Péter Tóth-Heyn

The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy.

Abstract The healthy term, and particularly the premature infant, is born with a very low glomerular filtration rate (GFR), controlled by a delicate balance of intrarenal vasoconstrictor and vasodilator forces. Vasoactive disturbances can easily further reduce the already low GFR. The newborn infant is thus prone to develop vasomotor nephropathy (VMNP) or acute renal failure (ARF). The main causes for ARF at this young age are prerenal mechanisms, and include hypotension, hypovolemia, hypoxemia perinatal asphyxia, and neonatal septicemia. Other causes include the administration of angiotensin converting enzyme inhibitors, indomethacin and tolazoline. The most-important factors governing the ultimate renal prognosis are the severity of the underlying disorder, the rapidity of an accurate diagnosis, prompt treatment, and avoidance of severe iatrogenic complications. The immediate treatment is of particular importance in VMNP, i.e., prerenal ischemic ARF, and consists of correcting abnormalities in fluid homeostasis and reduction of the complications of the acute azotemic state (uremia, hyperkalemia, acidosis, and hypertension). In severe and prolonged (established) ARF, temporary dialysis therapy may be indicated. Prerenal ARF with oliguria or anuria warrants immediate volume resuscitation. Special attention should be given to infants with congestive heart failure (CHF). The sick neonate with persistent oliguria and CHF should be treated with intravenous dopamine. Furosemide (FM) is the second line of therapy for babies with indomethacin-induced ARF. In most other conditions, the therapeutic effect of FM is limited to a transient increase in urine flow, without improving basic renal function. The special conditions of the maturing kidney have to be appreciated in order to protect babies from undue renal injury. With the increasing knowledge of the mechanisms governing the development of ARF, progress has been made in the development of new treatment modalities. For example theophylline, calcium antagonists, ATP-MgCl2, thyroxine, and a variety of cytokines may in the near future be used to prevent or ameliorate VMNP and/or recently established ARF. With a combination of time-honored and new therapeutic strategies, there may well be a brighter future for neonates with vasomotor, prerenal, ischemic ARF.

ROLE OF BRADYKININ IN THE NEONATAL RENAL EFFECTS OF ANGIOTENSIN CONVERTING ENZYME INHIBITION

The vascular effects of angiotensin converting enzyme inhibitors are mediated by the inhibition of the dual action of angiotensin converting enzyme (ACE): production of angiotensin II and degradation of bradykinin. The deleterious effect of converting enzyme inhibitors (CEI) on neonatal renal function have been ascribed to the elevated activity of the renin-angiotensin system. In order to clarify the role of bradykinin in the CEI-induced renal dysfunction of the newborn, the effect of perindoprilat was investigated in anesthetized newborn rabbits with intact or inhibited bradykinin B2 receptors. Inulin and PAH clearances were used as indices of GFR and renal plasma flow, respectively. Perindoprilat (20 microg/kg i.v.) caused marked systemic and renal vasodilation, reflected by a fall in blood pressure and renal vascular resistance. GFR decreased, while urine flow rate did not change. Prior inhibition of the B2 receptors by Hoe 140 (300 microg/kg s.c.) did not prevent any of the hemodynamic changes caused by perindoprilat, indicating that bradykinin accumulation does not contribute to the CEI-induced neonatal renal effects. A control group receiving only Hoe 140 revealed that BK maintains postglomerular vasodilation via B2 receptors in basal conditions. Thus, the absence of functional B2 receptors in the newborn was not responsible for the failure of Hoe 140 to prevent the perindoprilat-induced changes. Species- and/or age-related differences in the kinin-metabolism could explain these results, suggesting that in the newborn rabbit other kininases than ACE are mainly responsible for the degradation of bradykinin.

Association between Heat Shock Protein 72 Gene Polymorphism and Acute Renal Failure in Premature Neonates

