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Neonatal Renal FailureJ. BalasubramaniamKidney Care centre. Tirunelveli, Tamilnadu. IndiaRenal failure in neonate is a vexing problem for more than one reason. Trying to get at the cause of the renal failure, one has to consider the endless list of inherited and congenital diseases, scrutinize the perinatal events, consider maternal diseases, suspect the drugs used, and the habits of the mother, besides the usual checklist of pre renal, renal and post renal causes. Not all causes are treatable. All modalities of renal replacement therapy, pose practical difficulties, when undertaken for these unfortunate neonates. More than all these the decision to undertake treatment in the first place is more social and emotional than purely medical, considering the hopeless long-term prognosis of some of the causes of neonatal renal failure. Nevertheless medical advancements and the never - give - up attitude of some, have given useful life to many a children. Diagnosis of Renal Failure Decreased urine output and elevated serum creatinine form the basis for the diagnosis of renal failure in the neonate as in any other situation. Decreased urine output: Oliguria is when the urine output is < 0.5 - 1ml/kg/hr. The first urine is often not recorded when it is passed in the delivery room. Therefore, 'anuria' in the first day may be 'normal'! Likewise in Low Birth Weight (LBW) cases oliguria may be common due to pre renal causes. In some situations like aminoglycoside induced renal failure and congenital renal diseases with predominant tubular dysfunction oliguria may not be evident. Urine collection itself needs extra attention. a.- Suprapubic aspiration is the most reliable method, esp for detecting infection. b.- Diaper urine specimens are enough for pH and qualitative determinations of presence of glucose, protein, and blood. c.- Bag collections are adequate for specific gravity, pH, electrolytes, protein, glucose and sediments. d.- For quantification of the urine volume you need either bag collections or bladder catheterization. Catheterization is used if an infant has failed to pass urine by 36 – 48 hrs and is not hypovolemic. Rising plasma creatinine: Serum creatinine values on first two days reflect maternal values. Normally creatinine level falls quickly from 0.8 mg/dl at birth to 0.5 mg/dl at 5 - 7 days and reach a stable level of 0.3 to 0.4 by 9 days. (Refer Table 1). The rate of fall in creatinine is slower in premature infants as they start with a lower GFR. Anything outside this is considered abnormal. One has to be careful in interpreting creatinine (when estimated by Jaffe's method) in the presence of high bilirubin (which is not uncommon in the neonate). Creatinine level is spuriously low in the presence of high bilirubin. One can get around this problem by doing something called rate blanking. This compensates for the bilirubin up to about 30 mg/dl. Creatinine by immuno nephelometric method is not interfered by bilirubin or ketones. Estimation of Cystatin C, which is evolving as a better marker for estimation of renal function, would even be better. Table 1. Normal serum creatinine values in term and preterm infants 1
Causes of Renal Failure in Neonate I. Prerenal
Sepsis, Necrotizing enterocolitis Congenital heart disease
NSAIDs Adrenergic drugs II. Intrinsic or renal parenchymal
E.- Congenital anomalies (Refer Tables 4, 5, 6)
Polycystic kidney disease F.- Thromboembolic disease
G.- Nephrotoxins
H.- Maternal ingestion of drugs NSAIDS, ACEI, ARB III. Obstructive
J.- Ureterocele, Ureteropelvic / ureterovesical obstruction K.- Extrinsic tumors L.- Neurogenic bladder M.- Megacystis or megaureter syndrome Birth asphyxia and neonatal sepsis are still common; more so in developing countries where obstetric and newborn resuscitation facilities are not universally available yet. Combination of dehydration, sepsis, shock, and nephrotoxic drugs is not an uncommon situation in neonatal ICU. These lead to high incidences of neonatal renal failure. The inciting insults can sometimes be so subtle and occult that the cause of renal failure may seem unobvious. They are often reversible if identified and managed in time. Obstructive lesions should ideally be identified by prenatal ultrasonography. Late diagnosis and intervention reduce the chances of reversibility and the ultimate prognosis. In prenatally suspected obstruction, ultrasonography and voiding cystourethrography should be done ideally on the first day of life itself. Reno vascular thrombosis leading to renal failure and hypertension is becoming commoner following neonatal ICU treatment and frequent umbilical artery catheterization. Maternal drug intake is an important factor not to be underrated. Drug intake during pregnancy is generally detested by many for the fear of fetal malformations. Physicians are generally careful in the first two trimesters of pregnancy but tend to take risks in the last trimester. One has to keep in mind that though the full set of (1 million) glomeruli are achieved by 34 weeks of pregnancy, glomerular and tubular maturation goes on up to 2 months into post natal life. During renal development, immunoreactive COX-2 is first observed in mid-gestation embryonic stages, notably in cells undergoing induction and/or morphogenesis and for the duration of nephrogenesis (through postnatal wk 2). In the postnatal kidney, COX-2 expression is relatively low at birth, increases in the first two postnatal weeks, and gradually declines to low levels in normal adult rats. This expression pattern of COX-2 in the developing kidney is of interest because of the evidence that COX metabolites play important functional and developmental roles in the fetal kidney.11 So drugs like COX 2 inhibitors used in the last part of pregnancy can adversely affect the maturation of tubules and cause renal failure which can be irreversible. We have come across three unfortunate instances of neonatal chronic renal failure caused by maternal ingestion of nimesulide.4,5 Use of ACEIs during the second and third trimesters of pregnancy has been associated with a pattern of defects known as ACEI fetopathy. The predominant feature of the fetopathy is renal tubular dysplasia. Other associated conditions include hypocalvaria, intrauterine growth retardation (IUGR), and patent ductus arteriosus (PDA). These features may be related to fetal hypotension secondary to ACEI-induced decreases in fetal angiotensin or increased bradykinin.13 Although no adverse fetal effects have been linked to first trimester use of ACEIs, there has been no systematic evaluation of births to women with such exposures. Instances of neonatal renal failure caused by maternal ingestion of ACEI and ARB are not infrequent.6 Other rare causes of neonatal anuria and renal failure include hyperuricemia and urate nephropathy.12 Notwithstanding the above long list, only few etiologies are common. Here are the causes of the 36 cases of neonatal renal failure seen in our unit during 1 year.
