**4.3.3 Non steroidal anti-inflammatory drugs**

NSAIDs, such as ibuprofen and indomethacin are usually administered to preterm neonates to stimulate closure of a patent ductus arteriosus; this can occur in up to 80% of extremely preterm infants (Ellison et al., 1983). Importantly, there have been a number of studies that have reported adverse effects on both the structure and function of the preterm kidney following treatment with NSAIDs. For example, renal insufficiency, demonstrated by a significant increase in serum creatinine has been reported in infants following either antenatal or postnatal exposure to NSAIDs (Kang et al., 1999; Butler-O'Hara and D'Angio, 2002). Of concern, in a case-controlled study where renal impairment was reported in preterm neonates that had received indomethacin treatment for a patent ductus arteriosus, 24% of the babies suffered acute renal failure (Akima et al., 2004). In addition, in the rat model where, similar to the preterm infant, nephrogenesis is ongoing after birth, exposure to indomethacin, ibuprofen and gentamicin have all been shown to lead to renal injury in the immature kidneys. There was evidence of vacuolization of epithelium and loss of microvilli in proximal tubules, effacement of podocyte foot processes and irregularities of the basement membrane in the glomeruli and edema within the interstitium (Kent et al., 2007).

#### **4.3.4 Inotropes**

At birth, there is a marked change in hemodynamics, with a subsequent rise in blood pressure and heart rate (Teitel et al., 1987; Louey et al., 2000). Preterm birth causes an abrupt and premature shift in the circulation from the fetal to postnatal configuration at a time when the cardiovascular system is still relatively immature; as a result, it is often necessary for inotropes to be administered to preterm neonates when blood pressure remains abnormally low after birth (Kluckow and Evans, 2001; Osborn et al., 2002). Given the importance of renal blood flow to growth of the kidney it is important that future research examines how the hemodyamic transition at birth affects the development of the immature renal vasculature and/or nephrogenesis and what effect the administration of inotropes have on the developing kidney.

## **5. Conclusion**

Over the past decade, considerable advances have been made in our understanding of the effects of preterm birth on the developing kidney. Encouragingly, it has clearly been demonstrated that nephrogenesis continues after birth in the preterm neonate, however, glomerular abnormalities are commonly observed. Future research should be directed into the causes of these abnormalities, so that strategies can be implemented to maximise the

Effects of Preterm Birth on the Kidney 79

Behrman, RE, Lees, MH, Peterson, EN, De Lannoy, CW & Seeds, AE. (1970). Distribution of

Bell, EF & Acarregui, MJ. (2008). Restricted versus liberal water intake for preventing

Bellomo, R, Ronco, C, Kellum, JA, Mehta, RL & Palevsky, P. (2004). Acute renal failure -

Bertram, JF. (2001). Counting in the kidney. *Kidney Int*, Vol. 59, No. 2, (Feb 2001), pp. 792-

Bhatia, J. (2006). Fluid and electrolyte management in the very low birth weight neonate. *J Perinatol*, Vol. 26 Suppl 1, No. (May 2006), pp. S19-21, 0743-8346 (Print) Blackburn, S. 2003. Renal system and fluid and electrolyte homeostasis. In: Maternal, fetal

Bonamy, A, Bendito, A, Martin, H, Andolf, E, Sedin, G & Norman, M. (2005). Preterm Birth

Butler-O'Hara, M & D'Angio, CT. (2002). Risk of persistent renal insufficiency in premature

Celsi, G, Kistner, A, Aizman, R, Eklof, AC, Ceccatelli, S, de Santiago, A & Jacobson, SH.

Chen, CM, Wang, LF, Chou, HC, Lang, YD & Lai, YP. (2007). Up-regulation of connective

Chetty, A, Cao, GJ, Severgnini, M, Simon, A, Warburton, R & Nielsen, HC. (2008). Role of

*Cell Mol Physiol*, Vol. 295, No. 4, (Oct 2008), pp. L584-592, 1040-0605 (Print) Choker, G & Gouyon, JB. (2004). Diagnosis of acute renal failure in very preterm infants. *Biol* 

Christensen, EI & Birn, H. (2001). Megalin and cubilin: synergistic endocytic receptors in

*Neonate*, Vol. 86, No. 3, 2004), pp. 212-216, 0006-3126 (Print)

Contributes to Increased Vascular Resistance and Higher Blood Pressure in Adolescent Girls. *Pediatr Res*, Vol. 58, No. 5, 2005), pp. 845–849, 0031-3998 (Print) Bonventre, JV. (2007). Pathophysiology of acute kidney injury: roles of potential inhibitors of inflammation. *Contrib Nephrol*, Vol. 156, No. 2007), pp. 39-46, 0302-5144 (Print) Bueva, A & Guignard, J. (1994). Renal Function in the Preterm Neonates. *Pediatr Res*, Vol. 36,

infants following the prenatal use of indomethacin for suppression of preterm labor. *J Perinatol*, Vol. 22, No. 7, (Oct-Nov 2002), pp. 541-546, 0743-8346 (Print) Cataldi, L, Leone, R, Moretti, U, De Mitri, B, Fanos, V, Ruggeri, L, Sabatino, G, Torcasio, F,

Zanardo, V, Attardo, G, Riccobene, F, Martano, C, Benini, D & Cuzzolin, L. (2005). Potential risk factors for the development of acute renal failure in preterm newborn infants: a case-control study. *Arch Dis Child Fetal Neonatal Ed*, Vol. 90, No. 2005), pp.

(1998). Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring. *Pediatr Res*, Vol. 44, No. 3, (Sep 1998), pp.

tissue growth factor in hyperoxia-induced lung fibrosis. *Pediatr Res*, Vol. 62, No. 2,

matrix metalloprotease-9 in hyperoxic injury in developing lung. *Am J Physiol Lung* 

renal proximal tubule. *Am J Physiol Renal Physiol*, Vol. 280, No. 4, (Apr 2001), pp.

Vol. 108, No. 6, (Nov 15 1970), pp. 956-969, 0002-9378 (Print)

2008), pp. CD000503, 1469-493X (Electronic)

and neonatal physiology, 2 ed: Saunders.

