Proteinuria - Clinical Tree

Proteinuria can be detected by various means, and the most common is the dipstick test, a calorimetric assay that spots only albumin and not low-molecular-weight proteins. In addition, false-positive dipstick assessment can be seen with highly concentrated urine, alkaline urine, the presence of contrast media, vaginal secretions, or semen. False negatives are less common but can be seen with very dilute urine. Though 24-hour urine collection is the gold standard to quantify the proteinuria, spot urine protein-to-creatinine ratio can be used for initial confirmation after a positive screen with dipstick or to trend proteinuria ( Table 22.1 ). A ratio <0.2 protein mg/creatinine mg is considered normal in children older than 2 years of age and a ratio <0.5 mg/mg is considered normal in younger children between 6 months and 2 years of age. In timed collection, protein excretion >240 mg/m ² in 24 hours in children younger than 6 months of age and >150 mg/m ² in older children is considered abnormal, and over 40 mg/m ² /hr (>3 g/1.73 m ² /day) is considered nephrotic range. Qualitative analysis of protein in urine by immunonephelometry or electrophoresis helps distinguish glomerular from tubular proteinuria.

TABLE 22.1

Quantification of Proteinuria in Children

Modified from Flores FX. Clinical evaluation of the child with proteinuria. In: Kliegman FM, St. Geme J, eds. Nelson Textbook of Pediatrics . 21st ed. Elsevier; 2020:2749–2750.e1.

Method	Indications	Normal Range	Comments
Dipstick testing	Routine screening for proteinuria performed in the office	Negative or trace in a concentrated urine specimen (specific gravity: ≥1.020) Test interpretation: 1+ ∼30 mg/dL 2+ ∼100 mg/dL 3+ ∼300 mg/dL	False-positive test can occur if urine is very alkaline (pH >8.0) or very concentrated (specific gravity: >1.025), when there is pus, vaginal secretions, or semen present
24-hr urine for protein and creatinine ∗ excretion	Quantitation of proteinuria (as well as creatinine clearances)	<150 mg/m ² /24 hr	More accurate than spot urine analysis; inconvenient for patient; the creatinine content should be measured to determine whether the specimen is truly a 24-hr collection. The amount of creatinine in a 24-hr specimen can be estimated as follows: females, 15–20 mg/kg; males, 20–25 mg/kg
Spot urine for protein/creatinine ratio—preferably on first morning urine specimen	Semiquantitative assessment of proteinuria	<0.2 mg protein/mg creatinine in children older than 2 yr old <0.5 mg protein/mg creatinine in those 6–24 mo old	Simplest method to quantitate proteinuria; less accurate than measuring 24-hr proteinuria
Microalbuminuria	Assess risk of progressive glomerulopathy in patients with diabetes mellitus	<30 mg urine albumin per gram of creatinine on first morning urine	Therapy should be intensified in diabetics with microalbuminuria

Proteinuria in children can be transient, orthostatic, or persistent. Transient and orthostatic proteinuria are benign conditions and require no treatment. Several factors including fever, stress, hypovolemia, exercise, and seizures can lead to transient proteinuria ( Table 22.2 ). Orthostatic proteinuria is defined as increased protein in urine only when upright. In this condition, absence of proteinuria when horizontal and resting can be confirmed by documenting absence of protein in a first morning void. Split day/night urine collection is the gold standard to diagnose orthostatic proteinuria, which is a common benign cause of proteinuria, especially in adolescents. Persistent proteinuria requires meticulous evaluation to rule out renal pathology.

TABLE 22.2

Causes of Proteinuria

From Pais P, Avner ED. Fixed proteinuria. In: Kliegman RM, Stanton BF, St. Geme JW III, eds. Nelson Textbook of Pediatrics . 20th ed. Philadelphia: Elsevier; 2016:2520, Table 526.1.

Transient Proteinuria

Fever
Exercise
Dehydration
Cold exposure
Congestive heart failure
Seizure
Stress

Orthostatic (Postural) Proteinuria

Glomerular Diseases Characterized by Isolated Proteinuria

Idiopathic (minimal change) nephrotic syndrome
Focal segmental glomerulosclerosis
Mesangial proliferative glomerulonephritis
Membranous nephropathy
Membranoproliferative glomerulonephritis
Amyloidosis
Diabetic nephropathy
Sickle cell nephropathy

Glomerular Diseases with Proteinuria as a Prominent Feature

Acute postinfectious glomerulonephritis (e.g., streptococcal, endocarditis, hepatitis B or C virus, and HIV)
Immunoglobulin A nephropathy
Henoch-Schönlein purpura nephritis
Lupus nephritis
Serum sickness
Alport syndrome
Vasculitic disorders
Reflux nephropathy

Tubular Diseases

Cystinosis
Wilson disease
Lowe syndrome
Dent disease (X-linked recessive nephrolithiasis)
Galactosemia
Tubulointerstitial nephritis
Acute tubular necrosis
Renal dysplasia
Polycystic kidney disease
Reflux nephropathy
Drugs (e.g., penicillamine, lithium, NSAID)
Heavy metals (e.g., lead, gold, mercury)

NSAID, nonsteroidal antiinflammatory drug.

