEFINITION Either of the following present for > 3 months • Markers of kidney damage (one or more) ‣ Albuminuria ≥ 30 mg/day, or albumin-tocreatinine ratio ≥ 30 g/ g creatinine ‣ Urine sediment abnormalities ‣ Electrolyte and other abnormalities due to tubular disorders ‣ Abnormalities detected by histology ‣ Structural abnormalities detected by imaging ‣ History of kidney transplantation Decreased GFR: < 60 ml/min/1.73 m2 125 STAGING Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk. 126 APPROACH TO THE PATIENT WITH CKD Determine the duration of kidney disease • If > 3 months, CKD is confirmed • If not > 3 months or unclear, CKD is not confirmed. Patients may have CKD or AKI or AKI on top CKD, thus the test should be repeated accordingly. 127 Evaluation of causes: using data from history taking, physical examination, laboratory measures, imaging and renal biopsy Evaluation of GFR • Initial assessment: using serum creatinine and GFR estimating equation • More accurate ascertainment: using exogenous filtration marker Evaluation of albuminuria • Initial assessment: spot urine sample (prefer early morning urine sample) for reagent strip urinalysis (UA) • Confirmatory tests for quantitative measurement ‣ Spot urine sample (prefer early morning urine sample) for albumin-to-creatinine ratio (ACR) , urine protein-to-creatinine ratio (PCR) ‣ Timed urine sample for albumin excretion rate (AER) or total protein excretion rate 128 TREATMENT 129 Prevention of CKD progression Blood pressure control • BP target ‣ Individualize BP targets and agents according to age, underlying diseases, risk of CKD progression, and tolerance of treatment ‣ In patients with urine AER - < 30 mg/day (or equivalent): ≤ 140/90 mmHg - ≥ 30 mg/day (or equivalent): ≤ 130/80 mmHg • ACEI or ARB are recommended in patients with urine AER > 30 mg/day (or equivalent) • Kidney transplant recipients ‣ Target BP ≤ 130/80 mmHg ‣ BP-lowering agents depend on timing after transplantation, use of calcineurin inhibitor,degree of albuminuria, and other comorbidities • Insufficient evidence for combining ACEI and ARB therapy for prevent progression of CKD 130 Glycemic control • Glycemic control: target HbA1c about 7.0 % ‣ > 7.0% in individuals with comorbidities or limited life expectancy and risk of hypoglycemia ‣ Avoid <7.0% in patients at risk of hypoglycemia Lipid control • Lipid control: treatment depend on age of patients and other comorbidities ‣ Cholesterol-lowering Treatment ๏ Non-dialysis-dependent or kidney transplantat recipients ➡ Age 18 – 49 years: statin if presence one or more of the followings: known coronary disease, DM, prior ischemic stroke, estimated 10-year incidence of coronary death or non-fatal MI > 10% ➡ Age ≥ 50 years - eGFR ≥ 60 ml/min/1.73m2: statin - eGFR < 60 ml/min/1.73m2: statin or statin with ezetimibe ๏ Dialysis-dependent patients ➡ Not initiate statin or statin with ezetimibe ➡ If patients already receiving statin or statin with ezetimibe at time of initiation RRT: continue these agents 131 ๏ Kidney transplant recipients: statin ‣ Triglyceride lowering treatment: therapeutic lifestyle changes ‣ Target lipid: LDL-C < 70, HDL-C > 40, nonHDL-C <100, and TG <150 mg/dL Diet • Protein intake ‣0.8 g/kg/day in diabetic patients or eGFR < 30 ml/min/1.73 m2 ‣Avoid high protein intake > 1.3 g/kg/day • Sodium intake < 2 g/day (corresponding to 90 mEq/d of sodium or 5 g/d of sodium chloride), unless contraindicated • Potassium restriction: in case of hyperkalemia • Phosphate restriction: in case of hyperphosphatemia Lifestyle modification • Exercise: ≥ 30 minutes 5 times/week • Target BMI 20 – 25 kg/m2 • Stop smoking • Limiting alcohol intake: ≤ 2 standard drinks/day for male, and ≤ 1 standard drinks/day for female 132 Management of complications of CKD Anemia • Evaluation: annually in CKD stage 3, twice a year in CKD stage 4 or 5, and every 3 months in dialysis patients • Definition: Hb < 13.0 g/dL in male and < 12.0 g/dL in female • Evaluation causes of anemia: CBC, absolute recticulocyte count, iron study, B12 and folate level • Treatment ‣ Iron therapy in TSAT (transferring saturation) ≤ 30%, and serum ferritin ≤ 500 ng/ml ‣ ESA (erythrocyte stimulating agent) therapy ๏ Use with caution in patients with active or history of malignancy and history of stroke ๏ Address all correctable causes of anemia prior to initiation ๏ Initiation of ESA therapy: individualize ➡ In general, patients with Hb < 10.0 g/dL ‣ Target Hb: individualize ๏ In general, 10.0 – 11.5 g/dL, not intentionally increase > 13.0 g/dL 133 Metabolic bone disease • Evaluation of serum calcium, phosphate, PTH and alkaline phosphatase in eGFR < 45-60 ml/min/1.73 m2 • Target: ‣ Calcium and phosphate level in normal range ‣ Intact PTH (iPTH) ๏ Non-dialysis patients: no known optimal level, in case of iPTH level above normal limit: evaluate for hyperphosphatemia, hypocalcemia, and vitamin D deficiency ๏ Dialysis patients: 2 – 9 times of upper normal limit • Treatment ‣ Hyperphosphatemia: phosphate binders ๏ Available agents: calcium carbonate, calcium acetate, savelamer, lanthanum, aluminium hydroxide ๏ Calcium-based phosphate binders: restricting dose in patients with hypercalcemia, arterial calcification and/or adynamic bone ๏ Aluminum-containing phosphate binder: avoid long-term use ‣ High iPTH level ๏ Non-dialysis patients: calcitriol or vitamin D analogue ๏ Dialysis patients: : calcitriol or vitamin D analogue or combination with calcimimetic drug ๏ Severe hyperparathyroidism with fail to medical treatment: parathyroidectomy Metabolic acidosis • Target: normal range of serum bicarbonate level • Treatment: oral sodium bicarbonate in case of serum bicarbonate level < 22 mEq/L 134 Management of other aspects of CKD Cardiovascular disease (CVD) • Cardiovascular disease (CVD): considered at increased risk of CVD Peripheral arterial disease (PAD) • Medications ‣ Adjust drug dosage according to eGFR ‣ Avoid herbal remedies Imaging studies • Balance risk of contrast-induced AKI against diagnostic value and therapeutic implication of the investigation • Radiocontrast ‣ Avoid high osmolar agents ‣ Use of lowest possible radiocontrast dose ‣ Withdrawal of potentially nephrotoxic drugs before and after the procedure ‣ Adequate hydration with saline before, during and after the procedure ‣ Measurement of eGFR 48 – 96 hours after the procedure • Gadolinium-based contrast media 135 ‣ Not use in patients with CKD stage 5, unless there is no alternative test ‣ In patients with CKD stage 4-5 who require gadolinium-based contrast media, prefer