Urinary protein to creatinine ratio during the first month of life in very preterm infants-a prospective cohort study (PROTIPREMA).

BACKGROUND: Preterm infants have physiological proteinuria and values of urine protein to creatinine ratio (UPr/Cr) are higher compared to full-term infants during the first week of life. Few investigations explored the changes of proteinuria in very preterm infants (VPI, ≤ 31 weeks of gestation) older than a week, and it is unclear whether high and persistent proteinuria is associated with kidney injury in this population. This study aimed to (1) observe the changes of UPr/Cr during the first month of life in VPI and (2) describe clinical and biological variables associated with the changes of UPr/Cr. METHODS: Spot urine samples for UPr/Cr were collected on the first day of life (DOL1) and then on DOL2-3, DOL5-6, second week of life (WOL2), WOL3, and WOL4 in VPI cared for in a third-level NICU. We tested the relationship of UPr/Cr with perinatal variables and diseases. RESULTS: A total of 1140 urine samples were obtained for 190 infants. UPr/Cr values (mg/mmol) (median with interquartile) at DOL1, DOL2, DOL3, WOL2, WOL3, and WOL4 were, respectively, 191 (114-399), 226 (152-319), 225 (156-350), 282 (200-488), 308 (188-576), and 325 (175-664). At the multivariate analysis, lower gestational age (GA) and increasing postnatal age were the only variables significantly associated with higher UPr/Cr values (p < 0.001). There was wide intra- and interindividual variability in UPr/Cr, especially in infants with higher GA and clinical stability. CONCLUSIONS: In VPI, UPr/Cr is higher at lower GA and increases with advancing postnatal age. High persistent proteinuria is not associated with clinical and biological variables reflecting kidney injury during the first month of life. A higher resolution version of the Graphical abstract is available as Supplementary information.

When the progresses in neonatology lead to severe congenital nephron deficit: is there a pilot in the NICU?

Advances in the care of neonates to the extreme limits of viability have increased the risk of severe comorbidities in surviving preemies. The respiratory and the neurodevelopmental consequences of premature birth and/or intra-uterine growth retardation have been well described. Because of the usual clinical silence of the kidney, the long-term renal consequences of low birth weight have not been as well studied. A case report illustrates the risk factors associated with low birth weight and prematurity and discusses the pathogenesis of the late consequences of the congenital nephron deficit associated with a low birth weight. Practical recommendations are given for a tight follow-up of these newly born preemies.

Use of diuretics in the neonatal period.

The use of diuretics is extremely frequent in sick neonates, the more so in very premature newborn infants. The use of diuretics in patients whose kidney function is immature necessitates a thorough knowledge of renal developmental physiology and pathophysiology. This review presents the basic aspects of body fluid homeostasis in the neonate, discusses the development of kidney function, and describes the mechanisms involved in electrolyte and water reabsorption along the nephron. Diuretics are then classified according to the site of their action on sodium reabsorption. The use of diuretics in sodium-retaining states, in oliguric states, in electrolyte disorders, and in arterial hypertension, as well as in a few specific disorders, is presented. Common and specific adverse effects are discussed. Recommended dosages for the main diuretics used in the neonatal period are given. New developments in diuretic therapy are briefly mentioned.

Maturation of glomerular filtration rate in neonates and infants: an overview.

Glomerular filtration rate (GFR) increases progressively throughout fetal life, matures rapidly after birth according to gestational and post-menstrual age, and reaches adult values by 1-year post-natal age. GFR is considered the best marker of kidney function, and in clinical practice, estimated GFR is useful to anticipate complications, establish prognosis, and facilitate treatment decisions. This review article summarizes the maturation of glomerular filtration and the factors and conditions that modulate and impair developing glomerular filtration, and discusses the techniques available to assess GFR in neonates and infants. We focused on simple, reliable, easily available, and cheap techniques to estimate GFR, which may provide valuable information on the renal aspects of the clinical care of this group of patients.

Renal aspects of metabolic acid-base disorders in neonates.

Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and growing neonates. The kidney, which represents the crucial ultimate line of defense against disturbances of acid-base balance, undergoes a complex maturation process during the transition from a fetal to an extra-uterine environment. This review article summarizes the physiology of acid-base regulation by the immature human kidney and discusses disorders of acid-base balance, such as metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. In conditions of metabolic acidosis, the serum anion gap and the urinary anion gap can be useful tools to define the nature of the acidosis. Metabolic acidosis can reflect a decrease in glomerular filtration rate, or be the consequence of selective disorders of proximal or distal tubular function. Most tubulopathies associated with metabolic acidosis observed in neonates are primary, hereditary, isolated tubulopathies. Proximal renal tubular acidosis is characterized by bicarbonate wasting, while the distal types of renal tubular acidosis are secondary to distal acidification defects. All tubulopathies are associated with hypokalemia, with the exception of type 4 hyperkalemic distal renal tubular acidosis. The transporter defects in the various acid-base tubulopathies are now well defined. Treatment of the acidosis varies according to the site and mechanism of the defect. Chronic renal tubular acidosis or alkalosis severely impair growth and calcium metabolism. Early rational therapeutic intervention can prevent some of the consequences of the disorders and improves the prognosis.

Preterm Birth: Long Term Cardiovascular and Renal Consequences.

BACKGROUND: Cardiovascular and chronic kidney diseases are a part of noncommunicable chronic diseases, the leading causes of premature death worldwide. They are recognized as having early origins through altered developmental programming, due to adverse environmental conditions during development. Preterm birth is such an adverse factor. Rates of preterm birth increased in the last decades, however, with the improvement in perinatal and neonatal care, a growing number of preterm born subjects has now entered adulthood. Clinical and experimental evidence suggests that preterm birth is associated with impaired or arrested structural or functional development of key organs/systems making preterm infants vulnerable to cardiovascular and chronic renal diseases at adulthood. This review analyzes the evidence of such cardiovascular and renal changes, the role of perinatal and neonatal factors such as antenatal steroids and potential pathogenic mechanisms, including developmental programming and epigenetic alterations. CONCLUSION: Preterm born subjects are exposed to a significantly increased risk for altered cardiovascular and renal functions at young adulthood. Adequate, specific follow-up measures remain to be determined. While antenatal steroids have considerably improved preterm birth outcomes, repeated therapy should be considered with caution, as antenatal steroids induce long-term cardiovascular and metabolic alterations in animals' models and their involvement in the accelerated cellular senescence observed in human studies cannot be excluded.

Acute Renal Failure in the Neonate.

Acute renal failure (ARF) is a common disorder in high-risk neonates. ARF may be oliguric or nonoliguric, the latter having a better prognosis. Risk factors for ARF include prematurity, respiratory and vascular disorders, heart failure, congenital uropathies, and the use of nephrotoxic drugs. Chemical analysis of urine and ultrasounds help differentiate the nature and the type of ARF: prerenal, intrinsic, or postrenal. Conservative management of prerenal forms of ARF consists in carefully restoring cardiac output and controlling fluid and electrolyte balances. Early relief of obstruction is mandatory in severe postrenal forms of ARF. Renal replacement therapy is often necessary when ARF is secondary to intrinsic renal damage: peritoneal dialysis is the treatment of choice. Hemodialysis and continuous venovenous hemofiltration may be used in specific cases. Overall prognosis of ARF depends on the nature and severity of the renal injury that has led to renal failure.

The adverse renal effects of prostaglandin-synthesis inhibitors in the newborn rabbit.

