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