Bartter syndrome, also known as heterogeneous secondary aldosteronism, was named after Bartter, who first reported it in 1962. The syndrome is characterized by growth retardation, polyuria, hypokalemic alkalosis, elevated plasma renin and angiotensin and aldosterone, normal blood pressure, and hyperplasia and hypertrophy of the glomerular paraglomeruli. It is a relatively rare clinical condition and is easily misdiagnosed, and the age of onset is predominantly pediatric. Many clinical conditions, including diuretics, frequent chronic laxatives, neurotic vomiting, and chronic interstitial nephritis can also present with a similar syndrome cluster, but the latter is not referred to as this disease.
According to a retrospective study of 28 cases in Sweden, the estimated incidence is 19 per 1 million. It has been reported worldwide and in all races, but the incidence is higher in blacks and slightly more in women than in men. The earliest age of definitive diagnosis is 20 weeks of gestation, the earliest reported postpartum is 6 days, and it is detected as late as 50 years of age. Thus, the disease is commonly seen in children, with more than half of those presenting with symptoms before the age of 5 years. There is a clear familial predisposition to the development of the disease, but vertical inheritance is rare. A family with four patients in two consecutive generations has been reported, with a mode of inheritance consistent with autosomal recessive features.
Etiology and pathogenesis
The primary cause of the disease is inconclusive. Most scholars believe that it is an autosomal recessive disorder. There have been reports of 5 out of 9 siblings in a family and 4 cases in 2 consecutive generations of a family. Possible etiologies.
1. sodium chloride loss renal tubular defects.
It can be proximal tubular defect, distal tubular defect, distal and proximal tubular defect, medullary loop ascending thick segment defect, or a part of membrane defect, etc.
2, Potassium loss renal tubular defects.
3, excessive renal prostaglandin production.
In 1981, Dunn suggested that excessive renal prostaglandin production may be the cause of this disease. Prostaglandin increases renin secretion by direct action or by promoting urinary sodium excretion, thus promoting angiotensin II generation of aldosterone release and K+ excretion, prostaglandin has a direct effect on aldosterone synthesis, and also decreases vascular tone and alters vascular reactivity to vasoactive substances including angiotensin II . Although increased urinary Na+ excretion by prostaglandins may be due to nonspecific hemodynamic effects (similar to other vasodilators), prostaglandin E2 causes increased K+ excretion and hypokalemia due to decreased Na+ reabsorption from the collecting duct and C1- reabsorption from the crude segment of the ascending branches of the renal medulla. However, some scholars believe that this is not the primary pathogenesis of the disease, because increased prostaglandin production and excretion are not seen in some patients with the disease, and most patients only partially improve their symptoms when prostaglandin synthesis inhibitors are applied, and the loss of Cl and urinary concentration dysfunction are not reversed when NSAIDs are applied, even if urinary prostaglandin E2 excretion is completely normal, thus, increased prostaglandin is more likely to be secondary to the alteration. Angiotensin II, renin and pressor drugs may stimulate phospholipase A to increase renal production of prostaglandins, and low blood potassium may also increase renal synthesis of prostaglandin E2, which may turn to normal when water restriction is applied This suggests that the increased prostaglandin excretion in this disease is due to polyuria. As the application of indomethacin can sometimes normalize all the abnormal manifestations of the disease, it may be determined that some patients have primary prostaglandin overproduction, which plays an important role in the pathogenesis of the development of this disease.
4. The vascular wall is hyporesponsive to angiotensin II.
Bartter initially suggested that hyporesponsiveness of the vascular wall to angiotensin II was the cause of the disease. This results in reduced vascular tone, reduced renal perfusion, and stimulation of compensatory hypertrophy of the glomerular parietal apparatus, resulting in increased secretion of renin, angiotensin and aldosterone, increased K+ excretion, and hypokalemia. Because of the low vascular response to angiotensin II, the blood pressure is normal, but it does not explain why the patient has no sodium retention and increased blood volume.
5, Primary glomerular paraplegia hyperplasia.
6, Increased primary atrial natriuretic peptide.
Although there are several hypotheses, there is no theory that can satisfactorily explain the pathogenesis of this disease. Most scholars believe that the disease is caused by impaired renal tubular reabsorption of Cl- and Na+ ions.
