The genetic inheritance of CAKUT is multifactorial and complex. CAKUT is responsible for roughly 40% of cases of ESKF that typically becomes evident during the initial 3 decades of life. Studies suggest that CAKUT frequently results from mutations in individual (monogenic) genes; approximately 40 mutations have been identified to date (25 dominant and 15 recessive), outlined in ( Table 71.4 ). In approximately 30% of affected individuals, these malformations occur as part of a multiorgan genetic syndrome. Currently, more than 200 monogenic syndromes have been identified that involve the kidney and urinary tract. The genetics of kidney diseases are discussed in more detail in Chapter 44 .

The development of CAKUT is grounded in the disturbance of typical nephrogenesis, attributed to either environmental or genetic factors. Most genetic causes do not follow a clear Mendelian pattern of inheritance. Although many cases of CAKUT appear to be sporadic, with no other affected member in the same family, familial clustering is common, suggesting that the pathogenesis is influenced by genetic factors. Among affected family members carrying the same mutation, there is often variability in expressivity and penetrance, leading to a spectrum of renal phenotypes including agenesis, dysplasia, or isolated collecting system abnormalities such as hydronephrosis. Approximately 10% of those with a congenital solitary kidney have a first-degree relative with renal or urinary tract disease, frequently presenting asymptomatically. Multiple studies have confirmed an elevated recurrence risk for CAKUT among relatives, estimated to range from 4% to 20%. This underscores the hereditary nature of the condition and highlights the crucial importance of screening first-degree relatives.

Numerous studies have sought to explore the genetic predisposition of CAKUT. Roodhooft and colleagues conducted a study on individuals with bilateral renal agenesis or bilateral renal dysgenesis. Their findings revealed that 9% of first-degree relatives exhibited some form of kidney or urinary tract malformation. In a similar fashion, Bulum and colleagues studied 180 families with known CAKUT and identified new anomalies in 23% of asymptomatic first-degree relatives. In a study involving 232 families, conducted by van der Ven and colleagues, whole exome sequencing was employed to investigate CAKUT genotypes and found a potential single, novel monogenic CAKUT gene in 8% of families.

The predominant autosomal dominant single-gene defects leading to CAKUT are characterized by well-defined syndromic disorders, primarily arising from mutations in genes such as PAX2, HNF1B, SALL1, WT1, SIX1, and EYA1. In contrast, autosomal recessive defects are infrequent and often result in isolated CAKUT. The most common causes of autosomal recessive CAKUT are associated with mutations in FRAS1, FREM1, FREM2, and GRIP1.

Studies suggest that polymorphic variants in genes that control renal development and copy number variants (CNVs) contribute to the pathogenesis of CAKUT. CNVs are the most common form of genetic changes in the human genome, involving the gain or loss of DNA segments. The most commonly observed genomic disorder was the Chr.17q12 deletion, indicating the presence of the renal cyst and diabetes syndrome (RCAD). This was followed by the Chr.22q11.2 deletion, indicative of the DiGeorge/velocardiofacial syndrome.

Normal growth of the UB is dependent on TGF-β family member glial cell–line–derived neurotrophic factor (GDNF) signaling via the RET receptor and GPI-linked cell surface coreceptor (Gfra1). RET, a tyrosine kinase receptor, is present on the surface of ureteric cells and is coexpressed with Gfra1, whereas GDNF is expressed by MM cells. Mouse studies have demonstrated that genetic disruptions in the RET, GDNF, and Gfra1 genes can lead to impaired ureteric outgrowth and renal agenesis. Skinner and colleagues investigated the genetic makeup of 33 stillborn fetuses with renal aplasia or severe renal dysplasia and found human RET mutations were found in 37% of fetuses with bilateral renal agenesis and in 20% of fetuses with unilateral renal agenesis. These findings underscore the critical role of the GDNF signal in promoting the growth of the UB and Wolffian duct (WD). ^,

ROBO2, a cell surface receptor expressed in the nephrogenic mesenchyme, is linked to VUR and UTIs when disrupted. VUR is associated with reflux nephropathy due to the retrograde flow of urine from the bladder to the ureter. ^, Normally involved in axon guidance and cell migration, mutations to ROBO2 result in the formation of additional UBs that remain inappropriately connected to the nephric duct. It has been suggested that an ectopic position of the ureteral orifice in the bladder is associated with VUR, whereas ectopic positioning of the UB is associated with renal dysplasia.

In the mesenchyme surrounding the ureteric stalk, bone morphogenetic protein-4 (BMP4) is present. Its roles include preventing the abnormal development of ureteric tips while facilitating the elongation of the ureteric stalk. Furthermore, BMP4 exerts an inhibitory effect on the branching of UB tips, whereas GDNF has a positive regulatory role. As a result, mutations can lead to the development of cystic kidneys, hypoplastic kidneys, and hydroureter. Human studies have found an association between BMP4 mutations with renal dysgenesis and VUR.

After the UB invades the MM, it undergoes numerous branching cycles to establish the collecting duct system, responsible for directing urine flow to the bladder. The branching phase involves approximately 19 to 21 generations of branching events and is a major determinant of final nephron number as each UB branch tip induces a discrete subset of MM cells to undergo nephrogenesis.

PAX2 is a paired-box transcription factor located in the collecting duct, nephron progenitors, and epithelial components of the developing nephron. Deficiency of PAX2 is associated with autosomal dominant renal-coloboma syndrome (RCS), also known as papillorenal syndrome. RCS is characterized by optic nerve dysplasia (frequently described as a coloboma) and varied renal malformations, such as vesicoureteric reflux (VUR), renal hypoplasia, renal hypodysplasia, MCDK, oligomeganephronia, and horseshoe kidney. Studies by Chang and colleagues and Porteous and colleagues both show renal hypoplasia was the most prevalent congenital defect. Characteristic ocular features include an enlarged optic disk with blood vessels emanating from the periphery of the optic nerve head, rather than the center, and a wide spectrum of visual acuity, ranging from normal to severe impairment including blindness. In contrast, PAX2 overexpression results in epithelial hyperproliferation and the occurrence of renal cysts.

The PAX2 gene is located on chromosome 10q24-25. It encodes a transcription factor that belongs to the paired-box family of homeotic genes. During renal development, PAX2 is expressed in the WD, UB, and metanephric mesenchyme. Mice studies have shown that the absence of the PAX2 gene results in branching defects and significantly reduces the number of nephrons.

The GDNF-RET signaling pathway plays a vital role in not only ureteric outgrowth but also the essential process of ureteric branching. RET expressed on ureteric tip cells influences branch quantity and pattern by prompting surrounding mesenchymal cells to condense into epithelial vesicles, which then differentiate into nephron segments. Clarke and colleagues showed mice with a heterozygous mutation in RET resulted in a 22% reduction in glomerular density. This is supported by human studies that similarly showed infants with a common RET mutation (the RET[1476A] allele) have a 10% reduction in kidney volume. Signal transduction through the glial-derived neurotrophic factor (GDNF)–GDNF receptor α1 (GFRA1)–RET pathway is necessary for the UB to protrude from the nephric duct and grow toward the MM. Regulatory molecules, such as PAX2, EYA1, SIX1, SIX4, and HOXA11, which stimulate the GDNF– GFRA1–RET pathway, are essential for UB emergence and branching during the process of nephrogenesis. In addition, inhibitory molecules, such as ROBO2, FOXC1, FOXF1, and FOXP1, prevent ectopic or multiple UB formation.

In the MM, GDNF is essential for normal growth of the UB and branching morphogenesis. Sall1, Eya1, and Six1 positively control GDNF expression. Sall1 is a member of the Spalt family of transcriptional factors, and inactivation causes decreased GDNF expression, resulting in Townes-Brock syndrome (TBS). This syndrome is inherited in an autosomal dominant manner and is characterized by imperforate anus, preaxial polydactyly or triphalangeal thumbs, or a combination of both, along with external ear abnormalities, sensorineural hearing loss, and a spectrum of kidney, urogenital, and heart malformations including renal agenesis. The prevalence of TBS has been estimated to be 1:250,000, but overlap with VACTERL association (Vertebral defects, Anal atresia, Cardiac defects, Tracheo-esophageal fistula, Renal anomalies, and Limb abnormalities) may lead to an overascertainment of true prevalence.

EYA1, a DNA-binding transcription factor expressed in MM cells, together with SIX1, regulates the expression of GDNF, all of which play essential roles in the development of otic and branchial tissues. Mutations of EYA1 and SIX1 result in the autosomal dominant branchio-oto-renal (BOR) syndrome, which is characterized by kidney and urinary tract malformations and conductive, sensorineural, or combined hearing loss. Renal manifestations include unilateral or bilateral renal agenesis, hypodysplasia, as well as malformation of the lower urinary tract including VUR, pyelo-ureteral obstruction, and ureteral duplication. Branchiootic syndrome (BO) is a related disorder without renal anomalies, also caused by EYA1 mutations. BOR/BO syndromes have a prevalence of 1:40,000 in the general population and are responsible for 2% of profound deafness in children. ^,

Hedgehog (Hh) signaling plays a crucial role in tissue patterning, cell differentiation, and growth, and disturbances in this signaling pathway can lead to CAKUT. Binding of Hh ligand including Sonic Hedgehog (SHH) to its cognate cell surface receptor stimulates nuclear translocation of full-length GLI transcriptional activators and inhibits proteolytic processing of full length GLI3 to a shorter transcriptional repressor. SHH is located on human chromosome 7q36 and is localized to the epithelium of the presumptive ureter and medullary collecting ducts. Mutations in the SHH pathway are linked to VACTERL syndrome in humans, whereas deletions are associated with renal anomalies such as hydroureter. Smith-Lemli-Opitz Syndrome is an autosomal recessive condition resulting from a Hh loss-of-function mutation in the DHCR7 gene. This gene encodes for sterol delta-7-reductase, which is required to convert 7-dehydrocholesterol into cholesterol. The renal manifestations of Smith-Lemli-Opitz Syndrome include renal agenesis and hypodysplasia. ^, Truncating variations in the central third of the GLI3 gene in humans have been identified as responsible for development of the autosomal recessive Pallister-Hall Syndrome. These truncated variants are able to mimic the GLI3 repressor, which in SHH deficient mice, have resulted in various forms of CAKUT in 27%, with the most common being aplasia and hypoplasia followed by dysplasia, ectopic kidney, single kidney, and VUR.

Glypicans are a class of heparan sulfate proteoglycans that link to cells via a glycosyl–phosphatidylinositol anchor. Glypican-3 (GPC3) is essential for growth of the medullary kidney and regulates IGF-II activity. Mutations in GPC3 are associated with Simpson-Golabi-Behmel syndrome (SGBS). The pathogenesis of this X-linked disorder stems from disruption of GPC3’s ability to regulate cell proliferation and apoptosis during development, leading to selective UB overgrowth followed by destruction of medullary collecting ducts due to apoptosis. The renal manifestations of SGBS include: cystic kidneys and medullary renal dysplasia. ^, The cell signals regulated by GPC3 may be mediated by p57. In patients with Beckwith-Wiedemann syndrome, around 5% have mutations in p57. p57KIP2 is a cell cycle inhibitor at the G1/S phase and mutations are associated with medullary dysplasia.

