Longitudinale Betrachtung der Nierenfunktion von Kindern mit Bartter-Syndrom unter Indometacin-Therapie

Bartter syndrome is a rare hereditary renal dysfunction within the tubulopathies. Defects in 5 different genes coding for ion channels (type I-III) or their regulators (type IV and V) lead to reduced salt reabsorption, which in this form of tubulopathy particularly affects the ascending part of the loop of Henle. The clinical presentation is highly dependent on the type and extent of the defect and ranges from mild symptoms to life-threatening electrolyte imbalances. The major symptoms are caused by salt loss due to the absorption deficit and consist mainly of polyuria and polydipsia, as well as hypokalaemia. Some forms of Bartter syndrome are also particularly threatening due to their prenatal presentation with polyhydramnios and the subsequent problems, especially prematurity. A causal therapy is not yet available. However, some symptom control can be achieved by therapy with cyclooxygenase inhibitors. Due to the favourable effect-side effect profile, indomethacin is of crucial importance. Due to the hereditary channel defects, the sodium chloride influx is also reduced in the macula, which leads to increased expression of cyclooxygenase 2 and thus to increased prostaglandin E2 levels. This causes increased activation of the renin-angiotensin-aldosteron-system via increased renin secretion, which indirectly aggravates hypokalemic alkalosis. Cyclooxygenase inhibitors intervene in this process by inhibiting the synthesis of prostaglandin E2 from arachidonic acid. However, cyclooxygenase inhibitors have several side effects, of which nephrotoxicity is the most important in this context. The aim of this dissertation was to observe the renal function of children with Bartter syndrome, who were at least temporarily treated with cyclooxygenase inhibitors (mostly indomethacin), in a longitudinal development. Serum and collected urine levels in the long-term development were considered as well. Retrospectively and retrolectively collected data of the first 20 years of life of 23 patients with Bartter’s syndrome, who were treated at the University Hospital Marburg, were evaluated. Within this collective, the tendency to preterm birth due to polyhydramnios could be confirmed, and the birth weight was correspondingly below the norm. The observation of body height after completion of length growth also shows values slightly below the norm. In the longitudinal analysis of all levels for glomerular filtration, the largest proportion was in stage 2 of chronic kidney disease according to KDIGO. Also, when evaluating the transverse glomerular filtration rates after reaching adulthood, it was found that with 11 patients, the largest proportion had a normal glomerular filtration rate of more than 90 ml/min/1.73m2. None of the patients developed renal function impairment higher than stage 3a according to KDIGO. Another important marker of renal function impairment is the albumin/creatinine quotient. For this parameter, the majority of the values recorded were in grade A1. Only a small proportion reached the most severe degree of damage A3. As expected, the serum values for sodium, calcium, chloride, magnesium and alkaline phosphatase were predominantly found in the normal range. As also described in other sources, the vast majority of serum potassium measurements obtained 99 were below normal, which in combination with the elevated levels of standard bicarbonate represents the symptom complex of hypokalemic metabolic alkalosis as a typical presentation of Bartter's syndrome. Because of excessive activation of the renin-angiotensin-aldosteron-system, serum levels of both renin and aldosterone were predominantly elevated. Although therapy with a cyclooxygenase inhibitor was apparently able to reduce symptom severity, the reduction of prostaglandin E2 synthesis was not sufficient to completely prevent the excessive renin angiotensin-aldosteron-system activation. Contrary to what is described in different sources, in the present patient population, the majority of serum phosphate values obtained were within the normal range and slightly above normal, rather than confirming the tendency towards hypophosphataemia. It can be discussed that the tendency to higher phosphate values is due to increased tubular reabsorption, as a result of intravascular volume deficiency as well as metabolic alkalosis. In the evaluation of the urine collected over 24 hours, polyuria is of particular importance, which also manifested in the form of increased diuresis. From puberty onwards, this showed a decreasing tendency. With decreasing polyuria, the daily excretions per kilogram of body weight of sodium, potassium and calcium also decreased, while the levels for creatinine excretion, as expected, increased with increasing muscle mass. The correlation of indomethacin dose and glomerular filtration rate was weakly positive but not significant. In contrast, the negative correlation of indomethacin and proteinuria was significant. Accordingly, higher daily indomethacin doses were associated with lower proteinuria. Conclusively, a t-test was performed to answer the question of whether people with Bartter syndrome who received long-term therapy with a cyclooxygenase inhibitor (usually indomethacin) had impaired renal function compared to the normal population. The t-test showed no significant difference between the mean values of glomerular filtration rate in adulthood, so the null hypothesis (renal function in people with Bartter syndrome and long-term cyclooxygenase inhibitor administration (mostly indomethacin) is not worse than that of the normal population) could not be rejected. In order to be able to make a statement about the long-term outcome of the kidney function, further observation of the patient collective is necessary, as well as the measurement of the glomerular filtration rate with more sensitive markers, for example by the determination of cystatin C.