Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization (ORPHA:69063)
A rare, congenital glomerular disease due to maternal anti-neutral endopeptidase (NEP) alloimmunization characterized by severe renal failure and nephrotic syndrome at birth, which rapidly improves in the first weeks of life.
Epidemiology
The disorder has been described in 15 infants from 5 families originating from Portugal, the Netherlands, Italy, Germany and Morocco.
Clinical description
Presentation is at birth with nephrotic syndrome, acute renal failure (oligoanuria), or both. Very weak and transient proteinuria is also possible. Respiratory distress and hypertension may also be observed during the first days of life. Some degree of dysmorphism with retrognathism, low set ears and large fontanel may be observed in some cases.
Etiology
The disease is caused by the transplacental transfer of nephritogenic anti-NEP Abs (IgG1, IgG4 subtypes) from mothers with truncating mutations of the MME gene (3q25.2; coding for NEP), resulting in a loss of functional of MME. Absence of NEP induces an alloimmunization process, during pregnancy or following an earlier pregnancy, against the NEP antigen inherited by the fetus from the father. The Abs cross the placenta and bind to the NEP expressed on fetal podocytes, ultimately resulting in glomerular damage and proteinuria.
Diagnostic methods
Diagnosis is based on laboratory findings showing an increased serum creatinine concentration as well as the development of nephrotic-range proteinuria and hypoalbuminemia in the infant during the first days of life. Anti-NEP Abs may be detected in the infant's serum during the first couple of weeks after birth but disappear thereafter. Diagnosis of membranous nephropathy relies on the kidney biopsy. In some cases, it shows a severe and unusual form of membranous nephropathy, collapse of a majority of capillary tufts in the glomeruli with thickening of the capillary wall, and distension of Bowman's spaces. Marked tubular atrophy and severe lesions of the interlobular arteries and arterioles may also be observed. Immunofluorescence studies reveal subepithelial deposits of IgG in the glomeruli. Electron microscopy examination shows abundant electron-dense deposits typically containing annular formations on the outer aspect of the glomerular capillary wall and a marked atrophy of the brush border.
Differential diagnosis
The syndrome should be differentiated from other causes of early-onset membranous nephropathy such as congenital infections like syphilis and toxoplasmosis, and neonatal lupus erythematosus.
Antenatal diagnosis
Prenatal diagnosis is suspected from the 34th week of gestation by ultrasonography which may show oligohydramnios and enlarged fetal kidneys. NEP deficiency can be detected in women, using fluorescence-activated cell-sorter analysis, by incubating granulocytes with anti-NEP monoclonal Abs, or Western blotting of the urine with anti-NEP Abs. Dosage of IgG1 and IgG4 subtypes of anti-NEP Abs can be achieved in pregnant women by ELISA.
Genetic counseling
Transmission of NEP deficiency is autosomal recessive. Penetrance of the infant's renal disease is variable and depends on the quantity and quality of the mother's immune response (IgG4 (milder clinical symptoms) or IgG1 subclass antibodies). Mothers do not show any renal manifestations until the age of 40 when they develop peripheral demyelinating neuropathy.
Management and treatment
No cure exists. Management is mainly symptomatic and includes oxygenation ventilation for hypoxemia, administration of calcium-channel blockers and beta-blockers for blood-pressure control, management of nephrosis and renal failure if present. In neonates with severe presentation, i.e. renal failure and/or nephrotic syndrome, an exchange transfusion to eliminate circulating anti-NEP antibodies can be considered. From 4 weeks post-term, if proteinuria is still present, RAAS (renin-angiotensin-aldosterone system) inhibition may be started (usually captopril is the preferred agent, accompanied by gastroprotection). Intravenous polyclonal immunoglobulins and plasma exchanges may be envisaged in NEP-deficient mothers with increasing titers of anti-NEP IgG1 before pregnancy. Anti-CD20 therapy is another option but should be stopped 6 months before pregnancy.
Prognosis
Infants usually show a rapid improvement of renal failure and the nephrotic syndrome, although a severe form requiring prolonged dialysis may also be observed. Persistent albuminuria has been reported in some cases and postponed development of severe chronic renal failure may occur, especially in subsequent offspring of a NEP-deficient mother.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Dr Hanna DEBIEC  - Pr Pierre RONCO | ERKNet* - Dr Marina VIVARELLI | ERKNet*


                                * European Reference Network