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Pediatric Proteinuria: Evaluation & Management

This article by Prof. Abdullah Al Salloum discusses the evaluation and management of proteinuria and nephrotic syndrome in children, including clinical testing, protein handling by the kidneys, types of proteinuria, and the association between proteinuria and renal damage and cardiovascular disease.

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Pediatric Proteinuria: Evaluation & Management

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

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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 • < 0.2 mg protein/mg creatinine in children > 2 years • < 0.5 mg protein/1 mg creatinine in children 6-24 months old

  7. Protein Handling by the Kidneys in Normal Children • Normal rate of protein excretion • < 4mg/m2/hr • < 100mg/m2/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)

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

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

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

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

  17. Nonspecific Treatment Options for Persistent Proteinuria • 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

  18. 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

  19. 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 • 20-200 microgram/min/1.73m2 • 30-300 mg albumin/g creatinine • Overt proteinuria • Albuminuria >200 microgram/minute/1.73m2

  20. 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.

  21. 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

  22. Clinical Problems Associated with Children NS [A] Edema • Gravity dependent • Periorbital in the early morning hours 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.

  23. [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

  24. 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.

  25. [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

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

  27. 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)

  28. [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

  29. Approaches to treatment of NS [A] Prednisone/prednisolone Mainstay of treatment of NS Typical protocol: • 2 mg/kg/day (60mg/m2/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

  30. 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.

  31. 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

  32. [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

  33. [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

  34. [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

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

  36. 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

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