Evaluation of proteinuria begins with a detailed history and physical examination. Pertinent histories that help distinguish pathologic from benign proteinuria include history of respiratory symptoms concurrent with or preceding the proteinuria, presence of red urine, edema, positive family history of kidney disease, or hearing loss. Findings of edema and hypertension suggest pathologic proteinuria. Repeating urine dipstick in asymptomatic children with a negative history can eliminate unnecessary further testing for transient proteinuria. If still positive, spot urine protein-to-creatinine ratio can help confirm the presence of proteinuria. If confirmed, a first morning void protein-to-creatinine ratio can then identify orthostatic proteinuria. Once the benign conditions are ruled out in asymptomatic children, further testing is similar to that of symptomatic children and these children should be referred to nephrologists. This more detailed evaluation begins with 24-hour urine collection where possible, complete urinalysis, and sediment evaluation looking for glomerular or other parenchymal pathology that could be causing the proteinuria ( Fig. 22.1 ). Positive leukocyte esterase, nitrite, and presence of pyuria or bacteriuria suggest a urinary tract infection. If not resolved with treatment of infection, proteinuria will need further evaluation. Low molecular proteins, such as β2-microglobulin, α1-microglobulin, lysozyme, and retinol-binding protein, are found in tubular proteinuria as is seen in Fanconi syndrome or Dent disease. Red blood cell (RBC) casts are pathognomonic of glomerulonephritis . Serum chemistry including creatinine, BUN, electrolytes, albumin, and cholesterol will also help separate proteinuria secondary to glomerulonephritis or nephrotic syndrome. Lupus antibody studies, streptococcal infection, and complement C3 and C4 levels along with viral studies can help delineate the various causes of glomerulonephritis and nephrotic syndrome. Renal ultrasound should be considered to rule out any gross parenchymal etiology for the proteinuria, such as dysplastic kidney and cystic kidney disease. Renal biopsy may be indicated if there is evidence for worsening of proteinuria, hypoalbuminemia, deteriorating renal function, or a poor response to the initial therapy.

Differential diagnoses for proteinuria are extensive, as described in Table 22.2 . The initial evaluation of a patient with proteinuria is presented in Table 22.3 . Indications for a referral to a pediatric nephrologist are described in Table 22.4 . If there is obvious edema with proteinuria, the diagnostic evaluation noted in Table 22.3 advances directly to the second phase and, if necessary, to the third phase.

TABLE 22.3

Work-up of a Child with Proteinuria

Modified from Norman ME. An office approach to hematuria and proteinuria. Pediatr Clin North Am . 1987;34:545–562.

Pediatrician’s Work-up: Phase I

Early morning urinalysis to include examination of the sediment
Ambulatory and recumbent urinalyses for dipstick protein testing

Pediatrician’s Work-up: Phase II

Blood electrolytes, BUN, creatinine, serum proteins, cholesterol
Timed 12 hr urine collections, recumbent and ambulatory
Renal ultrasonography

Pediatric Nephrologist’s Work-up: Phase III

Complement, ANA, viral studies, genetic studies
Renal biopsy
Management of established renal disease

ANA, antinuclear antibody.

TABLE 22.4

When to Refer the Child with Proteinuria to a Nephrologist

Modified from Norman ME. An office approach to hematuria and proteinuria. Pediatr Clin North Am . 1987;34:545–561, Table 24.9 .

Persistent nonorthostatic proteinuria
A family history of glomerulonephritis, chronic renal failure, or kidney transplantation
Systemic complaints such as fever, arthritis or arthralgias, and rash
Hypertension, edema, cutaneous vasculitis, or purpura
Coexistent hematuria with or without cellular casts in the spun sediment
Elevated blood urea nitrogen and creatinine levels or unexplained electrolyte abnormalities
Increased parental anxiety

The combination of proteinuria, hypoalbuminemia, edema, and hyperlipidemia are the defining features of nephrotic syndrome. Nephrotic syndrome may be a result of many primary etiologic factors, with varying renal pathologic processes and long-term consequences. Proteinuria that causes edema is always clinically significant, although not all edema is secondary to proteinuria ( Table 22.5 ). All children with nephrotic syndrome invariably have “nephrotic range” proteinuria, necessitating detailed evaluation, and most require treatment. In rare cases, a child with asymptomatic proteinuria has nephrotic-range proteinuria. If there is concomitant hypoalbuminemia and hyperlipidemia, the work-up proceeds as if the child presented with nephrotic syndrome, despite the absence of edema. Even without hypoalbuminemia and hyperlipidemia, nephrotic-range proteinuria is less likely to be benign than is less marked asymptomatic proteinuria.