It is now believed that Bartter syndrome is an autosomal recessive disorder caused by mutations in the ion transport protein gene on renal tubular epithelial cells. Mutations in the NKCI2 gene have been identified in infantile Batter syndrome, which is located at 15q12-21, has 16 exons, encodes 1099 amino acids, and is a Na+-K+-2C1- channel with more than 20 mutant phenotypes. Classic Bartter syndrome is caused by mutations in the CICNKB gene, which is located at 1q38 and encodes a basolateral Cl- channel containing 687 amino acids, and about 20 mutant types have been identified. Adult Bartter syndrome, also known as Bartter-Gietlman syndrome, is caused by mutations in the thiazide-sensitive Na+-K+ channel gene (SCI12A3), which is located at 16q913 and encodes a 1,021 amino acid, and up to 40 mutations have been identified. In addition, mutations in the potassium channel gene (ROWK) have also been found in some patients. Therefore, Batter syndrome can be identified as a clinical syndrome caused by mutations in several of these ion channel genes.
Clinical presentation
The disease develops in about half of the cases in childhood. The youngest reported child is 6 days old, and the younger the age of onset, the more it affects growth and development.
The clinical manifestations of the disease are complex and varied, with hypokalemia predominating. Bartter’s syndrome is characterized by intermittent episodes of polyuria during the fetal period, resulting in excessive amniotic fluid at 22-24 weeks of gestation, requiring repeated amniotic fluid withdrawals to prevent preterm delivery.
In infancy, there are often polyhydramnios, polyuria, nausea, vomiting, loss of appetite, diarrhea, constipation, and unexplained fever, which can easily lead to dehydration. In addition, there are also signs of hypokalemia such as low muscle strength and symptoms of alkalosis such as intermittent hand and foot convulsions. When they grow older, 75% of them suffer from dwarfism, and about 1/3 of them have mental retardation.
The symptoms of hypokalemia are prominent in older patients, such as muscle weakness, polyuria combined with enuresis and vomiting, anorexia, thirst, nausea, and salt craving, with sudden onset and natural remission after several days. Although hypokalemia is severe, there is rarely limb paralysis, but there may be hand and foot convulsions. The sick child has no edema and normal blood pressure.
It has been reported that the most common symptom in children is growth retardation (51%), followed by muscle weakness (41%), wasting (3l%), polyuria (28%), convulsions (26%), and irritability (26%). The most common symptoms in the adult form are muscle weakness (40%), followed by fatigue (21%), convulsions (26%), and less common symptoms include light paralysis, abnormal sensory loss, nocturnal polyuria, constipation, nausea, vomiting and even intestinal obstruction, salt, vinegar or sour pickles, upright hypotension, short stature, mental retardation, gout, hypercalciuria, renal calcification, progressive renal failure, rickets, magnesium deficiency, and erythrocytosis. erythrocytosis, etc.
It is noteworthy that some patients (10% of children and 37% of adults) are asymptomatic and are diagnosed at the time of consultation for other reasons. Two patients with this disease have been reported to have a peculiar facial appearance with a large head, prominent forehead, triangular face, prominent auricles, large eyes, and drooping corners of the mouth.
Auxiliary examination
(i) Low blood potassium, mostly below 1.5 to 2.5 mmol/L. A sodium-restricted diet does not correct hypokalemia.
(ii) Urinary potassium excretion is still high in the presence of low blood potassium, mostly above 30 mmol/L.
(iii) metabolic alkalosis, blood pH mostly increases, sometimes up to 7.6, blood HCO3- concentration up to 40 mmol/L.
(iv) plasma renin activity and angiotensin II levels are significantly increased, and urinary aldosterone excretion is also increased.
(5) Increased urinary prostaglandin E2 and other prostaglandins of renal origin, and excessive excretion of urinary kinin-releasing enzyme.
(6) Induced increase in blood pressure [usually by 4.00 kPa (30 mmHg) systolic rise] and the concentration of intravenous angiotensin II required: significantly higher than in normal subjects.
(⑦) often have low blood calcium and magnesium.
(viii) renal biopsy showed marked hyperplasia of the glomerular parietal tissue, and electron microscopy showed a marked reduction in the endocrine granules of this cell, and in many cases a proliferation of interstitial cells in the renal medulla was seen.