Human transcription factor 2 gene (TCF2) encodes for HNF-1B, which is required for the development of the pancreas, kidneys, liver, and intestine. TCF2 mutations are associated with the initially named maturity-onset diabetes of the young type 5 (MODY5), though the term renal cysts and diabetes syndrome (RCAD) has gained relevance to highlight the renal phenotypes of this condition. Nonketotic diabetes mellitus is present in approximately 60% of all the cases reported, usually occurring before 25 years of age. Cystic kidney diseases encompass renal cysts, cystic dysplastic kidney, and hypoplastic familial glomerulocystic kidney (FGCKD). While TCF2 mutations were first identified in MODY5/RCAD, currently more than 40 renal abnormalities are known to be linked to TCF2 mutations/deletions. These include solitary functioning kidney, oligomeganephronia, atypical juvenile hyperuricemic nephropathy, autosomal dominant tubulointerstitial kidney disease (ADTKD), horseshoe kidney, bilateral hyperechogenic kidneys, renal agenesis, pelvicalyceal dilation, and MCDK. Decramer and colleagues studied 62 newborns/fetuses with antenatally diagnosed bilateral hyperechogenic kidneys and revealed that large genomic TCF2 deletions were the most frequent cause (29%). Similarly, Ulinski and colleagues investigated 80 children with an ultrasound-confirmed structural renal abnormality, of whom 31% were carriers of a TCF2 anomaly and 88% of those carriers were noted to have a heterozygous anomaly. Among the heterozygous anomaly cohort, 64% were found to have the complete deletion of TCF2.

Renal tubular dysgenesis (RTD) is a severe fetal condition characterized by absence/poor maturation of proximal renal tubules and anuria, resulting in oligohydramnios and Potter sequence—altered physical appearance of the neonate with typical facies, pseudoepicanthus, recessed chin, posteriorly rotated flattened ears, flattened nose, pulmonary hypoplasia, hip dislocations, joint contractures, clubbed feet, reduced fetal movement, and ossification abnormalities of the skull. In most cases, death occurs early due to pulmonary hypoplasia or refractory hypotension. Acquired causes include the donor twin of severe twin-to-twin transfusion syndrome, congenital hemochromatosis, major cardiac conditions, or in fetuses exposed to RAS blockers. Inherited cases are typically autosomal recessive and include mutations in the genes encoding renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE) or angiotensin II receptor type 1, with the majority occurring in ACE and REN, 65.5% and 20% of cases, respectively. Cases of RTD are typically diagnosed prenatally via ultrasound due to early oligohydramnios or anhydramnios, but it has been noted that some cases present with late-gestation oligohydramnios and normal second trimester ultrasound, highlighting the high level of suspicion required when treating oligohydramnios in spite of a normal second trimester renal ultrasound.

Chromodomain helicase DNA-binding protein 1–like protein (CHD1L) and chromodomain helicase DNA-binding protein-7 (CHD7) are part of the Snf2 family of helicase-related ATP-hydrolyzing proteins. This family of proteins plays a role in the formation of CAKUT via their effects on chromatin structure and accessibility. CHD7 causes the autosomal dominant CHARGE syndrome, named for its symptoms: coloboma, heart defects, atresia of choanae, retardation, genital anomalies, and ear anomalies. Additionally, renal abnormalities are seen in 20% of cases including horseshoe kidneys, renal agenesis, renal dysplasia, VUR, UVJ obstruction, posterior urethral valves, and renal cysts. The prevalence of CHARGE syndrome is 1:10,000 with a wide variation in severity and symptom expression. CHD1L is associated with hepatocellular carcinoma. Brockschmidt and colleagues identified CHD1L heterozygous missense mutations in 3 of 85 children affected with CAKUT.

Antenatal ultrasound imaging is the primary method in which 60% to 85% of CAKUT is diagnosed with a sensitivity of approximately 80%. The fetal kidney can be visualized at 12 to 15 weeks of human gestation, and screening antenatal ultrasound is recommended between 16 and 20 weeks of gestation. Ultrasound allows for detection of structural abnormalities, as well as quantification of amniotic fluid volume, which is primarily composed of urine produced by the fetal kidneys. ^, CAKUT may also become apparent during infancy or childhood due to UTIs, while in adolescence or adulthood, symptoms such as hypertension may arise.

Fetal ureters are not typically visualized on ultrasound. If they are observed, it may suggest potential concerns such as ureteral or bladder obstruction, or vesicoureteral reflux (VUR). Lower urinary tract obstruction, such as posterior urethral valves (PUV) in males, may present on ultrasound as a distended fetal bladder in the first trimester. In the second trimester, findings indicating PUV include oligohydramnios, bilateral hydronephrosis, and obstructive renal dysplasia.

The development of the kidney in utero is monitored using fetal renal length, standardized for gestational age. The mean combined kidney length (MKL) of 20.87 ± 0.75 mm and 41.41 ± 0.07 mm at 20 and 41 weeks, respectively, have been reported. Assessing renal function in utero is measuring amniotic fluid volume. Fetal urine production begins at 9 weeks of gestation. By 20 weeks of gestation and thereafter, fetal urine is the primary source of amniotic fluid. Insufficient amniotic fluid, or oligohydramnios may be caused bilateral renal dysplasia (or a critical defect in one kidney where a solitary kidney exists), bilateral ureteral obstruction, or obstruction of the bladder outlet. In the second trimester, severe oligohydramnios may cause lung compression and increased fluid losses via the trachea ultimately resulting in lung hypoplasia. The most severe consequence of oligohydramnios and pulmonary hypoplasia is Potter sequence. ^, In contrast, polyhydramnios is reflects an increased amount of amniotic fluid and is associated with intestinal and esophageal atresias, rather than renal structural abnormalities. Congenital Bartter syndrome or other abnormalities associated with fetal polyuria may be associated with polyhydramnios, which may precipitate preterm birth.

The composition of fetal urine is also used as a marker of renal function. Increases in urea and creatinine in the second and third trimesters observed in amniotic fluid and fetal urine are due to an increase in the GFR of the fetal kidneys and signify a maturation of their tubular function. Urine sodium and β-2-microglobulin decrease with increasing gestational age due to increasing reabsorption capacity of proximal tubular cells. Fetuses with bilateral renal dysplasia or severe bilateral obstructive uropathy present with increased sodium and β-2 microglobulin and reduced osmolality due to impaired resorption and renal function. In general, sodium and chloride concentration >90 mEq/L (90 mmol/L) and urinary osmolality <210 mOsmol/kg⋅H ₂ O (210 mmol/kg⋅H2O) are indicative of fetal renal tubular impairment and poor renal prognosis. In addition, urinary β-2-microglobulin levels >6 mg/L are predictive of severe renal damage with a sensitivity and specificity of 80% and 71%, respectively. ^,

A coordinated multidisciplinary approach including teams from obstetrics, pediatric nephrology, pediatric urology, and neonatology is required. It is critical to counsel families appropriately and clearly communicate diagnosis and prognosis. A diagnosis of CAKUT is often made antenatally. Some cases allow for surgical intervention before symptomatic consequences. Interventions that aim to relieve lower urinary tract obstruction include serial ultrasound-directed vesicocentesis, vesicoamniotic shunting, fetal cystoscopy, and valve ablation. These interventions aim to relieve urinary tract obstruction and promote pulmonary development. To date, little evidence exists that relief of urinary tract obstruction in utero prevents the development of associated renal dysplasia or renal scarring. In contrast, insertion of a bladder–amniotic cavity shunt in the fetus with an obstruction below the bladder neck can rescue oligohydramnios and pulmonary hypoplasia. ^,

Following delivery, a thorough history and examination must be undertaken in newborns with antenatally diagnosed/suspected CAKUT. This includes evaluation of the respiratory system to assess for pulmonary insufficiency; the abdomen to assess for masses indicating renal enlargement or MCDK; the ears, as outer ear abnormalities are associated with an increased risk of CAKUT; and the umbilicus, as a single umbilical artery is associated with an increased risk of CAKUT. Examination should also assess for Potter sequence resulting from severe oligohydramnios. ^,

An ultrasound within the first 24 hours post-birth is required for newborns with known/suspected bilateral renal malformations, a solitary malformed kidney, or a history of oligohydramnios to assess if bladder decompression is required. Newborns with unilateral renal malformations should be assessed via ultrasound between 48 hours and 1 week after birth as hydronephrosis may not be immediately evident. If severe hydronephrosis is detected on ultrasound, antibiotics (prophylactic dose, adjusted for age—amoxicillin, ampicillin, cotromixazole, trimepthoprim, and nitrofurantoin) should be commenced as prophylaxis for pyelonephritis and a voiding cystourethrography (VCUG) should be performed to assess if reflux is the underlying etiology and, if yes, the grade of the reflux. Serum creatinine concentration should be assessed in the newborn after the first 24 hours as prior levels reflect maternal creatinine. Creatinine should decline to normal values (serum creatinine 0.3 to 0.5 mg/dL [27–44 μmol/L]) within approximately 1 week in term infants and 2 to 3 weeks in preterm infants.67 Pediatric nephrology support is required from birth for optimal management of fluid and electrolytes.

Clinical outcomes in CAKUT vary widely from no symptoms whatsoever to CKD resulting in kidney failure during a period ranging from the newborn period to the fourth and fifth decades of life. Risk factors for mortality during infancy and early childhood include coexistence of renal and nonrenal disease, prematurity, low birth weight, oligohydramnios, and severe forms of renal–urinary tract malformation (agenesis and hypodysplasia). In a case series of 822 children with prenatally detected CAKUT who were followed for a median time of 43 months, Quirino and colleagues reported a mortality of 1.5% and morbidities including UTI, hypertension, and CKD in 29%, 2.7%, and 6% of surviving children, respectively. Sanna-Cherchi and colleagues found that 25% of 312 children born with bilateral CAKUT developed ESKF during the first two decades of life. Elevated serum creatinine, presence of proteinuria, and VUR were found to be associated with a higher risk of renal disease progression. A faster rate of decline of renal function in patients with CAKUT and CKD has been associated with a urine albumin-to-creatinine ratio >200 mg/mmol compared with <50 mg/mmol (eGFR–6.5 mL/min/1.73 m ² /year vs.–1.5 mL/min/1.73 m ² /year), and with more than two (vs. <2) febrile UTIs (eGFR–3.5 mL/min/1.73 m ² /year vs.–2 mL/min/1.73 m ² /year). A greater decline in eGFR occurs during puberty (eGFR–4 mL/min/1.73 m ² /year vs.–1.9 mL/min/1.73 m ² /year). A study examining the risk for dialysis in patients with CAKUT demonstrated a significantly higher risk for patients with a solitary kidney compared with nondisease controls. These results raise the possibility that the prognosis for a solitary apparently normal kidney may not be as “normal” as previously thought. Data from the European Dialysis and Transplant Association Registry showed that the mean age at which patients with CAKUT require dialysis and/or transplantation is 31 years indicates that children with CAKUT are at risk of developing a requirement for dialysis and/or transplantation as adults.