TABLE 22.5

Causes of Edema

Kidney Diseases

Acute glomerulonephritis
Nephrotic syndrome
Acute renal failure
Chronic renal failure

Heart Failure

Liver Failure

Nutritional and Gastrointestinal Disorders

Protein-calorie malnutrition
Protein-losing enteropathy
Nutritional edema (especially on refeeding)
- Iron deficiency anemia associated

Endocrine Disorders

Hypothyroidism
Mineralocorticoid excess

Miscellaneous

Hydrops fetalis
Venocaval obstruction
Capillary leak syndrome (systemic inflammatory response syndrome)
Turner syndrome (lymphedema)
Allergic reaction (periorbital edema)

Nephrotic Syndrome in Young Children

Differential Diagnosis

Three diseases constitute all cases of isolated nephrotic syndrome: minimal change disease (the most common), focal segmental sclerosis (also called focal glomerular sclerosis), and membranous glomerulopathy. These classifications are based on pathologic findings. Thus, these presentations could be primary or secondary due to other causes. In addition, nephrotic syndrome can be present along with glomerulonephritis (GN), such as postinfectious GN, immunoglobulin A (IgA) GN, or membranoproliferative GN. Systemic diseases also cause childhood nephrotic syndrome, accounting for 10% of cases. The three foremost considerations include systemic lupus erythematosus (SLE), IgA vasculitis (Henoch-Schönlein purpura), and hemolytic uremic syndrome. These diseases have extrarenal manifestations in addition to the proteinuria and must be considered in any child who presents with systemic illness and significant proteinuria. Hereditary forms of nephrotic syndrome are a genetically heterogeneous group of disorders representing a spectrum of hereditary renal diseases ( Table 22.6 and Fig. 22.2 ). Over 45 recessive or dominant genes have been associated with steroid-resistant nephrotic syndrome (SRNS)/hereditary nephrotic syndrome in humans ( Table 22.7 ). Several of the more common disorders along with other causes of nephrotic syndrome are noted in Tables 22.8 and 22.9 . Causes of congenital nephrotic syndrome (in infants 3 months of age or younger) are noted in Table 22.10 .

TABLE 22.6

Genetic Heterogeneity of Primary Nephrotic Syndrome and Syndromic Disorders Associated with Nephrotic Syndrome

Location	Phenotype	Inheritance	OMIM	Gene/Locus
Primarily Renal
1q23.3	Nephrotic syndrome, type 22	AR	619155	NOS1AP
1q25.2	Nephrotic syndrome, type 2	AR	600995	PDCN
1q42.13	Nephrotic syndrome, type 18	AR	618177	NUP133
3p21.31	Nephrotic syndrome, type 5, with or without ocular abnormalities	AR	614199	LAMB2
7q21.11	Nephrotic syndrome, type 15	AR	617609	MAGI2
7q33	Nephrotic syndrome, type 13	AR	616893	NUP205
10q22.1	Nephrotic syndrome, type 14	AR	617575	SGPL1
10q23.33	Nephrotic syndrome, type 3	AR	610725	PLCE1
11p13	Nephrotic syndrome, type 4	AD	256370	WT1
11p11.2	Nephrotic syndrome, type 19	AR	618178	NUP160
12p12.3	Nephrotic syndrome, type 6	AR	614196	PTPRO
12q14.1	Nephrotic syndrome, type 21	AR	618594	AVIL
12q15	Nephrotic syndrome, type 11	AR	616730	NUP107
16p13.13	Nephrotic syndrome, type 10	AR	615861	EMP2
16q13	Nephrotic syndrome, type 12	AR	616892	NUP93
17q22	Nephrotic syndrome, type 7	AR	615008	DGKE
17q22	Hemolytic uremic syndrome, atypical, susceptibility to, 7	AR	615008	DGKE
17q25.1	Nephrotic syndrome, type 17	AR	618176	NUP85
17q25.3	Nephrotic syndrome, type 8	AR	615244	ARHGDIA
19p13.2	Nephrotic syndrome, type 16	AR	617783	KANK2
19q13.12	Nephrotic syndrome, type 1	AR	256300	NPHS1
19q13.2	Nephrotic syndrome, type 9	AR	615573	COQ8B
Xq22.3	Nephrotic syndrome, type 20	XL	301028	TBC1D8B

