# Approach to Proteinuria in Children and Adults

## Introduction

**Proteinuria** is a hallmark of kidney disease and a critical marker for cardiovascular risk. In children, the most common cause of nephrotic-range proteinuria is **minimal change disease**, while in adults, **diabetic nephropathy** and **focal segmental glomerulosclerosis (FSGS)** predominate. The evaluation and management differ by age, with particular attention to distinguishing benign causes from progressive glomerular disease. Med-peds physicians must systematically approach proteinuria across the lifespan.

## Definitions and Quantification

### Normal Protein Excretion

Normal urine protein excretion: <150 mg/day in adults; <4 mg/m2/hour in children. **Albumin** is the predominant pathologic protein; normally <30 mg/day.

### Levels of Proteinuria

**Microalbuminuria** (moderately increased albuminuria): 30-300 mg/day; early marker of diabetic and hypertensive nephropathy. **Overt proteinuria**: >300 mg/day. **Nephrotic-range proteinuria**: >3.5 g/day in adults; >40 mg/m2/hour or urine protein-to-creatinine ratio (UPCR) >2.0 mg/mg in children.

### Methods of Measurement

**Urine dipstick**: Detects albumin; semi-quantitative; does not detect light chains or low-molecular-weight proteins. **Spot urine protein-to-creatinine ratio (UPCR)**: Correlates with 24-hour excretion; normal <0.2 mg/mg in children >2 years; <0.5 in infants. **Spot urine albumin-to-creatinine ratio (UACR)**: Preferred for diabetic nephropathy screening; normal <30 mg/g. **24-hour urine collection**: Gold standard but cumbersome; useful for quantifying total protein and specific proteins.

## Benign Causes of Proteinuria

### Transient Proteinuria

Caused by fever, exercise, dehydration, emotional stress, seizures. Resolves with elimination of the inciting factor. No further workup needed if repeat urinalysis is normal.

### Orthostatic Proteinuria

**Most common cause of persistent proteinuria in adolescents and young adults**. Proteinuria present only in the upright position; absent in first morning void. Diagnosed with **split urine collection**: first morning void (supine) vs. daytime specimen. Benign condition; does not require treatment or biopsy. Prevalence: up to 2-5% of adolescents; rare over age 30.

## Pathologic Causes of Proteinuria

| Cause | Age Group | Frequency | Steroid Response | Biopsy Needed? |
|-------|-----------|-----------|-----------------|---------------|
| Minimal change disease | Children 1-10 years | Most common (80%) | >90% responsive | Not if typical presentation |
| FSGS | Older children/adults | Common | Often resistant | Yes |
| Membranous nephropathy | Adults (White) | Most common primary NS in adults | N/A | Yes (anti-PLA2R can support) |
| Diabetic nephropathy | Adults | Most common overall cause | N/A | Not if typical diabetes + retinopathy |
| IgA nephropathy | All ages | Most common GN worldwide | N/A | Yes |
| Lupus nephritis | Young adults/adolescents | Important secondary cause | N/A | Yes (ISN/RPS classification) |

### Pediatric Causes

**Minimal change disease (MCD)**: Most common cause of nephrotic syndrome in children (80% of cases aged 1-10 years) Presents with edema, massive proteinuria, hypoalbuminemia, hyperlipidemia. **Steroid-responsive** in >90% of cases; empiric steroid trial without biopsy in typical presentations (age 1-12, no hypertension, no hematuria, normal complement, normal renal function) Frequent relapses are common; steroid-sparing agents (cyclophosphamide, calcineurin inhibitors, rituximab) for steroid-dependent disease. **FSGS**: More common in older children and adolescents; often steroid-resistant; higher risk of progression to ESRD. **Membranous nephropathy**: Rare in children; when present, consider secondary causes (lupus, hepatitis B) **IgA nephropathy**: Hematuria with variable proteinuria. **Congenital nephrotic syndrome**: Presents in the first 3 months of life; genetic causes (NPHS1, NPHS2 mutations)

### Adult Causes

**Diabetic nephropathy**: Most common cause of CKD and proteinuria in adults; microalbuminuria is the earliest marker. **FSGS**: Most common primary glomerular disease causing nephrotic syndrome in adults in the U.S.; associated with obesity, HIV, genetic variants (APOL1) **Membranous nephropathy**: Most common cause of primary nephrotic syndrome in White adults; anti-PLA2R antibodies in ~70%. **IgA nephropathy**: Most common glomerulonephritis worldwide; hematuria with proteinuria. **Lupus nephritis**: Proteinuria with active urine sediment; requires renal biopsy for classification. **Amyloidosis**: Consider in adults with nephrotic-range proteinuria and systemic symptoms; AL and AA types. **Multiple myeloma**: Light chain proteinuria; dipstick-negative (does not detect light chains); detected by urine protein electrophoresis.