Renal biopsy showed pathological changes such as membranoproliferative glomerulonephritis, interstitial nephritis, and renal calcification. Hyperplasia and hypertrophy of the paraglomerular apparatus are the main pathologic abnormalities in this condition, and all signs of increased renin synthesis can be seen from these cells. Electron microscopy reveals hypertrophy of the rough endoplasmic reticulum and the Golgi complex, which may be a renin deposition and increased renin synthesis. Immunocytochemistry has confirmed atrophy and marked flattening of the dense spot cells. The structural abnormalities of the dense patch caused abnormal renin secretion due to the failure of feedback regulation. Glomerular thylakoid cells proliferate and form crescent bodies, periglomerular fibrosis, especially smooth muscle cells of small arteries and tiny arteries are replaced by glomerular paracellular cells, thickening and sclerosis of small renal arteries reduce perfusion of the inlet arteries, which in turn can lead to increased renin secretion, which in turn acts on vascular smooth muscle to cause vasoconstriction, tubular atrophy and vacuole formation, and interstitial cell hyperplasia can be seen in the renal medulla, but it can disappear rapidly after potassium supplementation. The interstitial cell hyperplasia can be seen in the renal medulla but can disappear rapidly after potassium supplementation.
Overall, most cases have significant hypokalemia, usually below 2.5 mmol/L and as low as 1.5 mmol/L. Metabolic alkalosis is also common, with increased blood HCO3- (28-45 mmol/L) and increased or normal blood H+ values depending on metabolic mechanisms, hypokalemia or renal insufficiency. Hypochlorhydria and alkalosis are most severe in infants and children, with blood chlorine as low as (62±9) mmol/L.
Hyperreninemia, hyperaldosteronism, and insensitivity to angiotensin and pressor are also features of the laboratory tests for this disease.
Elevated blood and urine prostaglandins and increased excretion of bradykinin and renal vasopressin have also been reported.
The urine is hypotonic, with an alkaline pH, and the renal concentration and dilution function is often reduced, with proteinuria in about 30% of patients and reduced renal function in some patients.
Some patients may also have high urinary calcium, low blood phosphorus, low blood magnesium, increased intraerythrocytic sodium concentration and decreased sodium efflux, and occasionally hypercalciuria.
Diagnosis
The main points of diagnosis of this disease are.
1, hypokalemia (1.5 to 2.5 mmol/L).
2. High urinary potassium (>20mmol/L).
3, metabolic alkalosis (plasma HCO3->30mmol/L)
4.Hyporeninemia.
5, hyperaldosteronism.
6, Insensitivity to exogenous pressors.
7, Glomerular paraglomerular hyperplasia. Because typical glomerular paraglomerular hyperplasia must occur after years of hypokalemia, infant and child renal biopsy is only used as a reference indicator.
8. Hypochlorhydria (urinary chloride >20 mmol/L).
9, Blood pressure is normal.
10, urine specific gravity is normal.
11, Normal adrenal cortical function.
Differential diagnosis
1.Primary aldosteronism
There is hypokalemic alkalosis, but the blood renin and angiotensin II levels are reduced, and hypertension is combined with hypertension.
2.Reninoma
In addition to hypokalemic alkalosis, there is also obvious hypertension, and granulocytic tumor-like changes can be seen in the kidney pathology.
3.Liddle syndrome
It is a familial disease, with clinical manifestation of hypertension, blood potassium can also be reduced, with hyporeninemia and low aldosterone, the application of Amiloride or aminoglutethimide can significantly reduce hypertension.
4. Diuretic or laxative abuse or neurogenic self-induced vomiting
Similar symptoms may occur, and most of them can be diagnosed after history taking. However, in a few cases where the patient does not want to disclose the medical history, multiple urine biochemical tests can assist in the diagnosis. In cases of diuretic abuse, in addition to low potassium and low extracellular fluid (manifested by high renin activity), the urine contains high amounts of Na+ and Cl- excretion. In this case, urine examination should be continued several times, and if repeated examinations reveal either little Cl- or little Na+, it means that this is exactly the time when the diuretic is not used, and the previous manifestations are most likely caused by intermittent diuretic abuse. If necessary, the diagnosis can be fully confirmed by measuring diuretic and electrolyte excretion in the urine at the same time (only in very persistent cases). Furthermore, the hypomagnesemia in patients with true Bartter’s disease is often far more pronounced than that caused by diuretic application alone.