Diagnosis of NS in children requires significant proteinuria (>40 mg/h/m ² or ≥1000 mg/m ² /day) or urinary protein creatinine ratio (UPCR) ≥200 mg/mmol (2 mg/mg) or 3+ on urine dipstick plus hypoalbuminemia (<30 g/L) (see Table 71.6 ). Edema is a characteristic symptom of NS. Idiopathic NS is the most frequent glomerular disease in children and typically manifests between 1 and 10 years of age. Idiopathic NS is clinically classified on the basis of the response to corticosteroid therapy. Clinical remission is defined by a marked reduction in proteinuria (remission: <4 mg/m ² /h, ≤20 mg/mmol (0.2 mg/mg) UPCR or urine albumin dipstick of 0 to trace for 3 consecutive days). Reduction of proteinuria is associated with resolution of edema. Patients who enter clinical remission in response to daily glucocorticoid treatment alone are referred to as having steroid-responsive or steroid-sensitive NS (SSNS). The majority (80%–90%) of children older than 1 year of age have SNSS, while the remaining 10% to 20% are nonresponsive and classified as having steroid-resistant nephrotic syndrome (SRNS), defined as lack of remission within 4 weeks of treatment with prednisone at standard dose (see later). A majority of children who develop NS will experience at least one relapse of their disease. Clinical relapse is characterized by a recurrence of severe proteinuria (exceeding 40 mg/m ² /h, ≥200 mg/mmol [2 mg/mg] UPCR or urine albumin dipstick registering 3+ for 3 successive days), typically accompanied with edema recurrence. Frequently relapsing NS (FRNS) is characterized by either two or more relapses within 6 months of the initial response or four or more relapses within any 12-month period. Steroid-dependent NS (SDNS) describes cases in which a patient with SSNS experiences two consecutive relapses during recommended prednisone therapy (see later) for first presentation or relapse or within 14 days after steroid therapy discontinuation. These patients may require continued low-dose treatment with glucocorticoids or alternative steroid-sparing immunosuppressive/immunomodulatory treatment to prevent development of relapse and are at higher risk of progression to CKD or ESKF. ^{, ,} The definitions of the various clinical forms of nephrotic syndrome are outlined in Table 71.7 .

Childhood NS occurs at a reported rate of 4.7 (with a range of 1.15–16.9) cases per 100,000 children globally, exhibiting significant variation based on ethnic origin and geographic location. Several studies have investigated the disparities across ethnicities. South Asian children exhibit a greater occurrence of NS compared with the European population. In the United States, NS is more prevalent among African-American children compared with those of European descent ^{. ,} Furthermore, African-American children exhibit a higher propensity for FSGS on kidney biopsy (ranging from 42% to 72%) and, in general, have a higher risk of advancing to ESKF, compared with European children. NS is more common in boys, with a male/female ratio of 1.6:1 (1.7:1 for SSNS and 1.2:1 for SRNS), but this difference declines with age. The peak age of presentation is 1 to 4 years. ^, Age is a potential predictive factor of underlying histology. The median ages at presentation for minimal change nephrotic syndrome (MCNS), also named minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS), and membranoproliferative glomerulonephritis (MPGN), are 3, 6, and 10 years, respectively. Additionally, SSNS is more common in first-degree relatives of affected individuals with idiopathic NS reported in identical twins. Congenital nephrotic syndromes are associated with genetic mutations in the NPHS1 (nephrin), NPHS2 (podocin), and WT-1 genes. Familial and sporadic SRNS may be associated with NPHS2 mutations. ^, In patients with monogenic forms of SRNS, immunosuppressive treatment should be withdrawn since there is evidence supporting the ineffectiveness of this treatment.

Idiopathic nephrotic syndrome and genetically caused nephrotic syndrome form the group of primary nephrotic syndromes.

The podocyte is the primary target cell of injury during NS. All forms of this disease involve structural changes in podocytes, including cell swelling, as well as retraction and effacement (spreading) of the podocyte’s distal foot processes, leading to the formation of a diffuse cytoplasmic sheet overlying the glomerular basal membrane (GBM). Additional podocyte structural changes include the formation of vacuoles, development of occluding junctions with displacement of the normal slit diaphragms that extend between podocyte foot processes, and in some areas detachment of podocytes from the underlying GBM. These podocyte structural changes, along with detachment from the GBM, result in the proteinuria that characterizes NS. ^{, ,} Detailed discussion on the podocyte pathophysiology is outlined in Chapter 4 .

Extensive investigations over several decades have failed to identify a single unifying cause for idiopathic NS, though there is strong evidence of immune dysregulation, chiefly involving cell-mediated immunity. This theory is supported by the tendency of NS to manifest and relapse after viral infections or atopic episodes, the association with HLA antigens and Hodgkin lymphoma, and the therapeutic response to immunosuppressive therapy, namely glucocorticoids in about 80% to 90% of cases. Evidence for a pathophysiologic role of circulating antinephrin antibodies in idiopathic nephrotic syndrome has emerged.

In SRNS patients, up to 30% are diagnosed with a monogenetic disease.

More than 70 genes have now been identified, for which mutations of various types have been found to lead to childhood SRNS. These genes should be included in a next-generation sequencing panel unless the clinical phenotype is suggestive of a specific condition.

The secondary glomerulopathies associated with childhood NS include systemic diseases, highlighted in Table 71.8 . Examples include conditions such as SLE, IgA-vasculitis (nephritis), diabetes mellitus, sickle cell disease, and sarcoidosis. In addition, other secondary causes of disease include infections such as HIV, hepatitis B, and hepatitis C, malignancies such as leukemia and lymphoma, and drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) and ACE inhibitors (captopril). Finally, morbid obesity, allergies to food, bee stings, and even immunizations have all also been associated with the development of NS.

Edema, specifically gravity-dependent edema, is the most common presenting clinical symptom of NS. Edema may be generalized, especially in young children. Periorbital edema is typical and may be mistaken for an allergic reaction. The laboratory evaluation of children presenting with NS always begins with confirmation of the presence of proteinuria, hypoalbuminemia (<30 g/L), hyperlipidemia, and determination of the renal function. Proteinuria may be accompanied by hematuria, which can be either macroscopic or microscopic. Microscopic hematuria was found in 23% of children with MCD versus 48% of children with FSGS versus 59% of children with membranoproliferative glomerulonephritis (MPGN) in the International Study of Kidney Disease study. Hypertension is more common in FSGS or MPGN, with an incidence of approximately 50%, compared with MCD (∼21%). The clinical evaluation of children with nephrotic syndrome should emphasize the risk of prerenal acute kidney (AKI) injury due to intravascular hypovolemia in severe cases with severe edema.

Initial diagnostic workup is outlined in Table 71.8 and Fig. 71.9 . These summarize the clinical practice recommendations of the International Pediatric Nephrology Association (IPNA).

Algorithm for the initial management of a child with nephrotic syndrome.

From Trautmann 2022.

The prognosis for children with nephrotic syndrome is best predicted by the patient’s response to initial treatment and frequency of relapse during the first year after treatment. Therefore a kidney biopsy is not usually needed at initial presentation and instead is reserved for children with resistance to therapy or an atypical clinical course.

Kidney biopsy is recommended in all children diagnosed with SRNS unless there is a known genetic or secondary cause. In addition, a kidney biopsy may be indicated in case of a high index of suspicion for a different underlying pathology (e.g., macroscopic hematuria, systemic symptoms of vasculitis, and hypocomplementemia). Beyond the typical age of onset (≥12 years of age), a kidney biopsy may be helpful, as the probability of MCD decreases. Kidney biopsy is helpful to determine the diagnoses, as well as to determine the extent of tubular atrophy, interstitial fibrosis, and glomerulosclerosis as prognostic markers. ^, Genetic testing should be performed if possible in all children diagnosed with primary SRNS, particularly in familial cases, cases with extrarenal features, and those undergoing preparation for renal transplantation. This should include a comprehensive gene panel analysis (see earlier discussion), as well as genetic counseling for patients and their families. The genetic causes of podocyte disorders/nephrotic syndrome are listed in Table 71.9 .

Childhood NS is most often due to primary glomerulopathies, most commonly MCD (∼80%), followed with a large distance by FSGS (∼10%), as well as mesangial proliferative glomerulonephritis (MPGN), and membranous nephropathy (MN).

FSGS is a complex disease that describes different kinds of kidney defects, not exclusively linked with podocyte defect. We regard FSGS as a pattern of histologic injury rather than a disease. Historically it has been divided into primary or secondary etiologies, but integration of more robust clinical, histologic, and genetic knowledge of this disease has led to the proposal that FSGS be categorized into six forms: 1. primary FSGS, 2. (mal)adaptive FSGS, 3. APOL1 FSGS, 4. genetic FSGS, 5. virus-associated FSGS, and 6. medication/toxin-associated FSGS, the most common being primary and adaptive FSGS. All six forms share the common theme of podocyte injury and depletion. In primary FSGS, it has been suggested that the inciting factor of podocyte damage involves a circulating factor, possibly a cytokine. Recurrent FSGS, which occurs in some patients immediately (on a scale of hours to several weeks) post-transplant afterward, supports this theory. ^, In contrast, (mal)adaptive FSGS is thought to be due to persistent glomerular hyperfiltration, which may occur in conditions such as cyanotic congenital heart disease, sleep apnea, or conditions with reduced functional nephron mass such as renal dysplasia, reflux nephropathy, repeated episodes of AKI, or premature or small-for-gestational-age birth.

Over the past few decades, multiple protocols have been reported for the initial treatment of children presenting with NS. The initial widely accepted approach was reported by the International Study for Kidney Diseases in Children, which suggested treatment with prednisone in divided doses for 4 weeks at 60 mg/m ² /day (or 2 mg/kg/day up to a maximal dose of 80 mg/day), followed by a taper to 40 mg/m ² /day (or 1.5 mg/kg/day up to a maximal dose of 60 mg/day) for an additional 4 weeks.180 KDIGO guidelines recommend that oral glucocorticoids be given for 8 weeks (4 weeks of daily glucocorticoids followed by 4 weeks of alternate-day glucocorticoids) or 12 weeks (6 weeks of daily glucocorticoids followed by 6 weeks of alternate-day glucocorticoids). The 2022 IPNA clinical practice recommendations suggest a single daily morning dose rather than divided to increased adherence to therapy and reduce risk of hypothalamic–pituitary–adrenal (HPA) axis suppression and sleep disturbances: prednisone 4 weeks at 60 mg/m ² or 2 mg/kg (maximum dose 60 mg/day), followed by alternate-day prednisone at 40 mg/m ² or 1.5 mg/kg (maximum dose of 40 mg on alternate days) for 4 weeks, or prednisone 6 weeks at 60 mg(m ² or 2 mg/kg [maximum dose 60 mg/day]) followed by alternate-day prednisone at 40 mg/m ² or 1.5 mg/kg (maximum dose of 40 mg on alternate days) for 6 weeks. Hodson and colleagues conducted a meta-analysis of randomized control trials investigating corticosteroid therapy in NS and concluded a therapy duration of 3 to 7 months resulted in fewer relapses. This supported the previously held notion that a longer duration of treatment was more important than total dose in reducing the risk of relapse. This has been challenged by trials that postulate extending initial prednisolone treatment with an increasing dose and or longer treatment time does not improve clinical outcomes. The occurrence of relapses in follow-up may rather reflect the “natural” course of the disease, which may not be influenced by duration and cumulative dose of corticosteroid treatment.

