Glomerular Diseases

DONE BY : THA’ER AHMAD ALAJOU

Glomerular diseases Glomerular diseases may cause acute and chronic renal failure, and may follow a number of insults: immunological injury, inherited abnormality (e.g. Alport’s syndrome), metabolic stress (e.g. diabetes mellitus), deposition of extraneous materials (e.g. amyloid), or other direct glomerular injury.

The response of the glomerulus to injury varies according to the nature of the insult

Glomerular disease can be classified according to presentation to :

1. Nephrotic syndrome

2. Nephritic syndrome

Nephrotic syndrome Definition : a type of kidney disease that results in proteinuria, peripheral edema, hyperlipidemia, and hypoalbuminemia . •

Criteria :

Protein –creatinine ratio more than 3.5 mg /mg or 24 h. urin collection of protein of more than 3.5 g/24 hours

Hyperlipidemia

Hypoalbuminemia

Pathogenesis

the glomerulus becomes permeable to large molecules (e.g., albumin)

◦ this loss of albumin (proteinuria) results in hypoalbuminemia and edema

◦ associated with a hypercoagulable state ◦ pathophysiology unclear but may be due to loss of antithrombin and

plasminogen proteins

◦ increased lipid synthesis secondary to proteinuria ◦ this in turn results in hypercholesterolemia and hyperlipidemia

Classification Primary glomerular disease

◦ focal segmental glomerulosclerosis (THE MOST COMMON CAUSE OF PRIMARY NEPHTOTIC SYDROME )

◦ membranous nephropathy

◦ minimal change disease

Secondary causes ◦ diabetic nephropathy ( THE MOST COMMON CAUSE OF BOTH NEPHROTIC SYNDROME AND ESKD )

◦ systemic lupus erythematosus

◦ Amyloidosis……………..etc

Clinical sign and symptoms 1. Facial swelling is a common presenting feature in children and younger adults , with periorbital oedema often being the first evidence that something is wrong; oedema may progress to involve the whole body.

2.Adults tend to present with peripheral oedema affecting the ankles and legs, which may progress to involve the whole body.

3.Some patients may notice frothiness of their urine.

4. Recurrent infections and/or general fatigue, lethargy, poor appetite, weakness or episodic abdominal pain may cause presentation to a doctor.

Clinical sign and symptoms 5. Hyperlipidemia and increased atherosclerosis, most likely from the urinary loss of the lipoprotein markers or signals on the surface of chylomicrons and LDL that lead to the clearance of these lipids from the bloodstream.

6.Hypercoagulable states or thrombophilia, due to the urinary loss of natural anticoagulant proteins such as antithrombin, protein C, and protein S.

Spontaneous arterial or venous thrombosis due to hypercoagulability.

7. SOB with chest pain : MI or PE

8. SOB due to pleural effusion or ascites

9. Iron, copper, and zinc deficiency may be present as a result of the urinary loss of their transport proteins such as transferrin and ceruloplasmin.

Approach 1. History and physical examination.

2. Investigation :

Urine analysis.

Urine sediment examination

Urinary protein measurement (24h)

Serum albumin

Renal function tests.

coagulation screen.

LFTs (to exclude liver pathology); bone profile (calcium, phosphate, alkaline phosphatase).

Check for other systemic diseases and causes of nephrotic syndrome: ◦ ESR and CRP.

◦ Fasting glucose.

◦ Immunoglobulins, serum and urine electrophoresis.

◦ Autoimmune screen if an underlying autoimmune disease is suspected: autoantibodies and complement levels.

◦ Hepatitis B and hepatitis C; HIV.

CXR and abdominal or renal ultrasound to check for pleural effusion or ascites, the presence of two kidneys, the size and shape of the kidneys and for any urinary tract obstruction.

Consider complications: ◦ Lipids - hyperlipidaemia.

◦ Doppler ultrasound of leg veins in suspected deep vein thrombosis.

◦ Abdominal ultrasound, renal vein Doppler scan, venography of the inferior vena cava, CT and MRI scanning of the abdomen if renal vein thrombosis is suspected.

◦ Ventilation-perfusion scan - 'VQ' nuclear medicine lung scan; CT, pulmonary angiography for pulmonary embolism.

