EVALUATION & MANAGEMENT OF PROTEINURIA AND NEPHROTIC SYNDROME IN CHILDREN BY: PROF. ABDULLAH AL SALLOUM Consultant Paediatric Nephrologist Paediatric Department

Proteinuria Associated with progressive renal disease. Don’t delay and immediately investigate. – He may come to the emergency with need for dialysis. – The protein is toxic to the kidney. Involved in the mechanism of renal injury

Clinical Testing for Proteinuria Urinary dipstick first test to be done Screening test Color reaction between urinary albumin and tetrabromphenol blue Trace  15 mg/dl – Most of us have trace protein especially if standing (orthostatic proteinuria which is common in athletes and the young). 1 +  30 mg/dl borderline 2 +  100 mg/dl must know the cause. 3 +  300 mg/dl 4 +  2000 mg/dl

Urinary dipstick False-negative – Diluted urine False-positive – Alkaline urine (pH >8.0) – Concentrated urine (specific gravity >1:025) – Antiseptic contamination (Chlorhexidine, benzalkonium chloride) – After intravenouse radiograph contrast

Alternative Office Method Sulfosalicylic acid lead to precipitation of proteins including LMW proteins. If dipstick is positive we confirm by the first morning sample protein creatinine ratio, if we needed further confirmation (rarely needed and done) we do the 24 urine collection.

Quantitative estimate of proteinuria 24-hour urine collections Urinary protein/creatinine (pr/cr) ratio – Spot urine specimen – First morning specimen to avoid orthostatic proteinuria. – Normal values 2 years < 0.5 mg protein/1 mg creatinine in children 6-24 months old

Protein Handling by the Kidneys in Normal Children Normal rate of protein excretion – < 4mg/m 2 /hr – < 100mg/m 2 /day 50% Tamm-Horsfall protein 30% Albumin 20% other protein Restricted filtration of large proteins (albumin & Immunoglubulin) Proximal tabules reabsorb most of LMW protein (insulin, B2 microglobulin)

Protein Handling in Renal Disorders Excess urinary protein losses 1.Increase permeability of the glomeruli (glomerular). 2.Decrease reabsorption of LMW proteins by the renal tubules (tubular)

When suspecting proteinuria 1 st, dipstic. 2 nd, protein:creatinine ratio. 3 rd, 24 hour urine monitoring.

Types of proteinuria Transient – Fever – Stress – Dehydration – Exercise Orthostatic proteinuria – Excess urine protein in upright position but normal during recumbency – School age – < 1gm/m2/day – To rule out, take sample at night before sleep (positive for protein), and a sample at morning before eating (should be nill). Persistent proteinuria: – Proteinuria of ≥1 + (doctor said +2) by dipstick on multiple occasions.

Association Between Proteinuria and Progressive Renal Damage Persistent proteinuria should be viewed as a marker of renal disease and also as a cause of progressive renal injury.

Association Between Proteinuria and Cardiovascular Disease Severe persistent proteinuria is a long-term risk factor for atherosclerosis in children 1. Metabolic disturbances associated with proteinuria (hypercholeseterolemia, hypertriglyceridemia and hypercougalability 2.Hypertension 3.Renal insufficiency 4.Steroid therapy

After all investigations: – Proteinuria, edema (because of hypoalbuminemia not fluid retention), and hypoalbuminemia is consistent with nephrosis most commonly nephrotic syndrome seen in minimal change (increase in cholesterol as compensation from the liver when there is loss of protein). – Proteinuria, edema, hypertension, and hematouria is consistent with nephritic syndrome and most common example is APIGN.

In minimal change there is no changes in renal biopsy other than fusion of the podocytes. 80% will respond to steroid, 20% that will not respond will be either focal segmental or membrano-proliferative.

Evaluating Children with Proteinuria [A] First stage Complete history and physical examination (BP) Complete urinanalysis Urine dipstick before going to bed and after arise Blood level of Albumin, creatinine, cholesterol, electrolyte [B] Second stage Renal ultrasonography Measurement of serum C3, C4, complement Antinuclear antibody Serology for hepatitis B, C, ± HIV. Check for hepatitis C in membrane proliferative.

Renal biopsy is not routinely done unless in the following cases: 1.Infantile hematuria because immunosuppressant wont work.( any disease not responding to steroids) 2.Adolescents because its unlikely to be minimal change.(if minimal change is suspected its not done). 3.Persistant hematuria of unknown cause. 4.Deteriorating renal functions. 5.Proteinuria and persistent hypertension. 6.Low complement levels.

