This lecture was conducted during the Nephrology Unit Grand Ground by Medical Student rotated under Nephrology Division under the supervision and administration of Prof. Jamal Al Wakeel, Head of Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al Suwaida. Nephrology Division is not responsible for the content of the presentation for it is intended for learning and /or education purpose only.

Definition of Nephrotic syndrome Pathogenesis Etiology Clinical picture Diagnostic workup Pathological picture Complication Managements

Proteinurea ≥3.5 g/day (protein: creatinine ratio >3-3.5) Generalized Oedema Hypoalbuminaeia <3g/L

DAMAGED Proteinuria

Primary (idiopathic): Minimal change disease Most common cause in children Membranous Nephropathy Most common cause in Adults Focal Segmental Glomerulosclerosis MembranoProliferative Glomerulonephritis

Secondary to: DM (the leading cause of secondary nephrotic syndrome) SLE Amyloidosis Infections: Hepatitis B and C, HIV,syphilis, post-streptococcal Malignancy: multiple myloma, Hodgkin lymphoma, solid tumor Drugs (NSAIDs, gold, penicillamine,heavy metals etc).

Generalized Odema -The predominant feature -The face, particularly the periorbital area, is swollen in the morning& lower extremities and genital area later in the day -In advanced disease: the whole body (anasarca)  shortness of breath Frothy urine and urine dipstick proteinuria value of 3+ Symptoms & signs for secondary cause if present

24-hour urine collection  >3,5 g/day (nephrotic-range proteinuria) Alternative : calculating the total protein-to-creatinine ratio (mg/mg) on a random urine specimen. The history and physical examination  Systemic disease Serologic studies  (ANA), complement, hepatitis B and hepatitis C serologies and the measurement of cryoglobulins,serum or urine protein electrophoresis. Renal biopsy  required to establish the diagnosis in most of times.

BUN, creatinine, creatinin clearnce.Na, K,bicarbonates,chloride CBC, serum albumin, serum proteins, calcium, Lipid profile, Coagulation tests

Adults  Renal biopsy is mandatory for every nephrotic patient except the diabetic patient. In one study of adults with nephrotic range proteinuria, knowledge of the histology altered management >40%! Children  glucocorticoid therapy is usually begun empirically and a renal biopsy is performed only for glucocorticoid-resistant disease. -Management of patients with nephrotic syndrome. Swissmedwkly 2009 ;139(29-30): Knowledge of renal histology alters patient management in over 40 percent of patients. Nephrol Dial Transplant 1994; 9:1255.

10% of nephrotic syndrome cases in diabetes are due to other renal diseases *Presence atypical features such as 1-A rapidly progressive nephrotic syndrome 2-Acute renal failure 3-Presence of glomerular haematuria and/or absence of associated microvascular lesions (retinopathy, neuropathy ) Management of patients with nephrotic syndrome. Swissmedwkly 2009 ;139(29-30):

19 Histologic Pattern Key Pathologic Features MCD LM  Normal EM  Foot process fusion MN LM  Thickening of the GBM ‌ EM  Subepithelial deposits of IgG FSGS LM  Focal and segmental sclerosis of glomeruli EM  Focal or diffuse foot process effacement. MPGN LM  thickening of all capillary walls +cellular proliferation EM  The double-contour or tram-track appearance represents interposition of mesangial cell with the GBM -subendothelial (type I) or intramembranous (type II)

Due to loss of proteins in the urine Due to ↓ oncotic pressure Immunoglobulin  ↑susceptibility to infection antithrombin III and proteins C and S  Thromboembolism vit D–binding protein  vit D deficiency Transferrin  Iron deficiency anemia Hyperlipidaemia Hypovolemia  Acute renal failure Anasarca  risk of cellulitis, bacterial peritonitis with ascites,large pleural effusions or pulmonary edema

21 Disease- spsific Compli cation symptoms

Oedema Low salt diet Diuretics serial measurement of body weight Proteinuria ACE inhibitors or ARBs Hypoalbuminaemia High protein diet not indicated 0.8–1 g/kg/day Ref: Up to date online 17.3.

Hyperlipidaemia Regular Lipid profile Statin if severe long lasting nephrotic syndrome Control other CVD risk factors…target blood pressure 125/75 Thromboembolic risk Routin Prophylactic anticoagulation  not recommend High index of suspicion for thromboemboli Infections High index of suspicion Antipneumococcal and influenza vaccinations Ref: Up to date online 17.3.

24 Minimal change disease -Approximately 80% of adults with MCD respond to prednisone -Failure to respond may reflect an error in diagnosis; MCD is most commonly confused with early FSGS -Treatment with cytotoxic agents may be indicated in patients who are considered: A- steroid dependent  relapse while on corticosteroid therapy or requirement for continuation of steroids to maintain remission B-steroid resistant  No remission with using of steroid C-frequent relapsers  ≥ 3 relapses/Y

25 Membranous Nephropathy Because of the generally good outcome, treatment usually is reserved for patients with poor prognostic factors : (age >50, male gender, hypertension, reduced GFR, proteinuria >10 g/d, or marked interstitial fibrosis on renal biopsy) or severe symptomatic nephrotic syndrome Treatment options include high-dose alternate-day glucocorticoids in conjunction with a cytotoxic agent (e.g., chlorambucil or cyclophosphamide for 6-12 months and in nonresponders, cyclosporine for 12 months

26 Focal Segmental Glomerulosclerosis PrednisoneIt : not proven to be effective May reduce proteinuria and slow progression to ESRD. Resistant cases may respond to a combination of glucocorticoids and cytotoxic agents.

27 Membranoproliferative Glomerulonephropathy treatment has not been shown to improve disease-free survival the use of corticosteroids in children likely stabilizes disease. HCV-associated MPGN may improve with successful antiviral therapy

1-Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev Interventions for minimal change disease in adults with nephrotic syndrom e. Cochrane Database of Systematic Reviews 2008 Remains controversial with no proven benefit Cochrane reviews on the treatment of nephrotic syndrome in adults found: -weak benefit for disease remission and proteinuria in persons with membranous nephropathy -no benefit for mortality or need for dialysis with corticosteroid therapy for membranous nephropathy or minimal change disease

29 It is more clearly established that children respond well to corticosteroid treatment. Classically, minimal change disease responds better to corticosteroids than FSGS. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2009

30 Diabetic Nephropathy Treatment involves aggressive glucose control and aggressive BP control with ACE inhibitors or ARBs or both

Up to date Washington manual Nephrotic Syndrome in Adults: Diagnosis and Management. Am Fam Physician. 2009;80(10): Management of patients with nephrotic syndrome. Swissmedwkly 2009 ;139(29-30): Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev Interventions for minimal change disease in adults with nephrotic syndrom e. Cochrane Database of Systematic Reviews 2008 Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev Knowledge of renal histology alters patient management in over 40 percent of patients. Nephrol Dial Transplant 1994; 9:1255.