Daily dipstick testing until remission is recommended. In follow-up urine dipstick testing, twice weekly is suggested in the first year. In episodes of fever, infections, or suspected relapse (e.g., edema and positive dipstick), daily testing is recommended ( Table 71.11 ).

A majority of children with NS relapse within the first 6 months of initial therapy and approximately 50% to 60% develop frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS).199 Certain characteristics increase the likelihood of relapses, such as age younger than 3 years at onset, male gender, delayed time to remission (after 7 to 9 days), and occurrence of an early relapse (in the first 6 months after initial treatment). ^, Additionally, upper respiratory tract infections (URTIs) precede 71% of relapses, with respiratory syncytial virus (RSV) being the most commonly implicated viral trigger. The IPNA clinical practice recommendations do not recommend the routine use of a short course of low-dose daily PDN at the onset of an URTI for prevention of relapses but suggest considering a short course of low-dose daily PDN at the onset of an URTI in children who are already taking low-dose alternate-day PDN and have a history of repeated infection-associated relapses.

Relapses (urine dipstick ≥3 + (≥300 mg/dL) or UPCR ≥200 mg/mmol (≥2 mg/mg) on a spot urine sample on 3 consecutive days, with or without reappearance of edema) are managed by reinitiating a single daily dose of prednisolone at 60 mg/m ² until the urine is protein free for 3 days. The dose is then reduced to 40 mg/m ² on alternate days for 4 weeks, without a tapering schedule. ^, Children in whom the aforementioned measures fail to adequately control the disease can be classified as FRNS or SDNS. Those patients are at risk of developing significant signs and symptoms of steroid toxicity. In this case, several alternative treatments may be used ( Fig. 71.10 ). While these agents as a group can often reduce the frequency of relapses and are steroid sparing, many of them have significant toxicities of their own ( Table 71.12 ).

Algorithm for management of children with steroid-sensitive nephrotic syndrome.

From Trautmann 2022.

Cyclophosphamide is an alkylating agent used in both FRNS and SDNS at a dose of 2 mg/kg/day for 12 weeks (maximum cumulative dose of 168 mg/kg). It has been shown to induce remission at 2 years in 70% and 25%, for FRNS and SDNS, respectively. The benefit of cyclophosphamide is related to the length of treatment, with the optimal treatment being 8 to 12 weeks. Adverse effects include bone marrow suppression, alopecia, hemorrhagic cystitis, infection, gonadal dysfunction/infertility, hyponatremia, SIADH, and hypocalcemia. Chlorambucil is an alternative alkylating agent used at a dose of 0.1 to 0.2 mg/kg/day for 8 weeks with adverse effects including bone marrow suppression, seizures, infertility, and teratogenicity. ^,

Levamisole is an antihelminthic drug with immunostimulatory properties, which has been shown to significantly reduce relapse rates in both FRNS and SDNS, although some patients develop relapses shortly after discontinuation. Typical dosing includes administration of 2–2.5 mg/kg PO on alternate days (maximum dose 150 mg/day), and a typical treatment duration ranges from 4 months to a year. Adverse effects include leukopenia, agranulocytosis, hepatotoxicity, vasculitis, and encephalopathy. ^{, ,}

Mycophenolate mofetil (MMF) is a purine synthetase inhibitor. Treatment at doses of 25 to 30 mg/kg daily (1200 mg/m ² /day in two divided doses), significantly reduced relapse rates and spare the use of corticosteroids, though Bagga and colleagues noted cessation of therapy was associated with relapses. A significantly high interindividual variability of mycophenolic acid (MPA) exposure at a given dose of MMF exists. Gellermann and colleagues showed that at a dose of 800 to 1200 mg/m ² , the achieved MPA-AUC varied from 24 to 120 μg⋅h/mL, making therapeutic drug monitoring beneficial. An MPA area-under-the-concentration time curve of >50 mg × h/L should be aimed for. Adverse effects include serious infection, malignancy, embryo-fetal toxicity, leukopenia, abdominal pain, and diarrhea. MMF is not associated with nephrotoxicity, which is an advantage over the calcineurin inhibitors (CNI). Because of its efficacy and favorable toxicity profile compared with CNIs, a commentary to the German best practice guideline on INS in children suggests MMF as a primary alternative steroid-sparing agent.

CNIs include tacrolimus and cyclosporin, both of which are effective in the induction and maintenance of remission in FRNS and SDNS. CNIs exert their effects by decreasing T cell activity and stabilizing the podocyte actin cytoskeleton. Adverse effects of the CNIs include hirsutism, diabetes, hypertension, hyperkalemia, dyslipidemia, and gingival hyperplasia. Additionally, there is an increased risk of nephrotoxicity manifesting as irreversible interstitial fibrosis. Its incidence and severity appear to correlate generally with the duration and dose of drug exposure. Patients often relapse after discontinuation, so they are usually prescribed over a prolonged period. Patients on long-time therapy with cyclosporin or tacrolimus should be considered for kidney biopsy during follow-up. ^{, ,}

Rituximab is an anti-CD20 monoclonal antibody that may be used for SRNS, as well as SSNS and FRNS, and is given as 375 mg/m ² per dose for up to 4 weekly doses. The efficacy of this treatment has been reported in mostly small case series and uncontrolled trials, where it has been found generally to induce complete remission in approximately 25% of children with SRNS and partial remission in approximately 25% of children. Adverse effects include infusion-related reactions, which vary from mild (fever or rash) to severe (hypotension and bronchospasm). Rituximab-associated lung injury (RALI) is pulmonary toxicity that is typically temporary and reversible but may lead to potentially fatal complications including pulmonary fibrosis and interstitial pneumonitis and may present between 1 and 3 months after initiation of rituximab. Thus a chest radiograph should be obtained before initiation and periodically during treatment. ^, Some recipients of rituximab and other anti-CD20 monoclonal antibodies experience prolonged depletion of CD20 lymphocytes and significant impairment of immunoglobulin production with attendant attenuation of vaccine responses and susceptibility to certain pathogens, sometimes requiring regular supplementation with external immunoglobulins until immune system recovery. For FRNS and SDNS, rituximab is advised to be used as a second-line steroid-sparing agent in children due to its uncertain long-term safety profile.

Despite optimal management, approximately 10% of children with NS will initially present with or subsequently develop SRNS. Notably, before labeling a child as having SRNS, it is essential to exclude several potentially treatable causes for treatment failure including poor medication adherence, poor medication absorption, possible underlying infection, and possible malignancy. Once diagnosed with SRNS, a child’s risk for both the development of extrarenal complications of NS and the development of ESKF and/or CKD increases, with SRNS patients comprising 15% of all children with CKD requiring RRT. Furthermore, in cases where partial or complete remission is not attained, there is a 50% likelihood of progressing to ESKF within 5 years of diagnosis. For this reason, both the alternative treatments described earlier, as well as additional treatments, are often employed in an attempt to induce a complete remission of proteinuria.

The prognosis of SRNS is based on histopathologic findings at the time of diagnosis. ESKF-free survival rates in children with minimal change glomerulopathy (MCGN) were 92% at 5 years and 79% at 10 and 15 years compared with 69% 5-year, 52% 10-year, and 37% 15-year renal survival rates in children diagnosed with FSGS. The poorest outcomes were seen in patients with diffuse mesangial sclerosis (DMS) who have an 80% ESKF risk at 5 years after diagnosis.

The overall management of children with SRNS can be divided into three major categories: 1. supportive therapy, 2. immunosuppressive therapy, and 3. nonimmunosuppressive therapy.

The long-term outcome for childhood NS is excellent overall. The vast majority of children who develop NS will have SSNS, among whom approximately one-half of children will have no relapses or will have infrequent relapses (i.e., <4 relapses per year), and the other half will have frequent relapses (≥4 relapses per year, or FRNS). The risk for the development of CKD or ESKF among children with SSNS is <5%. This risk rises dramatically for children who present with or subsequently develop SRNS, where the risk of CKD and/or ESKF approaches 50% within 5 years. Newer follow-up studies have reported higher rates of relapse occurring in adulthood. In studies from Finland, the United Kingdom, Switzerland, and France, the rate of relapse during adulthood was reported to be 14%, 19%, 33%, and 42%, respectively.

MN has an estimated incidence of 0 to 12 per million in North America and 2 to 17 per million in Europe, with a 2:1 male predominance and equal incidence among regions and ethnicities. Among adults, it occurs at a frequency of about 1.2/100,000 population per year with a mean age of diagnosis at 50 to 60 years. In contrast, among children, MN occurs at only about 0.05 to 0.1/100,000 population per year, or approximately 10 to 20 times less commonly than in adults, and is more common in adolescents than younger children. ^,

In MN the glomerulus, particularly podocyte antigens, are targeted by circulating autoantibodies, which result in the formation of immune complexes (ICs), activation of complement, and massive proteinuria. MN can be either primary or idiopathic or secondary to a wide variety of causes. The many causes of MN in children are shown in Table 71.14 . ^,

Idiopathic MN is characterized by IC formation associated with the subepithelial layer of the GBM. Disease progression is characterized by subepithelial deposition, extending, and incorporation into the GBM, ultimately causing GBM remodeling. Idiopathic MN is predominantly driven by antibodies targeting the M-type phospholipase A2 receptor (anti-PLA2R). This receptor is a transmembrane glycoprotein located on the surface of podocytes and is implicated in approximately 85% of cases. Anti-PLA2R antibody titers have been demonstrated to be an excellent biomarker of disease activity in patients with MN, with levels being increased during relapses, absent during remissions, and rituximab-induced depletion of anti-PLA2R titers correlating with clinical responses. ^, Additionally, 3% to 5% of idiopathic MN cases are associated with thrombospondin type 1 domain containing 7A (THSD7A) (3%–5%) and 10% remain due to unidentified mechanisms. Secondary MN may arise secondary to lupus, cancer, drug reactions, or infectious disease and may be differentiated from idiopathic MN by atypical features such as mesangial proliferation and specific immunoglobulin and complement deposits.

The most common manifestation of MN is proteinuria, which may be accompanied by microscopic hematuria, though one study reported an incidence of macroscopic hematuria in almost 40% of patients. Additionally, 40% to 75% of patients present with nephrotic syndrome. Although hematuria is more frequently observed alongside proteinuria in children when compared with adults, hypertension and thromboembolic events are significantly less common in pediatric cases. ^{, ,} A kidney biopsy is the standard diagnostic method for MN, although this is not required to confirm the diagnosis in patients with nephrotic syndrome and a positive anti-PLA2R antibody test.

Due to the rarity of MN in the pediatric population, there is no standardized approach to therapy in children; thus treatment decisions for children with MN are usually derived from data published in adult populations. Notably, however, children typically have different comorbid factors compared with adults and inherently different life expectancies. These factors must be considered in making treatment decisions. Supportive care should be initiated in all patients, consisting of blood pressure control, ACE inhibitors/ARBs for proteinuria, statins for hyperlipidemia, and salt restriction with diuretics for edema, and a higher-protein diet may be advised to compensate for urinary protein losses.