use of macrocyclic chelate preparation • Bowel preparation ‣ Not use oral phosphate-containing bowel preparation Vaccination • Hepatitis B vaccine • Influenza vaccine: annually • Pneumococcal vaccine: every 5 years in CKD stage 4-5, nephrotic syndrome, DM, or those receiving immunosuppression 136 Renal replacement therapy (RRT) • Referral to nephrologists for plan of RRT in patients with eGFR < 30 ml/min/1.73 m2 • Topics for counselling with the patients: ‣ Indications for RRT ‣ Available modalities of treatment: hemodialysis, peritoneal dialysis, kidney transplantation and conservative treatment ‣ Advantages and disadvantages ‣ Complications ‣ Preparations ‣ Financial issues • Prepare the patients for RRT: vascular access, or Tenckhoff catheter implantation • Indications for RRT ‣ Presence of symptoms and signs attributable to CKD: serositis, acid-base or electrolytes disturbances, pruritus, inability to control volume status or blood pressure, malnutrition, cognitive impairment, encephalopathy ‣ eGFR < 7 ml/min/1.73 m2 ‣ Preemptive kidney transplantation in patients with irreversible CKD over 6-12 months with eGFR <20 ml/min/1.73 m2 137 แสดงการเปรียบเทียบการบำบัดทดแทนไตวิธีต่าง การฟอกเลือดด้วยเครื่องไตเทียม หลักการการ รักษา • ขจัดของเสียในเลือดด้วยการกรองผ่าน ตัวกรองเลือดโดยใช้เครื่องไตเทียม • ต้องมีการผ่าตัดต่อเส้นเลือดหรือใส่ท่อ ลักษณะและ สถานที่การ บำบัดทดแทน ไต พลาสติกในหลอดเลือดเพื่อใช้เป็นทาง สำหรับนำเลือดออกมาฟอก • ทำ 2-3 ครั้ง/สัปดาห์ ครั้งละ 4-5 ชม. และทำต่อเนื่องไปตลอด • พยาบาลเป็นผู้ทำให้ • ทำที่โรงพยาบาล / ศูนย์ไตเทียม การล้างไตทางช่องท้อง • ขจัดของเสียในเลือดโดยกรองผ่านเยื่อ บุช่องท้องเข้ามาอยู่ในน้ำยาที่ใส่ เข้าไปในช่องท้อง • ต้องมีการผ่าตัดต่อใส่ท่อพลาสติกฝัง ไว้ที่หน้าท้อง • ทำทุกวันโดยใส่และปล่อยน้ำยา 4-5 ครั้ง/วัน ทำต่อเนื่องไปตลอด • ผู้ป่วยหรือผู้ดูแลเป็นผู้ทำการล้างไต การปลูกถ่ายไต • ไตที่ปลูกถ่ายสามารถทำ หน้าที่ขับของเสียในเลือด ได้เหมือนหรือใกล้เคียงไต ปกติ • ต้องได้รับบริจาคจากญาติ สายตรง คู่สมรสหรือจากผู้ ป่วยที่เสียชีวิต • ทำการผ่าตัดปลูกถ่ายไตที่ โรงพยาบาลโดยแพทย์ ทางช่องท้องหลังจากได้รับการสอนวิธี • มาตรวจตามแพทย์นัด การทำ • ทำที่บ้านหรือที่ทำงาน • ต้องรับประทานยากด ภูมิคุ้มกันไปตลอด 138 การฟอกเลือดด้วยเครื่องไตเทียม การล้างไตทางช่องท้อง การปลูกถ่ายไต • มีการจำกัดชนิดอาหาร ผลไม้ และน้ำ มากกว่า • ไม่อิสระ ต้องเสียเวลามาห้องไตเทียม ข้อจำกัดใน การรับ ประทาน ความ สะดวก/อิสระ • มีการจำกัดผลไม้และน้ำน้อยกว่า โดยเฉพาะถ้าผู้ป่วยอยู่ไกลและไม่มีที่ • ไม่ต้องเสียเวลามาห้องไตเทียม ฟอกเลือดใกล้บ้าน • มาตรวจเฉพาะวันนัดหรือมีปัญหา • ถ้าจะไปท่องเที่ยวหลายวัน ต้องติดต่อกับ • ในการไปท่องเที่ยว ต้องนำถุงน้ำยาไป ห้องไตเทียมที่จะเดินทางไปล่วงหน้าซึ่ง ค่อนข้างยุ่งยาก • เนื่องจากการฟอกเลือดทำโดยพยาบาล ด้วย • เกิดความสะดวกแก่ญาติมากกว่า ถ้า ได้ดูแลผู้ป่วยที่บ้าน โดยเฉพาะอย่าง ผู้ป่วยที่มีความพิการทางร่างกายหรือ ยิ่งผู้ป่วยที่มีความพิการทางร่างกาย สมองก็สามารถทำได้ แต่อาจเกิดความ หรือสมอง • กินอาหารได้ใกล้เคียงปกติ • ดำรงชีวิตได้ใกล้เคียงคน ปกติ ต้องยินยาสม่ำเสมอ และตรงเวลา • มาตรวจตามแพทย์นัดหรือ เมื่อมีอาการผิดปกติ • ไปท่องเที่ยวที่ต่างๆ ได้ ปกติ ไม่สะดวกแก่ญาติ ถ้าต้องรับส่งผู้ป่วยใน เวลาที่ตัวเองทำงาน ภาวะ • ที่พบบ่อยคือการติดเชื้อในผู้ป่วยที่ใส่ท่อ แทรกซ้อนจาก พลาสติกไว้ในหลอดเลือดดำ ซึ่งอาจ การติดเชื้อ ทำให้เกิดภาวะติดเชื้อในกระแสเลือดได้ • ที่พบบ่อยคือการติดเชื้อบริเวณหน้า ท้องที่ใส่ท่อพลาสติก และสามารถ ลุกลามจนเกิดการติดเชื้อในช่องท้อง ได้ • ต้องระมัด ระวังอย่างมาก โดยเฉพาะในระยะแรกๆ ที่ ผู้ป่วยได้รับยากดภูมิคุ้มกัน ขนาดสูง ซึ่งอาจติดเชื้อ รุนแรงถึงชีวิตได้ 139 การฟอกเลือดด้วยเครื่องไตเทียม การล้างไตทางช่องท้อง การปลูกถ่ายไต • มักไม่มีปัญหาระหว่าง ผ่าตัดเนื่องจากได้รับการ • เสี่ยงต่อภาวะความดันโลหิตต่ำ หัวใจ ภาวะ แทรกซ้อนทาง หัวใจและ หลอดเลือด เต้นผิดจังหวะหรือกล้ามเนื้อหัวใจขาด • มีความปลอดภัยต่อผู้ป่วยที่มีโรค เลือดกำเริบ ถ้าผู้ป่วยมีการทำงานของ หัวใจหรือหลอดเลือดสมองมากกว่า หัวใจไม่ดี โดยเฉพาะอย่างยิ่งในรายที่ การฟอกเลือด ต้องดึงน้ำออกในปริมาณมาก • บางรายอาจมีความดันโลหิตสูงถ้ารับ • บางรายอาจมีความดันโลหิตสูง ถ้ารับ ประทานอาหารรสเค็ม ประทานอาหารรสเค็ม ประเมินและแก้ไขก่อนการ ปลูกถ่ายไต • เนื่องจากยากดภูมิคุ้มกันมี ผลเกี่ยวข้องกับปัจจัยเสี่ยง เช่น ความดันโลหิตสูง ไข มันสูง ทำให้มีผลต่อการ เกิดโรคหลอดเลือดและ หัวใจในระยะยาว อัตราการรอด • โดยรวมแล้วใกล้เคียงกับการล้างไตทาง • โดยรวมแล้วใกล้เคียงกับการฟอก ชีวิต ช่องท้อง เลือดด้วยเครื่องไตเทียม • ดีกว่ามากโดยเฉพาะหลัง จากปลูกถ่ายไตไปแล้ว 3 เดือน • ค่าผ่าตัด 150,000-250,000 บาท ค่าใช้จ่าย/ เดือน (บาท) • ค่าฟอกเลือด (2-3 ครั้งต่อสัปดาห์) 12,000-25,000 (ไม่รวมค่ายาอื่นๆ) • ค่าล้างไตทางช่องท้อง 15,000-25,000 • (ไม่รวมค่ายาอื่น) (ทำในโรงพยาบาลรัฐ) หลังจากนั้นค่ายากด ภูมิคุ้มกัน ~ 20,000 (3-6 เดือนแรก) - 15,000 (6-12 เดือนถัดมา) -10,000 (หลัง 1 ปี) 140 การฟอกเลือดด้วยเครื่องไตเทียม การล้างไตทางช่องท้อง • ข้าราชการสามารถเบิกได้ • ข้าราชการสามารถเบิกได้ 2,000 บาท ต่อการฟอกเลือด 1 ครั้ง และไม่จำกัด สิทธิการรักษา จำนวนครั้ง เบิกได้ทั้งในโรงพยาบาลรัฐ การบำบัด และเอกชนที่เข้าร่วม ทดแทนได้ที่ ใช้ได้ • ผู้ที่มีประกันสังคมยื่นขอสิทธิกับสำนักงาน ประกันสังคมเมื่ออนุมัติแล้วเบิกได้ 1,000-1,500 บาทต่อการฟอกเลือด 1 การปลูกถ่ายไต เมื่อรักษาในโรงพยาบาล • ข้าราชการสามารถเบิกได้ทั้งหมดเมื่อ รักษาในโรงพยาบาลรัฐ • ผู้ที่มีประกันสังคมยื่นขอสิทธิกับ รัฐ • ผู้ที่มีประกันสังคมยื่นเรื่อง ขอปลูกถ่ายไตกับ สำนักงานประกันสังคมเมื่ออนุมัติแล้ว สำนักงานประกันสังคมเมื่อ เบิกได้ไม่เกิน 20,000 บาทต่อเดือน อนุมัติจึงเบิกได้ตามข้อ กำหนดสำนักงานประกัน ครั้ง และไม่เกิน 3 ครั้งต่อสัปดาห์ สังคม • สิทธิบัตรทอง (ประกัน • สิทธิบัตรทอง (สปสช) ผู้ป่วยที่เริ่มฟอก สิทธิการรักษา เลือดหลัง 1 ตค. 2551 เบิกไม่ได้ ยกเว้น การบำบัด ถ้าผู้ป่วยมีข้อห้ามทางการแพทย์ต่อการ ทดแทนได้ที่ ล้างไตทางช่องท้องจึงจะเบิกได้ 1,500 ใช้ได้ บาทต่อการฟอกเลือด 1 ครั้ง และ ไม่ สุขภาพแห่งชาติ) ต้องไป • สิทธิบัตรทอง (ประกันสุขภาพแห่ง ชาติ) เบิกได้ทุกราย ในสถานพยาบาล ที่เข้าร่วม จำกัดจำนวนครั้ง สมัครเพื่อรอการปลูกถ่าย ไตกับโรงพยาบาลรัฐและ เอกชนที่เข้าร่วมเมื่ออนุมัติ จึงเบิกได้ตามข้อกำหนด ของสำนักงานสุขภาพแห่ง ชาติ การเตรียม ความพร้อม อื่นๆ • ต้องมีการผ่าตัดต่อเส้นเลือดล่วงหน้า อย่างน้อย 4 เดือน • ต้องมีการผ่าตัดต่อใส่ท่อพลาสติกฝัง ไว้ที่หน้าท้องล่วงหน้าอย่างน้อย 2 สัปดาห์ • ควรหลีกเลี่ยงการได้รับ เลือด 141 Hemodialysis 142 Peritoneal dialysis 143 Kidney transplantation 144 REFERENCES • Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Inter., Suppl. 2013;3:1-150. • Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Inter., Suppl. 2012;2:279-335. • Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Inter., Suppl. 2013;3:259-305. • Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Inter., Suppl. 