No. 5, 1994), pp. 572-577, 0031-3998 (Print)

(Aug 2007), pp. 128-133, 0031-3998 (Print)

F514-519, 1359-2998 (Print)

317-322, 0031-3998 (Print)

F562-573, 1931-857X (Print)

R204-212, 1466-609X (Electronic)

796, 0085-2538 (Print)

the circulation in the normal and asphyxiated fetal primate. *Am J Obstet Gynecol*,

morbidity and mortality in preterm infants. *Cochrane Database Syst Rev*, Vol. No. 1,

definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. *Crit Care*, Vol. 8, No. 4, (Aug 2004), pp.

number of functional nephrons at the beginning of life in the preterm infant in order to ensure long-term renal health. It is important that renal clinicians are made aware of the potential deleterious effects of preterm birth on developing glomerui, so they are aware of the renal vulnerability in subjects that are born preterm.

#### **6. References**


number of functional nephrons at the beginning of life in the preterm infant in order to ensure long-term renal health. It is important that renal clinicians are made aware of the potential deleterious effects of preterm birth on developing glomerui, so they are aware of

Abitbol, CL, Bauer, CR, Montane, B, Chandar, J, Duara, S & Zilleruelo, G. (2003). Long-term

Abitbol, CL, Chandar, J, Rodriguez, MM, Berho, M, Seeherunvong, W, Freundlich, M &

Adachi, J, Kumar, C, Zhang, Y, Olsen, JV & Mann, M. (2006). The human urinary proteome

proteins. *Genome Biol*, Vol. 7, No. 9, 2006), pp. R80, 1465-6914 (Electronic) Akima, S, Kent, A, Reynolds, G, Gallagher, M & Falk, M. (2004). Indomethacin and renal

Alejandre-Alcazar, MA, Kwapiszewska, G, Reiss, I, Amarie, OV, Marsh, LM, Sevilla-Perez, J,

Andreoli, SP. (2004). Acute renal failure in the newborn. *Semin Perinatol*, Vol. 28, No. 2, (Apr

Aperia, A, Broberger, O, Elinder, G, Herin, P & Zetterstrom, R. (1981). Postnatal

Arant, BS, Jr. (1987). Postnatal development of renal function during the first year of life. *Pediatr Nephrol*, Vol. 1, No. 3, (Jul 1987), pp. 308-313, 0931-041X (Print) Awad, H, el-Safty, I, el-Barbary, M & Imam, S. (2002a). Evaluation of renal glomerular and

Awad, H, el-Safty, I, el-Barbary, M & Imam, S. (2002b). Evaluation of renal glomerular and

Bacchetta, J, Harambat, J, Dubourg, L, Guy, B, Liutkus, A, Canterino, I, Kassai, B, Putet, G &

Bariety, J, Mandet, C, Hill, G & Bruneval, P. (2006). Parietal podocytes in normal human

Baumgart, S & Costarino, AT. (2000). Water and electrolyte metabolism of the micropremie. *Clin Perinatol*, Vol. 27, No. 1, (Mar 2000), pp. 131-146, vi-vii, 0095-5108 (Print)

*Scand*, Vol. 70, No. 2, (Mar 1981), pp. 183-187, 0001-656X (Print)

*Medical Sciences*, Vol. 324, No. 5, (Nov 2002a), pp. 261-266,

5, (Nov 2002b), pp. 261-266, 0002-9629 (Print)

445-452, 1523-1755 (Electronic)

No. 2, (Feb 2007), pp. L537-549, 1040-0605 (Print)

2004), pp. 112-123, 0146-0005 (Print)

*Nephrol*, Vol. 18, No. 9, (Sep 2003), pp. 887-893, 0931-041X (Print)

follow-up of extremely low birth weight infants with neonatal renal failure. *Pediatr* 

Zilleruelo, G. (2009). Obesity and preterm birth: additive risks in the progression of kidney disease in children. *Pediatr Nephrol*, Vol. 24, No. 7, (Jul 2009), pp. 1363-1370,

contains more than 1500 proteins, including a large proportion of membrane

impairment in neonates. *Pediatr Nephrol*, Vol. 19, No. 5, (May 2004), pp. 490-493,

Wygrecka, M, Eul, B, Kobrich, S, Hesse, M, Schermuly, RT, Seeger, W, Eickelberg, O & Morty, RE. (2007). Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia. *Am J Physiol Lung Cell Mol Physiol*, Vol. 292,

development of renal function in pre-term and full-term infants. *Acta Paediatr* 

tubular functional and structural integrity in neonates. *American Journal of the* 

tubular functional and structural integrity in neonates. *Am J Med Sci*, Vol. 324, No.

Cochat, P. (2009). Both extrauterine and intrauterine growth restriction impair renal function in children born very preterm. *Kidney Int*, Vol. 76, No. 4, (Aug 2009), pp.

glomeruli. *J Am Soc Nephrol*, Vol. 17, No. (Oct 2006), pp. 2770-2780, 1046-6673 (Print)

the renal vulnerability in subjects that are born preterm.

1432-198X (Electronic)

0931-041X (Print)

**6. References** 


Effects of Preterm Birth on the Kidney 81

Ervin, MG, Seidner, SR, Leland, MM, Ikegami, M & Jobe, AH. (1998). Direct fetal

Fawer, CL, Torrado, A & Guignard, JP. (1979). Maturation of renal function in full-term and

Fell, JM, Thakkar, H, Newman, DJ & Price, CP. (1997). Measurement of albumin and low

Finney, H, Newman, DJ, Thakkar, H, Fell, JM & Price, CP. (2000). Reference ranges for

Galaske, RG. (1986). Renal functional maturation: renal handling of proteins by mature and

Galinsky, R, Moss, TJ, Gubhaju, L, Hooper, SB, Black, MJ & Polglase, GR. (2011). Effect of

Giapros, V, Papadimitriou, P, Challa, A & Andronikou, S. (2007). The effect of intrauterine

Giapros, VI, Andronikou, SK, Cholevas, VI & Papadopoulou, ZL. (2003). Renal function and