19q13.2	Glomerulosclerosis, focal segmental, 1	AD	603278	ACTN4
11q22.1	Glomerulosclerosis, focal segmental, 2	AD	603965	TRPC6
6p12.3	Glomerulosclerosis, focal segmental, 3	CD2AP-AD	607832	CD2AP
14q32.33	Glomerulosclerosis, focal segmental, 5	INF2-AD	613237	INF2
15q22.2	Glomerulosclerosis, focal segmental, 6	AR	614131	MYO1E
10q24.31	Glomerulosclerosis, focal segmental, 7	AD	616002	PAX2
2q35	Glomerulopathy with fibronectin deposits 2	AD	601894	FN1
7p14.2	Focal segmental glomerulosclerosis 8	AD	616032	ANLN
9q33.3	Focal segmental glomerulosclerosis 10	AR	256020	LMX1B
1q32	Glomerulopathy with fibronectin deposits 1	AD	137950	GFND1
2q35	Glomerulopathy with fibronectin deposits 2	AD	601894	FN1
Systemic Disorders
1p33-p31.1	Forsythe-Wakeling syndrome	AR	613606
17q21.33	Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital	AR	614748	ITGA3
3p21.31	Pierson syndrome	AR	609049	LAMB2
15q25.2	Galloway-Mowat syndrome 1	AR	251300	WDR73
Xq28	Galloway-Mowat syndrome 2, X-linked	XLR	301006	LAGE3
14q11.2	Galloway-Mowat syndrome 3	AR	617729	OSGEP
20q13.12	Galloway-Mowat syndrome 4	AR	617730	TP53RK
2p13.1	Galloway-Mowat syndrome 5	AR	617731	TPRKB
21q22.3	Galloway-Mowat syndrome 6	AR	618347	WDR4
12q15	Galloway-Mowat syndrome 7	AR	618348	NUP107
1q42.13	Galloway-Mowat syndrome 8	AR	618349	NUP133
16p13.3	Congenital disorder of glycosylation, type Ik	AR	608540	ALG1
11p13	Denys-Drash syndrome	AD, SMu	194080	WT1
2q11.2	Autoimmune disease, multisystem, infantile onset, 2	AR	617006	ZAP70
4q21.1	Epilepsy, progressive myoclonic 4, with or without renal failure	AR	254900	SCARB2
2q35	Schimke immunoosseous dysplasia	AR	242900	SMARCAL1
10q24.32	Immunodeficiency, common variable, 10	AD	615577	NFKB2
9q33.2	Amyloidosis, Finnish type	AD	105120	GSN
16p13.2	Congenital disorder of glycosylation, type Ia	AR	212065	PMM2
11p13	Frasier syndrome	AD, SMu	136680	WT1
2q33.1	Autoimmune lymphoproliferative syndrome, type II	AD	603909	CASP10
1p31.3	Autoinflammation, immune disregulation, and eosinophilia	AD	618999	JAK1
Xp11.23	Congenital disorder of glycosylation, type IIm	SMo, XLD	300896	SLC35A2
4q31.3	Amyloidosis, familial visceral	AD	105200	FGA
11q23.3	Amyloidosis, 3 or more types	AD	105200	APOA1
12q15	Amyloidosis, renal	AD	105200	LYZ
15q21.1	Amyloidosis, familial visceral	AD	105200	B2M
2q24.2	Aicardi-Goutieres syndrome 7	AD	615846	IFIH1
3p21.1	Autoimmune lymphoproliferative syndrome, type III	AR	615559	PRKCD
6q13	Sialic acid storage disorder, infantile	AR	269920	SLC17A5
2q36.3	Alport syndrome 2, autosomal recessive	AR	203780	COL4A4
2q36.3	Alport syndrome 2, autosomal recessive	AR	203780	COL4A3
9q33.3	Nail-patella syndrome	AD	161200	LMX1B
Xq22.3	Alport syndrome 1, X-linked	XLD	301050	COL4A5
16p13.3	Familial Mediterranean fever, AR	AR	249100	MEFV
19p13.3	C3 deficiency	AR	613779	C3
12q24.31	Mucopolysaccharidosis-plus syndrome	AR	617303	VPS33A
10p13	Omenn syndrome	AR	603554	DCLRE1C
11p12	Omenn syndrome	AR	603554	RAG1
11p12	Omenn syndrome	AR	603554	RAG2
11p15.5	Nephropathy with pretibial epidermolysis bullosa and deafness	AR	609057	CD151
22q12.3	End-stage renal disease, nondiabetic, susceptibility to		612551	APOL1
22q12.3	Glomerulosclerosis, focal segmental, 4, susceptibility to		612551	APOL1
9q33.3	Ventriculomegaly with cystic kidney disease	AR	219730	CRB2
1q44	Muckle-Wells syndrome	AD	191900	NLRP3
12q13.3	Pseudo-TORCH syndrome 3	AR	618886	STAT2
Xq13.3	Intellectual disability, X-linked 98	XLD	300912	NEXMIF
15q26.1	Arthrogryposis, renal dysfunction, and cholestasis 1	AR	208085	VPS33B
11p15.4	Immunodeficiency 10	AR	612783	STIM1
14q32.32	Imerslund-Grasbeck syndrome 2	AR	618882	AMN
10p14	Hypoparathyroidism, sensorineural deafness, and renal dysplasia	AD	146255	GATA3
12q24.11	Hyper-IgD syndrome	AR	260920	MVK
Xp11.23	Immunodisregulation, polyendocrinopathy, and enteropathy, X-linked	XLR	304790	FOXP3
Xq26.2-q26.3	Lesch-Nyhan syndrome	XLR	300322	HPRT1
12q23.2	Microcephaly 24, primary, autosomal recessive	AR	618179	NUP37
1q21	Nephropathy-hypertension	AD	161900
15q22.31	Melorheostosis, isolated, somatic mosaic		155950	MAP2K1
7q11.23	Cutis laxa, autosomal dominant	AD	123700	ELN
2p21	Cystinuria	AD, AR	220100	SLC3A1
19q13.11	Cystinuria	AD, AR	220100	SLC7A9

AD, autosomal dominant; AR, autosomal recessive; SMo, somatic mosaicism; SMu, somatic mutation; TORCH, toxoplasmosis, other infections, rubella, cytomegalovirus, herpes simplex virus; XL, X-linked; XLD, X-linked dominant; XLR, X-linked recessive.