Children with asymptomatic, nonnephrotic proteinuria (urine protein-to-creatinine ratio <2.0 mg/mg), normal renal function, and minimal sclerosis on kidney biopsy are typically managed conservatively with ACEi or ARB as this group is at low risk of progressive renal disease. This approach can generally be expected to achieve only approximately 30% reduction in proteinuria, however, and thus would be insufficient for patients with more severe proteinuria.

The therapeutic approach for children with MN differs from adult therapy. Adults presenting with nephrotic-range proteinuria (urine protein-to-creatinine ratio >2 mg/mg) are recommended to be treated with a combination of oral corticosteroids and cyclophosphamide. In children, many patients may well have already had steroid treatment started as presumed initial management of childhood NS, which complicates the decision about the use of immunosuppression early in the disease course. Although no controlled trials have examined steroid treatment of MN in children, a report from 1966 found that steroid treatment of children with MN (80% with NS) resulted in a 50% remission rate for those with NS. Early outcomes of rituximab in adults have shown when given alone or in combination with steroids can induce remission in 60%, with reduction or disappearance of anti-PLA2R antibodies. The Membranous Nephropathy Trial of Rituximab (MENTOR) study comparing rituximab to cyclosporine in adults with MN found similar results in both therapies in achieving proteinuria remission at 12 months, though rituximab showed superiority at 24 months in sustaining long-term remission with a reduced incidence of relapses. Furthermore, in patients with anti-PLA2R-associated MN, the rituximab group exhibited a more rapid and substantial decline in anti-PLA2R autoantibody titer compared with the cyclosporine group. ^, In children, there is no concrete evidence to guide management in children with MN. KDIGO guidelines recommend treatment with prednisone for at least 8 to 12 weeks with the use of rituximab and CNIs. It is important to exclude secondary causes of MN such as SLE, chronic hepatitis B virus infection, or neoplasm. A newer treatment for MN is adrenocorticotropic hormone, which seems in adults to have relatively similar efficacy to that of steroids combined with alkylating agents, although no data are available for children.

In summary, while conservative treatment with ACE inhibitor or ARB therapy may suffice for children with modest proteinuria, immunosuppressive treatment appears necessary to induce remission in the majority of patients. There are few data to guide the treatment of MN specifically among children, therapy combining steroids with alkylating agents or CNIs appears to be reasonably effective, and the more recent introduction of rituximab appears to offer the potential for somewhat improved outcomes, potentially with fewer side effects.

Data documenting long-term outcomes in children with MN are scarce. However, reports from the North American Paediatric Renal Trials and Collaborative Studies (NAPRTCS) group and the USRDS suggest that the incidence of MN among children with CKD is 0.5% and that MN represents approximately 0.5% of all pediatric patients with ESKF. ^{, ,} MN is discussed in furter detail in Chapter 30 .

As the differential diagnosis of hematuria is wide ( Table 71.15 ), including both glomerular and nonglomerular causes, investigations must encompass microscopic urinalysis, detailed review of the personal and family medical history, a thorough clinical examination with focus on extrarenal disease manifestations and urologic causes (e.g., kidney stones, urethritis), and a complete laboratory workup (including blood and urine) to evaluate glomerular causes and renal ultrasound to exclude structural causes.

Glomerular hematuria is a manifestation of renal pathology and is characterized by urine sediment that consists of >5 red blood cells/high-power field together with acanthocytes, red cell casts, or mixed red and white cell casts. Nephritic syndrome presents with hematuria, impaired renal function, hypertension, decreased urine output, nonnephrotic proteinuria, and edema. It is typically a result of glomerular inflammation, which may be caused by postinfectious glomerulonephritis, infective endocarditis, IgA-nephropathy, lupus nephritis, Goodpasture disease, and vasculitides. The syndrome may range from an acute self-limiting disease to rapidly progressive glomerulonephritis (RPGN) or may progress to CKD. ^, Pathophysiology and treatment of the individual diseases are discussed later and in the relevant chapters elsewhere in this book.

TBMN is the most common cause of persistent glomerular hematuria in adults and children and has a prevalence of approximately 1%. In contrast to Alport syndrome, TBMN typically presents with isolated hematuria, with renal biopsy showing mild mesangial cell proliferation and slight matrix expansion. Additionally, TBMN is due to heterozygous COL4A3 or COL4A4 mutations and often represents the carrier state of autosomal recessive Alport syndrome. As a result, a spectrum of collagen IV–related disorders encompasses Alport syndrome at the severe end and TBMN at the milder end. There have also been proposals to classify Alport syndrome and benign familial hematuria/thin basement membrane nephropathy as forms of collagen IV–related renal disease or by Alport kidney disease or Alport spectrum.

Establishing the Diagnosis of Alport Syndrome and Thin Basement Membrane Nephropathy

AS and TBMN may exhibit similar clinical and ultrastructural characteristics, yet it is important to differentiate them due to the distinct risks of renal failure and other complications they pose to affected individuals and their family members. The diagnosis of AS is suspected when a patient presents with hematuria, as well as a positive family history of hematuria, chronic renal failure, or both; high-frequency SNHL; or pathognomonic ocular anomalies (dot-and-fleck retinopathy and anterior lenticonus). Confirmation of the diagnosis requires genetic testing or a renal biopsy revealing a lamellated GBM on EM in the right clinical setting. GBM thinning is associated with early stages of disease, while late stages of the disease are associated with thickening and multilamellation of the GBM ( Fig. 71.11 ). ^, In contrast, EM in TBMN demonstrates diffuse thinning of the GBM with a width <250 nm in the majority of capillary loops and at least 50% of individual capillaries. Notably, TBMN specimens will not demonstrate thickening or lamellation. ^,

Electron microscopy findings in thin basement membrane disease (TBMD) and Alport syndrome (AS).

(A) TBMD shows diffuse thinning of the glomerular basement membrane (GBM) lamina densa compared with that of age-matched controls (best established in the same laboratory). (B) AS shows an irregular GBM with thinning and thickening, the latter becoming more prominent over time and with splitting/fragmentation of the lamina densa resulting in a multilaminated/basket-weave appearance often containing stubs of cellular processes with electron-lucent areas and small electron-dense particles. (A and B: electron microscopy ×10,000.)

A new classification of Alport syndrome has been proposed that does not require a family history or evidence of disease progression. Women with heterozygous COL4A5 variants are classified as having X-linked Alport syndrome, not as carriers. It also eliminates the diagnosis of “thin basement membrane nephropathy” and considers individuals with heterozygous COL4A3 or COL4A4 variants to have autosomal dominant Alport syndrome. However, the classification is controversial due to the variability in Alport syndrome phenotypes, with some patients developing only mild, kidney-limited disease. Notably, patients with FSGS on kidney biopsy and a pathogenic variant in any of the COL4A3-5 genes would be considered to have Alport syndrome rather than a genetic form of FSGS under the proposal.

IgA-nephropathy (IgAN) is the most common form of chronic glomerulonephritis in children. IgA-vasculitis (previously known as Henoch-Schönlein purpura) is the most common vasculitis in children, with glomerulonephritis being its most common chronic manifestation. First described by Berger and Hinglais in 1968 among patients with macroscopic hematuria during viral upper respiratory infections, IgAN is now recognized as the most common primary glomerulopathy in the world. ^, While early on it was considered a benign disease, it is increasingly recognized that between 20% and 50% of adults and children ultimately developed ESKF. In contrast to IgAN, which is limited to the kidneys, IgA-vasculitis is a multisystem disease primarily affecting the skin, joints, gastrointestinal tract, and kidneys. ^, Because these diseases share many pathogenic and clinical features, however, their relevance in pediatric kidney disease is discussed together. For in-depth discussion of IgA-nephropathy and IgA-vasculitis, please see Chapter 33 .

IgAN is the most common glomerulonephritis worldwide with an incidence of approximately 0.06 to 4.2 per 100,000 population per year. Globally, there are distinct geographical and sex-based variations. There is increased prevalence in Far East Asia compared with Europe and North America and a low prevalence in Africa. Additionally, the male-to-female ratio is 3:1 in Europeans but 1:1 in East Asians. While IgAN occurs in both children and adults, it presents most commonly during the second and third decades of life. Among children, IgAN appears to generally occur with a male-to-female ratio of approximately 2:1. ^{, ,}

The worldwide incidence of IgA-vasculitis has been described between 3.5 and 26.7 per 100,000, thus occurring much more commonly than IgAN. However, only a minority (∼30%) of children with IgA-vasculitis develop glomerulonephritis, which is most commonly mild, and the incidence of clinically significant IgA-vasculitis–associated nephritis has been estimated to be potentially lower than that of IgAN. ^, It typically impacts children aged 5 to 15 years and is rarely observed in adults and infants. The age at which it manifests has been deemed an important factor in disease severity and prognosis.

IgAN is influenced by a combination of genetic and environmental factors, and the pathogenesis is described as a multi-“hit” process involving genetically susceptible variants encoding galactosylation, dysfunctional mucosal immune responses, and environmental triggers such as infection, alteration of microbiota, and food antigens. A key observation in patients with IgAN is the presence of circulating and glomerular ICs composed of galactose-deficient IgA1, an IgG autoantibody directed against the hinge region O-glycans, and C3. These pathways ultimately contribute to glomerulosclerosis and tubulointerstitial fibrosis, leading to loss of renal function. Serum levels of IgA are increased in 50% to 70% of patients with IgAN during active disease but return to normal during recovery. Evidence suggests that the precipitating event in IgAN, abnormal glycosylation of IgA1, appears to be an inherited trait rather than an acquired abnormality, but that different families may have differing molecular mechanisms of disease development. The inheritance pattern suggests an autosomal dominant trait with variable penetrance. Genome-wide association studies (GWASs) have identified 15 common risk variants, collectively accounting for approximately 6% to 8% of the overall disease risk. ^, The exact etiology of IgA-vasculitis nephritis remains unknown, yet all IgA-vasculitis nephritis patients have been found to have IgA1-circulating ICs of small molecular mass. Only those with nephritis have additional large-molecular-mass IgA1-IgG-containing circulating ICs.