Nonsteroidal anti-inflammatory drugs are frequently used during pregnancy (premature labor, polyhydramnios) and the immediate postnatal period (closure of patent ductus arteriosus). This article evaluates the renal effect of 3 nonspecific COX inhibitors (aspirin, indomethacin, and ibuprofen) in newborn rabbits. Five groups of anesthetized, ventilated, normoxemic 6-day-old rabbits (n = 52) were administered intravenous aspirin (40 mg/kg), indomethacin (2 mg/kg), and ibuprofen (0.02, 0.2, 2.0 mg/kg, respectively). Renal function and hemodynamics as assessed by inulin and para-aminohippuric acid clearances were measured before and in the hour after drug administration. In all groups of animals, the nonselective COX inhibitors induced an increase in renal vascular resistance and a consequent decrease in glomerular filtration rate and renal blood flow. Urine flow rate decreased significantly in all groups, except in the group receiving the lowest dose of ibuprofen. In newborn rabbits, aspirin, indomethacin, and ibuprofen induced intense renal vasoconstriction, which resulted in impaired renal function. This observation illustrates the major renal protective role played by the vasodilatory prostaglandins during the neonatal period, when the kidney is perfused at very low perfusion pressure. We conclude that all COX inhibitors should be administered with the same caution to the preterm neonate.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit.

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.

Nonselective cyclo-oxygenase inhibitors and glomerular filtration rate in preterm neonates.

The adverse effects of nonselective cyclo-oxygenase (COX) inhibitors on the immature kidney have been described in newborn rabbits, but it is much more laborious and difficult to study its relative impact on renal function in human neonates. Amikacin clearance was therefore used as surrogate marker to study the impact of nonselective COX-inhibitors on glomerular filtration rate. Clinical characteristics and amikacin clearance of infants on respiratory support were retrospectively collected. Results in neonates in whom either ibuprofen-lysine or acetylsalicylic acid was administered prophylactically to induce closure of a patent asymptomatic ductus arteriosus were compared to infants not cotreated with any COX-inhibitor (Mann-Whitney U-, chi-square tests). Amikacin clearance was calculated in 142 infants, of whom 50 were cotreated with ibuprofen and 33 with acetylsalicylic acid. There were no significant differences in clinical characteristics between the three groups. Compared to controls (0.52, range 0.09-2.33 ml/kg/min), a significant similar decrease in amikacin clearance in infants cotreated with ibuprofen (0.38, range 0.13-0.80 ml/kg/min, p<0.01) or acetylsalicylic acid (0.38, range 0.13-0.78 ml/kg/min, p<0.01) was demonstrated. Using amikacin clearance as marker, a significant and similar reduction in glomerular filtration rate was documented in preterm infants cotreated with ibuprofen or acetylsalicylic acid.

Renal aspects of the term and preterm infant: a selective update.

This review discusses new aspects of normal and abnormal renal development that expand insight into the adaptation of the neonatal kidneys to the stress of extrauterine life. Highlighted are some pitfalls in measuring glomerular filtration rate in the neonate mainly caused by postnatal fluctuations in serum creatinine levels. Serum creatinine levels are correlated with the authors' recent finding of tubular reabsorption of creatinine in the immature neonatal kidney. Renal maldevelopment in premature and small-for-date babies has been shown related to serious medical problems in adult life, including hypertension. This finding presents the pediatrician with a new role in the time-honored vocation of preventing disease. Mutations in several genes may be responsible for most cases of congenital or hereditary renal aberrations. Two renal disorders, congenital nephrotic syndrome and neonatal acute renal failure, and one form of treatment modality of newborn infants, renal replacement therapy, are discussed in detail. These conditions are rare in general pediatric practice, but they illustrate some of the new developments in the renal care of the newborn. A word of caution is offered about the use of nonsteroidal anti-inflammatory drugs during pregnancy and the newborn period. All nonsteroidal anti-inflammatory drugs administered indirectly to the unborn fetus and directly to the young newborn impair renal structure (fetus) and function (both fetus and newborn). The new data have been obtained with genetic and molecular biology techniques and with established methods of developmental renal physiology. A better understanding of the pathogenesis of neonatal renal disorders will result in new diagnostic procedures and improved preventive and therapeutic possibilities relevant to the neonate with a renal disorder.

[Diagnosis and management of urinary tract dilatations detected in utero]. / Diagnostic et prise en charge des dilatations des voies urinaires dépistèes in utero.