Nonspecific Treatment Options for Persistent Proteinuria 1.Dietary recommendations  Chronic renal insufficiency  Dietary protein restriction  Nephrotic syndrome: avoid an excess of dietary protein because it may: a. Worsen proteinuria b. Will not result in a higher serum albumin c. Recommendation: give recommended daily allowance of protein for age

2. Blood pressure control/inhibition of angiotensin effects ACE: and angiotensin II receptors blockers Reduce BP Reduce urinary protein excretion Decrease the risk of renal fibrosis ACE: are contraindicated during pregnancy

Approach to Proteinuria in Adolescents with insulin-dependent DM Good glycemic control is the first goal in preventing renal injury The first sign of renal injury in IDDM is microalbuminuria Microalbuminuria microgram/min/1.73m mg albumin/g creatinine Overt proteinuria Albuminuria >200 microgram/minute/1.73m2

Evaluation and Treatment of Patients with NS Definition – Heavy proteinuria, hypoalbuminemia, hypercholestremia and edema Prevalence 2-3 cases per 100,000 children The majority (80%) will have steroid responsive MCNS (no abnormal biopsy except fusion of podocytes. 20% are atypical who are steroid-resistant such as focal change and membrane proliferative.

Pretreatment Renal Biopsy in NS Infantile NS – Develops NS within the first year of life. – Biopsy to see the change and give immunosuppression. – 30% will respond well to steroid while others will respond poorly with increased risk of malignancy due to immunosuppression. Adolescence Persistent hematuria Hypertension Depressed serum complement Reduced renal function

Clinical Problems Associated with Children NS [A] Edema  Gravity dependent  Periorbital in the early morninghours then generalized or in the lower limbs while standing.  In lying down (abdomen, sacrum, peri-orbital)  Severe edema present as ascites, pleural effusions, scrotal or vulvar edema that may ruputre, skin breakdown.  Nephrotic and nephritic syndrome has the same picture, we do urine dipstick and measure the BP to differentiate.

[B] Electrolyte disturbances in NS 1.Hyponatremia ↑ antidiuretic hormone H2O→ > Na retention Total body Na > normal 2. Pseudohyponatremia Result from high lipid level Dependent on lab methodology 3. Pseudohypocalcemia Normal level of free ionized ca Low level of protein-bound ca

Patients with proteinuria are immunocompromised and are prone to infections most commonly varicella and most serious complication is encephalitis. Therefore you stop the steroid and start acyclovir.

[C]Infections 1.Varicella Varicella antibody should be obtained Varicella – zoster immunoglobulin within 72 hours of exposure Steroid should be tapered to 1 mg/kg/day Acyclorir or valacylovir if varicella does develop

2.Other infection Cellulitis 1  peritonitis The organisms usually Pneumococcus E-coli

Immunization in N.S. Live viral vaccines should not be given if patient on high dose of steroids Pneumococcal vaccine is recommended to all NS (off steroids) Varicella vaccine (varivax) in 2 doses regimen is safe and efficacious Antibodies to vaccines may fall during relapses (still contravesial)

[D] Hyperlipidemia Transient and severe hypercholesterolemia during relapses Persist in treatment-resistent NS Atherosclerosis in young NS Dietary modification : limited benefit Cholestyramine is approved in NS

Approaches to treatment of NS [A] Prednisone/prednisolone Mainstay of treatment of NS Typical protocol: 2 mg/kg/day (60mg/m 2 /day) (4+4 wks treatment) 4 wks daily steroid 4 wks every other day because with time steroid suppresses growth hormone. Recently: 6+6 weeks induce a higher rate of long remissions than the standard (4+4). 30mg/kg/day can be given in steroid resistant patients

Treatment of Relapses of NS 60-80% of patients will relapse Prednisolone 2mg/kg/day until the patient is free of proteinuria for 3 days then 4-6 wks of every other day treatment.

Side effects of Glucocorticoids (Must be discussed with the family) Cushingoid habitus Ravenous appetite Behavioral and psychological changes (mood liability) Gastric irritation (including ulcer) Fluid retention Hypertension Steroid-induced bone disease (avascular necrosis, bone demineralization) Decreased immune function Growth retardation Nigh sweats Cataracts Pseudotumor cerebri Steroid-related diabetes

[B] IV Pulse Steroids May give success in steroid-resistant NS High dose IV methylprednisolone 30 mg/kg (max 1 g) To be given every other day for 6 doses To continue in tapering regimen for period up to 18 months. Side Effects Hypertension Arrhythmias

[C] Cytotoxix Drugs 1. Cyclophosphamide Over 12 weeks Total cumulative dose 170 mg/kg Side Effects Bone marrow suppressions Oligospermia, azoospermia and ovarium fibrosis (If given close to puberty) Hemorrhagic cystitis Risk of malignancy 2. Chlorambucil May cause seizure

[D] Cyclosporin A Steroid dependent or resistant NS To be given after renal biopsy Relapses high after withdrawal Side Effects Hypertension Nephrotoxicity Hyperkalemia Hypomagnesemia Hypertrichosis Gingival hyperplasia

[E] Levamisole Weak steroid sparing drug Long term use Side Effects Neutropenia Rash Gastrointestinal disturbances Seizures

Other Practical Aspects of the Management of NS Fluid intake should be limited to double of insensible water loss in severely edematous NS Combined diuretics and IV albumin can be given in severe edema Diuretics should not be given in mild edema ACE: should not be given in the initial course of prednisolone because of the risk of hypotension and thrombosis in the diuretic phase ACE: can be given to steroid-resistant NS Schooling, activities, diet should be individualized