2012;2:337-414. • Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and the Treatment of Chronic Kidney Disease-Mineral and Bone disorder (CKD-MBD). Kidney Inter., 2009;76(Suppl 113): S1-S130. • Jellinger PS, et al. American Association of Clinical Endocrinologists’ Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract. 2012;18(Suppl 1):1-78. • กลวิชย์ ตรองตระกูล และ ไพฑูรย์ ขจรวัชรา. การป้องกันภาวะแทรกซ้อนและเตรียมการบำบัดทดแทนไต. ใน วรวรรณ ลิมปมน ตรี, บรรณาธิการ. คู่มือการจัดการดูแลผู้ป่วยโรคไตระยะเริ่มต้น.91-99. กรุงเทพมหานคร : บริษัท ยูเนียนอุลตร้าไวโอเลต จำกัด, 2555. ISBN 978616723671. 145 COMMON GENETICS KIDNEY DISEASES AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE 147 Epidemiology • Most common form of polycystic kidney diseases • Affected 1 in 800 live births, and 4 – 6 million worldwide • Autosomal dominant penetrance, but 5% of patients have spontaneous mutation Classification • Type I: caused by mutation in PKD1 gene • Type II: caused by mutation in PKD2 gene 148 Pathogenesis • Numerous site of PKD1 and PKD2 gene point mutations caused reduction in functional polycystin-1 and polycystin-2, their encoded proteins. • A “two-hit” mechanism: germ-line mutation of PKD1 and PKD2 with additional somatic mutation in wild-type gene to initiate the cysts formation Chromosomal Length of Abberant gene location transcript (kb) Protein encoded Molecular mass (kD) Type Frequency Type I 85 – 90% PKD1 16q13.3 14.5 Polycystin-1 462 Type II 10 – 15% PKD2 4q21 5.6 Polycystin-2 110 • Polycystin-1 is membrane receptor capable of interacting with extracellular substances as a sensors and signaling through phosphorylation pathways to activate the intracellular response. • Polycystin-2 is a calcium channel. • Polycystin-1 interacts with polycystin-2 and other proteins to form the complexes which can be found at the cell-matrix interface, cell-cell contacts and luminal cilium. Stimulation on these complexes cause calcium influx, which act as a intracellular second messenger, subsequently effect several signal-transduction cascades 149 and regulate cell proliferation, apoptosis, epithelial cell differentiation, polarity, adhesion, migration, cell shape, and tubular diameter. • The reduction in functional polycystin causes reduction in intracellular calcium and subsequently over activation of adenylate cyclase, increasing number of cyclic AMP, and lessening intracellular signal-transduction cascades results in ‣ Increase cell proliferation ‣ Increase fluid accumulation ‣ Alter cell polarity ‣ Matrix remodeling • All of these consequences lead to cyst formation in ADPKD patients. 150 Lorem ipsum dolor sit amet, consectetur adipisicing elit, sed do tempor incididunt ut labore et dolore magna aliqua. 151 Defects in the noncanoical Wnt/PCP pathway leading to renal cysts 152 Defects in the noncanoical Wnt/PCP pathway leading to renal cysts 153 Clinical manifestations • Two types of ADPKD have similar pathological and physiological features, but type II disease has a later onset of symptoms, thus patients with type II disease have ‣ Older mean age of ESRD: 54 years in type I and 74 years in type II ‣ Longer life expectancy: 53 years in type I and 69 years in type II • Progressive enlarge of kidney: mean increase in total kidney volume is 5.3%/year • Renal failure: patients with kidney volume > 1,500 ml have mean decreased in GFR 4.3 ml/min/year • Renal pain: found in 60% of patients, located at flank or abdomen ‣ Causes: renal infection, cyst hemorrhage, renal stone, or ADPKD itself • Hypertension: 50% of patients and increase to nearly 100% of patients with ESRD • Hematuria ‣ Imaging: to identify intraparenchymal or external hemorrhage, bleeding into the collecting system, solid tumors ‣ Renal colic: in some patients with hematuria ‣ Usually recovery in few days • Urinary tract infection • Renal stones: 20% of patients 154 ‣ Usually composed of uric acid and calcium oxalate ‣ Investigation of choice: CT scan of kidneys • Renal cell carcinoma: not frequent than in the normal population • Anemia: less frequent than in other renal diseases because of enhanced production of erythropoietin by polycystic kidneys • Extra-renal manifestations ‣ Polycystic liver disease: ๏ Most common extrarenal manifestations: 80% of patients ๏ Usually asymptomatic ๏ Associated with estrogen exposure: female, exogenous estrogen use, and repeated pregnancy ๏ Complications: cyst hemorrhage, infections, and rarely torsion or rupture ‣ Cyst in other organs: 5% in pancreas, 8% in arachnoid, and 40% in seminal vesicles ‣ Intracranial aneurysm: found in 16% and 6% of patients with and without family history of aneurysm ๏ Most often asymptomatic ๏ Ruptured: 35 – 55% risk of combined severe morbidity and mortality ๏ Screening for intracranial aneurysm ➡ Diagnostic tools: MR angiography (MRA) or CT angiography (CTA) ➡ Indications 155 - Family history of aneurysm or stroke - New onset of headache - Central nervous system symptoms or signs ➡ Management - Negative: repeat imaging every 5 – 10 years - < 7 mm-aneurysm: repeat imaging every ½ - 1 year - ≥ 7 mm-aneurysm: surgical treatment ‣ Other vascular malformation: dolichoectasias, thoracic aortic and cervicocephalic artery dissections, and coronary artery aneurysm ‣ Cardiac manifestations: mitral valve prolapsed 25% of patients, aortic insufficiency ‣ Colonic diverticulosis and diverticulitis ‣ Bronchiectasis 156 Diagnosis • Use radiologic imaging to demonstrate the number of cyst in kidney Criteria for diagnosis ADPKD type 1 Age Criteria 15 – 29 years 2 cysts, unilateral or bilateral 30 – 59 years 2 cysts in each kidney ≥ 60 years 4 cysts in each kidney Revised criteria for diagnosis ADPKD type 1 and type 2 Age Criteria 15 – 29 years 3 cysts, unilateral or bilateral 30 – 39 years 3 cysts, unilateral or bilateral 40 – 59 years 2 cysts in each kidney ≥ 60 years 4 cysts in each kidney Revised criteria for exclusion of ADPKD type 1 and type 2 Age Criteria 15 – 29 years 1 cyst 157 CT scan of the patient with ADPKD coronal view 158 Treatment Specific treatment • No any agents are able to reduce the kidney volume in patients with ADPKD Summary of the results from landmark randomized control studies in patients with ADPKD Decrease kidney volume Slowed increase in kidney volume Slowed decline in renal function Sirolimus No No No Everolimus No Yes No Somatostain No Yes No Tolvaptan No Yes Yes 159 Supportive treatment • BP Control ‣ Target BP ≤ 130/80 mmHg ‣ ACEI or ARB: drug of choice ‣ Salt restriction: NaCl < 6 g/day ‣ Diuretics: in case of fail to lower BP with 2 strategies above • Smoking cessation • Hematuria ‣ Bed rest ‣ Analgesics ‣ Hydration: to increase urine flow rate to 2 – 3 L/day ‣ Avoid sports which at a risk of abdominal trauma: such as