Gibson, I, Downie, T, More, I & Lindop, G. (1996). Atubular glomeruli and glomerular cysts

Gilbert, T, Gaonach, S, Moreau, E & Merlet-Benichou, C. (1994). Defect of nephrogenesis

Gilbert, T, Lelievre-Pegorier, M & Merlet-Benichou, C. (1990). Immediate and long-term

Goldenberg, RL, Culhane, JF, Iams, JD & Romero, R. (2008). Epidemiology and causes of

Gordjani, N, Burghard, R, Leititis, J & Brandis, M. (1998). Serum creatinine and creatinine

*Pediatr*, Vol. 148, No. 1998), pp. 143-145, 0340-6199 (Print)

*Physiol Renal Physiol*, Vol. No. (May 18 2011), pp. 1522-1466 (Electronic) Gallini, F, Maggio, L, Romagnoli, C, Marrocco, G & Tortorolo, G. (2000). Progression of renal

Vol. 15, No. 1-2, (Nov 2000), pp. 119-124, 0931-041X (Print)

Vol. 18, No. 1, (Jan 2003), pp. 46-52, 0931-041X (Print)

(Aug 1996), pp. 421-426, 0022-3417 (Print)

(May 1994), pp. 656-666, 0023-6837 (Print)

1990), pp. 445-450, 0931-041X (Print)

*Transplant*, Vol. 22, No. 1, (Jan 2007), pp. 96-103, 0931-0509 (Print)

*Med*, Vol. No. (Sep 14 2010), pp. 1476-4954 (Electronic)

022X (Print)

(Electronic)

6199 (Print)

(Electronic)

(Print)

glucocorticoid treatment alters postnatal adaptation in premature newborn baboons. *Am J Physiol*, Vol. 274, No. 4 Pt 2, (Apr 1998), pp. R1169-1176, 0002-9513 (Print) Faa, G, Gerosa, C, Fanni, D, Nemolato, S, Locci, A, Cabras, T, Marinelli, V, Puddu, M,

Zaffanello, M, Monga, G & Fanos, V. (2010). Marked interindividual variability in renal maturation of preterm infants: lessons from autopsy. *J Matern Fetal Neonatal* 

premature neonates. *Helv Paediatr Acta*, Vol. 34, No. 1, (Feb 1979), pp. 11-21, 0018-

molecular weight proteins in the urine of newborn infants using a cotton wool ball collection method. *Acta Paediatr*, Vol. 86, No. 5, (May 1997), pp. 518-522, 0803-5253

plasma cystatin C and creatinine measurements in premature infants, neonates, and older children. *Arch Dis Child*, Vol. 82, No. 1, (Jan 2000), pp. 71-75, 1468-2044

immature newborns. *Eur J Pediatr*, Vol. 145, No. 5, (Oct 1986), pp. 368-371, 0340-

intra-amniotic lipopolysaccharide on nephron number in preterm fetal sheep. *Am J* 

function in preterm neonates with gestational age < or = 32 weeks. *Pediatr Nephrol*,

growth retardation on renal function in the first two months of life. *Nephrol Dial* 

effect of aminoglycoside therapy during the first ten days of life. *Pediatr Nephrol*,


induced by gentamicin in rat metanephric organ culture. *Lab Invest*, Vol. 70, No. 5,

renal effects of fetal exposure to gentamicin. *Pediatr Nephrol*, Vol. 4, No. 4, (Jul

preterm birth. *Lancet*, Vol. 371, No. 9606, (Jan 5 2008), pp. 75-84, 1474-547X

clearance in healthy neonates and prematures during the first 10 days of life. *Eur J* 


Clark, AT & Bertram, JF. (1999). Molecular regulation of nephron endowment. *Am J Physiol*,

Clark, PM, Bryant, TN, Hall, MA, Lowes, JA & Rowe, DJ. (1989). Neonatal renal function

Clark, R, Thomas, P & Peabody, J. (2003). Extrauterine growth restriction remains a serious

Comper, WD, Haraldsson, B & Deen, WM. (2008). Resolved: normal glomeruli filter

Cooper, R, Atherton, K & Power, C. (2008). Gestational age and risk factors for

Cuzzolin, L, Fanos, V, Pinna, B, di Marzio, M, Perin, M, Tramontozzi, P, Tonetto, P &

Dalziel, S, Parag, V, Rodgers, A & Harding, J. (2007). Cardiovascular risk factors at age 30

Dieperink, HI, Blackwell, TS & Prince, LS. (2006). Hyperoxia and apoptosis in developing

Doyle, LW, Faber, B, Callanan, C & Morley, R. (2003). Blood pressure in late adolescence and

Drougia, A, Giapros, V, Hotoura, E, Papadopoulou, F, Argyropoulou, M & Andronikou, S.

Drukker, A & Guignard, JP. (2002). Renal aspects of the term and preterm infant: a selective update. *Curr Opin Pediatr*, Vol. 14, No. 2, (Apr 2002), pp. 175-182, 1040-8703 (Print) Ehrenkranz, RA. (2000). Growth outcomes of very low-birth weight infants in the newborn

Ellison, RC, Peckham, GJ, Lang, P, Talner, NS, Lerer, TJ, Lin, L, Dooley, KJ & Nadas, AS.