Renal biopsy under ultrasound; renal biopsy may be helpful to guide diagnosis and treatment but is not indicated in all patients with nephrotic syndrome.

Renal biopsy

Nephrotic range proteinuria is one of the major indications for a renal biopsy

Biopsies are absolutely contraindicated in the following situation:

- Uncontrolled bleeding diathesis

Biopsies are relatively contraindicated when:

1. Uncontrolled hypertension (>160/95)

2. Uncooperative patient

3. Patient unable to consent

4. Solitary kidney. This is a 'big decision' and should be carefully made by a consultant and the patient

5. Obstructed kidneys

6. Small kidneys (less than 10 cm; less than 9 cm in a small patient)

7. Anatomical abnormalities (eg vascular lesion)

8. Renal neoplasm, multiple cysts, abscess or pyelonephritis

Management principles 1. Diet and fluids:

◦ Reduce salt intake in the diet (avoid processed foods and adding salt to food).

◦ Give a diet with adequate calorific intake and sufficient protein content (1-2 g/kg daily).

◦ Fluid restriction is not usually necessary (if severe enough to need this then the patient may need admission).

2. Hyperlipidemia - does not initially require therapy but may do so if prolonged.

3. ACEI / ARBs for control of HTN and proteinuria

4. Edema: ◦ Edema is treated through diuretic therapy with furosemide (~1 mg/kg/day)

◦ Check weight regularly to assess response to diuretics and ensure fluid retention is not worsening, or that the patient is over-diuresed.

◦ Patients with very low albumin levels may not respond to diuretics and may require admission to receive intravenous albumin therapy.

Complications Complications of nephrotic syndrome include:

1. Decreased resistance to infections, due to urinary immunoglobulin loss.

2. Increased risk of venous thromboembolism. Adults with membranous nephropathy are at particular risk.

3. Acute kidney injury may rarely occur as a spontaneous complication of nephrotic syndrome. Acute kidney injury may also be caused by excessive diuresis, interstitial nephritis due to use of diuretics or NSAIDs, sepsis or renal vein thrombosis.

4. Chronic kidney disease may occur as a result of an underlying cause - eg, amyloidosis or diabetes.

5. Steroid-resistant nephrotic syndrome is associated with a high risk of developing end-stage kidney disease.

6. Increased risk of osteitis fibrosa cystica and osteomalacia due to loss of vitamin D-binding protein and its complexes in the urine, through a combination of calcium malabsorption and secondary hyperparathyroidism.

Referral and admission Initial management should focus on investigating the cause, identifying complications and managing the symptoms of the disease.

Most patients do not require acute hospitalisation.

All patients should be referred urgently to a nephrologist for further investigation.

Indications for acute admission include:

1. Severe generalised oedema, particularly if pleural effusion/oedema is causing respiratory compromise.

2. Tense scrotal/labial oedema.

3. Complications of the nephrotic state (eg, sepsis, pneumonia, myocardial infarction, deep vein thrombosis).

4. Inability to comply independently with therapy or with the condition in the family.

5. Any features of a possible nephritic syndrome such as haematuria, hypertension and impaired renal function parameters.

FSGS Some glomeruli ( focal ) , and part of the glomerulus ( segmental )

The leading cause of primary nephrotic syndrome , and the most common primary glomerular disease leading to ESRD in USA .

More common in blacks and Hispanics

Causes of FSGS :

Primary ,

Familial ,

Secondary to HIV ,

Sickle cell disease ,

Morbid obesity ,

Reflux nephropathy,

Heroin abuse .

Management ACE-I or ARBS to target a BP of less than 130/80 and control proteinuria ( to prevent or decrease

progression of disease )

For pateints with nephrotic range proteinuria or risk factors of progression to ESKD

immunosuppressive medications must be used ; including corticosteroids , and calcineurin

inhibitors , cyclophosphamide , mycophenolate mofitile , and Rituximab

Membranous glomerulonephritis The second leading cause of primary nephrotic syndrome ,

Has a predilection to occur in adults older than 50 ys .

Causes :

Primary

Secondary to :

SLE ,

Hepatitis B and C ,

Malaria

Malignancies ( solid tumors )

Medications ( e.g. NSAIDS )

Membranous glomerulopathy has the HIGHEST prevalence of renal vein thrombosis compared with other cause of nephrotic syndrome .