Only three of them required dialysis. Peritoneal dialysis was the chosen mode of renal replacement therapy. There were 4 deaths and the causes of death were non renal in three of them. Clinical Assessment
Physical examination: Look for abdominal masses. These are often renal or related to genito urinary system. Look for other congenital anomalies which are often associated with renal abnormalities. They are low set ears, ambiguous genitalia, anal atresia, abdominal wall defect, vertebral anomalies, meningomyelocele, pneumothorax, hemihypertrophy, persistant urachus, hypospadiasis, and cryptorchidism. (Refer Tables 4-6). Early in the clinical examination one has to differentiate between retention of urine from anuria due to renal failure.
Differentiate Incipient from Established Renal Failure
2. Renal failure indices (serum creatinine, Fractional Excretion of Sodium (FENa) and urine osmolality). Refer Table 2. 3. Cautious fluid challenge, if no signs of fluid overload or heart failure are present. Normal saline 10-20 ml/kg is infused over 1-2 h. If urine is produced, it is probable prerenal renal failure. If no urine or little urine is produced in 1 h post infusion, IV furosemide 1 mg/kg is given. If still no or only little urine is produced, it is probable parenchymal renal failure. Table 2. Renal failure indices in the oliguric neonate2
Interpretation of FENa When interpreting FENa, one has to keep in mind that the Na reabsorption capacity of premature kidney is limited, resulting in high FENa ( > 3%) even in prerenal states unlike in adults where it is < 1%. In premature neonates with oliguria, if FENa is <3%, we may assume that the renal failure is incipient and that there is enough residual renal function to retain salt. The usefulness of FENa is uncertain if a diuretic has been already given. When interpreting the urinary and blood biochemistry of the neonates one has to take note that there are differences between preterm, term,know how they differ from that of older children and adults. Refer Table 3. Table 3. Normal urinary and renal values in term and preterm infants
Differentiate acute from chronic renal failure: Clinical setting as shown by prenatal, natal and post natal events generally would tell about the reversibility of the renal failure. Pointers to underlying irreversible renal problem:
Unless proved otherwise it is better to treat one as reversible renal failure when one is not sure. Role of Radiology
If functional studies are required, scintigraphic radionuclide studies are used. It is useful in showing the position and relative function of the kidneys. Isotopes such as technetium-99m-diethylene triamine pentacetic acid (DTPA) or Mercaptoacetyltriglycine (MAG3) are good for assessing renal blood flow and GFR. Technetium-99m-dimercaptosuccinic acid (DMSA), an isotope which binds to the tubules, is helpful in assessing acute pyelonephritis and renal scarring from renal artery emboli, and to quantify renal cortex in neonates with renal dysplasia and hypoplasia Voiding cystourethrography (VCU) is to be performed at the earliest (preferably in the first day) in case of bilateral hydronephrosis. This would identify PUV and vesicoureteral reflex. There is no role for intravenous pyelography in the newborn. Renal Biopsy Renal biopsy is generally not required as the cause of renal failure is often evident clinically. In situations where it is especially required to ascertain the reversibility of the renal failure, renal biopsy is undertaken. Ideally it is done by open method. But we have performed USG guided closed percutaneous needle biopsies successfully. Figs 1 and 2.
