Jean-Pierre Guignard

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.

Why Do Newborn Infants Have a High Plasma Creatinine

Background. Plasma creatinine (Pcr) levels at birth are greatly elevated in relation to the size (and the muscle mass) of the newborn infant and remain so for 1 to 2 weeks. Particularly intriguing is the fact that Pcr levels are higher in preterm than in term infants and for a longer postnatal period. The smaller the birth weight, the higher the Pcr. This cannot be explained by maternal transfer of Pcr or by the absolute and relative (to adult body surface area) reduced glomerular filtration rate of the newborn. Perhaps the renal handling of creatinine is involved. Design. In 522 pairs of mothers and fetuses, maternal and fetal Pcr were compared from 16 weeks of gestation until term. Pcr was measured in 66 newborns of various birth weights and followed for 1 month. Creatinine clearance (Ccr) and inulin clearance (Cin) were measured simultaneously in adult (n = 8) and newborn (n = 20) New Zealand White rabbits. In the latter, nephrogenesis continues after birth and they are therefore a good animal model for the study of the renal function in premature infants. Patient. A case of a premature male infant is presented (gestation: 29 weeks; birth weight: 1410 g) suspected of having sepsis because of premature rupture of membranes and postpartum maternal fever. This suspicion was not confirmed. Blood chemistry evaluation showed a high Pcr at birth (0.85 mg/dL, 75 μmol/L), even higher than that of the mother (0.77 mg/dL, 68 μmol/L). The Pcr started to decrease after ∼1 week but remained elevated throughout 1 month of follow-up. Results. From the maternal-fetal Pcr measurements it was quite evident that during the second half of gestation the small molecular weight creatinine (113 dalton, 0.3 nm radius) of the mother and fetus equilibrates at all maternal Pcr levels. The newborn Pcr levels were not only high at the time of birth but remained so for more than 3 weeks. It was also shown that the smaller the infant the higher the Pcr levels. The results of the animal experimental data showed that adult rabbits had the normal physiologic pattern in which Ccr overestimates Cin (Ccr/Cin ratio >1.0). In contrast, the results in the newborn rabbits showed an unexpected underestimation of the Ccr vis-à-vis Cin (Ccr/Cin ratio <1.0). This means, as is explained at length in the “Discussion” of this article, that the preterm newborn infant reabsorbs creatinine along the renal tubule. Conclusion. The riddle of the high Pcr levels in term and particularly in preterm newborns seems to be solved. Once the umbilical cord is severed, the perfect intrauterine maternal-fetal biochemical balance is disturbed. Thereafter, the already transferred exogenous, adult-level creatinine will rapidly disappear in the first urine specimens passed by the now autonomous newborn infant. A new steady state is achieved in due time, based on independent neonatal factors. One of these factors is the unusual occurrence of tubular creatinine reabsorption. We hypothesize that this latter temporary phenomenon is attributable to back-flow of creatinine across leaky immature tubular and vascular structures. With time, maturational renal changes will impose a barrier to creatinine. From that point onwards, total body muscle mass, glomerular filtration rate, and tubular secretion will in health determine the Pcr level of the individual. plasma creatinine, tubular handling of creatinine, newborn, premature infants.

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.

Long-Term Effects of In Utero Exposure to Cyclosporin A on Renal Function in the Rabbit

The number of pregnant women who receive cyclosporin A (CsA) after transplantation or for autoimmune disease has increased. CsA and its metabolites can cross the placental barrier and thus interfere with fetal development. It was shown previously that rabbits that were exposed in utero to 10 mg/kg per d CsA from the 14th to the 18th day of gestation presented a 25% nephron reduction. Thus, this study was conducted to assess the long-term systemic and renal effects of a CsA-induced nephron reduction. Twenty-two pregnant New Zealand white rabbits were randomly divided into two groups: Twelve received 10 mg/kg per d CsA from day 14 to day 18 of gestation, and 10 were used as controls. Rabbits that were born to these animals were evaluated at 4, 11, 18, and 35 wk of life. Pups that were exposed antenatally to CsA presented first a permanent nephron deficit; second, glomerular, tubular, and intrarenal hemodynamics dysfunction; third, enlarged kidneys with numerous tubular and glomerular lesions; and, fourth, an endothelin-dependent systemic hypertension that worsened with age. In utero exposure to CsA induced a nephron reduction that led to systemic hypertension and progressive chronic renal insufficiency in adulthood. A long-term clinical survey is mandatory in infants who are born to mothers who were treated with cyclosporin during pregnancy.