Slowly progressive disease

presence of sub epithelial immunoglobulins containing deposits around basement membrane

Pts with membranous glomerulopathy have increase risk for thrombosis compared to other etiologies

LM :

Diffuse thickening of basement membrane .

EM :

Subepithelial deposits along basement

membrane , granular deposition of

immunoglobulin and complements along GBM

Management Around 2/3 of pateints with membranous GN undergo spontaneous complete or partial remission ( hence no need for treatment ) ,

The decision to treat is dependent on the clinical features and risk of disease progression

Only Supportive treatment is required in most cases with treatment of hyperlipidemia , and hypercoagulable state , including it’s complications namely renal vein thrombosis .

Screening for possible underlying solid tumors is also warranted in some cases .

Follow up every 1-3 months of both proteinuria and GFR is required .

Minimal change disease The most common cause of nephrotic syndrome in pediatric age group .

Pathology : light microscopy and immunofluorescence are normal , ( NIL DISEASE )

Electron microscopy shows effacement of podocyte foot processes .

Causes :

Idiopathic ,

Associated with atopic diseases

Lymphomas ,

Thymoma ,

Infectious mononeucleosis

Drugs like :Gold , penicillamine , rifampicine

Treatment Most pateints with MCG are responsive to daily or alternate day prednisolone , at 1 mg /kg/day or 2 mg /kg /eod , for 8-16 weeks , with complete remission achieved in 70 % of cases .

Immunosuppresive therapy is used for.

Excellent prognosis

Nephritic syndrome

Nephritic syndrom It’s an Inflammatory process that involves glomeruli (damage involving the basement membrane ,capillary endothelium , and mesangium) (while in nephrOtic syndrome the main structure to be damaged is Podocyte)

Due to the glomeruli damage:

filtration barrier is weakened and enables passage of proteins ,erythrocytes

↓GFR Oliguria & ↑BUN/Cr ratio

↑Hydrostatic pressure Hypertension & Edema

Classic presentation: Hematurea (RBCs)

Proteinuria (<3.5g/day)

Swelling/edema

Fatigue (uremia)

Hypertension

Azotemia

Decreased GFR

Causes Could be classified Primary ( idiopathic) v.s. Secondary

Or classified as Immune mediated v.s. Pauci-immune

Rapid progressive glomerulonephritis (RPGN) It’s not a disease by itself but it caused by other GN disease , such as :

1. ANTI GBM

2. ANCA GN

3. Immune complex GN

Characterized by :

1. Loss of GFR <50%

2. Extensive glomerular crescents after ruptured capillary wall which leading to accumulation of macrophages , fibroblast and fibrin within the bowmen space

This is lead to crescent picture on microscope (Crescentic GN ) > so definitive diagnosis by renal biopsy.

Treatment is glucocorticoid (start early to protect GFR) and cyclophosphamide ( after biopsy)

Anti-GBM antibodies disease Goodpasture’s Syndrome It is an idiopathic renal and lung disease characterized by ANTI GBM antibody.

IgG antibodies develop against the GBM (alpha-3 chain to type IV collagen ) , deposited in a linear patter.

Classic case:

Young adult, Male present with Hemoptysis & Hematuria , when lung involvement more than 65% pt may present with hemoptysis , cough and SOB.

Treatment usually is Plasmapheresis using albumin replacement for 1-2 weeks ,followed by corticosteroids and cyclophosphamide for 3-6 months , Maintenance with azathioprine for 1-2 years

Post-infectious GN GN secondary to bacterial infection most commonly the nephritogenic strains of streptococcus (group A beta hemolytic streptococci). causing a type III hypersensitivity reaction

Immune complexes deposit in subendothelial space.

Common in children (can also occur in adults)

Classic case:

Child presented 2-3 weeks following strep throat infection or 6 weeks post impetigo with Nephritic syndrome findings

Clinical manifestations

Post-infectious GN Good prognosis in children (95% recover completely)

Adults have worse prognosis (About 60% recover)

No specific therapy (supportive with management of high blood pressure and fluid overload , spontaneous resolution is expected )

IgA Nephropathy Berger’s Disease

Most common form glomerulonephritis in adults worldwide.