About 1% of the newborns show abnormalities of the urinary tract, representing 25% of the antenatally detected malformations. Most of these urinary abnormalities are detected by prenatal ultrasound between the 14th and the 22nd week of gestation. Their outcome is determined during the first weeks of pregnancy and depends on the degree of renal impairment and the presence of associated extrarenal malformations. Establishing the outcome is often difficult, however it can be predicted by ultrasound and biochemistry of fetal urine. Prenatal management should consist in follow-up and careful organisation of the postnatal management of congenital uropathies. Every antenatally dilated urinary tract requires postnatal investigation. Postnatal ultrasound on the 3rd to 4th day of life is recommended for confirming or excluding urinary abnormalities. In case of persistence, ultrasound has to be completed by other radiologic methods. Voiding cystourethrography and/or nuclear renography allow to identify the origin of the observed abnormalities. Apart from a few situations needing immediate correction, surgical treatment is rarely indicated. The principal of postnatal management is prevention of urinary tract infections by antibiotic prophylaxis and a close follow-up until adulthood.

[Urinary calculi epidemiology in children]. / Epidémiologie de la lithiase urinaire chez l'enfant.

We identified 40 pediatric patients with urolithiasis. There were 27 boys and 13 girls. Initial symptoms were abdominal pain, with or without microscopic hematuria in 40% of the cases, and urinary tract infection/pyelonephritis in 25% of the cases. Stones were made of struvite (35% of the cases), calcium-phosphate (25%) or calcium-oxalate (20%). The high prevalence of struvite stones reflects the importance of urinary tract infection a major cause of urolithiasis in that specific age group. Hypercalciuria was the most common urinary biochemical abnormality, found in more than 50% of the children. In the absence of a spontaneous passage of the stone, extra-corporeal shock wave lithotripsy represents an excellent therapeutic option. This article emphasizes the importance of stone analysis and extensive biochemical investigations in children with urolithiasis, in order to avoid recurrence and potential progression towards chronic renal failure.

Lymphomatoid granulomatosis in a renal transplant patient.

Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive pulmonary angiitis considered as a variant of the lymphoproliferative disorder group. Patients with organ transplantation are at an increased risk for post-transplant lymphoproliferative disorders secondary to their immunosuppression. However, lymphomatoid granulomatosis has rarely been described in patients with renal transplantation. It often presents with severe pulmonary signs. We describe a case whose initial presentation was an isolated VIth nerve palsy. We review the radiological and pathological findings and discuss the etiopathogenesis and therapeutic options of this particular lymphoproliferative disorder. With careful and stepwise reduction in her immunosuppression, our patient showed a complete disappearance of her lymphomatoid granulomatosis, and she is clinically well more than 3 years after the diagnosis, with good kidney function.

The effects of losartan on renal function in the newborn rabbit.

The low GFR of newborns is maintained by various factors including the renin-angiotensin system. We previously established the importance of angiotensin II in the newborn kidney, using the angiotensin-converting enzyme inhibitor perindoprilat. The present study was designed to complement these observations by evaluating the role of angiotensin-type 1 (AT(1)) receptors, using losartan, a specific AT(1)-receptor blocker. Increasing doses of losartan were infused into anesthetized, ventilated, newborn rabbits. Renal function and hemodynamic variables were assessed using inulin and para-aminohippuric acid clearances as markers of GFR and renal plasma flow, respectively. Losartan 0.1 mg/kg slightly decreased mean blood pressure (-11%) and increased diuresis (+22%). These changes can be explained by inhibition of the AT(1)-mediated vasoconstrictive and antidiuretic effects of angiotensin, and activation of vasodilating and diuretic AT(2) receptors widely expressed in the neonatal period. GFR and renal blood flow were not modified. Losartan 0.3 mg/kg decreased mean blood pressure significantly (-15%), probably by inhibiting systemic AT(1) receptors. GFR significantly decreased (-25%), whereas renal blood flow remained stable. The decrease in filtration fraction (-21%) indicates predominant efferent vasodilation. At 3 mg/kg, the systemic hypotensive effect of losartan was marked (mean blood pressure, -28%), with decreased GFR and renal blood flow (-57% and -51%, respectively), a stable filtration fraction, and an increase in renal vascular resistance by 124%. The renal response to this dose can be considered as reflex vasoconstriction of afferent and efferent arterioles, rather than specific receptor antagonism. We conclude that under physiologic conditions, the renin-angiotensin is critically involved in the maintenance of GFR in the immature kidney.