Engle, W. (1986). Development of fetal and neonatal renal function. *Semin Perinatol*, Vol. 10,

Ervin, MG, Berry, LM, Ikegami, M, Jobe, AH, Padbury, JF & Polk, DH. (1996). Single dose

71, No. 3, (Mar 1983), pp. 364-372, 0031-4005 (Print)

No. 1986), pp. 113-124, 0146-0005 (Print)

1996), pp. 645-651, 0031-3998 (Print)

mid-life. *Int J Epidemiol*, Vol. No. (Jul 25 2008), pp. 1464-3685 (Electronic) Cullen, L, Young, R & Bertram, J. (2000). Studies on the effects of gentamicin on rat

assessment. *Arch Dis Child*, Vol. 64, No. 9, (Sep 1989), pp. 1264-1269, 1468-2044

problem in prematurely born neonates. *Pediatrics*, Vol. 111, No. 2003), pp. 986-990,

nephrotic levels of albumin. *J Am Soc Nephrol*, Vol. 19, No. 3, (Mar 2008), pp. 427-

cardiovascular disease: evidence from the 1958 British birth cohort followed to

metanephric development *in vitro*. *Nephrology*, Vol. 5, No. 2000), pp. 115-123, 1440-

Cataldi, L. (2006). Postnatal renal function in preterm newborns: a role of diseases, drugs and therapeutic interventions. *Pediatr Nephrol*, Vol. 21, No. 7, 2006), pp. 931-

following pre-term birth. *Int J Epidemiol*, Vol. 36, No. 4, 2007), pp. 907-915, 0300-

mouse lung mesenchyme. *Pediatr Res*, Vol. 59, No. 2, (Feb 2006), pp. 185-190, 0031-

very low birth weight. *Pediatrics*, Vol. 111, No. 2, (Feb 2003), pp. 252-257, 1098-4275

(2009). The effects of gestational age and growth restriction on compensatory kidney growth. *Nephrol Dial Transplant*, Vol. 24, No. 1, (Jan 2009), pp. 142-148, 1460-

intensive care unit. *Clin Perinatol*, Vol. 27, No. 2, (Jun 2000), pp. 325-345, 0095-5108

(1983). Evaluation of the preterm infant for patent ductus arteriosus. *Pediatrics*, Vol.

fetal betamethasone administration stabilizes postnatal glomerular filtration rate and alters endocrine function in premature lambs. *Pediatr Res*, Vol. 40, No. 5, (Nov

Vol. 276, No. 4 Pt 2, (Apr 1999), pp. F485-497, 0002-9513 (Print)

(Electronic)

1797

1098-4275 (Electronic)

938, 0931-041X (Print)

5771 (Print)

3998 (Print)

(Electronic)

(Print)

2385 (Electronic)

432, 1533-3450 (Electronic)


Effects of Preterm Birth on the Kidney 83

Iacobelli, S, Bonsante, F, Ferdinus, C, Labenne, M & Gouyon, JB. (2009). Factors affecting

Itabashi, K, Ohno, T & Nishida, H. (2003). Indomethacin responsiveness of patent ductus

Johansson, S, Iliadou, A, Bergvall, N, Tuvemo, T, Norman, M & Cnattingius, S. (2005). Risk

Kang, NS, Yoo, KH, Cheon, H, Choi, BM, Hong, YS, Lee, JW & Kim, SK. (1999).

Keijzer-Veen, MG, Devos, AS, Meradji, M, Dekker, FW, Nauta, J & van der Heijden, BJ.

Keller, G, Zimmer, G, Mall, G, Ritz, E & Amann, K. (2003). Nephron number in patients with

Kent, AL, Jyoti, R, Robertson, C, Gonsalves, L, Meskell, S, Shadbolt, B & Falk, MC. (2009).

Kistner, A, Celsi, G, Vanpee, M & Jacobson, SH. (2000). Increased blood pressure but normal

Kistner, A, Jacobson, L, Jacobson, S, Svensson, E & Hellstrom, A. (2002). Low gestational age

*Biol Neonate*, Vol. 76, No. 5, (Nov 1999), pp. 261-265, 0006-3126 (Print) Keijzer-Veen, M, Schrevel, M, Finken, M, Dekker, F, Nauta, J, Hille, E, Frolich, M & van der

*Nephrol*, Vol. 25, No. (Mar 2010a), pp. 499-507, 1432-198X (Electronic) Keijzer-Veen, MG, Dulger, A, Dekker, FW, Nauta, J & van der Heijden, BJ. (2010b). Very

No. 4, (Oct 2007), pp. 542-551, 1523-6838 (Electronic)

4406 (Electronic)

0031-3998 (Print)

2000), pp. 215-220, 0931-041X (Print)

*Pediatr*, Vol. 143, No. 2, (Aug 2003), pp. 203-207, 0022-3476 (Print)

No. 10, (Nov 2007), pp. 587-592, 0735-1631 (Print)

No. 1, (Mar 1992), pp. 33-57, 0095-5108 (Print)

postnatal changes in serum creatinine in preterm infants with gestational age <32 weeks. *J Perinatol*, Vol. 29, No. 3, (Mar 2009), pp. 232-236, 1476-5543 (Electronic) Iacobelli, S, Loprieno, S, Bonsante, F, Latorre, G, Esposito, L & Gouyon, JB. (2007). Renal

function in early childhood in very low birthweight infants. *Am J Perinatol*, Vol. 24,

arteriosus and renal abnormalities in preterm infants treated with indomethacin. *J* 

of high blood pressure among young men increases with the degree of immaturity at birth. *Circulation*, Vol. 112, No. 2005), pp. 3430-3436, 1524-4539 (Electronic) Jones, DP & Chesney, RW. (1992). Development of tubular function. *Clin Perinatol*, Vol. 19,

Indomethacin treatment decreases renal blood flow velocity in human neonates.

Heijden, B. (2005). Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation. *J Am Soc Nephrol*, Vol. 16, No. 9, 2005), pp. 2762-2768, 1046-6673 (Print)

(2010a). Reduced renal length and volume 20 years after very preterm birth. *Pediatr* 

preterm birth is a risk factor for increased systolic blood pressure at a young adult age. *Pediatr Nephrol*, Vol. 25, No. 3, 2010b), pp. 509-516, 1432-198X (Electronic) Keijzer-Veen, MG, Kleinveld, HA, Lequin, MH, Dekker, FW, Nauta, J, de Rijke, YB & van

der Heijden, BJ. (2007). Renal function and size at young adult age after intrauterine growth restriction and very premature birth. *Am J Kidney Dis*, Vol. 50,

primary hypertension. *N Engl J Med*, Vol. 348, No. 2, (Jan 9 2003), pp. 101-108, 1533-