The presentation of IgAN ranges from isolated hematuria to significant proteinuria to AKI and even CKD with a 10-year risk of progression to ESKF of 26%, though the 2 most common features are asymptomatic hematuria and progressive kidney disease. ^, Macroscopic hematuria is the initial presentation of approximately 75% of childhood cases in the United States, although only in 26% of cases in Japan. ^, The hematuria is often associated with an upper respiratory infection and resolves within 2 to 4 days. Less commonly it occurs in association with other infections associated with the mucosal system, such as sinusitis or diarrhea. Other less common presentations include microscopic hematuria with proteinuria, isolated microscopic hematuria, and isolated proteinuria. Even less commonly (∼10% of cases), IgAN can present with macroscopic hematuria with reversible AKI, CKD, or rarely with RPGN. ^{, , ,} Hypertension is present in approximately 31% to 58% of children at presentation, although it is usually not severe unless AKI is also present. Prognostic factors that confer a favorable outcome include minimal proteinuria with no proteinuria, whereas hypertension, persistent hematuria, and decreased eGFR at diagnosis are associated with poorer outcomes. ^{, , ,}

Children with IgA-vasculitis nephritis typically present far earlier (∼4–6 years) than those with IgAN (∼10–30 years), although like IgAN, IgA-vasculitis nephritis can present at any age. Most cases of IgA-vasculitis occur in the autumn and winter with proposed triggers including URTIs, medications, vaccinations, and malignancies. The typical presentation includes a lower extremity purpuric rash, often associated with colicky abdominal pain, and sometimes arthritis. In a review of adults, joint involvement, glomerulonephritis, and gastrointestinal involvement were found in 62%, 70%, and 53% of patients, respectively. The renal manifestations of IgA-vasculitis nephritis at presentation may range from no involvement to severe nephritic and/or NS. ^, Abnormal urinalysis indicating hematuria and/or proteinuria is seen in approximately 35% of children with IgAV. Approximately 25% of children with an abnormal urinalysis will also have macroscopic hematuria. Notably, children with IgA-vasculitis nephritis are approximately twice as likely to develop NS than those with IgAN, usually occurring within 1 to 2 months of onset of IgA-vasculitis. ^{, ,}

Because no specific serologic biomarker exists to diagnose IgAN, confirmation of the diagnosis depends on kidney biopsy and identification of IgA deposits in the glomerular mesangium. A large review of published biopsy studies found 100% of IgAN biopsies had positivity for IgA, 43% had positivity for IgG, and 54% for IgM. Laboratory evaluation generally includes the workup for glomerulonephritis including serum creatinine, serum albumin, serum C3/C4 levels, serum antinuclear antibody (ANA), antinuclear cytoplasmic antibody (ANCA), antistreptolysin O Titre, as well as a complete urinalysis and urine protein-to-creatinine ratio determination. Diagnosis of IgA-vasculitis nephritis includes the clinical features of IgA-vasculitis in combination with evidence of renal involvement on urinalysis and urine protein-to-creatinine ratio. Serum IgA levels are not reliable biomarkers because they are elevated in both IgAN- and IgA-vasculitis. Serum C3 and C4 levels typically remain within the normal range for both diseases. This distinction helps differentiate IgAN from conditions like PIGN, MPGN, or SLE nephritis, which often present with hypocomplementemia. The pediatric IgAN risk score is modified from the adult International IgAN Prediction Tool and can accurately predict the risk of a 30% decline in eGFR or ESKD in children with IgAN. IgAN KDIGO guidelines recommend performing kidney biopsies with symptoms (hematuria, proteinuria, normal C3) to confirm the diagnosis (and rule out other diagnoses) and assess the degree of inflammation/presence of necrosis, but they do not suggest a timeframe. The mesangial hypercellularity (M), endocapillary proliferation (E), segmental sclerosis/adhesion (S), tubular atrophy/interstitial fibrosis (T), and cellular or fibrocellular crescents (C) (MEST-C) score in conjunction with the Oxford Classification of IgAN in children can be used to predict risk of progression and support treatment decision making.

The treatment of IgAN differs between children and adults. The pediatric population with IgAN is more limited and more complex to study, and whether children should be treated the same as adults remains uncertain. Suggested treatments for adults with IgAN have placed a greater focus on conservative therapies, focusing more on nonimmunosuppressive treatment with ACE inhibitors and ARBs, whereas suggested treatments for children with IgAN tend to be more active, often including immunosuppression. This field is changing rapidly and there may be more focused therapies in the near future. For detailed discussion of the therapeutic approach to IgA, see Chapter 33 .

For those children who remain asymptomatic but who have more active disease, as reflected by a first morning urine protein-to-creatinine ratio of >0.5 mg/mg (>56.5 mg/mmol), ACE inhibitors and/or ARBs are generally indicated. The use of ACEI and/or ARB in pediatric patients with IgAN has been shown to be safe and to reduce proteinuria. The sodium glucose cotransporter 2 (SGLT2) inhibitors are indicated in adults and are likely a useful addition, especially in children with persistent proteinuria. Blood pressure control is important. Children with IgAV tend to receive nonsteroidal antiinflammatory drugs for joint pains and inflammation; these drugs should be discontinued if renal disease develops.

In children who present with nephrotic-range proteinuria or NS, additional treatment is required. Immunosuppressive treatment including corticosteroid therapy and possibly addition of cyclophosphamide, azathioprine, mycophenolate mofetil, or tacrolimus may be indicated. The most common protocol is oral prednisone 1 to 2 mg/kg/day (maximum dose 60 mg/day) for 4 weeks tapered over 4 to 6 months, though intravenous methylprednisolone may also be used.340 Though typically reserved for patients with more active disease, it has been suggested corticosteroids reduce the risk of progression to ESKF, regardless of initial eGFR and in direct proportion to the extent of proteinuria. A Japanese RCT investigating immunosuppressive treatments for IgAN found the addition of prednisone, azathioprine to heparin-warfarin, and dipyridamole was associated with a significant reduction in proteinuria, serum IgA concentration, mesangial IgA deposition, and glomerulosclerosis. Short courses of low-dose steroids are given in IgAV periodically for abdominal or joint symptoms. These have no impact on the development of kidney disease as doses are not high enough for treatment effects.

Other immunosuppressive therapies including MMF, cyclophosphamide, CNIs, and rituximab are less often used due to a relative lack of clear evidence to support more widespread use. KDIGO guidelines do not recommend mycophenolate mofetil in IgAN. Cyclophosphamide has shown promise in adult IgAN but not pediatric cases, and a limited effect has been seen with CNIs and rituximab. ^, TRF-budesonide has shown efficacy as a potential second-line treatment in pediatric IgAN, though further large-scale studies are required. Other future therapies currently under investigation include hydroxychloroquine combined with RAS inhibitors, inhibitors of endothelin-1 receptors, inhibitors of the BAFF-TNF receptor family, and several complement inhibitors including eculizumab.

Some nonimmunosuppressive treatments for IgAN have reported varied success. Fish oil, vitamin E, and tonsillectomy had uncertain effects on improving proteinuria or preventing eGFR decline. The KDIGO guidelines suggested tonsillectomy not be performed in patients with IgAN without a clinical indication beyond IgAN. The Chinese herbal medicine Sairei-to (TJ-114), although not widely used, was found to be more effective than no treatment in a randomized controlled trial by the Japanese Pediatric IgA Nephropathy Treatment Study Group, conducted in children with mild IgAN disease treated for 2 years.

The long-term outcome for children with IgAN is highly variable. Approximately one-third of children will experience a complete remission of disease. Long-term studies have reported the development of progressive CKD in 9% at 15 years from diagnosis and ultimately ESKF in 20% to 27% of children. However, mild cases of IgAN in children might be missed with manifestation of irreversible damage only decades after the true onset, as 50% of subjects with IgAN enter renal replacement treatment before the age of 50 years.

In general, poor clinical prognostic indicators include persistent high-grade proteinuria and hypertension, while poor histologic prognostic indicators include higher percentages of glomeruli with crescents, adhesions or sclerosis, significant tubulointerstitial changes, subepithelial electron-dense deposits, or lysis of the GBM.

For children with IgA-vasculitis nephritis, long-term outcomes are less clear due to marked variability in disease severity among the reported cases. The risk of progression to end-stage renal disease requiring dialysis in children varies from 2.5% to 25%, but it is on average around 8%.

KD is a vasculitis that typically involves the mucosa and skin and is known to also preferentially affect coronary vessels. This common vasculitis is defined by a child having at least 5 days of fever, accompanied by four of the following five criteria: 1. edema, erythema, or desquamation of the hands, feet, or perineal area; 2. bilateral nonpurulent conjunctival injection; 3. polymorphous exanthema (primarily truncal); 4. oral and pharyngeal mucosal injection; and 5. cervical lymphadenopathy (typically unilateral). KD only rarely has renal manifestations, which can include sterile pyuria, proteinuria, AKI with tubulointerstitial changes, and rarely renal artery aneurysms. Nephrotic syndrome has also been reported, although it appears to remit spontaneously without glucocorticoid therapy.

PAN is now defined as a necrotizing arteritis involving small or medium arteries, without evidence of antineutrophil cytoplasmic antibodies or vasculitis in venules, capillaries, or arterioles. While uncommon in both children and adults, specific criteria for diagnosing pediatric PAN have been published. ^, This disease is specifically distinguished from microscopic polyangiitis (MPA) pathologically by its lack of ANCAs or necrotizing glomerulonephritis and clinically by its higher incidence of gastrointestinal symptoms and peripheral neuropathy. Clinical presentation typically includes fever, skin lesions, and/or myalgia, with involvement of the kidneys, heart, and/or lungs occurring in 15% to 20% of children. Notably, the major renal manifestations result from involvement of medium-sized vessels and include renovascular hypertension and aneurysms with the potential for rupture or hemorrhage. Treatment generally includes oral and/or IV glucocorticoids combined with cyclophosphamide.

Systemic lupus erythematosus (SLE) is a common systemic inflammatory autoimmune disease that can affect many organ systems. While renal involvement may not be present at the initial disease presentation, most children with SLE will develop renal involvement at some point in their disease, and lupus nephritis often becomes among the most significant predictors of morbidity and mortality among children with SLE. For example, data from adults have reported that approximately 10% of patients who develop lupus nephritis will progress to ESKF. This section does not address the initial diagnosis of SLE but focuses instead on the diagnosis and treatment of lupus nephritis among children previously diagnosed with lupus. Lupus nephritis is discussed in more detail in Chapter 31 .

Approximately 20% of lupus cases are diagnosed during childhood with an annual incidence of 0.3 to 2 cases per 100,000 childhood population and a higher prevalence in certain ethnic groups, such as African American, Hispanic, and Asian populations. ^, Lupus nephritis occurs in 50% to 82% of children in comparison with 20% to 40% of adults with SLE. SLE is notable for its strong predilection for females, with the female-to-male ratio ranging from 1.3:1 among prepubertal children to 4.5:1 among adolescents to 8 to 15:1 among adults. The age of onset in pediatric SLE varies, but it most commonly presents during adolescence, with a peak incidence between 12 and 16 years of age.

The diagnosis of lupus nephritis in patients with SLE may be clinically subtle, making screening urinalyses (at least yearly) of all patients with SLE important. The most common clinical manifestations of lupus nephritis include proteinuria (100%), which may range from mild to NS (50%), followed by microscopic hematuria (80%), tubular abnormalities (70%), and AKI (60%). In children with SLE in whom nephritis is suspected, the renal evaluation should include a urinalysis and renal function panel and renal biopsy should be considered.

The approach to the treatment of lupus nephritis is similar in adults and children as outlined in Fig. 71.12 . Hydroxychloroquine is recommended for all patients with lupus to reduce the risk of flares, ESKF, and mortality, with a daily dose of <5 mg/kg to avoid retinopathy. Children on hydroxychloroquine require regular ophthalmologic follow-up. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the preferred supportive renoprotective therapies.

Treatment strategies for the different classes of LN definitions.