Fig. 22.2, Relative distribution of steroid-resistant nephrotic syndrome (SRNS)-causing genes by their age of onset. Percentages of families in an international cohort with SRNS that manifested at 25 years of age and resulted from variants in monogenic genes are interconnected by lines between age groups and shown in different colors for each causative gene ( lower panel for recessive genes, upper panel for dominant genes). NPHS1 variants (red), LAMB2 (orange), and PLCE1 (dark blue) have early age of onset and are rarely found in patients older than 6 years. The dominant genes INF2 (light blue) and TRPC6 (brown) manifest in early adulthood, and WT1 (black) shows a biphasic distribution with a first peak at 4–12 months and a second peak for age of onset beyond 18 years (upper panel). These findings are compatible with the notion that variants in recessive disease genes are found more frequently in early-onset disease, whereas variants in dominant genes more frequently cause adult-onset disease.

TABLE 22.7

Genetic Causes of Nephrotic Syndrome Categorized According to the Location of Abnormal Proteins in Podocytes

From Tae-Sun Ha, MD. Genetics of hereditary nephrotic syndrome: a clinical review. Korean J Pediatr . 2017;60(3):55–63.

Gene	Protein	Inheritance	Locus	Phenotypes
Slit Diaphragm and Adaptor Proteins
NPHS1	Nephrin	AR	19q13.1	CNS, SRNS (NPHS1)
NPHS2	Podocin	AR	1q25–q31	CNS, SRNS (NPHS2)
PLCE1	Phospholipase C, ε1	AR	10q23	DMS, SRNS (NPHS3)
CD2AP	CD2-associated protein	AD/AR	6p12.3	SRNS (FSGS3)
FAT1	FAT1	AR	4q35.2	NS, ciliopathy
Cytoskeleton Components
ACTN4	α-Actinin-4	AD	19q13	Late-onset SRNS (FSGS1)
INF2	Inverted formin-2	AD		SRNS (FSGS5), Charcot-Marie-Tooth disease with glomerulopathy
MYH9	Myosin, heavy chain 9	AD	22q12.3–13.1	Macrothrombocytopenia with sensorineural deafness, Epstein syndrome, Sebastian syndrome, Fechtner syndrome
MYO1E	Myosin IE	AR	15q22.2	Childhood-onset SRNS (FSGS6)
ARHGDIA	Rho GDP-dissociation inhibitor (GDI) a1	AR	17q25.3	Childhood-onset SRNS (NPHS8), seizures, cortical blindness
ARHGAP24	Arhgap24 (RhoGAP)	AD	4q22.1	Adolescent-onset FSGS
ANLN	Anillin	AD	7p14.2	FSGS8
GBM and Basal Membrane Proteins and Related Components
LAMB2	Laminin subunit β2	AR	3p21	Pierson syndrome DMS, FSGS (NPHS5)
ITGB4	Integrin-β4	AR	17q25.1	Epidermolysis bullosa, anecdotic cases presenting with NS and FSGS
ITGA3	Integrin-β3	AR		Epidermolysis bullosa, interstitial lung disease, SRNS/FSGS
CD151	Tetraspanin	AR	11p15.5	Epidermolysis bullosa, sensorineural deafness, ESRD
EXT1	Glycosyltransferase	AR	8q24.11	SRNS
COL4A3,4	Collagen (IV) α3/α4	AD/AR	2q36–q37	Alport syndrome, FSGS
COL4A5	Collagen (IV) α5	XD	Xq22.3	Alport syndrome, FSGS
Apical Membrane Proteins
TRPC6	Transient receptor potential channel 6	AD	11q21–q22	SRNS (FSGS2)
EMP2	Epithelial membrane protein 2	AD	16p13.2	Childhood SRNS/SSNS (MCD) (NPHS10)
Nuclear Proteins
WT1	Wilms tumor protein	AD/AR	11p13	SRNS (NPHS4), Denys-Drash syndrome, Frasier syndrome, WAGR syndrome
LMX1B	LIM homeobox transcription factor 1-β	AD	9q34.1	Nail-patella syndrome, NS
SMARCAL1	HepA-related protein	AR	2q35	Schimke immunoosseous dysplasia
PAX2	Paired box gene 2	AD	10q24.3–q25.1	Adult-onset FSGS (FSGS7), renal coloboma syndrome
MAFB	A transcription factor	AD	20q11.2–q13.1	Carpotarsal osteolysis progressive ESRD
LMNA	Lamins A and C	XD	1q22	Familial partial lipodystrophy, FSGS
NXF5	Nuclear RNA export factor 5	XR	Xq21	SRNS/FSGS cardiac conduction disorder
GATA3	GATA binding protein 3	AD	10p14	HDR syndrome (hypoparathyroidism, sensorineural deafness, renal abnormalities)
NUP93	Nucleoporin 93kD	N/A	16q13	SRNS
NUP107	Nucleoporin 107kD	N/A	12q15	Early-childhood-onset SRNS/FSGS
Mitochondrial Proteins
COQ2	4-Hydroxybenzoate polyprenyltransferase	AR	4q21–q22	Early-onset SRNS, CoQ10 deficiency
COQ6	Ubiquinone biosynthesis monooxygenase COQ6	AR	14q24.3	NS with sensorineural deafness, CoQ10 deficiency
PDSS2	Decaprenyl-diphosphate synthase subunit 2	AR	6q21	Leigh syndrome, CoQ10 deficiency, FSGS
MTTL1	Mitochondrially encoded tRNA leucine 1 (UUA/G)	Maternal	mtDNA	Mitochondrial diabetes, deafness with FSGS, MELAS syndrome
ADCK4	aarF domain containing kinase 4	AR	19q13.1	Childhood-onset SRNS (NPHS9), CoQ10 deficiency
Lysosomal Proteins
SCARB2	Scavenger receptor class B, member 2 (LIMP II)	AR	4q13–q21	Action myoclonus-renal failure syndrome, lysosomal storage disease
NEU1	Sialidase 1
NEU1	N-Acetyl-α-neuraminidase	AR	6p21.33	Nephrosialidosis, SRNS
Other Intracellular Proteins
APOL1	Apolipoprotein L1	AR	22q12.3	FSGS in African-Americans (FSGS4)
PTPRO	Tyrosine phosphatase receptor-type O (GLEPP1)	AR	12p12.3	SRNS (NPHS6)
CRB2	Crumbs homolog 2	AR	9q33.3	Early-onset familial SRNS (FSGS9)
DGKE	Diacylglycerol kinase-ε	AR	17q22	Atypical hemolytic uremic syndrome, membranoproliferative lesions (NPHS7)
ZMPSTE24	Zinc metalloproteinase	AR	1q34	Mandibuloacral dysplasia, FSGS
PMM2	Phosphomannomutase 2	AR	16p13.2	CDG syndrome, FSGS
ALG1	β1,4 Mannosyltransferase	AR	16p13.3	CDG syndrome, congenital NS
CUBN	Cubilin	AR	10p13	Childhood-onset SRNS megaloblastic anemia
TTC21B	IFT139 (a component of intraflagellar transport-A)	AR	2q24.3	Nephronophthisis (NPHP12), FSGS
WDR73	WD repeat domain 73	AR	15q25.2	Galloway-Mowat syndrome, SRNS/FSGS

