CC BY
916
MEDICAL SCIENCES / «COyyOMUM-JOUTMaL» #19(142), 2022
UDC 616.61-008.6-036.1-071-053.3
Koliubakina L. V., Kretsu N.M.
Bukovinian State Medical University, Chernivtsi, Ukraine DOI: 10.24412/2520-6990-2022-19142-16-19
PECULIARITIES OF CONGENITAL NEPHROTIC SYNDROME COURSE IN A NEONATE
(A CLINICAL CASE)
Abstract.
Congenital nephrotic syndrome (CNS) is a hereditary disease caused by gene mutations and it is inherited according to the autosomal-recessive mechanism. The diseases may be manifested during the antenatal period or during the first three months of life. Clinical signs of CNS are massive hypoproteinemia, proteinuria, and diffuse swellings. The therapeutic approach of congenital nephrotic syndrome mostly consists of symptomatic therapy. Molecular-genetic study is a "gold" standard concerning genotyping of the disease.
The article presents a clinical case on clinical-paraclinical, pathomorphological and molecular-genetic peculiarities of congenital nephrotic syndrome Finnish type course manifested at the early neonatal period.
Keywords: congenital nephrotic syndrome, neonate, molecular-genetic examination.
Introduction. Congenital nephrotic syndrome (CNS) is a rare hereditary kidney disease caused by developmental disturbances of the structural-functional unit - nephron, and is characterized by massive hypoproteinemia, proteinuria, and diffuse swellings. The disease is possible to be verified during the intrauterine development at the 15-21st week of gestation by detection of alpha-fetoprotein level in the amniotic fluid followed by manifestation of the clinical signs during the first three months of life [3,5].
CNS can be clinically manifested as an isolated or syndrome form with multisystem signs. Genetic examination gives grounds to isolate primary CNS caused by gene mutations in one of the five genes (NPHS1, NPHS2, WT1, LAMB2, PLCE1) or chromosomal defects, and the secondary one associated with other diseases of a systemic or renal genesis [2,11].
According to the epidemiological studies, annual sickness rate among isolated forms of CNS ranges on an average from 2 to 7 cases per 100 000 of children. Today CNS Finnish type remains the most comprehensively studied. It was first found among the Finnish population, its rate is 1:8200 of the live-born, though it can be verified in children of various ethnic origin [1,4].
Congenital nephrotic syndrome Finnish type (type 1) is caused by mutations of NPHS1 gene (found in 1994) and localized in the chromosome 19q13.1 [OMIM 2563000]. At present over 180 mutations of this gene are described (including deletion, missense-, nonsense-mutations etc.) found in 98% of children among the Finnish population and in 39-80% of other nationalities [10]. The mechanism of inheritance of CNS FT is autosomal-recessive.
NPHS1 gene encodes synthesis of nephrin, a transmembrane protein, by podocytes - "zip-fastener" protein of the glomerular basal membrane preventing penetration of protein from blood to urine. NPHS1 mutations result in the inability of the slit diaphragm to function adequately.
Congenital nephrotic syndrome Finnish type is clinically manifested by a specific complex of symptoms: high proteinuria level (up to 20 g/L) with fluctuation of the parameter to hypoproteinuria (less 10 g/L),
hyperlipidemia that can increase with advance of the disease and swellings till the development of anasarca. In anamnesis of children with this pathology placental hypertrophy (about 25-50% of the body weight of a ne-onate), low body weight at birth, poor appetite, and weakness are found. Usually a neonate possesses phe-notype features including a small nose with a low bridge and dilated vertices [8]. Other signs may include thrombotic complications due to imbalance between coagulative and anticoagulative systems of hemostasis. Lowered oncotic pressure and electrolytic disorders are associated with circulating blood volume deficiency promoting microcirculatory disorders and blood rheo-logical properties. Due to the loss of immunoglobulins, complement factors B and D, the patients present an increased susceptibility to bacterial infections and sepsis development [9]. Because of the loss of thyroid hormones with urine clinical signs of hypothyroidism may develop which requires control of the markers of the thyroid gland function [8].
Today the results of genetic study are an alternative method to renal biopsy as a standard of diagnostics and choice of therapeutic approach of CNS in children [9].
The standard treatment of CNS FT is conservative and mostly symptomatic. It consists of continuous infusions with albumin substitution, antibacterial and an-ticoagulative therapy, correction of electrolytic disorders, indication of thyroid gland agents with the substitutive purpose (in case the diagnosis of hypothyroidism is confirmed) [7].