rugby, boxing • Urinary tract infection ‣ Lower tract: treat as in general population ‣ Upper tract ๏ Acute pyelonephritis, or symptomatic cyst infection ๏ Required hospitalization ๏ Drug of choice: fluoroquinolone ‣ In men: radiologic and urologic evaluation is indicated • Renal stones: treat as in general population • ESRD: ‣ RRT ๏ Peritoneal dialysis or hemodialysis may be used ๏ Kidney transplantation - Similar outcome to non-AKPKD patients - Identification of ADPKD in related living donors are requied: MRI KUB and/or genetic testing • Renal pain: analgesics, transcutaneous stimulation, local injections of anesthetics, laparoscopic 160 or opened surgical unroofing of cysts, or laparoscopic renal denervation • Liver cysts ‣ Avoid exposure to estrogens, or least as possible ‣ Partial hepatectomy: in severe liver enlargement • Pregnancy ‣ Generally uncomplicatied in case of normal BP and renal function ‣ Increase risk of severe hypertension and preeclampsia, particularly in patients who have hypertension and renal impairment before conception 161 References • Torres VE, and Grantham JJ. Cystic diseases of the kidney. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1626-1669. • Granthham JJ. Autosomal dominant kidney disease. N Engl J Med 2008;359:1477-85. • Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151-164. • Hildebrant F, et al. Ciliopathies. N Engl J Med 2011;364:1533-1543. • Grantham JJ, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006;354:2122-2130. • Ravine D, et al. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994;343:824-27. • Pei Y, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am So Nephrol 2009;20:205-212. • Perico N, et al. Sirolimus therapy to halt the progression of ADPKD. J Am Soc Nephrol 2010;21:1031-1040. • Serra AL, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disase. N Engl J Med 2010;363:820-829. • Walz G, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010;363:830-840. • Hogan MC, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol 2010;21:1052-1061. • Torres VE, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367:2407-2418. 162 ALPORT’S SYNDROME 163 Epidemiology • Accounts for 0.4% of adults with ESRD in United States Pathogenesis • Type IV collagen composed of 6 genetically distinct α chains, α1(IV)- α6(IV) monomer, which are encoded from COL4A1 - COL4A6, respectively. • Three of α chain monomers form into only 3 sets of protomers which are designated as α1.α1.α2(IV), α3.α4.α5(IV) and α5.α5.α6(IV). Triple helical organization of the type IV collagen family 164 • These protomers pair into 3 canonical set of hexamers to from networks, which are α1.α1.α2(IV)-α1.α1.α2(IV), α3.α4.α5(IV)-α5.α5.α6(IV) and α1.α1.α2(IV)-α5.α5.α6(IV). Assembly and network organization of collagen IV protomers 165 • During the embryonic development, component of GBM structure is change from α1.α1.α2(IV)-α1.α1.α2(IV) network to α3.α4.α5(IV)-α5.α5.α6(IV) network to form a mature GBM. Normal glomerular development and the change of networks component of GBM structure 166 • Mutations in the COL4A3, COL4A4, COL4A5 genes which encode α3, α4 and α5 chain collagen type IV, a component of glomerular basement membrane (GBM), results in arrest of switching of GBM network. The GBM in the patients with Alport’s syndrome become persistence of α1.α1.α2(IV)-α1.α1.α2(IV) network results in dysconfiguration of GBM. Glomerular development and the abnormal switching of networks component of GBM structure in the patients with Alport’s syndrome 167 Genetics • X-linked inheritance ‣ 85% of patients ‣ Mutations in COL4A5 gene encoding α5(IV) collagen chain ‣ Located on chromosome Xq26-48 COL4A3 and COL4A4 gene encoding α3(IV) and α4(IV) collagen chain ‣ Located on chromosome 2q35-37 ‣ Severity similar to X-linked inheritance • Autosomal dominant ‣ Rare ‣ Male predominate: ESRD at age of 30 – 40 years, deafness ‣ Missense mutations in COL4A3 and COL4A4 gene encoding α3(IV) and α4(IV) collagen chain ‣ Female: varying in severity, but less severe than in male patients ‣ Less severity; benign familial hematuria or thin basement membrane disease ‣ Concomitant deletion mutations in COL4A6 gene encoding α3(VI) chain are associated with leiomyomatosis • Autosomal recessive ‣ 15% of patients ‣ Homozygous or compound heterozygous nonsense mutations, missense mutations, frame shifts, small deletions, or splice variants in 168 Clinical manifestations • Hematuria: often the presenting sign • Severity of disease depend on the mutations • High-tone sensorineural hearing loss: 80% of patients • Ocular defects: 40% of patients ‣ Anterior lenticonus: 25% of patients ‣ Perimacular dots and flecks ‣ Posterior polymorphous dystrophy (PPMD) ‣ Microcornea, arcus cornealis, iris atrophy, cataracts, • Family history of deafness and renal failure 169 Diagnosis • Electron microscopic findings in renal biopsy • Immunostaining of α3(IV) and α5(IV) collagen from skin or renal tissue [ Skin collagen networks composed of α1.α1.α2(IV)-α5.α5.α6(IV) ] α5(IV) X-linked Normal Male Female α3(IV) Autosomal recessive X-linked Autosomal recessive Normal Male Female GBM + - Mosaic - + - Mosaic - Skin basement membrane + - Mosaic + + - - - 170 Renal pathology • Light microscope: nonspecific, normal or nearly normal, segmental to diffuse mesangial cell proliferation, matrix increase, and thickening of the glomerular capillary wall Treatment • No proven therapy • Control hypertension with ACEI • Light microscope: nonspecific, normal or nearly normal, segmental to diffuse mesangial cell proliferation, matrix increase, and thickening of the glomerular capillary wall • Electron microscope: thin GBM thicken over time into multilamellations and lucent spaces results in split appearance of the basement membrane; “basket weaving appearance” 171 References • Appel GB, Radhakrishnan J, and D’Agati VD. Secondary glomerular disease. In: Taal MW, et al. editor. Brenner & Rector’s The Kidney. 9th ed. Philadephia: Elsevier Saunders; 2012. p 1192-1277. • Hudson BG, et al. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med 2003;348:2543-2556. 