∗Proteinuria: 0.5 g/24 hour or UP:CR >50 mg/mmol in a urine sample; ∗∗persistent proteinuria: presence of proteinuria for >3 months; DMARD: MMF, AZA, CNI, intravenous CYC; +severe disease, e.g., impaired eGFR, estimated glomerular filtration rate (1 g/m ² /day), biopsy-proven crescentic glomerulonephritis. AZA, Azathioprine; CNI, calcineurin inhibitors; CsA, ciclosporin; CYC, cyclophosphamide; DMARD, disease-modifying antirheumatic drug; GC, corticosteroids; LN, lupus nephritis as classified by the ISN/RPS 2003 classification system; MMF, mycophenolate mofetil; MP, methylprednisolone; RTX, rituximab; TAC, tacrolimus.

(From Groot N, de Graeff N, Marks SD, et al. European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative. Annals of the Rheumatic Diseases . 2017;76[12], 1965–1973.)

Immunosuppressive therapy for lupus nephritis is determined by biopsy-determined class and the degree of activity versus chronicity. ^, The Single Hub and Access Point for Paediatric Rheumatology in Europe (SHARE) guidelines for class I and II lupus nephritis suggest low-dose oral glucocorticoids, tapering over 3 to 6 months, with disease-modifying antirheumatic drugs (DMARDs) like MMF or AZA for persistent proteinuria. For children with class III and IV ± V lupus nephritis with signs of activity on the kidney biopsy, induction therapy should include high-dose glucocorticoids combined with either MMF or cyclophosphamide. MMF is favored due to its improved safety profile, particularly for pediatric patients. The regimen typically consists of pulse intravenous methylprednisolone for 1 to 3 days, followed by daily oral prednisone at 1 to 2 mg/kg/day tapered over a few months down to a maintenance dose. MMF dosing is typically 1200 to 1800 mg/m ² / per day (maximum dose 1500 mg twice daily) for 6 months followed by maintenance dosing. ^, Therapeutic drug monitoring of MMF is beneficial in optimizing therapeutic efficacy as there exists high interindividual variability of mycophenolic acid (MPA) exposure at a given dose of MMF. Cyclophosphamide may be given intravenously (500–1000 mg/m2 monthly for ∼6 months), or less commonly orally (2 mg/kg daily for ∼6 months), to be most commonly followed by MMF as maintenance therapy. Newer therapies such as belimumab and voclosporine may be used in combination with other therapies from induction. Belimumab is a monoclonal antibody that inhibits the activity of the B cell survival cytokine BAFF (B cell activating factor). In the large BLISS-LN RCT in adults, it has shown favorable outcomes of primary renal efficacy (43% vs. 32%; P=0.03) and complete renal response (CRR) (30% vs. 20%; P=0.02) compared with the placebo group when added to MMF or reduced-dose cyclophosphamde. Voclosporin is a cyclosporin analog that has shown to be superior in adults to standard induction therapy (with MMF and corticosteroids) at both 24 weeks (CRR: 32.6% [low-dose] vs. 27.3% [high-dose] vs. 19.3% [placebo]) and 48 weeks (CRR: 49.4% [low-dose] vs. 39.8% [high-dose] vs. 23.9% [placebo]). In 2021, voclosporin was approved for the treatment of lupus nephritis in adults in combination with background immunosuppression. If voclosporine is not available, other CNIs (i.e., tacrolimus or cyclosporine) can be used.

Maintenance-phase treatment typically includes low-dose oral glucocorticoids, along with agents such as MMF, with or without CNIs or azathioprine if MMF is not available or not tolerated.391 Low-dose cyclosporine and tacrolimus have shown promise, with complete renal remission occurring in 45.5% patients at 6months and 71.4% after 3 years. The optimal duration for maintenance-phase treatment of lupus nephritis remains uncertain, although suggested durations have ranged from approximately 3 years to as long as 8 years. ^, SHARE and KDIGO both recommend immunosuppression for at least 3 years.

Because of therapeutic advances in recent decades, 10-year survival rates are now approximately 90%. Despite these advances, only 55% of children with class III and IV lupus nephritis achieve renal remission and a 25% to 50% rate of lupus nephritis flares on therapy. The rate of kidney failure in high-income countries from pediatric lupus nephritis is about 15%. Long-term follow-up and close collaboration among pediatric rheumatologists, nephrologists, and other specialists are essential for optimizing outcomes and managing potential complications. Key issues must be considered including adherence, which may support the use of intravenous medications; growth, which encourages limiting glucocorticoid exposure; fertility, particularly as patients near adolescence, which favors minimizing cyclophosphamide use; prophylaxis against infections during the induction phase, minimization of the long-term effects of glucocorticoid use, and psychosocial factors, such as school attendance and peer socialization.

Complement plays a central role in the pathogenesis of IC-MPGN and C3G. The enhanced rate of C3 activation is evidenced by low serum C3 and increased levels of MAC/C5b-9 seen in patients with C3G and MPGN. Control of C3 convertase is normally regulated by the inhibitors: complement factor H (CFH), factor I (FI), and membrane-cofactor protein (MCP). It is now believed that central to the pathogenesis of these diseases is dysregulation of the alternative pathway (AP) C3 convertase in the circulation via one or more of the following mechanisms:

• •

  Autoantibodies to components of the AP C3 convertase such as C3 nephritic factor stabilizing this complex, thus prolonging its natural decay.

• •

  Mutations in or autoantibodies to CFH resulting in the absence or loss of function of CFH.

• •

  Mutations in C3 or CFB resulting in their gain of function with an exceedingly stable AP C3 convertase.

Overactivation of the C3 convertase leads to the deposition of C3 degradation products, such as C3b and iC3b, in the kidney, along with downstream products like C3d, which likely play a critical role in the development of C3G. However, the possibility that C3G may partially result from impaired clearance of these C3 degradation products from the glomeruli, especially in patients without clear signs of systemic or local complement alternative pathway (CAP) activation, warrants further investigation. In <10% of cases, dysregulation of AP C3 convertase is due to inactivating mutations in the genes coding for CFH, FI, or MCP or activating mutations in the genes coding for the two main components of the C3 convertase, C3 and factor B.

The complexity of the complement system and increasing understanding of the pathogenesis and availability of targeted therapies highlight the crucial role of complete genetic and biochemical analyses in the advanced management of IC-MPGN/C3G patients.

MPGN and C3G (C3GN and DDD) are rare diseases with an annual incidence of 1 to 2 per million (both pediatric and adult). ^, The median age of affected patients spans from 12 to 15 years (DDD) up to 28 years, with approximately 38% to 40% of cases manifesting the disease during childhood, with a slight male predominance. The clinical manifestations of MPGN and C3G typically include hematuria, proteinuria (up to nephrotic range), hypertension, and impaired kidney function. ^, There is notable symptom overlap between different subtypes of the diseases. Classic MPGN often manifests with features of both acute nephritic syndrome and nephrotic syndrome. Nephritic phenotypes are common in early-stage presentations with proliferative lesions on biopsy, while nephrotic phenotypes are more prevalent in advanced cases with repair and sclerosis. Crescentic MPGN is associated with rapidly progressive glomerulonephritis (RPGN). Hypocomplementemia is a key feature in MPGN, with low levels of both C3 and C4 typically seen in IC-MPGN and low C3 and normal C4 levels seen in C3 glomerulopathy and alternative-pathway dysfunction. It should be noted that a normal C3 level does not necessarily exclude the possibility of alternative-pathway dysfunction. ^, The risk of ESKF is comparable in C3G and IC-MPGN (4%–41% vs. 9%–41%).

Extrarenal features may be associated with C3G (DDD and C3GN) and MPGN. Ocular abnormalities including drusen-like deposits, which appear similar in both the Bruch membrane and the glomerular basement membrane, have been described with an associated risk of long-term visual impairment of approximately 10%. ^, Additionally, acquired partial lipodystrophy (aPL), which is characterized by the loss of subcutaneous fat in the upper half of the body, may precede the renal manifestations of C3G and may be associated with decreased C3 levels and the presence of C3NeF. ^,

MPGN and C3G most commonly present as acute nephritis or NS, though there is considerable clinical overlap with presentations of other forms of renal disease. Complement analysis (e.g., C3 and C4 levels, CFB levels, C3b breakdown products, and soluble C5b-9) may be useful; however, normal results do not exclude the diagnosis. The measurement of nephritic factors or other complement autoantibodies (e.g., anti-CFH, CFB, and C3b) may also be supportive; however, these assays are neither standardized nor widely available and lack diagnostic specificity. Genetic complement testing may be valuable and is—particularly in the background of the increasing number of identified disease-causing mutations in the CFHR locus—highly recommended and discussed further in Chapter 36 . Ultimately, the diagnosis is finalized by renal biopsy. The renal pathologic characteristics on biopsy vary significantly between subtypes of MPGN. Additionally, within the same subgroup of MPGNs, and even in a given patient, these features can differ from one kidney biopsy to a subsequent one. Kidney biopsy findings and eGFR are the best predictors of disease progression.

The differential diagnosis of a setting of nephritic/NS with hypocomplementemia (in particular, low C3 and C4 levels) is narrow and mainly includes IC-MPGN/C3G and SLE. Features that support a diagnosis of SLE include arthralgias; rashes; and neurologic, hepatic, lung, or cardiac involvement combined with laboratory evidence of immune dysregulation including antibody-mediated hemolysis, leukopenia, coagulopathy, myositis, or hepatitis. Postinfectious glomerulonephritis (PIGN) represents an acute form of C3G, possibly accompanied by elevated antistreptolysin (ASO) titer or anti-DNase titers, which may resolve spontaneously. Some patients initially present with PIGN and later develop C3G, necessitating careful differentiation during the diagnostic process. Persistence of low C3 for >3 months in a child thought to have PIGN should prompt consideration of C3G and kidney biopsy. As MPGN and C3G may present with normal complement levels, they should also be considered in any differential diagnosis for glomerular disease even with normal C3 and C4 levels. CFHR5 nephropathy, caused by a heterozygous mutation in the CFHR5 gene, leads to autosomal dominant inheritance of glomerulonephritis and kidney failure and has so far been reported only in individuals from Cyprus. However, it should also be considered in patients outside Cyprus who present with persistent microscopic hematuria and synpharyngitic gross hematuria, with or without a family history of ESKF.

Currently, there is no universally effective treatment for primary C3G and IC-MPGN, and current management strategies aim to control renal inflammation and target symptoms. General management is similar to other proteinuric glomerulopathies including a low-salt diet, treatment of hypertension, and treatment of dyslipidemia. Additionally, ACEi or ARBs are used in many patients with IC-MPGN/C3G due to their antiproteinuric and antihypertensive effects, as well as their association with better renal survival. ^, Treatment of arterial hypertension and CKD/ESKF follows established standards.

Current KDIGO guidelines suggest a trial of mycophenolate mofetil (MMF) with low-dose oral glucocorticoids for patients with moderate severity primary C3G described as proteinuria >0.5 g/day despite supportive therapy or moderate inflammation on renal biopsy or abnormal kidney function. Among pediatric patients with MPGN I treated with MMF and prednisone for a mean of 40 months, 56% achieved complete or partial remission. However, treatment failed in all patients with decreased C3 levels at diagnosis. ^{, ,}

Various alternative treatment protocols, including CNIs, cyclophosphamide, intravenous methylprednisolone boluses, monoclonal antibodies, and plasmapheresis, have been suggested for patients who do not respond initially. However, there are limited data available regarding the outcomes of these approaches.