After the body weight of 7 kg is gained the majority of patients require bilateral nephrectomy to prevent massive proteinuria and kidney failure development. Early kidney transplantation when the body weight is 9-10 kg increases the chances for a favourable prognosis, but post-transplantation relapse may occur. CNS course is unfavorable due to a rapid development of the terminal stage of chronic kidney failure [6].
Objective of the study is on the basis of the clinical case to expand knowledge of pediatricians and neo-
«COyyOMUM-JMTMaL» #M№)), 2022 / MEDICAL SCIENCES
17
natologists concerning clinical-paraclinical and patho-morphological peculiarities of CNS FT course at the neonatal age.
The study is conducted according to the Helsinki declaration on ethical principles for medical research involving human subjects. An informed consent was obtained from the child's parents to carry out all the clinical-paraclinical examinations.
Clinical case: a boy M., was born in Chernivtsi Regional Perinatal Center from the I pregnancy developing with underlying acute respiratory viral infection of the mother with hyperthermia at the term of 30 weeks, chronic pyelonephritis (the pregnant woman took Ceftriaxone) and dropsy of amnion. Ultrasound investigation (USI) at the term of gestation of 30-31 weeks found kidney pyeloectasia and the signs of antenatal fetal infection. Genealogical anamnesis is complicated: on the mother's side - cardiovascular pathology, bronchial asthma; on the father's side - oncopathology. It was the first physiological labor at the term of gestation of 34 weeks due to premature rupture of the fetal membranes (waterless period - 48 hours). During labor the mother developed fever to subfebrile values. The boy was born with the body weight of 2 200 grams, body length - 47 cm. Apgar score - 7-7.
Immediately after birth the child's condition was assessed as moderate severity which was caused by cerebral depression syndrome, swellings (especially on the buttocks), belching during breastfeeding. During the first day the child's condition was characterized by a negative dynamics due to respiratory disorders, neurological symptoms (intensified hypotension and hypore-flexia), intensified swelling syndrome, and reduced nutritive status. After additional examination considering anamnesis and clinical manifestation the following diagnosis was made: «Early neonatal sepsis, septicopye-mia period - pneumonia, pyelonephritis, complicated by the signs of multiple organ failure with lesions of the respiratory system and digestive tract. CNS FT (hypo-proteinuria, massive proteinuria, glucosuria)? Acute kidney failure (with nitric secretion kidney function preserved). Polyserositis: hydropericarditis, peripheral swellings». The term of gestation - 34 weeks. Treatment: respiratory support, infusion therapy with partial parenteral feeding introducing albumin; antibacterial, substitutive therapy with parenteral introduction of immunoglobulins, which enabled to make the child's condition stable and transport the child to the intensive care unit for additional examination and treatment at the Municipal Nonprofit Institution (MUI) «Chernivtsi Regional Pediatric Clinical Hospital».
At the moment of hospitalization to the neonatal resuscitation unit child's general condition was severe due to respiratory disorders (respiratory failure 1-2 stage), diffuse swelling syndrome. The complex of nephrotic syndrome symptoms was confirmed at the resuscitation unit: hypoproteinuria (whole protein level -from 11,3 to 30,1 g/L (norm - 60-80 g/L), albumin level - from 13,2 to 20,2 g/L (norm - 38-54 g/L), increased cholesterol level in the blood serum - from 2,3 to 5,99 mmol/L (norm - 1,3-5,2 mmol/L), triglycerides - from 1,33 to 3,38 mmol/L (norm - 0-1,7 mmol/L). Pro-
teinuria level ranged from 0,99 g/L to 4,917 g/L, specific gravity was at the level of 1006-1010, glucosuria - from 6,0 to 111 mm/dm3. Electrolytic disturbances were not found. Examination for TORCH-infection (toxoplasma, other agents, rubella, cytomegalovirus, and herpes simplex) gave negative results. To exclude systemic diseases the level of double-stranded DNA, antibodies of class G immunoglobulins (its values were 0,05 MO/ml (positive - >46,0 MO/ml) ) were determined in the blood serum. Examination found the signs of transient hypothyroidism. Thus, blood analysis for thyroid hormones found the following: thyroid-stimulating hormone - 7,6 mc Mo/ml (norm - 0,3-4,0 mc Mo/ml), free thyroxin level - 7,2 pmol/L (norme - 9,020,0 pmol/L), triiodothyronine - 0,9 nmol/L (norm -1,2-3,2 nmol/L). USD of the kidneys found the following: both kidneys enlarged in size with increased echogenicity of the parenchyma and decreased cortical-me-dullar differentiation; left pyeloectasia.