Does extreme prematurity affect kidney volume at term corrected age? *J Matern Fetal Neonatal Med*, Vol. 22, No. 5, (May 2009), pp. 435-438, 1476-4954 (Electronic) Kent, AL, Maxwell, LE, Koina, ME, Falk, MC, Willenborg, D & Dahlstrom, JE. (2007). Renal

glomeruli and tubular injury following indomethacin, ibuprofen, and gentamicin exposure in a neonatal rat model. *Pediatr Res*, Vol. 62, No. 3, (Sep 2007), pp. 307-312,

renal function in adult women born preterm. *Pediatr Nephrol*, Vol. 15, No. 3-4, (Dec

associated with abnormal retinal vascularization and increased blood pressure in adult women. *Pediatr Res*, Vol. 51, No. 6, 2002), pp. 675–680, 0031-3998 (Print)


Gortner, L, Bernsau, U, Brand, M, Hellwege, HH, Hieronimi, G, Jorch, G, Reiter, HL &

Gubhaju, L & Black, MJ. (2005). The baboon as a good model for studies of human kidney development. *Pediatr Res*, Vol. 58, No. 2005), pp. 505-509, 0031-3998 (Print) Gubhaju, L, Sutherland, MR, Yoder, BA, Zulli, A, Bertram, JF & Black, MJ. (2009). Is

Gunnarsson, GO, Gudmundsson, S, Hokegard, K, Stale, H, Kjellmer, I, Hafstrom, O &

Gwira, JA, Wei, F, Ishibe, S, Ueland, JM, Barasch, J & Cantley, LG. (2005). Expression of

Hendrickx, A, Bollert, J & Houston, M. (1971). *Embryology of the Baboon* The University of

Hentschel, R, Lodige, B & Bulla, M. (1996). Renal insufficiency in the neonatal period. *Clin* 

Hinchliffe, SA, Lynch, MR, Sargent, PH, Howard, CV & Van Velzen, D. (1992a). The effect of

Hinchliffe, SA, Sargent, PH, Chan, YF, van Velzen, D, Howard, CV, Hutton, JL & Rushton,

Hinchliffe, SA, Sargent, PH, Howard, CV, Chan, YF & van Velzen, D. (1991). Human

Hoppe, CC, Evans, RG, Moritz, KM, Cullen-McEwen, LA, Fitzgerald, SM, Dowling, J &

Huynh, TK, Bateman, DA, Parravicini, E, Lorenz, JM, Nemerofsky, SL, Sise, ME, Bowman,

*Comp Physiol*, Vol. 292, No. 1, (Jan 2007), pp. R462-469, 0363-6119 (Print) Huang, HP, Tsai, IJ, Lai, YC, Cheng, CH & Tsau, YK. (2007). Early postnatal renal growth in

Vol. 50, No. 2007), pp. 652-683, 0009-9201 (Print)

26, No. 2, 1998), pp. 107-114, 0300-5577 (Print)

Chicago Press, 0226327124/0-226-32712-4, London.

(Jun 1991), pp. 777-784, 0023-6837 (Print)

No. 5, (Nov 2009), pp. 528-532, 1530-0447 (Electronic)

*Nephrol*, Vol. 46, No. 1, (Jul 1996), pp. 54-58, 0301-0430 (Print)

*Gynaecol*, Vol. 99, No. 4, (Apr 1992a), pp. 296-301, 0306-5456 (Print)

(Electronic)

684, 0031-3998 (Print)

0344-0338 (Print)

(Print)

Versmold, H. (1991). Drug utilization in very premature infants in neonatal intensive care units. *Dev Pharmacol Ther*, Vol. 17, No. 3-4, 1991), pp. 167-171, 0379-8305 (Print) Gotsch, F, Romero, R, Kusanovic, J, Mazaki-Tovi, S, Pineles, B, Erez, O, Espinoza, J &

Hassan, S. (2007). The fetal inflammatory response syndrome. *Clin Obstet Gynecol*,

nephrogenesis affected by preterm birth? Studies in a non-human primate model. *Am J Physiol Renal Physiol*, Vol. 297, No. 6, (Dec 2009), pp. F1668-1677, 1522-1466

Marsal, K. (1998). Cerebral Doppler blood flow velocimetry and central hemodynamics in the ovine fetus during hypoxemia-acidemia. *J Perinat Med*, Vol.

neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. *J Biol Chem*, Vol. 280, No. 9, (Mar 4 2005), pp. 7875-7882, 0021-9258 (Print) Hack, M, Schluchter, M, Cartar, L & Rahman, M. (2005). Blood pressure among very low

birth weight (<1.5 kg) young adults. *Pediatr Res*, Vol. 58, No. 4, (Oct 2005), pp. 677-

intrauterine growth retardation on the development of renal nephrons. *Br J Obstet* 

DI. (1992b). "Medullary ray glomerular counting" as a method of assessment of human nephrogenesis. *Pathol Res Pract*, Vol. 188, No. 6, (Aug 1992b), pp. 775-782,

intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. *Laboratory Investigation*, Vol. 64, No. 6,

Bertram, JF. (2007). Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure. *Am J Physiol Regul Integr* 

premature infants. *Nephrology*, Vol. 12, No. 6, (Dec 2007), pp. 572-575, 1320-5358

TM, Polesana, E & Barasch, JM. (2009). Reference values of urinary neutrophil gelatinase-associated lipocalin in very low birth weight infants. *Pediatr Res*, Vol. 66,


Effects of Preterm Birth on the Kidney 85

McGrath-Morrow, SA & Stahl, J. (2001). Apoptosis in neonatal murine lung exposed to

Mehta, RL, Kellum, JA, Shah, SV, Molitoris, BA, Ronco, C, Warnock, DG & Levin, A. (2007).

*Pediatr Nephrol*, Vol. 8, No. 2, (Apr 1994), pp. 175-180, 0931-041X (Print) Methven, S, MacGregor, MS, Traynor, JP, Hair, M, O'Reilly, DS & Deighan, CJ. (2011).