[Glomerular filtration markers in pediatrics]. / Marqueurs de la filtration glomérulaire en pédiatrie.

The assessment of glomerular filtration rate (GFR) is critical for the diagnosis and management of renal diseases in pediatric nephrology. Ideally, it requires the measurement of the renal clearance of a filtration marker. Inulin, an exogenous marker, is the only compound the excretion of which occurs exclusively by glomerular filtration, with no tubular handling. Therefore, inulin clearance provides the most accurate method to measure GFR and is considered as the "gold standard", at all ages including very premature neonates. However, inulin dearance is cumbersome and alternative methods are used in clinical practice. If urine is available, endogenous creatinine clearance is the most reliable method. When urine collection is difficult to obtain, GFR can be estimated by the plasma concentration of endogenous markers mainly eliminated by glomerular filtration, such as creatinine, or the more recently described cystatin C and beta 2-microglobulin. When the endogenous production of these markers is constant, their plasma concentration reflects glomerular filtration; it increases with decreasing renal function. However, in pediatric patients creatinine production depends on muscle mass, which significantly increases with linear growth, as well as age and gender. Mathematical formulas taking these parameters into account have thus been developed. Among these, the so-called "Schwartz formula" is often used and is a reliable estimate of GFR in children. Finally, radionuclide renal scans can be used to evaluate the separate glomerular function of each kidney.

[Normal values in pediatric nephrology]. / Les normes en néphrologie pédiatrique.

The presence of renal disease can be excluded on the basis of a few simple tests: some of them are performed at the bed side: the assessment of miction frequency and urine flow rate, urine analysis by dipstick, urine specific gravity and osmolality. All these simples tests provide valuable information. When suspected, a functional defect can be confirmed by analyzing the urinary excretion of urine solutes, such as proteins, glucose and electrolytes. Imaging studies such as ultrasonography and radioisotopic scintigraphy can define the size and the separate function of the kidneys. The assessment of blood pressure is mandatory in childhood, the more so when renal disease is suspected. Normal values for all these parameters vary as a function of age, body weight and body surface area. They are briefly described here.

Renal effects of adenosine A1-receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine in hypoxemic newborn rabbits.

The key role of intrarenal adenosine in mediating the hypoxemic acute renal insufficiency in newborn rabbits has been well demonstrated using the nonspecific adenosine antagonist theophylline. The present study was designed to define the role of adenosine A1 receptors during systemic hypoxemia by using the specific A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Renal function parameters were assessed in 31 anesthetized and mechanically ventilated newborn rabbits. In normoxia, DPCPX infusion induced a significant increase in diuresis (+44%) and GFR (+19%), despite a significant decrease in renal blood flow (RBF) (-22%) and an increase in renal vascular resistance (RVR) (+37%). In hypoxemic conditions, diuresis (-19%), GFR (-26%), and RBF (-35%) were decreased, whereas RVR increased (+33%). DPCPX administration hindered the hypoxemia-induced decrease in GFR and diuresis. However, RBF was still significantly decreased (-27%), whereas RVR increased (+22%). In all groups, the filtration fraction increased significantly. The overall results support the hypothesis that, in physiologic conditions, intrarenal adenosine plays a key role in regulating glomerular filtration in the neonatal period through preferential A1-mediated afferent vasoconstriction. During a hypoxemic stress, the A1-specific antagonist DPCPX only partially prevented the hypoxemia-induced changes, as illustrated by the elevated RVR and drop in RBF. These findings imply that the contribution of intrarenal adenosine to the acute adverse effects of hypoxemia might not be solely mediated via the A1 receptor.

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.