Heat shock protein (HSP)70 plays an important role in the ischemic tolerance of fetal and neonatal kidney. We have investigated the association of genetic polymorphisms of the constitutive HSP70 (HSP73) and the inducible HSP70 (HSP72) encoding genes with the risk of acute renal failure (ARF) in very low birth weight (VLBW) neonates. Thirty-seven VLBW neonates with ARF and 93 VLBW neonates without ARF were enrolled in the study. The presence of HSP72 (1267)AG and HSP73 (190)GC polymorphism was analyzed from dried blood samples by PCR and restriction length fragment polymorphism. Allelic prevalence was related to reference values obtained in 131 healthy adults. Stepwise binary logistic regression was applied to determine the independent effect of the established risk factors to the development of ARF. Sixteen of 37 VLBW neonates with ARF and 18 of 93 VLBW neonates without ARF were homozygous for HSP72 (1267)G allele (p ≤ 0.01). The association between HSP72 (1267)GG genotype and ARF remained at the level of significance (p = 0.05) when it was adjusted for established risk factors of neonatal ARF. Prevalence of HSP72 (1267)GG was also higher in VLBW neonates than in the reference population (p < 0.05) and in VLBW neonates with infant respiratory distress syndrome than in those without (p < 0.001). We found that in VLBW neonates carrying HSP72 (1267)GG genetic variation, which is associated with low inducibility of HSP72, the risk of ARF was increased. Therefore, VLBW neonates with (1267)GG might express less HSP72 and might be less protected against ARF.

Genetic polymorphisms and risk for acute renal failure in preterm neonates

Acute renal failure (ARF) affects about 10% of severely ill neonates. Recent studies have shown that genetic polymorphisms of proteins that play a role in neonatal physiology may contribute to individual susceptibility to both ARF and its risk factors. Our review summarizes the data collected to date. Studies have shown that the risk of preterm neonates for ARF is directly associated with a combination of high tumor necrosis factor-α producer and low interleukin-6 producer genotypes, as well as with low heat shock protein 72 producer genotype. Premature birth is itself the most important risk factor for a number of complications, including ARF, and recent studies have also shown an association between several maternal and fetal cytokine genetic polymorphisms and increased inflammatory response in preterm neonates. These polymorphisms could also be associated with increased risk for disorders such as sepsis and necrotizing enterocolitis, which lead to renal hypoperfusion and ARF. Genetic polymorphisms of the renin-angiotensin-aldosterone system have not been shown to directly influence risk for ARF. They may, however, be associated with patent ductus arteriosus, poor postnatal adaptation, and heart failure, which are all prevalent risk factors for ARF.

Variance of ACE and AT1 receptor gene does not influence the risk of neonatal acute renal failure

Abstract. High neonatal activity of the renin-angiotensin system (RAS) is crucial for the maintenance of glomerular filtration of the newborn. The aim of the present study was to investigate whether genetic polymorphisms leading to lower angiotensin converting enzyme activity (ACE) or impaired functionality of angiotensin II (AII) type 1 receptor (AT1R) might predispose very low birth weight newborns (VLBWs) to the development of acute renal failure (ARF). The medical records of 110 VLBW infants were analyzed. ARF developed in 42 of them during the first postnatal week, while 68 neonates exhibited normal renal function. The ACE I/D polymorphism and the A1166C variants of AT1R were determined from dried blood samples. The frequency of the ACE I allele did not differ in ARF and non-ARF groups (0.307 and 0.284); the frequency of the AT1R C1166 variant was also the same in ARF and non-ARF groups (0.250 and 0.227). Although low activity of RAS has been implicated in the development of neonatal ARF and data indicated that the functionality of RAS is influenced by the I/D variants of the ACE gene and the A1166C variant of the AT1R gene, we could not demonstrate any effect of these polymorphisms on the development of ARF in VLBW infants.

Endogenous Bradykinin Regulates Renal Function in the Newborn Rabbit

The developmental changes in the activity of the renal kallikrein-kinin system (KKS) are related to the hemodynamic changes occurring in the neonatal kidney. In order to clarify the functional importance of the renal KKS in the developing kidney, the effect of the bradykinin B2 receptor antagonist HOE-140 was investigated in newborn rabbits. Effective blockade of bradykinin effect by HOE-140 was demonstrated in 10 rabbits. In 10 additional animals the subcutaneous injection of 300 µg/kg HOE-140 resulted in an increase in renal vascular resistance with a consequent decrease in renal blood flow. Glomerular filtration rate did not change significantly, while the filtration fraction rose, indicating preferential efferent arteriolar constriction. Urine flow rate increased as well as the fractional excretion of potassium. No change in sodium excretion was observed. The present data suggest a regulatory role for the renal KKS in the immature kidney under basal conditions. By inducing predominant efferent arteriolar vasodilation, the KKS appears to play a key role in regulating the neonatal glomerular microcirculation. This is in sharp contrast with the mature kidney, where the KKS predominantly acts on tubular function as a diuretic-natriuretic factor.