Miall, LS, Henderson, MJ, Turner, AJ, Brownlee, KG, Brocklebank, JT, Newell, SJ & Allgar, VL.

infants. *Pediatrics*, Vol. 104, No. 6, (Dec 1999), pp. e76, 1098-4275 (Electronic) Moniz, CF, Nicolaides, KH, Bamforth, FJ & Rodeck, CH. (1985). Normal reference ranges for

Moran, SM & Myers, BD. (1985). Course of acute renal failure studied by a model of creatinine kinetics. *Kidney Int*, Vol. 27, No. 6, (Jun 1985), pp. 928-937, 0085-2538 (Print) Moritz, KM, Johnson, K, Douglas-Denton, R, Wintour, EM & Dodic, M. (2002). Maternal

Moritz, KM, Wintour, EM, Black, MJ, Bertram, JF & Caruana, G. (2008). Factors influencing

Moritz, ML & Ayus, JC. (2005). Preventing neurological complications from dysnatremias in children. *Pediatr Nephrol*, Vol. 20, No. 12, (Dec 2005), pp. 1687-1700, 0931-041X (Print) Nagai, J & Takano, M. (2004). Molecular aspects of renal handling of aminoglycosides and

Nathanson, S, Moreau, E, Merlet-Benichou, C & Gilbert, T. (2000). In utero and in vitro

Nenov, VD, Taal, MW, Sakharova, OV & Brenner, BM. (2000). Multi-hit nature of chronic

Oh, W, Poindexter, BB, Perritt, R, Lemons, JA, Bauer, CR, Ehrenkranz, RA, Stoll, BJ, Poole, K

*Embryol Cell Biol*, Vol. 196, No. 2008), pp. 1-78, 0301-5556 (Print)

Vol. 11, No. 5, (May 2000), pp. 874-884, 1046-6673 (Print)

3, (Jun 2004), pp. 159-170, 1347-4367 (Print)

1549 (Print)

(Electronic)

468-472, 0021-9746 (Print)

0013-7227 (Print)

1062-4821 (Print)

2538 (Print)

hyperoxia. *Am J Respir Cell Mol Biol*, Vol. 25, No. 2, (Aug 2001), pp. 150-155, 1044-

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. *Crit Care*, Vol. 11, No. 2, 2007), pp. R31, 1466-609X (Electronic) Merlet-Benichou, C, Gilbert, T, Muffat-Joly, M, Lelievre-Pegorier, M & Leroy, B. (1994).

Intrauterine growth retardation leads to a permanent nephron deficit in the rat.

Comparison of urinary albumin and urinary total protein as predictors of patient outcomes in CKD. *Am J Kidney Dis*, Vol. 57, No. 1, (Jan 2011), pp. 21-28, 1523-6838

(1999). Plasma creatinine rises dramatically in the first 48 hours of life in preterm

biochemical substances relating to renal, hepatic, and bone function in fetal and maternal plasma throughout pregnancy. *J Clin Pathol*, Vol. 38, No. 4, (Apr 1985), pp.

glucocorticoid treatment programs alterations in the renin-angiotensin system of the ovine fetal kidney. *Endocrinology*, Vol. 143, No. 11, (Nov 2002), pp. 4455-4463,

mammalian kidney development: implications for health in adult life. *Adv Anat* 

strategies for preventing the nephrotoxicity. *Drug Metab Pharmacokinet*, Vol. 19, No.

exposure to beta-lactams impair kidney development in the rat. *J Am Soc Nephrol*,

renal disease. *Curr Opin Nephrol Hypertens*, Vol. 9, No. 2, (Mar 2000), pp. 85-97,

& Wright, LL. (2005). Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants. *J Pediatr*, Vol. 147, No. 6, (Dec 2005), pp. 786-790, 0022-3476 (Print) Ortiz, LA, Quan, A, Weinberg, A & Baum, M. (2001). Effect of prenatal dexamethasone on

rat renal development. *Kidney Int*, Vol. 59, No. 5, (May 2001), pp. 1663-1669, 0085-


Kluckow, M & Evans, N. (2001). Low systemic blood flow in the preterm infant. *Semin* 

Kutz, P, Horsch, S, Kuhn, L & Roll, C. (2009). Single-centre vs. population-based outcome

Kwinta, P, Klimek, M, Drozdz, D, Grudzien, A, Jagla, M, Zasada, M & Pietrzyk, JJ. (2011).

Lahra, MM & Jeffery, HE. (2004). A fetal response to chorioamnionitis is associated with

Lavery, AP, Meinzen-Derr, JK, Anderson, E, Ma, Q, Bennett, MR, Devarajan, P & Schibler,

Lodrup, AB, Karstoft, K, Dissing, TH, Nyengaard, JR & Pedersen, M. (2008). The association

Lorenz, JM, Kleinman, LI, Ahmed, G & Markarian, K. (1995). Phases of fluid and electrolyte

Lorenz, JM, Kleinman, LI, Kotagal, UR & Reller, MD. (1982). Water balance in very low-

outcome. *J Pediatr*, Vol. 101, No. 3, (Sep 1982), pp. 423-432, 0022-3476 (Print) Louey, S, Cock, ML, Stevenson, KM & Harding, R. (2000). Placental insufficiency and fetal

sheep. *Pediatr Res*, Vol. 48, No. 6, (Dec 2000), pp. 808-814, 0031-3998 (Print) Luyckx, VA & Brenner, BM. (2005). Low birth weight, nephron number, and kidney disease. *Kidney Int Suppl*, Vol. No. 97, (Aug 2005), pp. S68-77, 0098-6577 (Print) Manalich, R, Reyes, L, Herrera, M, Melendi, C & Fundora, I. (2000). Relationship between

Mathieson, P. (2004). The cellular basis of albuminuria. *Clin Sci*, Vol. 107, No. 2004), pp. 533 -

Matos, P, Duarte-Silva, M, Drukker, A & Guignard, JP. (1998). Creatinine reabsorption by

Matsushita, K, van der Velde, M, Astor, BC, Woodward, M, Levey, AS, de Jong, PE, Coresh,

McCormick, MC. (1985). The contribution of low birth weight to infant mortality and

data of extremely preterm infants at the limits of viability. *Acta Paediatr*, Vol. 98,

Assessment of long-term renal complications in extremely low birth weight children. *Pediatr Nephrol*, Vol. 26, No. 7, (Jul 2011), pp. 1095-1103, 1432-198X

early survival after preterm birth. *Am J Obstet Gynecol*, Vol. 190, No. 1, (Jan 2004),

