Dr Jishanth M
Prof Dr A Gowrisankar’s Unit, M4
*Mr A SHANMUGAM, 28 yr/M,
*Unmarried, working in a shop,
*admitted on 27-11-2007 with inability to speak, motor weakness of R UL and LL, preceded by 2 days h/o fever to a private hospital.
*No h/o HTN/DM/Epilepsy
*No family history of similar illness.
*O/E patient was conscious, co-operative, disoriented at time, BP-120/80 mm Hg, all peripheral vessels are palpable,
*(R) Hemiparesis+, Plantar ↑on R, ↓on L.
*RBS 102 mg%
*BU 35
*S Cr 1.2
*Na+ 135
*K+ 4
*TC 11200
*P82 L15 E3
*CXR showed f/o LRTI
*ECG Normal
*CT Scan showed Left MCA territory acute infarct and a small infarct in right parietal region.
*Urine albumin+,
*ANA negative, CRP negative
*LFT normal
*Total Cholesterol 255 mg%, TG 230, HDL 49, LDL 123,
*IgM/IgG ACL Ab negative,
*RA factor negative.
*Patient was given anti-edema measures, Aspirin, Atorvastatin and other supportive therapies.
*ECHO was normal,
*Ultrasound abdomen showed mild splenomegaly, otherwise normal. RK 106/46mm, LK 111/43mm, Corticomedullary echo pattern normal.
*HIV- negative.
*Thrombophilia profile- normal
*Patient improved, apparently normal, started walking, continued atorvastatin/aspirin.
*6 months later patient developed hypertension, for which he was started on Ramipril,
*BU 36, S Cr 1.28,
*Urine Alb 1+.
*One year after the stroke, patient developed facial puffiness and was evaluated for renal cause.
*BU 42, S Cr 1.8
*Urine showed albumin 3+
*24 hr urine protein 5.5 g/day
*Ultrasonogram- normal sized kidneys
Medical Renal disease+, Splenomegaly+
*Dopplerstudy of renal arteries normal
*Serum Calcium- 8.1 mg%
*Serum Uric Acid 6.9 mg%
*FBS 90/ PPBS 118, Urine sugar-negative
*ANA neg, CRP neg
*HIV neg
*HBsAg neg, Anti HCV negative
*PT 11.7s(12s), aPTT 20s(30s)
*IgG/IgM ACL Ab negative
*CXR normal, ECG normal
*Peripheral smear study -normal.
*Patient underwent renal biopsy which showed segmental sclerosis with mesangial proliferation, focal tubular atrophy, and Immunofluroscence showed mesangial and peripheral deposits in IgA, C3c and IgM with fibrinogen.
*Patient was given diuretics and steroid. Elevated renal parameters came down, BU 28, S Cr 1.1.
*Patient continued Ramipril, Atorvastatin, Aspirin.
*Patient was put on prednisolone.
*After 3 months RBS 238, BU 32, S Cr 1.3,
*BP 110/90 mmHg,
*Serum total protein 5.8 g%, Alb 3.8, Globulin 2g
*Urine albmin 3+.
*Steroids were slowly tapered off.
*Sugar levels came down.
*BP was fluctuating.
*2 years after the initial stroke, patient developed swelling of left lower limb associated with pain,
*Doppler study showed left popliteal vein thrombosis extending upto adductor canal,
*Blood Sugar 99, BU 28, S Cr 1.2
*Na+ 138, K+ 3.9
*CX- normal
*Urine albumin 2+
*Cholesterol 182
*S Total protein 5.9 g, Albumin 3.7, Glob 2.2.
*Patient again readmitted and continued Atorvastatin, Prednisolone, Ramipril, +Acitrom 3 mg OD.
*At discharge 24 hr urine protein was 1.7g,
*BP 140/90 mmHg,
*Protein C 42.3(70-140),
*Protein S 54.9(60-150),
*Serum Homocysteine 16.50(5.9-16),
*Anti thrombin III level-normal.
*He was discharged with advice to continue aspirin, atorvastatin, ramipril, acitrom, and prednisolone.
*After 3 months 24 hr urine protein was 360 mg and steroid was slowly tapered.
*BU 27, S Cr 0.7, RBS 92 mg%.
*Ultrasonogram-no splenomegaly.
Scanty glomeruli with sclerosing proliferative glomerulonephritis, focal tubular atrophy and abundant IgA deposits, consistent with
“IgA Nephropathy”
*To rule out remote possibilities of pauci-immune glomerulonephritis, ANCA antibodies were done- both were negative.
