Introduction
Background
Diagnosis
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Heavy proteinuria: ≥50 mg/kg/day (or ≥40 mg/m2/h), or a proteinuria/creatininuria ratio >2 (mg/mg)
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Serum albumin < 25 g/L
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Edema
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Start adequate therapy as early as possible.
Primary Nephrotic Syndrome (95% in children 0–12 years) | |
Idiopathic nephrotic syndrome (80-90% in children 2–8 years) | |
Steroid-sensitive nephrotic syndrome | |
Steroid-resistant nephrotic syndrome | |
Genetic nephrotic syndrome (isolated or syndromic) | |
(95 -100% in children <3 months | |
50 - 60% in children 4–12 months) | |
Secondary Nephrotic Syndrome (5% in children 0–12 years) | |
- Vasculitides/autoimmune diseases (SLE, Microscopic polyangiitis, Goodpasture, IgA vasculitis) | |
- Infections (HBV, HCV, HIV, EBV, Mycoplasma, CMV, PVB19, Treponema, Toxoplasma, malaria, parasites) | |
- Drugs (Tiopronin, Penicillamine, Gold Salts, Pamidronate, Interferon, Everolimus, antiretroviral and chemotherapy drugs) | |
- Diabetes | |
- Cancer (Lymphoma, Leukemia) |
Investigations at initial presentation
History | Family | General | Past | Current |
---|---|---|---|---|
Questions | NS in the family | Pre/peri-natal history | Systemic diseases (autoimmune, neurological, metabolic, congenital, cancer) | Timing and characteristics of edema |
Other kidney diseases in the family | Growth | Past infections | Associated signs/symptoms (macro/microscopic hematuria, fever, oliguria, vomiting, abdominal pain, hypertension, skin rash, arthralgia…), | |
Other diseases in the family | Age at onset of symptoms | Travel/infections | ||
Drugs/poisons |
Clinical parameters | Edema | Signs/symptoms of hypovolemia | Signs/symptoms of infectious/systemic disease |
---|---|---|---|
▪ Heart rate ▪ Respiratory rate ▪ Blood pressure ▪ O2 saturation ▪ Body weight | ▪ Periorbital ▪ Pretibial ▪ Genital ▪ Ascites ▪ Bowel wall edema ▪ Pleural effusion ▪ Pulmonary edema ▪ Anasarca | ▪ Abdominal pain ▪ Tachycardia ▪ Cold hands/feet ▪ Oliguria ▪ Capillary refill >2 s | ▪ Fever ▪ Skin rash ▪ Purpura ▪ Arthritis |
Tests | Blood | Urine |
---|---|---|
Mandatory | ▪ Complete Blood Count (CBC) ▪ BUN, creatinine ▪ Electrolytes (including ionized calcium) ▪ Serum total protein, albumin ▪ Cholesterol, triglycerides ▪ CRP ▪ Coagulation (including ATIII) ▪ Immunoglobulins ▪ Complement (C3, C4) | ▪ Urinalysis (early morning sample) ▪ 24-h proteinuria or Proteinuria/creatininuria (uP/uCr) |
Additional | ▪ Auto-immune markers (ANA, DS-DNA, ENA, ANCA) ▪ Thyroid function ▪ Infections (HBV, HCV, HIV, ParvoB19, CMV, EBV, pneumococcus, salmonella, treponema, mycoplasma…) | ▪ Urine sodium |
Discharge and follow up
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We suggest that, once discharged, patients should perform urine dipstick tests:
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every other day during steroid tapering and during the first month after steroid withdrawal, then two/three times weekly.
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daily, in the case of infection or positive stick.
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immediately, in the case of edema
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Corticosteroid use for the first episode of INS
Medication
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PDN or prednisolone can be used indifferently for the treatment of a first episode of NS
Dosing of prednisone
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We suggest that PDN be given at 60 mg/m2/day, with a maximum dose of 60 mg/day.
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We suggest that PDN can either be given in a single daily dose in the morning or in two divided doses (08.00 and 20.00).
Treatment protocol
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We suggest that PDN (60 mg/m2, maximum 60 mg) be given daily in a single dose or divided into 2 doses for 6 weeks, followed by a single dose of 40 mg/m2, maximum 40 mg PDN on alternate days for another 6 weeks, without any tapering of the dose.
Prednisone (PDN) | Dosage | Duration |
---|---|---|
Treatment of the first episode | ||
60 mg/m2 (maximum 60 mg) | in single or 2 divided doses | 6 weeks |
40 mg/m2 (maximum 40 mg) | on alternate days | 6 weeks |
Treatment of the first relapse | ||
60 mg/m2 (maximum 60 mg) | in a single or 2 divided doses | Until urine protein is negative for 5 days |
40 mg/m2 (maximum 40 mg) | on alternate days | 4 weeks |
First relapse
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In the case of a first relapse, PDN should be given daily at a dose of 60 mg/m2/day (maximum 60 mg/day) in a single dose or divided into 2 doses, until urine protein has been negative 5 days. Thereafter, a single alternate-day dose of 40 mg/m2 (maximum 40 mg) should be continued for 4 weeks and then stopped.