Patients with laxative abuse also often show low extracellular fluid volume, and urinary Na+ excretion should be very low. If metabolic acidosis is present in combination, it mostly indicates that more NH4+ will be excreted together with Cl-. Therefore, urinary Na+ rather than Cl- reflects the volume of extracellular fluid. Low Na+ with high Cl- in the urine suggests that NH4+ is being excreted in excess from the urine due to metabolic acidosis or hypokalemia. Conversely, if the urine is predominantly Na+ without Cl- or HCO3-, this indicates that the acid being excreted is an organic anionic acid.
Neurotic emesis is common in some women who wish to use emesis to lose weight. At this time most of the HCl in the stomach has been lost, so the urine contains very little Cl-, urine containing Na+ is still more, but alkaline can confirm the diagnosis.
5, loss of magnesium renal tubular lesions
Generally no growth disorder, kidney biopsy is also no specific performance above.
6.Gitelman’s syndrome
Gitelman syndrome is a variant of Bartter syndrome, also known as low urinary calcium, low blood magnesium Bartter syndrome. This disease is an autosomal recessive inheritance of renal tubular disease, clinical hypokalemia, hypomagnesemia, hypocalcemia, metabolic alkalosis, high renin, high aldosterone and normal blood pressure a disease. Urinary calcium and urinary creatinine ratio (urinary calcium / urinary creatinine) ≤ 0.2, and Bartter syndrome patients urinary calcium / creatinine > 0.2. Gitelman syndrome patients 100% have low blood magnesium, urinary magnesium increased.
7, other diseases
Part of the chronic interstitial nephritis including lupus nephritis, dry syndrome, etc. can also show similar clinical manifestations of the disease, can be diagnosed from the systemic symptoms of the underlying lesions.
Treatment
1. Potassium supplementation
Long-term high-dose oral potassium chloride to correct hypokalemia, dose >10mmol/(kg?d), sometimes up to 500mmol/d in older children, but high dose can cause stomach discomfort and diarrhea, difficult to tolerate.
2.Potassium-preserving diuretics
Spironolactone (Ativan) 10-15mg/(kg?d) or Aminopterin 10mg/(kg?d) can be used.
3.Prostaglandin synthetase inhibitors
Such as anti-inflammatory pain, ibuprofen, aspirin can improve clinical symptoms, correct hyperreninemia and hyperaldosteronism. Indomethacin (anti-inflammatory pain) is the most effective, the dose of 2-5mg/(kg?d), in order to avoid water and sodium retention, it is appropriate to start with a small dose. In cases resistant to indomethacin (anti-inflammatory pain), ibuprofen may be used instead at 25-30 mg/kg/day or aspirin at 30-100 mg/kg/day. prostaglandin synthase inhibitors alone do not alter renal potassium loss.
Among the 10 patients reported by Dillan, 6 cases treated with indomethacin (anti-inflammatory pain) for 6 to 24 months were significantly improved with accelerated growth, but 1 case developed duodenal ulcer after high dose application.
4.Angiotensin II converting enzyme inhibitors
Such as captopril (mercaptopropionic acid), has certain efficacy, the dose is 0.5 to 1mg/(kg?d), divided into 3 oral doses.
5.Punarolol (Tipsan)
β-adrenergic blocking drugs can reduce the activity of renin but the effectiveness has not been confirmed.
6, magnesium chloride
Used to correct hypomagnesemia.
Combined application of the above drugs, such as potassium and potassium retention diuretic and small doses of indomethacin (anti-inflammatory pain) when combined, better than the application of a drug alone.
Prognosis
If the syndrome is followed up for a long time and treatment is adhered to, clinical symptoms may be relieved to some extent, and dwarfism may improve with a delayed pubertal growth spurt, allowing height to catch up to normal levels. Interruption of treatment is often followed by death from infection, electrolyte disturbances and chronic renal failure. Very few children with mild disease have a better prognosis.
Those with infantile onset have severe symptoms, 1/3 have mental retardation, and may die from dehydration, electrolyte disturbances, and infection.
After the age of 5 years, almost all of them have growth retardation, and some of them show progressive renal insufficiency or even develop acute renal insufficiency. Of the 11 reported deaths, 10 were under the age of 1 year, mostly due to dehydration, electrolyte disturbances or recurrent infections, and most of the older patients and adults died of chronic renal failure.