![Differential diagnosis of proteinuria organized by age and severity](illustration-proteinuria-differential-by-age.jpg)

## Evaluation

### Initial Workup (Both Populations)

Confirm proteinuria on repeat specimen (rule out transient causes) **First morning UPCR**: Confirms or excludes orthostatic proteinuria. **Complete urinalysis with microscopy**: Assess for hematuria, casts, cellular elements. **Serum albumin, creatinine, BUN, lipid panel**. **Complete blood count** and comprehensive metabolic panel.

### Additional Studies

**Complement levels (C3, C4)**: Low in PIGN, MPGN, lupus nephritis. **ANA, anti-dsDNA, ANCA**: For suspected autoimmune disease. **Hepatitis B and C serology**: Associated with membranous and MPGN. **HIV testing**: Associated with FSGS (collapsing variant) **Anti-PLA2R antibodies**: For suspected primary membranous nephropathy in adults. **Serum and urine protein electrophoresis (SPEP/UPEP)**: For suspected myeloma or amyloidosis. **Renal ultrasound**: Assess kidney size, echogenicity, and structure.

### Kidney Biopsy Indications

**Children**: Atypical nephrotic syndrome (age <1 or >12, hematuria, hypertension, low complement, renal insufficiency, steroid resistance) **Adults**: Most cases of nephrotic syndrome require biopsy for diagnosis (except clear diabetic nephropathy in the setting of established diabetes with retinopathy) Biopsy guides treatment and prognosis.

![Evaluation algorithm for proteinuria in pediatric and adult patients](illustration-proteinuria-evaluation-algorithm.jpg)

## Management Principles

### Non-Specific Measures (All Patients)

**ACE inhibitors or ARBs**: First-line antiproteinuric therapy; reduce intraglomerular pressure and proteinuria by 30-50%. **SGLT2 inhibitors**: Significant renoprotective benefit in adults with proteinuric CKD (DAPA-CKD, EMPA-KIDNEY trials); emerging pediatric data. **Blood pressure control**: Target <130/80 in adults with proteinuria; age-appropriate targets in children. **Dietary sodium restriction**: <2 g/day to enhance efficacy of RAAS blockade. **Statin therapy**: For persistent hyperlipidemia in nephrotic syndrome.

### Disease-Specific Treatment

**Minimal change disease**: Prednisone 2 mg/kg/day (max 60 mg) for 4-6 weeks, then taper; steroid-sparing agents for frequent relapsers. **FSGS**: Prolonged steroid trial (16 weeks), calcineurin inhibitors for steroid-resistant disease; rituximab for refractory cases. **Membranous nephropathy**: Observation for low-risk; rituximab or cyclophosphamide-based regimens for high-risk (Ponticelli protocol) **Diabetic nephropathy**: Optimize glycemic control, RAAS blockade, SGLT2 inhibitors, finerenone (mineralocorticoid receptor antagonist) **Lupus nephritis**: Mycophenolate or cyclophosphamide induction; maintenance with mycophenolate.

![Treatment approach for nephrotic syndrome by age group](illustration-nephrotic-syndrome-treatment.jpg)

## Clinical Pearls

Orthostatic proteinuria is the most common cause of persistent proteinuria in adolescents; a first morning UPCR <0.2 confirms the diagnosis. In children aged 1-10 with typical nephrotic syndrome, empiric steroid therapy without biopsy is standard; atypical features warrant biopsy. ACE inhibitors/ARBs are first-line antiproteinuric therapy in both populations; SGLT2 inhibitors provide additional renoprotection in adults. Dipstick urinalysis does not detect light chain proteins; SPEP/UPEP is essential when myeloma is suspected. Proteinuria >1 g/day in adults is an independent risk factor for CKD progression and cardiovascular events.

## References

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4. Vivarelli M, Massella L, Ruber B, et al. Is the long-term outcome of childhood nephrotic syndrome improving? *Nephrol Dial Transplant*. 2017;32(10):1674-1681.