Diagnosis and treatment of edema in nephrotic syndrome
Pathophysiology of edema in nephrotic syndrome
Treatment of edema in nephrotic syndrome
Management of edema in nephrotic syndrome | |
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Mild edema | ▪ sodium restriction ▪ fluid restriction |
Moderate edema | ▪ sodium restriction ▪ fluid restriction ▪ loop diuretic ▪ potassium sparing diuretic for prolonged therapy |
Severe/refractory edema | ▪ sodium restriction ▪ fluid restriction ▪ loop diuretic +/− potassium sparing diuretic ▪ thyazide diuretic ▪ albumin, followed by a bolus of furosemide |
Mild edema
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We suggest that mild edema be managed with salt and fluid restriction only
Moderate edema
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We suggest that moderate edema be treated with a loop diuretic, with the addition of a potassium-sparing diuretic in the case of prolonged therapy
Severe/refractory edema
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We suggest the co-administration of a thiazide diuretic in cases of severe edema unresponsive to oral or i.v. loop diuretics.
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We suggest albumin infusions in patients with severe edema unresponsive to oral or i.v. loop diuretics
Hypovolemia
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We suggest interrupting diuretic therapy immediately in case of hypovolemia and its prompt intravenous correction if clinical signs are present.
Infections and immunization in children with INS
Infections
Prophylactic interventions
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We do not recommend administering either i.v. immunoglobulin or prophylactic antibiotics to children.
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We suggest that rapid diagnosis and antibiotic treatment of infections are the most effective interventions.
Varicella-zoster virus infections
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We suggest the use of oral acyclovir following exposure to chickenpox in non-immune patients.
Vaccines
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We suggest that patients on high-dose steroids should not be given live attenuated vaccines.
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Once first episode treatment has been completed, the varicella vaccine is recommended three months after corticosteroid discontinuation.
Vaccine | Inactivated/Live, Attenuated | High dose steroids | Low dose steroids |
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Hepatitis B | I | YES | YES |
Pertussis | I | YES | YES |
Diphtheria | I | YES | YES |
Tetanus | I | YES | YES |
Polio (Salk) | I | YES | YES |
H. Influenzae type B | I | YES | YES |
Pneumococcal | I | YES | YES |
Meningococcal | I | YES | YES |
Flu | I | YES | YES |
Human Papillomavirus | I | YES | YES |
Varicella | LA | NOa,b
| NOc
|
Measles | LA | NOa,b
| NOc
|
Mumps | LA | NOa,b
| NOc
|
Rubella | LA | NOa,b
| NOc
|
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We suggest that all unimmunized children with NS should receive the pneumococcal vaccine.
Thromboembolism in INS
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We do not suggest thrombophilia screening in children with INS at presentation unless there is a family history of thrombotic events at a young age (<50 years) or known abnormalities of pro-thrombotic coagulation factors.
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There are no indications for anticoagulant/antiplatelet prophylaxis in children with INS at presentation.
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We suggest the use of anticoagulant/antiplatelet prophylaxis in children with a concomitant cardiovascular abnormality (who would usually already be under prophylactic anticoagulant/antiplatelet treatment) or a central venous catheter (CVC) (almost impossible at the onset of illness).
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The greatest care must also be taken in patients with NS and a concomitant septic state, and/or in the presence of a CVC, for whom an antiplatelet/anticoagulant therapy should be considered.
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In cases of a persistent nephrotic condition in children with SRNS and whose edema is difficult to control, thrombophilia screening, as well as antiplatelet/anticoagulant prophylaxis may be considered.
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Secondary thrombocytosis usually does not require treatment. In the presence of active NS and a platelet count >1.000.000/mmc, we suggest aspirin prophylaxis.
Drug | Indication | Dosage | Monitoring |
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Unfractionated heparin | Begin at the time of the acute event and continue for 5–10 days. Suspend on day 6 after OAT start, if INR on target. (Grad 1C +). Minor use in the last decade. | 75 UI/kg bolus in10 min Initial maintenance dose: >1 year: 28 UI/Kg/h >1 year. 20 UI/Kg/h Then adjust to maintain aPTT between 60–85 s. | aPTT Therapeutic target: between 60–85 s. |
Low molecular weight heparin (LMWH) | More used in the last decade in the treatment of thromboembolism in children | Enoxaparin Dosage (>2 months) Therapeutic: 100 UI/kg every 12 h Prophylactic: 50 UI/ kg every 12 h If clearance <60 ml/min) dosage must be adjusted on renal function | Anti Xa: blood samples 4 h after drug administration Therapeutic target: 0.5.1 UI/mL Prophylactic target: 0.3-0.5 UI/mL |
Oral anticoagulants (warfarin) | Begin with heparin therapy until the target INR(2–3) is reached. Continue for 3 months, in absence of predisposing factors like NS. Continue for 6 months in presence of predisposing factors, like NS, or in cases of recurrent thrombosis. Vitamin K antagonists more used for older children (frequent blood check) | In pediatric patients > 10 Kg: 0.2 mk/Kg/day | INR Target: 2-3 |
Aspirin | If PLT >1.000.000 /mmc with concomitant NS | Empirical antiplatelet dosage in pediatrics: 1–5 mg/kg/day | |
Fibrinolytic agents | No data on fibrinolytic treatment of thrombotic events in pediatric patients with NS. |
Gastroprotection
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We do not recommend the routine use of prophylactic PPIs in combination with steroid therapy in NS.