Pajzsmirigy- autoimmunitás elofordulása 1-es típusú diabéteszes gyermekekben

UNLABELLED It is well known that patients suffering from an autoimmune disease are more prone to develop another one, too. The authors have previously shown frequent occurrence of celiac disease in patients with type 1 diabetes mellitus compared to the background population. Autoimmune thyroid disease, the most common autoimmune disease associated with type 1 diabetes mellitus, generally occurs after the manifestation of diabetes, in the second decade of life. The aim of the study was to investigate the prevalence of thyroid autoimmunity as well as the frequency of autoimmune thyroid disease in patients with type 1 diabetes mellitus. Their aim was also to compare the prevalence of autoimmune thyroid disease in patients with type 1 diabetes mellitus and in those with type 1 diabetes mellitus and celiac disease. METHODS Screening was performed in 268 patients with type 1 diabetes mellitus alone and in 48 children with type 1 diabetes mellitus and celiac disease, with anti-peroxidase and anti thyroglobulin antibody. In case of autoantibody positivity, testing thyroid function and ultrasonography confirmed the autoimmune thyroid disease. According to the results, frequency of autoantibody positivity was significantly higher in diabetic patients suffering from celiac disease (type 1 diabetes mellitus: 43 (16%), type 1 diabetes mellitus + celiac disease: 16 (33,3%), p < 0,01). Hypothyroidism due to thyroiditis was also more prevalent in patients with type 1 diabetes mellitus and celiac disease. CONCLUSIONS Due to increased risk, the authors emphasise the need of frequent screening for autoimmune thyroid disorder in patients with type 1 diabetes mellitus and celiac disease.

Bradykinin in the Newborn Kidney

The hemodynamics of the newborn kidney is governed by several hyperactive vasoactive substances, such as angiotensin II, endothelin, atrial natriuretic peptide, nitric oxide, and prostaglandins [1]. Until recently, the function of the vasodilating and diuretic peptide bradykinin in the renal hemodynamics of the newborn remained ill defined. In 1994, El-Dahr [2] reviewed exciting new data on the development of the renal kallikrein-kinin system (KKS). These data, especially the high expression of bradykinin B2 receptors, suggested a regulatory role for the peptide in the newborn kidney as an endogenous vasodilator. Moreover, a growth-regulating role and a perfusionpromoting role have been proposed for bradykinin. While the morphological development of the renal KKS has been widely investigated, there were no data on the physiological function of the system. The present review summarizes the presently available data on the development and function of the neonatal renal KKS.

Bradykinin and hypoxemia-induced renal changes in the newborn rabbit

Abstract. Acute hypoxemia causes a decrease in glomerular filtration rate (GFR) and renal blood flow (RBF) in newborns. These changes are partly mediated by local-acting vasoactive factors. We have previously shown that bradykinin (BK) has a vasodilatory role in the basic regulation of neonatal hemodynamics. The purpose of the present study was to evaluate whether BK can modulate the severe renal vasoconstriction associated with hypoxemia in the newborn rabbit. The effect of systemic hypoxemia (PaO2 approximately 40 mmHg) on renal function was investigated in 9 newborn rabbits (controls) and in 8 animals in which BK-B2 receptors were blocked by Hoe 140 (300 μg/kg subcutaneously), given prior to the induction of hypoxemia. The studies were performed under pentobarbital anesthesia at the age of 5 – 9 days. In control animals, acute hypoxemia caused a significant decrease in GFR and RBF and an increase in renal vascular resistance. Similar glomerular hemodynamic changes were observed in BK-B2 receptor-blocked newborn rabbits. These results indicate that BK does not play a significant role in the renal vascular changes of the hypoxemic-stressed newborn.

Role of continuous subcutaneous glucose monitoring in intensive care

Critical care associated with stress hyperglycaemia has gained a new view in the last decade since the demonstration of the beneficial effects of strong glycaemic control on the mortality in intensive care units. Strong glycaemic control may, however, induce hypoglycaemia, resulting in increased mortality, too. Pediatric population has an increased risk of hypoglycaemia because of the developing central nervous system. In this view there is a strong need for close monitoring of glucose levels in intensive care units. The subcutaneous continuous glucose monitoring developed for diabetes care is an alternative for this purpose instead of regular blood glucose measurements. It is important to know the limitations of subcutaneous continuous glucose monitoring in intensive care. Decreased tissue perfusion may disturb the results of subcutaneous continuous glucose monitoring, because the measurement occurs in interstitial fluid. The routine use of subcutaneous continuous glucose monitoring in intensive care units is not recommended yet until sufficient data on the reliability of the system are available. The Medtronic subcutaneous continuous glucose monitoring system is evaluated in the review partly based on the authors own results.