172 APPROACH TO COMMON SYMPTOMS IN NEPHROLOGY EDEMA 174 Localized edema • Vascular abnormalities ‣ Increased venous pressure ๏ Deep vein thrombosis ๏ Venous insufficiency ๏ Vena cava obstruction ‣ Decreased arteriolar resistance ๏ Calcium channel blocker (CCB) • Lymphatic obstruction ‣ Malignancy ‣ Infection ‣ Hypothyroidism ‣ Congenital anomalies of lymphatic system ETIOLOGIES • Increased capillary permeability ‣ Inflammation ‣ Angioedema 175 Generalized edema - Anti-GBM • Liver diseases: cirrhosis - Immune complex disease • Heart diseases: congestive heart failure - Pauci-immune glomerulonephritis ‣ Mechanical abnormalities • Other causes of hypoalbuminemia ๏ Pericardial disease ‣ Protein-losing enteropathy ๏ Myocardial disease ‣ Malnutrition ๏ Endocardial disease ‣ Electrical abnormalities ๏ Bradyarrhythmia ๏ Tachyarrhythmia • Kidney diseases ‣ AKI, AKI on top CKD, CKD ‣ Glomerular diseases ๏ Nephrotic syndrome - Primary causes - Secondary causes ๏ Nephritic syndrome (NS) 176 APPROACH TO THE PATIENTS 177 History taking General appearance Body weight change, prolong fever HEENT Dry eyes, dry mouth, sinusitis CVS history of heart disease, cardiovascular risk factors (DM, hypertension, dyslipidemia, smoking), orthopnea, paroxysmal nocturnal dyspnea (PND), chest pain RS History of smoking, hemoptysis GI Jaundice, alcohol drinking, family history of liver disease, viral hepatitis (blood transfusion, unsafe sex, IVDU, tattoo) , constipation, palpable intraabdominal lymph nodes KUB Edema (location, duration, onset, intermittent edema), urine (volume, foamy urine, hematuria, nocturia, passing stone), polyuria GU Bleeding per vagina, palpable breast mass, abnormal nipple discharge NS Seizure, psychosis, polyneuritis multiplex Dermatology Rash, photosensitivity, hair loss, oral ulcer Rheumatology Arthritis Hematology Palpable lymph nodes, fever, night sweat, anemia, abnormal systemic bleeding, bone pain Infections Respiratory tract, skin and soft tissue infection with lag period, synpharyngitis, chronic infection Medications CCB, drug allery, antibiotics (penicillin, quinolone, vancomycin, colistin, aminoglycoside), contrast exposure, NSAIDs, D-penicillamine, PTU, gold, hydralazine, heroine Family history Sensorineural hearing loss, eye disease, chronic kidney disease 178 Physical examination Vital signs Body temperature, BP, pulsus paradoxus General appearance Body weight, sign of chronic liver disease HEENT Anemia, jaundice, cervical lymphadenopathy, oral ulcer, thyroid examination, exophthalmos, lid lag/retraction, keratoconjunctivitis sicca, xerostomia, parotid gland enlargement, Schirmer test, tender on sinus, saddle nose deformity, pinch purpura, raccoon eye, tongue indentation, anterior lenticonus CVS JVP, Kussmaul sign, PMI, heaving, thrill, murmur, pericardial rub, peripheral bruit (carotid, subclavian, abdominal) RS Tracheal deviation, decreased breath sound, consolidation sign, wheezing Abdomen Liver and spleen examination, shifting dullness, fluid thrill, bimanual palpation, full bladder Extremities Edema, should pad sign, nail dystrophy, absent of patella GU Breast mass, abnormal nipple discharge, PV examination NS Polyneuritis multiplex, flapping tremor, visual acuity, Tinel and phalen test, whispering sound Skin Tattoo, malar and discoid rash, photosensitivity, hair loss, peau d’orange skin, vasculitis lesion, dark, pigmented skin and ulcer at medial malleolus area 179 Key to differential diagnosis • Localized edema • Generalized edema ‣ Liver diseases: cirrhosis ‣ Heart diseases: mechanical abnormalities, electrical abnormalities ‣ Renal diseases: AKI, AKI on top CKD, RPGN, CKD and NS, nephritic syndrome ‣ Hypoalbuminemia of other causes 180 COMMON CAUSES 181 Causes Symptoms and signs Investigations CCBinduced edema Dihydropyridine CCB, 1st 6 months of initiation, high dose Stable BW - Cirrhosis Jaundice, alcohol drinking, family history of liver disease, viral hepatitis (blood transfusion, unsafe sex, IVDU, tattoo) Jaundice, liver and spleen examination, shifting dullness, fluid thrill, tattoo marks LFT, USG upper abdomen Heart disease CV risk factors, orthopnea, PND, chest pain, palpitation Arrthythmia, JVP, Kussmaul sign, PMI, heaving, thrill, murmur, pericardial rub, peripheral bruit EKG, cardiac markers, CXR Foamy urine, edema UA, UPCI, 24-hr urine protein, Cr, MN solid tumor albumin, lipid, HBsAg, Anti-HCV, FSGS heroine, obesity, HBV/HCV/HIV infection, Anti-HIV, ANA, Anti-dsDNA, CXR, Nephrotic MPGN chronic infection, HCV EKG, calcium, CBC, SPEP, serum syndrome LN malar rash, discoid rash, oral ulcer, arthritis, alopecia, vasculitis free light chain, FBS, CA screening lesion (CXR, FOBT, PV, mammogram, Amyloidosis polyuria, constipation, anemia, bone pain, raccoon USG abdomen) eye, pinch purpura, Tinel and Phalen test 182 Causes Nephritic syndrome Symptoms and signs Investigations Hematuria, hypertension, edema IgAN synpharyngitis UA, UPCI, 24-hr urine protein, PIGN lag period after URI or skin infection Cr, complement, Anti-HCV, MPGN chronic inflammation, HCV, palpable purpura ANA, Anti-dsDNA, ANCA, LN malar rash, discoid rash, oral ulcer, arthritis, alopecia, vasculitis lesion CXR, EKG, Rheumatoid factor ANCA-associated disease hemoptysis, sinusitis, saddle nose deformity, wheezing, mononeuritis multiplex (numbness, weakness) Protein-losing enteropathy Edema Albumin, cholesterol, stool α1 anti-trypsin ADPKD Abdominal distension, bimanual palpation USG KUB Alport’s syndrome More common in male, sensorineural hearing loss, anterior lenticonus Skin and/or renal biopsy CCB: calcium channel blocker, CV: cardiovascular, CXR: chest x-ray, FOBT: fecal occult blood test, IVDU: intravenous drug abuse, USG: ultrasound 183 OLIGURIA AND ANURIA 184 DEFINITION • Oliguria: urine output <400 ml/day • Anuria: urine output <100 ml/day 185 ETIOLOGIES • AKI, AKI on top CKD, CKD • Nephritic syndrome: AGN, RPGN, CGN 186 APPROACH TO THE PATIENTS • Nocturia, history of intermittent edema: onset of renal disease ‣ Days to week: acute onset, suggests AKI ‣ Weeks to months: subacute onset, suggests RPGN ‣ More than 3 months: late onset, suggests CKD ‣ Hematuria (see in “Hematuria”) 187 POLYURIA AND POLYDIPSIA 188 DEFINITION • Urine output >3 L/day 189 ETIOLOGIES Solute dieresis Water diuresis • Non-electrolytes diuresis • Primary polydipsia (PP) ‣ Hyperglycemia • Diabetes insipidus (DI) ‣ High protein intake ‣ Osmotic diuretic: mannitol, sorbitol • Electrolytes diuresis ‣ Diuretics ‣ Intravenous fluid ‣ Central DI (CDI) ๏ Pituitary disease: post pituitary surgery, craniopharyngioma, intracerebral hemorrhage, intracranial tumor (primary, metastasis), Sheehan’s syndrome, sarcoidosis, histiocytosis X, tuberculosis ๏ Pregnancy: diabetes insipidus of pregnancy (vasopressinase), lymphocytic hypophysitis ๏ Familial CDI ‣ Nephrogenic DI (NDI) ๏ Electrolytes abnormalities: hypercalcemia, hypokalemia ๏ Drug-induced nephrogenic DI: lithium, cisplatin, foscanet, amphotericin B, demeclocycline, methoxyflurane, foscanet ๏ Miscellaneous: obstructive