*It is the commonest form of glomerulonephritis resulting in ESRD throughout the world
also known as
IgA nephritis,
Berger's disease,
Synpharyngitic glomerulonephritis
*Prevalence 25-50/1,00,000
*Male preponderence, peaks in 2/3rd decade
*Rare familial clustering
Signs and symptoms
*classic presentation ( 40-50% ) is
episodic frank haematuria after URTI (synpharyngitic) or
microscopic haematuria
*microscopic haematuria and proteinuria (20-30%)
*nephrotic syndrome(5%)
*acute renal failure(5%)
*chronic renal failure(5%)
*Immunohistochemical findings of mesangial deposition of IgA*light microscopy: mesangial cell
proliferation is the commonest feature
*What is “MEST”…Global IgA Consortium Project*
*• Mesangial proliferation 0/1
*• Endocapillary proliferation 0/1
*• Segmental sclerosis/adhesion 0/1
*• Tubular atrophy /interstitial fibrosis 0/1/2
*indolent progressive nature
*15% to 40% of adults and children will progress to ESRD
*15 to 20% develop ESRD within 10 years of onset
*30 to 35% develop ESRD within 20 years of onset
*Deposits of Immunogloblin A (IgA) in a blotchy pattern in the mesangium (on immunofluroescence), the HEART of the renal glomerulus
*The tissue changes gradually from being hypercellular to depositing extracellular matrix proteins, and finally fibrosis
*A recently advanced theory focuses on abnormalities of the IgA1 molecule. IgA1 is one of the two immunoglobulin subclasses that is O-glycosylated on a number of serine and threonine residues in a special proline-rich hinge region.
*Deficiency of these sugars appears to lead to polymerisation of the IgA molecule in tissues, especially the glomerular mesangium.
*IgAN can recur after renal transplant - caused by a problem in the immune system rather than the kidney itself.
Immunofluorescence Periodic acid-Schiff stain
*Genetic factors
*Chr 6q 22-23
*Aberrancy of structure of IgA1 molecules
Glycosylation aberrancy -> aggregation, CIC formation,
*Increased levels of IgA and IgA-containing complexes
Overproduction or defective clearance
*Endogenous or exogenous antigens
CIC formation, IgA renal deposition
*Immunological defects
(allergy, complement, coagulation, ...)
“AUTOIMMUNE DISEASE”
Genetic aspects (Progression)
ACE gene polymorphism
Angiotensinogen gene polymorphism
*High Blood Pressure and persistant level of proteinuria are the major (known) independent determinants of progression
*Conservative
*Blockers of the renin-angiotensin system
*Corticosteroids
*Fish oil (n-3 Polyunsaturated Fatty Acids) supplementation
*Cyclophosphamide
*Mycophenolate mofetil (MMF)
*CONSERVATIVE TREATMENT
*normal renal function,
*normotension and
*only minor urinary abnormalities
*isolated microscopic haematuria, and/or
*mild proteinuria
*keep such patients under review
*Up to 23% of patients will have a spontaneous complete remission.
*BLOCKERS OF THE RENIN-ANGIOTENSIN SYSTEM
*Reduction in proteinuria is considered to be the hallmark of effective treatment in preserving renal function in nondiabetic renal diseases.
*ACEi and more recently angiotensin II type 1 receptor blockers (ARB) control blood pressure and proteinuria
*Controls both proteinuria and hypertension(modifiable risk factors for progression of disease)
*Superior to other antihypertensive drugs in lowering proteinuria by virtue of their capacity to reduce intraglomerular pressure.
*CORTICOSTEROIDS
*Steroid does not appear to consistently offer any beneficial effect other than modest amelioration of proteinuria.
*The only exception is in children with IgA deposition in the setting of minimal change nephrotic syndrome. Such patients respond to corticosteroid promptly.
*In adults, in view of the toxicities associated with steroid therapy, it should be considered only when proteinuria persists >1 g/24 h despite optimal BP control and maximum RAS blockade.
Fish oil (n-3 Polyunsaturated Fatty Acids) supplementation
*The rationale of using fish oil in IgAN is based on the premise that n-3 PUFAs alter the production or action of cytokines and eicosanoids evoked by the initial or repeated immunological renal injury, alleviating ongoing renal inflammation and glomerulosclerosis (hallmarks of progressive renal disease)
*Mayo investigators published their long-term data in 1999 to conclude that early and prolonged treatment with fish oil slows renal progression for high-risk patients with IgAN.
*Still under debate.
*CYCLOPHOSPHAMIDE
*Cytotoxic agent
*Only if high risk for progression to ESRD
*Only one study suggested efficacy of cyclophosphamide followed by azathioprine in conjunction with high-dose prednisolone in patients who are at very high risk for progression (ESRD predicted in all cases within 5 yr). (Ballardie )
*Insufficient evidence to justify the use in IgAN except in crescentic IgAN with rapidly progressive renal failure
*Mycophenolate mofetil (MMF)
*The rationale is its selective suppressive effects on lymphocyte proliferation and antibody formation
*Hong Kong data showed that a 6-month course of MMF (0.75 to 1 g b.d.) can induce lasting remission (up to 72 weeks of follow up ) of proteinuria in at risk patients (i.e. those with persistent proteinuria >1g/day despite full RAS inhibition and normal BP, but had histology that did not reveal advanced sclerosis). ( Tang S )
*Beijing data suggested that MMF is more effective than prednisone in reducing proteinuria in patients with urinary proteinuria > 2 g/d. ( Chen X )
*Male gender
*proteinuria (especially > 2 g/day),
*hypertension
*smoking
*hyperlipidaemia
*older age
*familial disease
*elevated serum creatinine
*kidney biopsy: interstitial scarring
Risk factors for ESRD
*Harrison’s Principles of Internal Medicine: 17ed
*Proteinuria:How to evaluate an important finding: WAQAR KASHIF, MD Department of Medicine,
Medical College of Wisconsin,Milwaukee(Review)
* IgA nephropathy:The Value of Proteinuria, Daniel Cattran,CNC-ASN,Philadelphia, PA,2008
*UpToDate 17.1