CNIs have been used with variable success. One study demonstrated efficacy of the combination of low-dose steroids and CNI in patients with refractory MPGN with respect to reduction of proteinuria and decline in renal function in 94% after 2 years. In five adult steroid and cyclophosphamide-resistant MPGN patients, the combination of steroids and tacrolimus resulted in complete or at least partial remission in all patients after 24 weeks or longer. ^, In two children with MPGN and suboptimal response to long-term prednisone, a rapid and complete remission was achieved with tacrolimus. In another two patients with DDD, low-dose prednisone and cyclosporine A were able to induce remission. ^, In another study no treatment benefit of CNI was found in DDD patients.

Rituximab has been suggested for treatment of C3G and Ig-MPGN, although this too has not shown consistent benefit. Several case reports of MPGN (in particular, IC-MPGN) patients describe partial or complete remission after administration of rituximab (in 50% combined with steroids). By contrast, two DDD patients did not show any improvement in proteinuria or renal function but were rescued by eculizumab therapy. ^,

Eculizumab is an anti-C5 monoclonal antibody that prevents C5 activation and TP induction with the formation of the terminal complement complex (C5b-9). It has also been investigated in treatment of C3G with mixed outcomes. A retrospective trial in France showed 23% of patients resulted in a global clinical response, 23% had a partial clinical response, and 54% had no response. It has been suggested that eculizumab may be beneficial in treating inflammatory aspects of the disease with no or limited impact on C3 and immunoglobulin deposits. Some patients with specific complement mutations or dysregulation may benefit. Cost is usually a barrier. If successful, patients require lifelong vaccination and prophylaxis against meningitis.

Long-term outcome data for MPGN patients—in particular, applying the new classification—are limited. Disease progression occurs regardless of the underlying MPGN subtype in 40% to 50% of patients within 10 years of diagnosis. ^, Renal function (eGFR), nephrotic-range proteinuria, hypertension, and age at presentation are negatively correlated with long-term renal outcome. ^, In addition, the presence of glomerular crescents or DDD on biopsy are independent predictors of disease progression.

Recurrence of MPGN and DDD post-transplantation has been well described with recurrence rates ranging from 10% to 100%. However, the impact of disease recurrence on allograft survival remains controversial. Applying the new classification, MPGN recurrence rates for renal grafts are reported as 43%, 55%, and 60% for MPGN, DDD, and C3GN, respectively. The impact on allograft survival was not reported. In another study with 13 transplants, all of the 6 DDD and 4 of the 7 C3GN patients had disease recurrence, with graft failure occurring in 3 patients with DDD and 3 with C3GN. Overall, 5-year allograft survival years was 69%. Recent studies have shown eculizumab therapy is associated with lower rates of recurrence of C3GN and allograft loss.

The similar presentation of aHUS with other conditions can pose a diagnostic challenge. Prompt diagnosis and early initiation of therapy are essential for both TTP and aHUS to avert end-organ damage. The diagnosis of TMA is defined by clinical criteria including hemolytic anemia, thrombocytopenia, and renal and extrarenal disease manifestations. The three most likely diagnoses are STEC-HUS, aHUS, TTP, and less commonly, secondary-HUS from genetic abnormalities or vitamin B ₁₂ metabolism defects. ^, Fig. 71.13 outlines the diagnostic algorithm. Chapter 36 provides an overview of complement activation markers relevant to the identification of diagnoses/conditions possibly underlying secondary TMA.

Algorithm for workup of atypical hemolytic uremic syndrome.

(From Raina R, Krishnappa V, Blaha T, et al. Atypical hemolytic-uremic syndrome: an update on pathophysiology, diagnosis, and treatment. Ther Apher Dial. 2019;23[1]:4–21.)

STEC-HUS has a peak incidence in children <5 years old and typically follows a specific clinical sequence: Diarrhea developing 2 to 12 days after ingestion of the disease-causing bacteria (e.g., E. coli O157:H7) is initially nonbloody but becomes bloody in 60% to 90% of cases after 1 to 3 days. Microbiologic identification of E. coli in the stool via culture or polymerase chain reaction (PCR), detection of antilipopolysaccharide (LPS) antibodies specific for disease-causing bacteria, and Shiga toxin (ST) detection in blood via PCR supports the diagnosis. ^, TTP affects 0.1 per million children per year and is typically characterized by an ADAMTS13 activity level of <10%. Detection of anti-ADAMTS13 autoantibodies (inhibitors) or identification of an ADAMTS13 mutation confirms the diagnosis of TTP. ^, Secondary-HUS must be considered in patients with associated conditions/drugs outlined in Table 71.18 in which the treatment is withdrawal of an offending drug or treating a triggering condition.

In contrast, aHUS is a diagnosis of exclusion, which can be made once secondary TMA, STEC-HUS, and TTP are ruled out, and it requires relatively comprehensive evaluation of the complement pathway. Enzyme-linked immunosorbent assays (ELISA) allow for the individual assessment of the complement CP, LP, and AP. This involves assessing blood levels of C3, factor H, I, and B, as well as screening for anti–factor H antibodies. Flow cytometry is employed to examine membrane-cofactor protein (MCP) (CD46). Additionally, next-generation sequencing is conducted for genes, including CFH, CFI, CFB, C3, MCP, DGKE, and THBD.

Over the past 20 years, extensive genetic screening has identified the underlying genetic cause in about 50% of patients with TMA. Newer techniques such as whole-exome sequencing and whole-genome sequencing have allowed for a broader approach to genetic screening, and several mutations in genes not associated with the complement system were discovered in patients and families with aHUS/TMA. Although their prevalence is low, genetic testing applying next-generation sequencing should be considered in patients without complement alterations, who are unresponsive to complement-targeted therapy, such as eculizumab, and in patients presenting with specific clinical characteristics. Identification of the underlying genetic defect will guide treatment decisions and inform discussions about inheritability, long-term outcomes, transplantation, and posttransplant recurrence risk. Table 71.19 highlights the approach to various forms of TMA in children. Further discussion on workup and therapies for complement-related disorders can be found in Chapter 36.

Secondary TMA is a complication that can arise in various medical conditions including renal and stem cell transplantation, autoimmune diseases, and drug therapies. In transplant patients, both de novo and recurrent TMA can occur, often related to genetic mutations affecting the complement pathway, and treatment options include complement-targeted therapies like eculizumab. Patients with autoimmune conditions such as SLE and ANCA-associated vasculitis may also develop TMA, with complement dysregulation playing a central role in its pathogenesis. Drug-induced TMA is another subtype, often triggered by immunosuppressive or chemotherapeutic agents and managed through drug withdrawal and immunomodulatory treatments. Across these conditions, early diagnosis, genetic testing, and targeted therapy are crucial to improving outcomes.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cystic kidney disease. Genes involved in ADPKD include PKD1, PKD2, and less commonly ALG5, ALG8, ALG9, DNAJB11, GANAB, IFT140, and NEK8. Prognosis is based on allelic heterogeneity, genetic complexity, and the presence of cystic kidney disease modifier genes. ADPKD can be diagnosed in children due to symptomatic presentation, family screening, or incidental findings during abdominal imaging performed for unrelated reasons. Symptomatic presentations of ADPKD in children include nocturnal enuresis and polyuria due to impaired urinary concentration, systemic hypertension (affecting 20% of children), abdominal or back pain, and, less commonly, kidney cyst infections or gross hematuria. Although children with classic ADPKD typically maintain normal kidney function, hyperfiltration is observed in around 20%. Management of ADPKD in children is currently limited to supportive measures including blood pressure control, high water intake, salt intake restriction, maintaining a normal body mass index, and physical activity. Monitoring of the cyst burden and kidney length by ultrasonography is indicated in symptomatic children with ADPKD. ACE inhibitors or ARBs are used to manage hypertension. Tolvaptan has shown promise in slowing total kidney volume growth and kidney function decline, with clinical trials in children. Monitoring for extrarenal manifestations such as intracranial aneurysms is indicated in older children/late adolescence or those with strong family histories.

Autosomonal recessive polycystic kidney disease (ARPKD) is a rare cystic kidney disease that is generally diagnosed in the neonatal or infancy period, less likely during childhood, and rarely during adulthood. It is due to mutations in PKHD1 and DZIP1L, which affect fibrocystin/polyductin protein, leading to defects in tissue differentiation and cell proliferation in the kidney, liver, and pancreas. Severe cases of ARPKD manifest prenatally with enlarged hyperechoic kidneys, oligohydramnios, or anhydramnios, leading to the Potter sequence. Postnatal ARPKD presentation in infancy shows the presence of bilateral flank masses, enlarged hyperechoic kidneys, and bilateral cysts (usually <1 cm). At least 50% of ARPKD individuals progress to ESKF within the first decade of life. Extrarenal complications include hepatic fibrosis, resistant hypertension, and biliary abnormalities predisposing to cholangitis; therefore affected children require close follow-up by gastroenterologists with regular endoscopy to detect varices and surveillance for hepatic fibrosis. Some children will require liver transplantation.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder that manifests with kidney malformations and extrarenal features, such as retinal degeneration, polydactyly, obesity, hypogonadism, and developmental delay. Pathogenic variants in BBS1-BBS10 genes are commonly associated with BBS, with some variants also implicated in other ciliopathies. BBS10 variants tend to result in more severe phenotypes. In milder cases, prenatal ultrasonography may reveal normal kidneys, kidney cysts, or urinary tract malformations, while severe forms may show enlarged, hyperechoic kidneys lacking corticomedullary differentiation. Children with BBS can sometimes exhibit an ADPKD-like phenotype because certain BBS proteins regulate ciliary trafficking of the polycystin 1 protein. Due to the phenotypic overlap with other cystic kidney diseases, genetic analysis is crucial for diagnosis.

Meckel syndrome is an autosomal recessive ciliopathy, presenting with large polycystic kidneys, hepatic fibrosis, and occipital encephalocele. It is primarily linked to gene variants in MKS1, TMEM216, and TMEM67, with more than 10 loci identified. These genes encode transition zone proteins essential for ciliogenesis, and severe cases often exhibit enlarged kidneys and oligohydramnios on prenatal ultrasonography. Genetic testing is essential for diagnosis and counseling regarding pregnancy continuation and recurrence risk.

Nephronophthisis (NPHP) is a group of autosomal recessive disorders characterized by progressive tubulointerstitial fibrosis, inflammation, and kidney cysts. The condition is linked to more than 20 different genes, most commonly NPHP1, which encode proteins localized to the cilia, basal body, or centrosomes in kidney epithelial cells. These proteins interact with polycystin proteins, affecting cellular adhesion and signaling. NPHP can occur in isolation or as part of syndromic ciliopathies, such as Joubert syndrome, Senior-Loken syndrome, or short-rib thoracic dysplasia. NPHP presents in three subtypes based on the age of onset: infantile, juvenile, and adult-onset. The juvenile subtype, associated primarily with NPHP1 variants, is the most common, leading to ESKF around age 13. Other features include polydipsia, polyuria, anemia, and hepatic fibrosis. Adult-onset NPHP presents similarly but with a later onset of KF. Heterozygous carriers of NPHP including parents are generally asymptomatic, but they may carry the genetic risk for these ciliopathies.