Management: While managing neonates one has to keep in mind the fact that, at birth, renal homeostasis is limited in healthy preterm infants (e.g., the maximum ability to concentrate urine is 700 to 800 mOsm/L). In extreme-low-birth-weight (ELBW) infants, renal function cannot be described as "homeostatic," and fluid and electrolyte balance is precarious. Problems are greatest in infants <1250 g BW. They include the following:
Fluid challenge is undertaken in case of suspected hypovolemia. We give 10 to 20 ml/kg over 1 hour if there is no evidence of cardiac failure. Diuretics are used (1 – 2 mg/kg) in the event of fluid overload. Fluid intake is based on the neonate’s hydration status. It should match the insensible loss and ongoing losses. Insensible loss is 30 ml/kg/day in full term neonates and 50 – 70 ml/kg/day in preterms. The composition of fluid infusion should consider three main goals:
We have not found low dose dopamine useful. We avoid IV mannitol for the fear of fluid overload and pulmonary edema. We find xanthine derivative (aminophylline), an anti adenosine agent, extremely useful in renal dysfunction associated with hypovolemia, septicemia, and severe jaundice. There is good scientific basis for its use. Many an incipient renal failure has been reversed successfully in our unit. We use 5 mg/kg loading dose given over 2 hrs which is followed by 0.3mg/kg /hr infusion. Infusion is discontinued if there is no response after 48 hours8. In spite of many clinical reports and the work by David Moskowitz, we feel that the role of aminophylline in acute renal failure appears to be underrated. Treat hyperkalemia, if found, appropriately. Nutrition management: Increase calorie intake to 25 kcal/kg; protein restriction to 0.5 gm/kg/day. Ensure phosphate restriction and calcium supplementation Avoid nephrotoxic drugs and adjust dosage of essential drugs. Dialysis: When the clinical status of the neonate deteriorates in spite of all above measures, dialysis is to be considered. Particularly, life threatening hyperkalemia > 8.0 mEq/L, severe acidosis and continuing fluid overload would call for urgent dialysis. Raising creatinine alone is not an indication for dialysis. Before embarking on dialysis ethical factors must be considered. Consider the following issues: 1. Is the renal defect reversible? 2. How long is dialysis likely to be required? 3. Other medical problems and their reversibility. 4. Parental views. Generally one need not hesitate to undertake dialysis in a neonate weighing > 1.5 kg who is likely to survive without severe neurological deficits and whose renal disease is reversible. Peritoneal dialysis (PD) Peritoneal dialysis is the more practical mode of renal replacement therapy in neonates. Generally 20 – 30 ml/kg body weight of dialysate is used for the PD cycles and continued for 24 to 48 hours. Short periods of dialysis using stiff PD catheters can tide over most situations of acute renal failures. Intermittent PD may be restarted after 2 -3 days if renal failure persists. We have undertaken extended periods of PD (upto 7 days ) using the same catheter without complications. Flexible Tenchoff CAPD catheters may be implanted when the duration of dialysis is expected to be longer. PD using small volume exchanges is better tolerated by critically ill neonates.7
There are instances of dangerous hyperkalemias and renal failures in sick neonates helped by exchange transfusions given in our unit9. It is worthwhile to keep this option in mind in hopeless situations. Hemodialysis is generally difficult in neonates and it is to be undertaken only in centres which have experience. However the ethical factors mentioned above are to be considered even more rigorously before embarking on hemodialysis. It is true that, presently the picture looks gloomy for the majority of neonates with renal failure. New knowledge gained regarding renal and other organ development is shedding more light on the genesis of not only congenital and hereditary diseases but also on late adult onset diseases. These new understandings will definitely have a positive bearing on the many diseases which are presently believed to untreatable and hopeless. ‘Thrifty gene’ hypothesis and Barker’s hypothesis reveal that genetic factors may interact with altered intrauterine growth in determining the risk of cardiovascular and renal diseases Low birth weight (LBW), which reflects adverse effects on development in utero, contribute to many adult onset diseases including ESRD14 genetic. This could explain the rise in renal disease in high-risk population. The association is mediated through impaired nephrogenesis and reduction in nephron population caused by intrauterine malnutrition. The renal disease epidemic in developing countries may partly be the legacy of greatly improved survival of LBW babies over the last four decades. Disease rates should eventually plateau as birth weights continue to improve, if postnatal risk factors can also be contained. Our recent learning of role of COX 2 in renal development, presence of ACE gene, gene location of various cystic and other diseases, mechanisms of cyst development etc are closing the gaps in our understanding of many renal diseases. All these are bound to be translated into prevention, early diagnosis, better treatment options and thereby better prognosis for the neonates with renal failure in the near future. Acknowledgement: Dr. S. Raju, Dr. Mohamed Thamby, Dr. M. Nagarajan, Dr. A. Subramanian, Dr. M. Nambiyappan, and Dr. V.T. Rajesh, Pediatricians, Tirunelveli, were gracious enough to allow me to study their patients.
Appendix: Table 4. Congenital abnormalities with renal components
Table 5.
Table 6.
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