KR. (2008). Urinary NGAL in premature infants. *Pediatr Res*, Vol. 64, No. 4, (Oct

between renal function and structural parameters: a pig study. *BMC Nephrol*, Vol. 9,

homeostasis in the extremely low birth weight infant. *Pediatrics*, Vol. 96, No. 3 Pt 1,

birth-weight infants: relationship to water and sodium intake and effect on

growth restriction lead to postnatal hypotension and altered postnatal growth in

weight at birth and the number and size of renal glomeruli in humans: a histomorphometric study. *Kidney Int*, Vol. 58, No. 2, (Aug 2000), pp. 770-773, 0085-

the newborn rabbit kidney. *Pediatr Res*, Vol. 44, No. 5, (Nov 1998), pp. 639-641,

J & Gansevoort, RT. (2010). Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. *Lancet*, Vol. 375, No. 9731, (Jun 12 2010), pp.

childhood morbidity. *N Engl J Med*, Vol. 312, No. 2, (Jan 10 1985), pp. 82-90, 0028-

*Neonatol*, Vol. 6, No. 1, (Feb 2001), pp. 75-84, 1084-2756 (Print)

No. 9, (Sep 2009), pp. 1451-1455, 1651-2227 (Electronic)

(Electronic)

2538 (Print)

0031-3998 (Print)

4793 (Print)

2073-2081, 1474-547X (Electronic)

538,

pp. 147-151, 0002-9378 (Print)

2008), pp. 423-428, 1530-0447 (Electronic)

No. 2008), pp. 18, 1471-2369 (Electronic)

(Sep 1995), pp. 484-489, 0031-4005 (Print)


Effects of Preterm Birth on the Kidney 87

Ross, B, Cowett, R & Oh, W. (1977). Renal functions of low birth weight infants during the

Schmidt, I, Chellakooty, M, Boisen, K, Damgaard, I, Kai, C, Olgaard, K & Main, K. (2005).

Schreuder, MF, Wilhelm, AJ, Bokenkamp, A, Timmermans, SM, Delemarre-van de Waal,

Siegel, SR & Oh, W. (1976). Renal function as a marker of human fetal maturation. *Acta Paediatr Scand*, Vol. 65, No. 4, (Jul 1976), pp. 481-485, 0001-656X (Print) Siewert-Delle, A & Ljungman, S. (1998). The impact of birth weight and gestational age on

Stapleton, F, Jones, D & Green, R. (1987). Acute renal failure in neonates: Incidence, etiology and outcome. *Pediatr Nephrol*, Vol. 1, No. 1987), pp. 314-320, 0931-041X (Print) Sulyok, E, Varg, F, Gyory, E, Jobst, K & Czaba, I. (1979). Postnatal development of renal

Sutherland, MR, Gubhaju, L & Black, MJ. (2011a). Stereological assessment of renal

Sutherland, MR, Gubhaju, L, Moore, L, Kent, AL, Dahlstrom, JE, Horne, RS, Hoy, WE,

Sweeney, W & Avner, E. 2004. The kidney - Embryogenesis and anatomic development of

Takieddine, F, Tabbara, M, Hall, P, Sokol, RJ & King, KC. (1983). Fetal renal maturation.

Teitel, DF, Iwamoto, HS & Rudolph, AM. (1987). Effects of birth-related events on central

Thayyil, S, Sheik, S, Kempley, ST & Sinha, A. (2008). A gestation- and postnatal age-based

Thomson, MA, Yoder, BA, Winter, VT, Martin, H, Catland, D, Siler-Khodr, TM & Coalson,

Tomlinson, PA. (1992). Low molecular weight proteins in children with renal disease. *Pediatr* 

*Perinatol*, Vol. 28, No. 3, (Mar 2008), pp. 226-229, 0743-8346 (Print)

*Nephrol*, Vol. 6, No. 6, (Nov 1992), pp. 565-571, 0931-041X (Print)

*Hypertens*, Vol. 11, No. 1998), pp. 946-953, 0895-7061 (Print)

No. 2011a), pp. 25-33, 1421-9670 (Electronic)

62, No. 4, 1983), pp. 311-314, 0001-6349 (Print)

2011b), pp. 1533-3450 (Electronic)

pp. 1054-1062, 1073-449X (Print)

ed: Saunders (Elsevier).

(Print)

Saxen, L. (1987). *Organogenesis of the Kidney* Cambridge University Press, Cambridge.

(Print)

(Print)

0022-3476 (Print)

1774-1778, 1555-905X (Electronic)

first two months of life. *Pediatr Res*, Vol. 11, No. 1977), pp. 1162-1164, 0031-3998

Impaired kidney growth in low-birth-weight children: Distinct effects of maturity and weight for gestational age. *Kidney Int*, Vol. 68, No. 2005), pp. 731-740, 0085-2538

HA & van Wijk, JA. (2009). Impact of gestational age and birth weight on amikacin clearance on day 1 of life. *Clin J Am Soc Nephrol*, Vol. 4, No. 11, (Nov 2009), pp.

blood pressure in adult life. A population-based study of 49-year-old men. *Am J* 

sodium handling in premature infants. *J Pediatr*, Vol. 95, No. 1979), pp. 787-792,

development in a baboon model of preterm birth. *Am J Nephrol*, Vol. 33 Suppl 1,

Bertram, JF & Black, MJ. (2011b). Accelerated Maturation and Abnormal Morphology in the Preterm Neonatal Kidney. *J Am Soc Nephrol*, Vol. No. (Jun 2

the kidney. In: Polin R, Fox W, Abman S, editors. Fetal and Nenatal Physiology, 3

Studies on urinary beta 2 microglobulin the neonate. *Acta Obstet Gynecol Scand*, Vol.

blood flow patterns. *Pediatr Res*, Vol. 22, No. 5, (Nov 1987), pp. 557-566, 0031-3998

reference chart for assessing renal function in extremely premature infants. *J* 

JJ. (2004). Treatment of immature baboons for 28 days with early nasal continuous positive airway pressure. *Am J Respir Crit Care Med*, Vol. 169, No. 9, (May 1 2004),


Osborn, D, Evans, N & Kluckow, M. (2002). Randomized trial of dobutamine versus

Parikh, CR, Lu, JC, Coca, SG & Devarajan, P. (2010). Tubular proteinuria in acute kidney

Parravicini, E. (2010). The clinical utility of urinary neutrophil gelatinase-associated lipocalin

Parravicini, E, Nemerofsky, SL, Michelson, KA, Huynh, TK, Sise, ME, Bateman, DA, Lorenz,

Polglase, GR, Hooper, SB, Gill, AW, Allison, BJ, McLean, CJ, Nitsos, I, Pillow, JJ & Kluckow,

Rakow, A, Johansson, S, Legnevall, L, Sevastik, R, Celsi, G, Norman, M & Vanpee, M. (2008).