ACTN4, actinin-alpha 4; ADCK4, AarF domain containing kinase 4; AD, autosomal dominant; ALG1, asparagine-linked glycosylation protein 1; ANLN, anillin; APOL1, apolipoprotein L1; AR, autosomal recessive; ARHGAP24, Rho GTPase-activating protein 24; ARHGDIA, Rho GDP dissociation inhibitor (GDI) alpha; CD2AP, CD2-associated protein; CDG syndrome, congenital disorders of glycosylation; CNS, congenital nephrotic syndrome; COQ2, coenzyme Q2 4-hydroxybenzoate polyprenyltransferase; COQ6, coenzyme Q6 monooxygenase; CoQ10, coenzyme Q10; CRB2, Crumbs family member 2; DGKE, diacylglycerol kinase epsilon; DMS, diffuse mesangial sclerosis; EMP2, epithelial membrane protein 2; ESRD, end-stage renal disease; EXT1, exostosin 1; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GLEPP-1, glomerular epithelial cell protein 1; HDR syndrome, hypoparathyroidism, sensorineural deafness, and renal abnormalities; ITGA3, integrin alpha 3; ITGB4, integrin beta 4; INF2, inverted formin, FH2 and WH2 domain containing; LAMB2, laminin beta 2; LIMP2, lysosome membrane protein 2; LMX1B, LIM homeobox transcription factor 1 beta; MAFB, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B; MELAS syndrome, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MTTL1, mitochondrially encoded tRNA leucine 1 (UUA/G); MYH9, myosin heavy chain 9, nonmuscle; MYO1E, Homo sapiens myosin IE; N/A, not available; NPHS1, nephrin; NPHS2, podocin; NS, nephrotic syndrome; NUP93, Nucleoporin 93 kD; NUP107, Nucleoporin 107 kD; PDSS2, prenyl (solanesyl) diphosphate synthase, subunit 2; PLCE1, phospholipase C, epsilon 1; PTPRO, protein tyrosine phosphatase receptor type O; SCARB2, scavenger receptor class B, member 2; SMARCAL, SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily a-like 1; SRNS, steroid-resistant nephrotic syndrome; TRPC6, transient receptor potential cation channel, subfamily C, member 6; TTC21B, tetratricopeptide repeat domain 21B; WAGR syndrome, Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome; WDR73, WD repeat domain 73; WT1, Wilms tumor 1.