Molecular-genetic examination found two mutations of NPHS1 gene, the variant c.2053G>T (p.Gly685Cys) and c.2746G>A (p.Ala916Thr) in ho-mozygous state in particular, which confirmed the diagnosis of CNS FT. Molecular-genetic examination of both parents found two mutations of NPHS1 gene, the variant c.2053G>T (p.Gly685Cys) and c.2746G>A (p.Ala916Thr) in heterozygous state in particular.
In the process of treatment to correct hypoalbu-minemia, hypovolemia and swelling syndrome several infusions were given: 20% albumin solution in the dose of 1 g/kg/day during 3-4 hours; to decrease proteinuria level angiotensin-converting enzyme inhibitor (Capto-pril in the dose of 0,2 mg/kg/day) was indicated, in the course of replacement therapy the child was given L-thyroxin in the dose of 2 mkg/kg/day. Considering associated immune deficiency state a combined antibacterial therapy and immunoglobulins (bioven mono) for intravenous infusions in the dose of 200 mg/kg/day were indicated. Considering increasing anemic syndrome single transfusion of packed red blood cells in the volume of 10 ml/kg was given, and Erythropoietin in the dose of 2000 MO every 7 days was indicated till the sixth month of age.
After the child's condition was stabilized on the 27th day the child was transferred to the pathological neonatal department. The child's general condition remained severe due to general swelling syndrome with prevailing localization on the face and lower limbs. Skin was pale, the turgor and elasticity of tissues was reduced. General hypotension and hyporeflexia remained. The child was breastfed. The therapy continued at the department under clinical-paraclinical monitoring.
After examination and treatment of the child the diagnosis was made: «Early neonatal sepsis, septicopy-emia period: purulent meningitis, neonatal infection of the urinary tract, pneumonia. CNS FT. Hypoxic-is-chemic encephalopathy, II stage, central nervous system inhibition syndrome. Early premature babies anemia of a severe degree and erythropoietin-dependent. Transient hypothyroidism. Femoral joint dysplasia. Prematurity - 34 weeks».
18
MEDICAL SCIENCES / «ШУУШШУОУМ-ШУГМаУ» #19(142), 2022
At the age of 1,5 month the child was transferred to the specialized nephrological department for further treatment at the Municipal Pediatric Clinical Hospital in Chernivtsi.
In spite of a complex of the measures conducted against the ground of a sharp deterioration of condition the case resulted in lethal outcome at the age of 5 months 6 days.
Autopsy found the following pathomorphological macroscopic changes of the kidneys: the kidneys are enlarged in size - 5,6хЗ,7хЗ,4 cm each, the capsule is easily removed, the renal surface is smooth, the shape retained, greyish-yellowish in color. The pattern is disturbed on the section - wide cortex with multiple cysts. The renal pelvises are dilated.
Microscopic examination of the biopsy patho morphological changes of the kidneys are found in the form of vascular plethora, stasis, sludge, erythrocyte aggregation. Hyaline, fibrin, erythrocyte clots, small-focal hemorrhages, hyaline-droplet epithelial dystrophy of the sinuous tubules, microcysts of the canaliculi with radial dilation from the capsule to juxtaglomerular area. Epithelium of the cysts is cubic eosinophilic, with eosinophil hyaline drops. Fetal glomeruli, minor arteries with thickened walls are found. Focal interstitial fibrosis, focal lymphoid infiltrations are detected.
