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.

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.

[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.

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.

Mermaid syndrome: virtually no hope for survival.

Sirenomelia, also called the mermaid syndrome is a severe malformation involving multiple organs and characterized by partially or completely developed lower extremities fused by the skin. The birth of a "mermaid" is very rare (1.2-4.2 cases for 100,000 births); most are stillborn, or die at or shortly after birth. The case of a living female neonate with dipodic simelia (fusion of well-developed legs) is presented. No prenatal diagnosis was made and the newborn had an uneventful neonatal course following Cesarean section delivery. The complex and striking malformation was obvious at birth and further evaluation revealed very poorly functioning kidneys, associated with abnormal anorectum, urogenital tract, and external genitalia, as well as a pelvic malformation. Supportive care was applied because of the poor prognosis and the child died at 7 weeks of age, due to renal failure.

Severe hypertension and massive proteinuria in a newborn with renal artery stenosis.

Renal vein thrombosis and the congenital nephrotic syndrome have been associated with nephrotic-range proteinuria/nephrotic syndrome and hypertension in the newborn period. We describe a newborn with severe hypertension and proteinuria secondary to unilateral renal artery stenosis. Proteinuria completely disappeared with blood pressure control (with sodium nitroprusside and an angiotensin-converting enzyme inhibitor). Although renin was not measured, we speculate that proteinuria might have been induced by a high renin state, and was controlled by the angiotensin-converting enzyme inhibitor.

Correlation between plasma and urine phenylalanine concentrations.

In this pilot study, we show that plasma phenylalanine concentration can be predicted from urine concentration if the age of the patient is taken into consideration. This observation could open the way to a new monitoring of phenylketonuric patients in which painful frequent blood sampling, mandatory to adapt the low phenylalanine diet, could be mostly replaced by urinalysis. Compliance to treatment would be improved and hence also the ultimate mental development. Since this study was based on a small number of patients, validation of the model in a large multicentric survey is needed before it can be recommended.

Nimesulide, a cyclooxygenase-2 preferential inhibitor, impairs renal function in the newborn rabbit.

Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 microg/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 microg.kg(-1).min(-1) infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (-5, -23, and -44%), GFR (-12, -23, and -47%), and renal blood flow (-23, -23, and -48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period.

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.

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.

Organic acids in the second morning urine in a healthy Swiss paediatric population.

Organic acid analysis is used for the early detection/ exclusion and for the follow-up of inherited disorders of amino acid and organic acid metabolism. Urinary organic acid concentrations in 417 healthy Caucasian children (1 day to 17 years of age) were determined after liquid solid extraction, as their trimethylsilyl derivatives, by gas chromatography and mass spectrometry. Concentrations of most of the organic acids adjusted for creatinine tend to decrease with age. No differences were found between gender except for the Krebs cycle intermediates in the older age groups. In neonates, the immaturity of the neonatal kidney led to a much larger variation of organic acid levels when related to creatinine. The low number of subjects (n = 36-52) per age class resulted in large 95% confidence intervals of the percentiles used for decision. This must be taken into account when using the data for exclusion or diagnosis of disorders.

Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity.

We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. As exogenous adenosine infusion mimics the haemodynamic changes that characterize acute renal failure (ARF), we wanted to know whether adenosine was a mediator in this model and whether an adenosine receptor blocker could prevent the CsA-induced ARF. Group 1 were untreated controls. Group 2 received CsA (25 mg/kg per day) for 5 days. Renal function parameters were measured, showing ARF in all animals compared to controls. Theophylline (1 mg/kg i.v. bolus) was then administered and renal function was reassessed. Theophylline significantly reduced renal vascular resistance (-8%) and increased renal blood flow (RBF) (+20%), glomerular filtration rate (GFR) (+50%), filtration fraction (+24%) and diuresis (+73%), suggesting that adenosine was involved in the CsA-induced ARF. In group 3, theophylline (30 mg/kg per day) was given concomitantly with CsA for 5 days. GFR was normalized, but theophylline did not hinder the drop in RBF seen with CsA alone in group 2. Microscopy observation of the kidneys showed that chronic theophylline administration aggravated the morphological changes induced by CsA alone. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with an adenosine-mediated afferent arteriolar constriction which cannot be prevented by concomitant theophylline administration.