The Renal Hemodynamic Effects of Ibuprofen in the Newborn Rabbit

In early childhood, nonsteroidal anti-inflammatory drugs are mainly used to either prevent or treat premature labor of the mother and patent ductus arteriosus of the newborn infant. The most frequently used prostaglandin-synthesis inhibitor is indomethacin. Fetuses exposed to indomethacin in utero have been born with renal developmental defects, and in both the unborn child and the term and premature newborn this drug may compromise renal glomerular function. The latter has in the past also been observed when i.v. indomethacin or i.v. acetylsalicylic acid (aspirin) were administered to newborn rabbits. The present experiments were designed to evaluate whether ibuprofen has less renal side effects than indomethacin, as claimed. Three groups of anesthetized, ventilated, normoxemic neonatal rabbits were infused with increasing doses of ibuprofen (0.02, 0.2, 2.0 mg/kg body weight) and the following renal parameters were measured: urine volume, urinary sodium excretion, GFR, and renal plasma flow. Renal blood flow, filtration fraction, and the renal vascular resistance were calculated according to standard formulae. Intravenous ibuprofen caused a dose-dependent, significant reduction in urine volume, GFR, and renal blood flow with a fall in filtration fraction in the animals receiving the highest dose of ibuprofen (2 mg/kg body weight). There was a very steep rise in renal vascular resistance. Urinary sodium excretion decreased. These experiments in neonatal rabbits clearly show that acute i.v. doses of ibuprofen also have significant renal hemodynamic and functional side effects, not less than seen previously with indomethacin.

In utero exposure to immunosuppressive drugs.

The number of pregnant women receiving immunosuppressants for anti-rejection therapy or autoimmune diseases is increasing. All immunosuppressive drugs cross the placenta, raising questions about the long-term outcome of the children exposed in utero. There is no higher risk of congenital anomalies. However, an increased incidence of prematurity, intrauterine growth retardation (IUGR) and generally low birth weight has been reported, as well as maternal hypertension and preeclampsia. The most frequent neonatal complications are those associated with prematurity and IUGR, as well as adrenal insufficiency with corticosteroids, immunological disturbances with azathioprine and cyclosporine, and hyperkalemia with tacrolimus. The long-term follow-up of infants exposed to immunosuppressants in utero is still limited and experimental studies raise the question whether there could be an increased incidence at adult age of some pathologies including renal insufficiency, hypertension and diabetes.

Long-term followup of renal functional reserve capacity after unilateral nephrectomy in childhood

PURPOSE We establish renal function and renal reserve capacity in the long-term followup of unilateral nephrectomy in childhood. MATERIALS AND METHODS We recalled 37 subjects who underwent unilateral nephrectomy during childhood (age less than 16 years) to determine glomerular filtration rate, renal plasma flow and functional renal reserve capacity after oral protein loading. Interval since nephrectomy was 0.5 to 10 years in 10 cases, 11 to 20 in 13 and more than 20 years in 14, during which regular repeated renal function tests were done at our hospital. None of the patients had hypertension or significant proteinuria and all developed normally into adults. A group of 7 healthy normal subjects with 2 kidneys served as controls. RESULTS Creatinine clearance increased 34% immediately after surgery from a mean plus or minus standard error value of 78.6 +/- 6 to 105.4 +/- 7.2 ml. per minute per 1.73 m.2, peaked 2 to 6 months postoperatively and then plateaued (approximately 125 ml. per minute per 1.73 m.2). This level of renal function was sustained for more than 20 years. At the present testing glomerular filtration rate and renal plasma flow were not different from those of the controls. Renal reserve capacity was normal (stable) only during the first decade after unilateral nephrectomy (approximately 6% decrease), and it decreased by 50% at 10 to 20 and 66% at 20 to 30 years later. CONCLUSIONS This long-term followup study demonstrates that a single remnant human kidney continues to function normally for more than 20 years. The prolonged increased workload does not interfere with normal development and maturation. The renal reserve capacity decreased significantly during the years may, however, indicate a vulnerability of the single kidney and raises the possibility of renal functional impairment with much longer followup.