uropathy, interstitial renal disease, sickle cell disease, amyloidosis ๏ Congenital NDI 190 APPROACH TO THE PATIENTS 191 History taking General appearance Fever, night sweat, weight loss HEENT Surgical scar at head, tinnitus CVS - RS Chronic cough, hemoptysis GI Dysphagia, bowel habit change, anorexia, KUB Urine volume, frequency (day:night), nocturia, onset of polyuria GU Postpartum hemorrhage, bleeding per vagina, LMP NS Blur vision (diabetic retinopathy), bitemporal hemianopia, psychiatric disease Endocrinology DM and control, steroid use Dermatology - Rheumatology - Hematology Anemia, bone pain, abnormal bleeding Infections Contact to tuberculosis patient Medications lithium, cisplatin, foscanet, amphotericin B, demeclocycline, methoxyflurane, foscanet, mannitol, diuretics, TPN, protein intake Family history DM 192 Physical examination Vital signs BP, PR General appearance Body weight HEENT Anemia, jaundice, cervical lymphadenopathy CVS JVP RS Treacheal deviation, sign of consolidation, pleural effusion Abdomen Liver and spleen examination, fundal height Extremities Skin turgor GU Breast mass, abnormal nipple discharge, PV examination NS Visual field, fundoscopic examination (DR), general neurological examination and screening for psychiatric disorders Skin Shin spot 193 Common causes Causes Symptoms and signs Investigations Medication mannitol administration, high protein intake include TPN, diuretic use Hyperglycemia history or family history of DM, poor FPG, HbA1c, BUN, Cr, urine Sp.gr., uOsm Solute diuresis control DM, steroid use, recurrent infection, diabetic retinopathy, shin spot Primary polydipsia DI Psychiatric disease, more polyuria in daytime Urine Sp.gr., uOsm, water deprivation test, low to normal serum sodium Nocturia, weight loss Central DI head trauma, neurosurgery, postpartum Urine Sp.gr., uOsm, water deprivation test, hemorrhage, prefer cool drinks, sudden onset, normal to high serum sodium, electrolyte, nocturia, pregnancy, malignancy (weight loss, anorexia, bowel habit change, dysphagia, bleeding per calcium, albumin, phosphate, CBC, bone vagina, fever night sweat, tinitus), abnormal palpable survey, CT brain, MRI pituitary protocol mass, bitemporal hemianopia, PV (posterior pituitary bright spot in MRI Nephrogenic DI medication (lithium, cisplatin, foscanet, pituitary presence in 95% of patients amphotericin B, demeclocycline, methoxyflurane, without CDI, absence in 20% of normal foscanet), multiple myeloma (bone pain, anemia), aging) malignancy (constitutional symptoms, localized symptoms), tuberculosis, gradual onset 194 Key to differential diagnosis • Solute dieresis: uOsm >300 mOsm/kgH2O, uOsm / sOsm > 0.9 ‣ Electrolyte ‣ Non-electrolyte • Water dieresis: uOsm <250 mOsm/kgH2O, uOsm / sOsm < 0.9 ‣ Primary polydipsia ‣ DI ๏ Central ๏ Nephrogenic 195 Water deprivation test • Procedure ‣ NPO: initiation of test depends on the severity of DI ๏ Routine case: after dinner of the day before the test ๏ More severe case: early in the morning of the test ‣ At the start of the test: obtain sOsm, uOsm, serum electrolyte, plasma AVP ‣ Hourly: measure of urine volume, uOsm, body weight, blood pressure ‣ Endpoint: any of the followings ๏ Body weight decreases by ≥3% ๏ Presence of orthostatic hypotension ๏ uOsm change <10% over 2 consecutive measurements ๏ Serum sodium > 145 mEq/L ‣ At the endpoint ๏ Obtain sOsm, uOsm, serum electrolyte, plasma AVP ๏ Administer of AVP 5 U or DDAVP 1 µg subcutaneously ‣ Hourly: measure of uOsm, urine volume for 2 hours • Interpretation 196 ‣ After water restriction ๏ uOsm >600 mOsm/kgH2O suggests primary polydipsia ๏ uOsm <600 mOsm/kgH2O suggests DI and minority of primary polydipsia ‣ After AVP/DDAVP administration ๏ Unequivocal uOsm ➡ < 10% increase: NDI, primary polydipsia ➡ > 50% increase: CDI ๏ Equivocal uOsm ➡ 10-50% increase - Non-diagnostic result - Need correlation between sOsm and plasma AVP level 197 HEMATURIA 198 DEFINITION • Presence of RBCs > 3 cells/HPF • Gross hematuria: presence of RBCs in urine enough to turn it in red or brown • Microscopic hematuria: detectable RBCs only in microscopic examination 199 ETIOLOGIES Negative heme in urine Porphyrins prophyria, lead poisoning, pellagra Drugs adriamycin, chloroquine, desferoxamine, levodopa, methyldopa, metronidazole, nitrofurantoin, phenazopyridine, phebolphthalein, phenytoin, prochlorperazine, quinine, rifampicin, sulfonamide Foods artificial food coloring, beets, blackberries, blueberries, fava beans, paprika, rhubarb Positive heme in urine Hemoglobinuria (hemolysis) Myoglobinuria (rhabdomyolysis) Nonhematuria Hematuria Upper tract pyelonephritis, nephrolithiasis, hypercalciuria, hyperuricosuria, trauma, papillary necrosis, ureteral stricture, sickle cell disease, renal infarction, arteriovenous malformation, renal tuberculosis, ADPKD, renal cell carcinoma, transitional cell carcinoma of renal pelvis or ureter Non-glomerular in origin Lower tract cystitis, urethritis, prostatitis, bladder polyp, Schistosoma haematobium infection Uncertain Exercise hematuria, benign hematuria, over-anticoagulation, factitious hematuria Glomerular in origin Gross hematuria IgAN, PIGN, pauci-immune GN, LN, MPGN Microscopic hematuria Immune complex diseases (IgAN, PIGN, LN, MPGN), pauci-immune GN, anti-GBM (anti-GBM disease, Goodpasture’s syndrome), Hereditary nephritis (Alport’s syndrome, thin basement membrane disease), other glomerular diseases (FSGS, MN) 200 APPROACH TO THE PATIENTS 201 History taking General appearance Body weight change, fever HEENT sinusitis CVS Orthopnea, paroxysmal nocturnal dyspnea (PND) RS Wheezing, hemoptysis GI Jaundice, alcohol drinking, family history of liver disease, viral hepatitis (blood transfusion, unsafe sex, IVDU, tattoo) , constipation, palpable intraabdominal lymph nodes KUB Urine (volume, foamy urine, hematuria, nocturia, passing stone) GU Bleeding per vagina, palpable breast mass, abnormal nipple discharge NS Seizure, psychosis, polyneuritis multiplex, subarachnoid hemorrhage Dermatology Rash, photosensitivity, hair loss, oral ulcer Rheumatology Arthritis Hematology Palpable lymph nodes, fever, night sweat, anemia, abnormal systemic bleeding, bone pain Infections Respiratory tract, skin and soft tissue infection with lag period, synpharyngitis, chronic infection Medications NSAIDs, PTU, hydralazine, anti-TNF, minocycline, methydopa, INH, chlorpromazine, pyrazinamide, D-penicillamine, heroine Family history Sensorineural hearing loss, eye disease, chronic kidney disease 202 Physical examination Vital signs Body temperature, BP