TABLE 22.8

Causes of Childhood Nephrotic Syndrome

Modified from Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet . 2003;362:629–638; from Pais P, Avner ED. Fixed proteinuria. In: Kliegman RM, Stanton BF, St. Geme JW III, eds. Nelson Textbook of Pediatrics . 20th ed. Philadelphia: Elsevier; 2016:2522, Table 527.1.

Idiopathic Nephrotic Syndrome

Minimal change disease
Focal segmental glomerulosclerosis
Membranous nephropathy
Glomerulonephritis associated with nephrotic syndrome–membranoproliferative glomerulonephritis, crescentic glomerulonephritis, immunoglobulin A nephropathy

Genetic Disorders Associated with Proteinuria or Nephrotic Syndrome

Over 100 genetic syndromic disorders are associated with proteinuria; the more common disorders are listed below (see Tables 22.6, 22.7, and 22.10 )

Nephrotic Syndrome (Typical)

Finnish-type congenital nephrotic syndrome (absence of nephrin)
Focal segmental glomerulosclerosis (variants in nephrin, podocin, MYO1E , α-actinin-4, TRPC6)
Diffuse mesangial sclerosis (variants in laminin β ₂ chain)
Denys-Drash syndrome (variants in WT1 transcription factor)
Congenital nephrotic syndrome with lung and skin involvement (integrin α ₃ variant)
Mitochondrial disorders (rare association, steroid resistance, MELAS)

Proteinuria with or Without Nephrotic Syndrome

Nail-patella syndrome (variant in LMX1B transcription factor)
Alport syndrome (variant in collagen 4 biosynthesis genes)

Multisystem Syndromes with or Without Nephrotic Syndrome

Galloway-Mowat syndrome
Charcot-Marie-Tooth disease
Jeune syndrome
Cockayne syndrome
Bardet-Biedl syndrome

Metabolic Disorders with or Without Nephrotic Syndrome

Alagille syndrome
α ₁ -Antitrypsin deficiency
Fabry disease
Glutaric acidemia
Glycogen storage disease
Hurler syndrome
Partial lipodystrophy
Mitochondrial cytopathies
Sickle cell disease

Secondary Causes of Nephrotic Syndrome

Infections

Endocarditis
Hepatitis B, C
HIV-1
Infectious mononucleosis
Malaria
Syphilis (congenital and secondary)
Toxoplasmosis
Schistosomiasis
Filariasis

Drugs

Captopril
Penicillamine
Gold
Nonsteroidal antiinflammatory drugs

Pamidronate
Interferon
Mercury
Heroin
Lithium

Immunologic or Allergic Disorders

Vasculitis syndromes
Castleman disease
Kimura disease
Bee sting
Food allergens
Serum sickness

Associated with Malignant Disease

Lymphoma
Leukemia
Solid tumors

Glomerular Hyperfiltration

Oligomeganephronia
Morbid obesity
Adaptation to nephron reduction

TABLE 22.9

Causes of Nephrotic Syndrome in Infants Younger Than 1 Year

From Kliegman RM, Greenbaum LA, Lye PS. Practical Strategies in Pediatric Diagnosis and Therapy . 2nd ed. Philadelphia: Saunders; 2004:418.

Secondary Causes

Infections
Syphilis
Cytomegalovirus
Toxoplasmosis
Rubella
Hepatitis B
HIV
Malaria
Toxins
Mercury
Other
Systemic lupus erythematosus
Syndromes with associated renal disease
Nail-patella syndrome
Lowe syndrome
Nephropathy associated with congenital brain malformation
Denys-Drash syndrome: Wilms tumor
Hemolytic uremic syndrome

Primary Causes

Congenital nephrotic syndrome (see Table 22.10 )
Diffuse mesangial sclerosis
Minimal change disease
Focal segmental sclerosis
Membranous nephropathy

TABLE 22.10

The Etiology of Congenital (3 Months of Age or Younger) Nephrotic Syndrome (CNS)

From Jalanko H. Congenital nephrotic syndrome. Pediatr Nephrol . 2009;24:2121–2128 ( Table 1 , p. 2122).