Nitric oxide in the developing kidney

Abstract. Although nitric oxide (NO) has a well-established role in regulating renal function in the adult, recent studies point to perhaps an even more critical role for NO in maintaining basal renal blood flow (RBF) and glomerular filtration rate (GFR) in the developing kidney. The immature kidney has enhanced renal hemodynamic and functional responses to stimulation and inhibition of NO synthesis when compared with the adult, and these increased responses are not mediated by prostaglandins. Increased intrarenal activity of NO in the developing kidney counter-regulates the highly activated renin angiotensin system by modulating the angiotensin II-mediated vasoconstriction of the developing renal vasculature, the angiotensin II effects on GFR, as well as renin release. Localization studies demonstrate that NO acts on neonatal RBF and stabilization of GFR through an intrarenal distribution of the synthesizing enzyme, nitric oxide synthase, that is different from that of the adult. The developing kidney is dependent on NO to maintain RBF and GFR during periods of hypoxemia, protecting against renal injury, such as acute renal failure. In summary, NO is vital in the developing kidney to maintain normal physiological function and to protect the immature kidney during pathophysiological stress.

Risk factors for chronic rejection in pediatric renal allograft recipients

Abstract. To determine the risk factors predictive of graft loss from chronic rejection in pediatric renal allograft recipients, we reviewed the collaborative study database of the Société de Néphrologie Pédiatrique which registered 314 grafts from January 1987 to December 1991. Of the 289 grafts analyzed, 71 failed during follow-up, chronic rejection being the most common cause of graft loss (35%). The clinical features of the chronic rejection group (n = 25) were compared with those of the group without failure (n = 218). The variables tested by monovariate analysis were cyclosporine dose at 1 year, donor type, donor and recipient age, and acute rejection episodes. The incidence of graft loss due to chronic rejection was 4% (4/109) in patients who had no acute rejection and 16% (21/134) in those with at least one acute rejection episode (P = 0.002). Donor age (≤5 years) was a risk factor for chronic rejection (P = 0.024). Recipient age and donor type were not significantly different between the chronic rejection group and the control group. Using time-dependent covariates, the risk factors were an acute rejection episode (P = 0.003) and low cyclosporine doses at 1 year (P = 0.02). We conclude that acute rejection and low cyclosporine doses in these pediatric patients were risk factors for graft loss due to chronic rejection.

The Newborn Rabbit: A Model for Studying Hypoxemia-Induced Renal Changes

The newborn rabbit was used as an experimental model for studying renal changes during normocapnic hypoxemia. Renal extraction of p-aminohippuric acid (PAH), as assessed in 15 normoxemic and 8 hypoxemic rabbits amounted to 54.6 +/- 3.7 and 45.7 +/- 4.6%, respectively (NS). Changes in glomerular filtration rate (GFR), and renal blood flow (RBF) as assessed by inulin and PAH clearances, respectively, were determined during normoxemia and subsequent hypoxemia in 8 additional anesthetized and mechanically ventilated newborn rabbits. Normocapnic hypoxemia (PaO2 = 38.6 +/- 2.1 mm Hg) induced a significant fall in GFR from 2.10 +/- 0.21 to 1.51 +/- 0.18 ml/kg/min (p less than 0.01), in filtration fraction (p less than 0.01) and U/P inulin ratio (p less than 0.01). RBF, renal vascular resistance and urine flow rate did not change significantly. In comparison with other immature animal species the newborn rabbit appears a valuable and inexpensive model for the study of acute hypoxemia-induced renal changes.