Most common cause of repeated episodes of hematuria (nephritic).

Typically cause hematuria 2 days post URTI or Diarrheal illness.

Could primarily affect the kidney or could be a part of a wider spectrum of diseases including HIV , celiac disease , alcoholic liver disease and IBD .

It is the renal manifestation of Henoch-Schonlein purpura .

Over time leads to ESRD and HD (50% patients)

Affect mainly Males ,especially Asian or white population.

IgA Nephropathy Berger’s Disease

IgA Immune complexes deposit in mesangium.

Bx. under immunofluorescence:

Granular apperance (IgA)

Classic case:

Recurrent episodes hematuria since childhood, follow URI or diarrheal illness, Slowly worsening renal function (BUN/Cr) over time, Possible progression to ESRD and HD (20yrs+)

Don’t confuse with other glomerular disorders

1) Post-strep GN: weeks after infection

2) IgA GN: days after infection

3) Minimal change: nephrotic syndrome after URI

IgA Nephropathy Berger’s Disease

Patients who have IgA nephropathy with a low risk of progressive disease should be treated with ACE-I to maintain a goal 24 hour urine protein excretion of less than 1 g /24 hours , and a blood pressure of less than 130 / 80 .

Immunosuppressive therapy must be considered for:

1- patients with persistent proteinuria ( more than 1g/24 h) ,

2-progressive kidney dysfunction,

3-or histological findings indicative of RPGN ( like crescents )

This includes pulse corticosteroids and cyclophosphamide followed by azathioprine with ACE-I .

Few studies shows that Fish Oil have role in delay some of the late complications of IgA nephropathy

Henoch-Schonlein Purpura IgA nephropathy + extra-renal involvement

Skin: palpable purpura on buttocks/legs

GI: abdominal pain, melena

Joint pains

Most common childhood systemic vasculitis

Diffuse IgA deposition

Tissue biopsy: demonstrates IgA

Lupus Nephritis They are subdivided into 6 types, here in nephrtic syndrome we are concern with

type lll (Focal Proliferative lupus nephritis) & type IV (Diffuse Proliferative lupus nephritis).

Focal: less than 50% glomeruli affected

Diffuse: More than 50% glomeruli affected

Anti-dsDNA Subendothelial deposits

Lupus Nephritis If we take a Bx. we will see

Under light microscope: capillary loops thickened

“Wire looping”

Under immunofluorescence: Granular apperance

“Full house” immunofluorescence (IgG, IgA, IgM, C3, C1q)

Lupus Nephritis Usually we take Bx. To know the severity to decide the prepare treatment.

Treatment is Glucocorticoids with mycophenolate for sever proliferative disease

** mycophenolate is superior to cyclophosphamide and has fewer side effects

Membranoproliferative glomerulonephritis

Also called mesangiocapillary GN.

Immune complex formation secondary to chronic antigen stimulation.

Common causes are :

1. Chronic indolent infections including hepatitis C, syphilis , mastoiditis …etc. .

2. Autoimmune such as Sjogren , lupus …etc.

3. Essential cryoglobulinemia ( types I and II )

4. Malignancies such as carcinomas , sarcomas , lymphomas and leukemias .

immune-complex and/or complement protein deposition in the mesangium and sub endothelium of the capillaries this results in proliferation of the mesangial and remodeling of the capillary wall

We usually treat them with:

1. Corticosteroids

2. Immunosuppressive agents

3. Antiplatelets

More than 50 % progress to advanced CKD .

Vasculities syndrome Most patients ANCA positive (c-ANCA or p-ANCA)

All vasculities are associated with Fever + weight loss.

Churg-Strauss syndrome (p-ANCA): they present with Eosinophilia, history of resistant asthma.

Wegener's Granulomatosis (c-ANCA): they present with upper respiratory findings (sinusitis/otitis)

All can lead to pauci-immune nephritis

Alport Syndrome Hereditary Nephritis

Genetic Mutations in alpha-3, alpha-4, or alpha-5 chains of type IV collagen.

Chains found in basement membranes kidney, eye, ear

Inherited: X-linked

Classic triad:

Hematuria, Hearing loss, eye abnormalities

Look for child with triad and family history

Thank you !