Nephrotic syndrome

Isra’a zboon

Huda Etoom

• 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 <3 g / dl

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

Symptoms • 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.

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

• Some patients may notice frothiness of their urine.

• Hypercoagulability may manifest as venous or arterial thrombosis - eg, deep vein thrombosis, myocardial infarction.

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

Clinical signs of nephrotic syndrome include:

• Oedema (oedema of dependent parts or generalised oedema are the main clinical findings): periorbital oedema (facial oedema may be found in children), lower limb oedema, oedema of the genitals, ascites.

• Tiredness.

• Leukonychia.

• Breathlessness: pleural effusion (occasionally, severely hypoalbuminaemic cases may have pleural effusions or ascites), acute kidney injury.

• Breathlessness with chest pain: pulmonary embolism, myocardial infarction.

• Dyslipidaemia: eruptive xanthomata, xanthelasmata.

Investigations • Urine dipstick analysis: proteinuria and check for microscopic haematuria.

• Midstream urine for microscopy, culture and sensitivities to exclude urinary tract infection.

• Quantify proteinuria using an early morning urinary protein:creatinine ratio or albumin:creatinine ratio.

• Maltese cross in urin sediment

• coagulation screen.

• Renal function tests.

• 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.

………….Continuation

• CXR and abdominal or renal ultrasound scan (especially if renal function is abnormal): 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:

- Uncontrolled hypertension (>160/95)

- Uncooperative patient

- Patient unable to consent

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

- Obstructed kidneys

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

- Anatomical abnormalities (eg vascular lesion)

- Renal neoplasm, multiple cysts, abscess or pyelonephritis

Management principles • 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).

• Hyperlipidaemia - does not initially require therapy but may do so if prolonged.

• Oedema: • Oedema 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.

• Other forms of nephrotic syndrome are less treatment-responsive; angiotensin-converting enzyme (ACE) inhibitors are frequently used in adults to some effect

Complications • Complications of nephrotic syndrome include:

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

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

• 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.

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

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

• 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 .

• This accounts for 25% of cases of nephrotic syndrome in adults and is.

•

• Presentation :

Primary form present with nephrotic syndrome

Decrease in GFR .

Secondary form have typically asymptomatic subnephrotic proteinuria

• Hematuria and HTN are often present.

• More common in blacks and Hispanics

• Causes of FSGS :

• Primary ,

• Familial ,

• hyperfiltration

• Secondary to HIV ,

• Sickle cell disease ,

• Morbid obesity ,

• Reflux nephropathy,

• drugs.

• Immune :

Considered main pathogenic factor , where leukocyte produce soluble circulating factor directly target the podocyte .

Not yet identfied , but it supported by cases of FSGS occur immediately after transplant and respond to plasmapheresis

• Genetic : ( children and adult )

PT Mutation in podocyts specific proteins for example ( nephrin ,podocin ,formin )

These mutation mostly occur with infant , adult not responding to steroids therapy and in family history of ESKD African carry 5 times more risk for FSGS than european ,

• Hyperfiltration :

Seen classically in obese pt , premature birth , single kidney

• Drugs :

Lithium , interferon , heroin , pamidronate

• Kidney Bx :

Focal Sclerosis (of glomeruli )< 50 % and

segmental sclerosis ( not entire glomeruli )

Deposition of fat droplets

• EM :

Loss of podocyte

Management

• ACE-I or ARBS to target a BP of less than 130/80 and control proteinuria ( to forstall progression of disease )

• immunosuppressive medications must be used

• corticosteroids ,

• If not responding use immunosuppresive drugs

• calcineurin inhibitors , cyclophosphamide ,Alkylating agent, mycophenolate mofitile , and Rituximab(second line)

• It has a fair to poor prognosis. It is generally resistant to steroid therapy—

• Patients develop renal insufficiency within 5 to 10 years of diagnosis.

• The course is progressive to ESRD.

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 .