General appearance Body weight, sign of chronic liver disease HEENT Anemia, jaundice, cervical lymphadenopathy, oral ulcer, thyroid examination, exophthalmos, lid lag/ retraction, tender on sinus, saddle nose deformity, anterior lenticonus CVS JVP, PMI, murmur RS Tracheal deviation, decreased breath sound, consolidation sign, wheezing, creptiation Abdomen Liver and spleen examination, shifting dullness, fluid thrill, bimanual palpation Extremities Edema, should pad sign, nail dystrophy, absent of patella GU Breast mass, abnormal nipple discharge, PV examination NS Polyneuritis multiplex, flapping tremor, visual acuity, Tinel and phalen test, whispering sound Skin Tattoo, malar and discoid rash, photosensitivity, hair loss, vasculitis lesion 203 Key to differential diagnosis red-brown urine Non-hematuria • Negative heme in urine: drugs, food, porphyrins • Positive heme without RBC in urine ‣ Hemoglobinuria (hemolysis): low serum haptoglobin, indirect hemolytic evidences ‣ Myoglobinuria (rhabdomyolysis) Picture A The pictures show urine of the patient with rhabdomyolysis from electrical injury on A) 1st day (comparing with black plastic board on the right) 204 Hematuria Hematuria: RBC >3 /HPF in urine • Only in gross hematuria: 3 glass test ‣ Initial hematuria: bleeding from urethra ‣ Terminal hematuria: bleeding from bladder ‣ Total hematuria: bleeding from kidney or ureter • Microscopic hematuria ‣ Non-glomerular hematuria ๏ Urinary tract infection (UTI) ๏ No UTI ➡ Imaging: plain KUB, IVP, ultrasound, CT scan ➡ Cystoscopy: in age >40 years old or high index of suspicious ➡ Cytology: in age <40 years old or low index of suspicious ‣ Glomerular hematuria: blood test and renal biopsy 205 Differentiate glomerular versus non-glomerular hematuria Glomerular hematuria Non-glomerular hematuria Urine color Dark red, brown, cola colored, smoky Bright red Clots - + Proteinuria >500 mg/d + - RBC morphology Dysmorphic Isomorphic Hypertension + - Edema + - Urinary voiding symptoms - + Back or flank pain + + Renal function Reduced Normal Family history + + Trauma - + Upper respiratory tract infection + - Fever, rash + - 206 Complement levels in acute glomerulonephritis Low C3 and C4 Lupus nephritis Cryoglobulinemia Bacterial endocarditis Shunt nephritis MPGN type 1 Low C3 and normal C4 Normal C3 and C4 Post-infectious GN MPGN type II (dense deposition disease) Polyarteritis nodosa ANCA-associated GN Hypersensitivity vasculitis Henoch-Scholein purpura Anti-GBM disease Goodpasture’s syndrome IgA nephropathy 207 PROXIMAL MUSCLE WEAKNESS 208 ETIOLOGIES • Myopathy ‣ Inflammatory myopathy ๏ Dermatomyositis ๏ Polymyositis ๏ Inclusion-body myositis ๏ Infections: HIV, influenza, coxackie virus, Trichinella spiralis ‣ Non-inflammatory myopathy ๏ Electrolyte imbalances: hypokalemia, hyperkalemia, hypophosphatemia, hypermagnesemia, hypocalcemia, hypercalcemia ๏ Endocrinopathies: hyperthyroidism, Cushing syndrome, DM ๏ Metabolic causes: glycogen storage diseases, lipid storage myopathy, mitochondrial disease ๏ Muscular dystrophy (MD): Duchene MD, Becker MD, fascioscapulohumeral MD, limb-girdle MD, scapuloperoneal syndrome ๏ Congenital myopathies: central core disease, Nemalin myopathy, centronuclear myopathy • Neuromuscular junction (NMJ) disease ‣ Presynaptic defect: Lambert-Eaton myasthenic syndrome, Botulism, neurotoxin snake venom ‣ Postsynaptic defect: myasthenia gravis • Polyneuropathy: Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), porphyria ๏ Drugs: corticosteroid, statin, colchicines, chloroquine, alcohol, zidovudine 209 APPROACH TO THE PATIENTS Differentiate site of lesions of muscle weakness • Upper motor neuron: long tract signs • Lower motor neuron ‣ Distal muscle weakness ‣ Proximal muscle weakness ๏ Anterior horn cell diseases: history of lead exposure, poliomyelitis, familial spinal atrophy ๏ Peripheral neuropathy: loss of sensation ๏ NMJ diseases: fluctuation of symptoms ๏ Myopathies: no loss of sensation, no fasciculation, normoreflexia ➡ Family history of muscle weakness, specific sites of muscle weakness, hepatosplenomegaly ➡ History of infections, muscle pain, malignancy ➡ Skin lesions: V sign, shawl sign, guttron papules ➡ Medications ➡ Check electrolytes, phosphate, magnesium, calcium ➡ Check plasma glucose, morning cortisol, thyroid function ➡ Check CPK 210 HYPERTENSION IN THE YOUNG 211 DEFINITION • Hypertension at the age of onset <20 years 212 ETIOLOGIES • Renal diseases ‣ Renovascular diseases: renal artery stenosis (fibromuscular dysplasia, atherosclerosis), polyarteritis nodosa ‣ Renal parenchymal diseases: nephritic syndrome, chronic kidney disease • Endocrinopathies: hypothyroidism, hyperthyroidism, acromegaly, pheochromocytoma, Cushing syndrome, hyperaldosteronism, congenital adrenal hyperplasia • Cardiovascular diseases: coarctation of aorta, Takayasu’s arteritis • Lung diseases: obstructive sleep apnea • Drugs: estrogen, herbs, amphetamine, cocaine, NSAIDs, corticosteroid, decongestants, diet pills, psychiatric drugs (buspirone, carbamazepine, clozapine, fluoxetine, lithium, tricyclic antidepressant, cyclosporine) • Pregnancy-induced hypertension: preeclampsia, eclampsia • Neurological diseases: dysautonomia, increased intracranial pressure 213 APPROACH TO THE PATIENTS 214 History taking • Medications, last menopausal period, history of claudication, snoring, endocrinopathies • Coarctation of aorta: BP 4 extremities, delayed radiofemoral pulses, associated diseases (Turner syndrome) • Family history of DM, hypertension: suggests essential hypertension Physical examination • HEENT: lid lag, lid retraction, thyroid examination, cushingoid appearances, enlarged tongue, cutis verticis gyrata • CVS: unequal pulses, bruits (abdominal, renal, subclavian) • Extremities: spade hands • Genitalia: ambiguous genitalia • NS: bilateral hemianopia, fundus examination (silver wire, copper wire appearance, A:V ratio, AV nicking) 215 Investigations • Serum electrolytes, urine electrolytes, sOsm, uOsm • BUN, creatinine, UA • Doppler renal ultrasound, renal artery MRA, renal angiogram • EKG: LVH • CXR: rib notching, reverse three sign • Aldosterone-renin ratio (ARR) ≥20 ng/dL per ng/mL/hour: plasma aldosterone concentration (PAC) ≥15 ng/dL, plasma renin activity (PRA) <1.0 ng/mL/hour • Urine VMA, urine metanephrine, plasma metanephrine, imaging, MIBG scan • Thyroid function test • 1-mg overnight dexamethasone suppression test • Serum IGF-1 216 ANCA-ASSOCIATED GLOMERULONEPHRITIS (ANCA-ASSOCIATED GN) Definition • Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, arterioles, and