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We suggest that PPIs should be used only in selected cases manifesting with gastric symptoms resistant to treatment with malgadrate or alginate, or with any other risk factor (gastroesophageal reflux, esophageal disease, concomitant need for other gastrotoxic therapies).
Supplementation with calcium and vitamin D
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We do not suggest calcium and vitamin D supplementation in children at first episode or in SSNS unless vitamin D deficiency has been predicted or demonstrated.
Treatment of hyperlipidemia
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We do not recommend the use of lipid-lowering treatments at INS onset
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We do not recommend low fat diets for children at INS onset
Steroid Resistant Nephrotic Syndrome (SRNS)
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It is reasonable to define SRNS as a lack of remission despite 4 weeks of treatment with PDN at the dose of 60 mg/m2/day, followed by 3 high-pulse doses of Methylprednisolone (500 mg/m2) and another two weeks of PDN at the dose of 60 mg/m2/day
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We suggest that kidney biopsy be performed after the first four weeks of therapy; the continuation of steroid treatment depends on the histological findings.
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We suggest that mutational analysis should be offered to patients with congenital, early onset (<12 m) NS or sporadic, familial SRNS or syndromes associated with NS
Gene | Inheritance | Characteristic signs and features |
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NPHS1 | AR | CNS/NS |
NPHS2 | AR | CNS,NS - childhood and adult onset |
CD2AP | ? | Early-onset NS |
PLCe1 | AR | Early-onset NS |
TRPC6 | AD | Adult onset NS |
PTPRO | AR | Childhood-onset NS |
WT1 | Sporadic; AD | Adult onset NS, Denys-Drash and Fraiser Syndromes |
LMX1B | AR | Nail-Patella Syndrome/NS only |
SMARCALI | AR | Schimke immuno-osseous dysplasia |
E2F3 | Chromosomal deletion | Early-onset NS and mental retardation |
NXF5 | X-linked recessive | NS with co-segregating heart block disorder |
PAX2 | AD | Adult onset NS |
ACTN4 | AD | Adult onset NS |
MYH9 | Risk allele | Adult onset NS |
INF2 | AD | Familial/sporadic NS |
SYNPO | ? | Adult onset NS |
APOLI | Complex/AR | Adult onset NS |
MYO1E | AR | Early or Adult onset NS |
ARHGAP24 | AD | Adult onset NS |
ARHGDIA | AR | CNS |
ANLN | AD | Adult onset NS |
EMP2 | AR | Childhood-onset NS |
CUBN | AR | Intermittent nephritic range proteinuria and epilepsy |
GPC5 | Risk allele | Adult onset NS |
PODXL | AD | Early or Adult onset NS |
TTC21B | AR | NS with tubulointerstitial involvement |
CLTA4 | Risk allele | Sporadic NS |
MTTL1 | ? | MELAS syndrome; NS+/− deafness and diabetes |
tRNAlle | ? | Deafness, NS, epilepsy, and dilated cardiomyopathy |
tRNAAsn | ? | Multiorgan failure and NS |
tRNATyr | ? | Mitochondrial cytopathy and NS |
COQ2 | AR | Mitochondrial disease/isolated nephropathy |
COQ6 | AR | NS with sensorineural deafness |
ZMPSTE24 | AR | Mandibulosacral dysplasia with NS |
ADCK4 | AR | NS |
CYP11B2 | Risk allele | NS, IgA nephropathy |
LAMB2 | AR | Pierson S.; CNS with ocular abnormalities; isolated early-onset NS |
ITGB4 | AR | NEP syndrome-NS, epidermolysis bullosa and pulmonary disease |
ITGA3 | AR | Epidermolysis bullosa and pyloric atresia + NS |
LMNA | AD | Famlial partial lipodystrophy + NS |
CD151 | AR | NS, pretibilial bullous skin lesions, neurosensory deafness, bilateral lacrimal duct stenosis, nail dystrophy, thalassemia minor |
Indications for kidney biopsy
Before treatment | • Onset at less than 12 months or more than 12 years of age |
• Initial macroscopic hematuria | |
• Persistent hypertension and/or microscopic hematuria and/or low plasma C3 | |
• Secondary NS (Henoch-Schoenlein purpura, systemic lupus erythematosus, etc.) | |
• NS associated with syndromes | |
• Renal failure not related to hypovolemia | |
After treatment | • Steroid Resistance |
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A renal biopsy should be recommended in patients <12 months or >12 years of age at the onset of NS or when secondary NS is suspected.