• Pathophysiology Is not well clear

• Disorder in T or B CELLS , produce a factor affect podocyte , resulting in massive proteinuria

• Sudden onset nephrotic syndrome

• Acute kidney injury in 25 % of cases

• 20 % of adult pt have microscopic hematuria

• Causes :

Idiopathic ,mostly

Associated with atopic diseases , like ?

Lymphomas ,

Thymoma ,

Infectious mononeucleosis

atopy

Drugs like :Gold , penicillamine , rifampicine

………….etc .

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

Membranous glomerulopathy

• Leading cause of nephrotic in white adults .

• Peak incidence between 30 - 50 of age

• Adult pts

• 75 % primary (eg, antibodies to phospholipase A2 receptor)PLA2 receptor AB

75 % of pt with primary have detectable AB .

• 25 % secondary (Solid tumor, SLE, HEP B, Drugs such as penicillamine , NSAIDs , Gold)

• Slowly progressive edemaProteinuria

KFT :mostly preserved

• 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

• MNG:

• Observed for 6 - 12 months on conservative therapy

• before initiating a course of immunosuppresive therapy

• This allows for spontaneous remission to occur 30 % in 1 year

• With persistent proteinuria :

Steroids

Alkylatinbg agent

Calcineurin inhibitor (cyclosporin or tacrolimus

Secondary nephrotic syndrome

• Secondary to systemic diseases , most commonly diabetes ( diabetic nephropathy ) , amyloidosis , SLE , HIVAN, Hepatitis B , and multiple myeloma .

DIABITIC NEPHROPATHY • Has incidence of:

10 % over 25 years among pt with type 1 DM

12% over 25 years among pt with type 2 .

Most common and important cause of ESRD.

DM nephropathy often preceded by retinopathy , neuropathy , macrovascular complications

Pathologic types

• Nodular glomerular sclerosis (Kimmelstiel–Wilson syndrome)—hyaline

deposition in one area of glomerulus—pathognomonic for DM

• Diffuse glomerular sclerosis—hyaline deposition is global. This also occurs in

HTN.

• Isolated glomerular basement membrane thickening.

• If diagnosis is uncertain , kidney Bx is required

• The classic finding in Bx :

• Nodular mesangial sclerosis with glomerular and tubular

basement thickening

• Absence of immune deposits

Microalbuminuria …….macroalbuminuria……….nephrotic range ….progressive decline in GFR and CKD ESKD .

• Microalbuminuria/proteinuria

• If microalbuminuria is present, strict glycemic control is critical. Tight blood glucose has been shown to limit progression from microalbuminuria to clinical proteinuria.

• *Without effective treatment, the albuminuria gradually worsens—HTN usually develops during the transition between microalbuminuria and progressive proteinuria. Persistent HTN and proteinuria cause a decrease in glomerular filtration rate (GFR), leading to renal insufficiency and eventually ESRD.

• HTN increases the risk of progression of diabetic nephropathy to ESRD. Control BP aggressively.

• Initiate ACE inhibitors or ARB immediately. These agents are proven to decrease the rate of progression of nephropathy.

Screening :

Yearly in type 2 dm ,5 years from onset of type 1

Microalbuminuria is the screening test!

microalbuminuria means levels of albumin are between 30 and 300 mg per 24 hours. But the dipstick for urine becomes trace positive at 300 mg of protein per 24 hours.

It usually takes 1 to 5 years for microalbuminuria to advance to full-blown proteinuria. However,

with proper treatment (i.e., using ACE inhibitors to BP) this can be prolong

Approach:

• Glycemic control(Once diabetic nephropathy has progressed to the stage of proteinuria or early renal failure, glycemic control does not significantly influence its course)

• BP control(Target BP in PT with DM and HTN and or CKD < 130 / 80)

• ACE or ARBS and dietary restriction of protein are recommended.

• Adding K sparing diuretic in small studies to be safe and effective to reduce proteinuria , but with risk of hyperkalemia .

Thank you