The final postmortem diagnosis was made on the basis of the mentioned above. The major diagnosis -«CNS FT with autosomal-recessive type of inheritance, primary form, hormone-resistant». Complications -«Multiple organ incompatibility (by clinical signs). DIC-syndrome: multiple paravascular hemorrhages under the pulmonary pleura and epicardium, in the liver, adrenals, kidneys, adipose renal tissue, under the mucous membrane of the stomach, serous membrane of the intestines, soft cerebral membranes; desolation of the heart chambers and major vessels; stasis, sludge of the erythrocytes, fibrin and erythrocyte clots in the vessels of the microcirculation; general venous plethora of the internal organs. Acute focal lung emphysema. Pulmonary edema. Focal lung atelectasis. Dystrophic changes of the internal organs. Cerebral edema and its pia mater. Periventricular bilateral leukomalacia of the cerebral substance. Ascites (150 ml), hydropericarditis (3 ml). Anasarca. Axidental involution of the thymus III degree». Comorbid diagnosis - «congenital developmental defect of the urinary tract: bilateral pyeloec-tasia. Left hydrocele. Umbilical hernia. Severe erythro-poietin-dependent anemia (by clinical signs). Asymptomatic bacteriuria (by clinical signs)».
Conclusions: CNS can be formed during the in-trauterine development and is clinically manifested after birth by the total clinical key signs: hypoproteinuria, massive proteinuria, swellings and hyperlipidemia that can increase with advance of the disease. It was this complex of symptoms that became crucial for making the diagnosis and confirmed by the results of molecular-genetic examination of the child and parents.
References.
1.Barratt M, Avner ED, Harmon WE. (1999). Pediatric Nephrology. Fourth Edition. Lippincott Wil-liams&Wilkins. A Wolters Kluwer Company: 765-774.
2.Bernward GH, Bettina M, Christopher NV et al. (2007). Nephrotic syndrome in the first jear of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1 and LAMB2). Pediatrics. 119 (4): 907-919.
3.Brady T, Mitra A, Hooks J. (2014). Maternal serum alpha-fetoprotein level peak at 19-21weeks gestation and subsequently decline in a NPHS1 sequence variant heterozygote; implications for prenatal diagnosis of congenital nephrosis the of Finnish type. Prenat Diagn. 34: 1-3. doi: 10.1002/pd.4375.
4.Holmberg C, Antikainen M, Ronnholm K et al. (1995). Management of congenital nephrotic syndrome of the Finnish type (Review). Pediatr Nephrol. 9: 8793.
5.Jalanko H, Holmberg C, Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Emma F, Goldstein SL. (2016). Congenital Nephrotic Syndrome. In: Pediatric Nephrology. Springer-Verlag, Berlin Heidelberg. 1: 753-769. doi: 10.1007/978-3-662-43596-0-78.
6.Jalanko Н, Holmberg C. (2009). Congenital nephrotic syndrome. Pediatric Nephrology. Editors Avner ED, Harmon WE, Niaudet P, Yoshikawa N. Springer. 1: 601-619.
7.Luchaninova VN, Moskvina EA, Shavkin AL, Zvereva AYu, Kruchina MK. (2019). Vrozhdennyiy nefroticheskiy sindrom: trudnosti diagnostiki i lech-eniya. Tihookeanskiy meditsinskiy zhurnal. 4: 95-97. [Лучанинова ВН, Москвина ЕА, Шавкин АЛ, Зверева АЮ, Кручина МК. (2019). Врожденный нефро-тический синдром: трудности диагностики и лечения. Тихоокеанский медицинский журнал. 4: 9597].
8.Mauch T, Vernier R, Burke B, Nevins T. (1994). Nephrotic syndrome in the first year of life. Pediatric Nephrology. Ed. Holliday MA, Barrat TM, Avner ED. Baltimor: Williams&Wilkins: 788-803.
9.Maydannik VG. (2012). Nasledstvennyie vari-antyi nefroticheskogo sindroma u detey. Mezhdunarod-nyiy zhurnal pediatrii, akusherstva i ginekologii. 2 (3): 95-104. [Майданник ВГ. (2012). Наследственные варианты нефротического синдрома у детей. Международный журнал педиатрии, акушерства и гинекологии. 2 (3): 95-104].
10.Morozov SL, Dlin VV, Suhorukov VS, Vo-ronkova AS. (2017). Molekulyarna nefropatologiya: novyie vozmozhnosti diagnostiki zabolevaniy pochek. Rossiyskiy vestnik perinatologii i pediatrii. 62 (3): 3236. [Морозов СЛ, Длин ВВ, Сухоруков ВС, Ворон-кова АС. (2017). Молекулярная нефропатология: новые возможности диагностики заболеваний почек. Российский вестник перинатологии и педиатрии. 62 (3): 32-36].
11.Salomon R, Cubler MC, Niaudet P. (2000). Genetics of the nephrotic syndrome. Curr Opin Pediat. 12: 129-134.