Primary CNS

Nephrin gene variants ( NPHS1 , Finnish type of CNS [CNF])

Podocin gene variants ( NPHS2 )

WT1 gene variants (Denys-Drash, isolated CNS)

LamB2 gene variants (Pierson syndrome, isolated CNS)

PLCE1 gene variants

LMX1B variants (nail-patella syndrome)

LamB3 gene variants (Herlitz junctional epidermolysis bullosa)

Mitochondrial myopathies

CNS with or without brain and other malformations (no gene defect identified as yet)

Secondary CNS

Congenital syphilis

Toxoplasmosis, malaria

Cytomegalovirus, rubella, hepatitis B, HIV

Maternal systemic lupus erythematosus

Neonatal autoantibodies against neutral endopeptidase

Maternal steroid–chlorpheniramine treatment

Minimal Change Disease

Most cases of nephrotic syndrome in children are caused by minimal change nephrotic syndrome, defined as normal histologic features of the kidney by light microscopy and immune stains. Preschool-aged children constitute the age group in which minimal change nephrotic syndrome is most common. Patients often present with asymptomatic edema, which may manifest as swollen or puffy eyes upon awakening in the morning; increasing abdominal girth (increased waist or belt size) from ascites; pedal or leg edema, which causes difficulty in putting on their regular-sized shoes, especially after being upright during the daytime; or swelling in other sites, such as the scrotum, penis, vulva, and scalp. Tense edema or ascites is occasionally painful.

Minimal change nephrotic syndrome is slightly more common in males than in females. The hallmark of this disease is total clearing of the proteinuria with oral prednisone therapy. A common misconception is that neither hematuria nor hypertension is present in children with minimal change disease. Microscopic hematuria and hypertension are present in up to 20% of children who have minimal change disease. The BUN or serum creatinine level may also be elevated in up to 30% of the cases, usually from prerenal causes. Serum complement studies are normal. Older age, hematuria, hypertension, and azotemia may occur with minimal change nephrotic syndrome, but the combination suggests another disease.

Diagnosis

Studies that would help confirm that a patient with nephrotic syndrome has minimal change disease include urinalysis; serum chemistry including BUN, creatinine, albumin, and cholesterol levels; and complements and lupus antibody titers.

The urinalysis would be expected to show 3+ to 4+ protein, which is correlated with a urine concentration of 300–2,000 mg/dL. The urine may also occasionally yield positive results for blood. Microscopic examination of the urine sediment often shows oval fat bodies and/or refractile granular casts, which are seen when there is significant lipiduria. Red blood cells might also be present, but it is unusual to see red blood cell casts. Their presence would suggest a diagnosis of glomerulonephritis (see Chapter 23 ).

The complement C3 and C4 levels are normal in minimal change disease and are depressed in some other causes of nephritis (see Chapter 23 ). The serum cholesterol values are elevated in minimal change nephrotic syndrome and are usually >250 mg/dL; levels in the range of 500–600 mg/dL may occur. The serum albumin concentration is invariably <2.5 and often <2.0 g/dL. A renal biopsy is not immediately indicated because most patients (>90%) with minimal change disease respond to prednisone, a response that is considered diagnostic.

Treatment

With a presumptive diagnosis of minimal change nephrotic syndrome, it is recommended that patients be placed on a therapeutic course of prednisone, 60 mg/m ² /day or 2 mg/kg/day, up to a maximum of 60 mg for 4–6 weeks, followed by a dose of 40 mg/m ² or 1.5 mg/kg (maximum 40 mg) given every other day for another 6 weeks. In most patients, there is total resolution of proteinuria within 10–21 days of initiating therapy. Patients who do not respond to prednisone therapy should be considered candidates for a renal biopsy to guide further therapy.

Total clearing of proteinuria in response to prednisone is an excellent prognostic sign. Very few patients progress to renal failure, although many patients (∼80%) who initially respond to prednisone therapy with total clearing of proteinuria may have relapses and require intermittent prednisone therapy for many years. Approximately 18% of patients treated with prednisone for minimal change nephrotic syndrome respond to therapy and never experience a relapse.

Patients with recurrent nephrotic syndrome are subgrouped into those who experience frequent and infrequent relapses. A patient with infrequent relapse has fewer than two relapses in any 6-month period; a person with frequent relapse has two or more relapses within 6 months. Prednisone should be reinitiated at a dose of 60 mg/m ² /day or 2 mg/kg/day until a maximum of 60 mg/day and continued until the urine test results are negative for protein for 3 consecutive days. After that, alternate-day prednisone is given at a dose of 40 mg/m ² or 1.5 mg/kg (maximum 40 mg) in the morning for another 4 weeks and then discontinued altogether. Relapses are frequent during the influenza virus seasons; any minor upper respiratory infection may trigger a relapse of nephrotic syndrome. Patients who suffer infrequent relapses may be treated with prednisone alone.

Patients with frequently relapsing nephrotic syndrome may be steroid dependent and require constant daily prednisone therapy to maintain a remission. Because constant daily prednisone has significant untoward side effects (growth failure, cushingoid facies, osteoporosis, cataracts, opportunistic infections, hypertension, and glucose intolerance), other therapies need to be considered. A renal biopsy is recommended prior to initiating alternative agents to confirm the diagnosis of minimal change nephrotic syndrome. Treatment strategies with corticosteroid-sparing agents for patients with frequent relapse who develop steroid-related adverse effects include alkylating agents, cyclophosphamide or chlorambucil, and more recently rituximab.

Complications of Nephrotic Syndrome

Even in patients with the frequent relapse variant of minimal change disease, the incidence of renal failure is only 1%. The reported mortality rate remains higher, at approximately 5%.

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