small arteries), associated with myeloperoxidase (MPO) ANCA (anti-neutrophil cytoplasmic antibodies) or proteinase 3 (PR3) ANCA. Not all patients have ANCA Related terms • Pauci-immune glomerulonephritis Epidemiology • Incidence 3.9 cases / 1,000,000 people • Renal-limited ANCA-associated vasculitis 23 – 25% • ANCA-negative pauci-immune GN 27 – 38% Related Glossary Terms Drag related terms here Index Find Term Chapter 1 - Common glomerular diseases APPROACH TO THE PATIENTS SUSPECTED GLOMERULAR DISEASES Clinical presentations of glomerular diseases • Proteinuria: varying in degree of proteinuria, more specific in proteinuria > 2 g/day • Glomerular hematuria • Decreased GFR: oliguria, anuria, uremic symptoms • Salt and water retention: edema, hypertension Differentiate between glomerular syndromes • Nephritic syndrome versus nephrotic syndrome Nephritic syndrome Decreased of GFR: edema, oliguria, hypertension, azotemia Active urine sediments: dysmorphic RBC, RBC cast Subnephrotic-ranged proteinuria Nephrotic-ranged proteinuria Hyperlipidemia Nephrotic syndrome Hypoalbuminemia Edema Lipiduria: oval fat body, fatty cast • Asymptomatic versus symptomatic • Define onset of disease: history of urine volume and characters change, nocturia, edema, broad cast in urine (subacute to chronic onset), ultrasound kidney ‣ Acute onset: days to week ‣ Subacute onset: weeks to month Related Glossary Terms Drag related terms here Index Find Term Chapter 1 - Nephritic syndromes CHRONIC KIDNEY DISEASE (CKD) Definition Either of the following present for > 3 months • Markers of kidney damage (one or more) ‣ Albuminuria ≥ 30 mg/day, or albumin-to-creatinine ratio ≥ 30 g/ g creatinine ‣ Urine sediment abnormalities ‣ Electrolyte and other abnormalities due to tubular disorders ‣ Abnormalities detected by histology ‣ Structural abnormalities detected by imaging ‣ History of kidney transplantation • Decreased GFR: < 60 ml/min/1.73 m2 Related Glossary Terms Drag related terms here Index Find Term Chapter 1 - Common glomerular diseases ETIOLOGIES OF NEPHROTIC SYNDROME (NS) Secondary NS • Infections: HBV, HCV, HIV, tuberculosis, infective endocarditis, visceral abscess, shunt nephritis • Autoimmune diseases: SLE, rheumatoid arthritis, SjÖgren syndrome • Medications: NSAIDs, gold, D-penicillamine, heroin • Malignancies: hematologic malignancy (Hodgkon’s and non Hodgkin’s lymphoma, plasma cell dyscrasia), solid tumors • Metabolic abnormalities: DM, hypertension, obesity • Miscellaneous diseases: reflux nephropathy, analgesic, nephron loss, amyloidosis Related Glossary Terms Drag related terms here Index Find Term Chapter 1 - Asymptomatic proteinuria GLOMERULAR HEMATURIA Hematuria • Bed rest • Analgesics • Hydration: to increase urine flow rate to 2 – 3 L/day • Avoid sports which at a risk of abdominal trauma: such as rugby, boxing Related Glossary Terms Drag related terms here Index Find Term Chapter 1 - Approach to the patients with suspected of glomerular diseases HEMATURIA Definition • Presence of RBCs > 3 cells/HPF • Gross hematuria: presence of RBCs in urine enough to turn it in red or brown • Microscopic hematuria: detectable RBCs only in microscopic examination Related Glossary Terms Drag related terms here Index Find Term Chapter 5 - Oliguria and anuria IGA NEPHROPATHY (IGAN) Definition • Predominance of IgA deposits, either alone or with IgG, IgM, or both in the glomerular mesangium Epidemiology • Most common primary glomerular disease • Occurs in all age groups • Most common at age of 10 – 20 years, 80% of patients are age of 16 – 35 years at the time of biopsy • More common in males than females: male / female ratio 2:1 to 6:1 Pathogenesis • Multi-hit mechanism ‣ Hit 1: Increased circulating galactose-deficient (at hinge region of heavy chain) IgA1 ‣ Hit 2: Production of anti-glycan antibodies that recognize galactose deficient IgA1 ‣ Hit 3: Formation of pathogenic circulating immune complexes from autoantigen (galactose-deficient IgA) and O-glycanspecific antibodies ‣ Hit 4: Deposition of pathogenic immune complexes in the mesangium, activation of mesangial cells, and induction of glomerular injury Related Glossary Terms Drag related terms here Index Find Term Chapter 2 - Approach to the patients with AKI MINIMAL CHANGE DISEASE (MCD) Related terms • Lipoid nephrosis • Minimal change glomerulopathy Epidemiology • 10 – 15% of primary glomerular syndrome in adults • 70 - 90% of nephrotic syndrome in children under age of 10 year, and 50% of older children • Male : female ratio 2:1 – 3:1 Pathogenesis • Remains unclear • Most likely a consequence of abnormal regulation of T cells Etiologies and classification • Primary MCD • Secondary MCD ‣ Infections: virus, parasite ‣ Drugs: NSAIDs, gold, lithium, interferon, ampicillin, rifampin, trimethadione, tiopronin ‣ Tumors: Hodgkin’s disease, lymphoma, leukemia, solid tumors ‣ Allergies: food, dust, bee stings, pollen, poison ivy, poison oak, dermatitis herpitiformis ‣ Others: SLE, following hematopoietic cell transplantation Related Glossary Terms Drag related terms here Index Find Term Chapter 1 - Common glomerular diseases NEPHRITIC SYNDROMES ETIOLOGY Immune complex glomerulonephritis • Lupus nephritis (LN) • Post-infectious glomerulonephritis (PIGN) • IgA nephropathy (IgAN) and Henoch-SchÖnlein purpura (HSP) • Subacute bacterial endocarditis • Membranoproliferative glomerulonephritis (MPGN) • Cryoglobulinemia Anti-glomerular basement membrane (GBM) • Anti-GBM disease • Goodpasture’s syndrome Pauci-immune glomerulonephritis • ANCA-associated glomerulonephritis ‣ Granulomatosis with polyangitis (GPA) or Wegner’s granulomatosis ‣ Eosinophilic granulomatosis with polyangitis (EGPA) or ChurgStrauss syndrome ‣ Microscopic polyangiitis (MPA) ‣ Renal limited pauci-immune glomerulonephritis • Double positive disease Related Glossary Terms Drag related terms here Index Find Term Chapter 1 - Nephritic syndromes POST-INFECTIOUS GLOMERULONEPHRITIS (PIGN) Definition • An immunologic response of the kidney that occurs following a nonrenal infection Related terms • Bright disease • Streptococcus-related glomerulonephritis • Post-streptococcal glomerulonephritis Epidemiology • Incidence and prevalence are lower in developed countries • Incidence 0.6 – 39.24 and prevalence 0.02 – 10.14 cases / 100,000 population • Median age of onset 36 – 58 years • High prevalence in DM, alcoholism • 30 – 50% associated with gram negative bacilli infection Related Glossary Terms Drag related terms here Index Find Term Chapter 2 - Approach to the patients with AKI