Ralston, SH, Caine, N, Richards, I, O'Reilly, D, Sturrock, RD & Capell, HA. (1988). Screening

*Ann Rheum Dis*, Vol. 47, No. 9, (Sep 1988), pp. 759-763, 0003-4967 (Print) Rodriguez-Soriano, J, Aguirre, M, Oliveros, R & Vallo, A. (2005). Long-term renal follow-up

Rodriguez, MM, Gomez, AH, Abitbol, CL, Chandar, JJ, Duara, S & Zilleruelo, GE. (2004).

Romero, R, Espinoza, J, Goncalves, LF, Kusanovic, JP, Friel, LA & Nien, JK. (2006).

Romero, R, Gomez, R, Ghezzi, F, Yoon, BH, Mazor, M, Edwin, SS & Berry, SM. (1998). A

Rosner, MH. (2009). Urinary biomarkers for the detection of renal injury. *Adv Clin Chem*,

Infants. *Pediatr Dev Pathol*, Vol. 7, No. 2004), pp. 17-25, 1093-5266 (Print) Romero, R, Chaiworapongsa, T & Espinoza, J. (2003). Micronutrients and intrauterine

133, No. 5 Suppl 2, (May 2003), pp. 1668S-1673S, 0022-3166 (Print)

Vol. 11, No. 5, (Oct 2006), pp. 317-326, 1744-165X (Print)

Vol. 49, No. 2009), pp. 73-97, 0065-2423 (Print)

Vol. 47, No. Pt 4, (Jul 2010), pp. 301-312, 1758-1001 (Electronic)

Vol. 276, No. 6 Pt 2, (Jun 1999), pp. R1825-1832, 0002-9513 (Print)

2, (Feb 2002), pp. 183-191, 0022-3476 (Print)

698X (Electronic)

(Print)

(Print)

584, 0931-041X (Print)

0002-9378 (Print)

dopamine in preterm infants with low systemic blood flow. *J Pediatr*, Vol. 140, No.

injury: a critical evaluation of current status and future promise. *Ann Clin Biochem*,

in the neonatal ICU. *Curr Opin Pediatr*, Vol. 22, No. 2, (Apr 2010), pp. 146-150, 1531-

JM & Barasch, JM. (2010). Urinary neutrophil gelatinase-associated lipocalin is a promising biomarker for late onset culture-positive sepsis in very low birth weight infants. *Pediatr Res*, Vol. 67, No. 6, (Jun 2010), pp. 636-640, 1530-0447 (Electronic) Petershack, JA, Nagaraja, SC & Guillery, EN. (1999). Role of glucocorticoids in the

maturation of renal cortical Na+-K+-ATPase during fetal life in sheep. *Am J Physiol*,

M. (2009). Cardiovascular and pulmonary consequences of airway recruitment in preterm lambs. *J Appl Physiol*, Vol. 106, No. 4, (Apr 2009), pp. 1347-1355, 8750-7587

Renal volume and function in school-age children born preterm or small for gestational age. *Pediatr Nephrol*, Vol. 23, No. 8, (Aug 2008), pp. 1309-1315, 0931-041X

for proteinuria in a rheumatology clinic: comparison of dipstick testing, 24 hour urine quantitative protein, and protein/creatinine ratio in random urine samples.

of extremely low birth weight infants. *Pediatr Nephrol*, Vol. 20, No. 2005), pp. 579-

Histomorphometric Analysis of Postnatal Glomerulogenesis in Extremely Preterm

infection, preterm birth and the fetal inflammatory response syndrome. *J Nutr*, Vol.

Inflammation in preterm and term labour and delivery. *Semin Fetal Neonatal Med*,

fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. *Am J Obstet Gynecol*, Vol. 179, No. 1, (Jul 1998), pp. 186-193,


**4** 

**Renal Potassium Handling and** 

**Leading to Hypokalemia** 

Jelena Stojanovic and John Sayer

*Institute of Genetic Medicine* 

*Newcastle University Newcastle upon Tyne United Kingdom* 

**Associated Inherited Tubulopathies** 

Regulation of intracellular and extracellular potassium concentration is a fundamental process vital for cellular metabolism. Potassium intake, from the diet, is carefully balanced with excretion of potassium via the renal tract and gastrointestinal losses. Following a potassium load, extra-renal buffering of potassium occurs in peripheral tissues prior to its excretion. Thus potassium regulation is achieved by both short term and long term mechanisms. It has become clear that a series of potassium ion channels and transporter proteins have physiologically important roles throughout the length of the nephron. Our knowledge of normal physiological mechanisms has been increased by studying molecular defects responsible for variety of disorders associated with potassium transport. Studying renal tubular epithelial cell proteins and their regulation has improved the understanding of

Here, we review the normal renal tubular handling of potassium and discuss the molecular basis of clinical syndromes associated with hypokalemic alkalosis and hypokalemic forms of

Glomerular filtration produces >160 L of filtrate per day in a healthy adult, and 99% of this volume and majority of filtered solutes are reabsorbed along the nephron. The filtrate is identical to that of plasma with respect to water and solutes of low molecular weight, such

The proximal convoluted tubule is responsible for reabsorption of glucose, amino acids, phosphate, sodium and low-molecular weight proteins. Around 65% of filtered sodium is reabsorbed in the proximal tubule. Potassium reabsorption is closely coupled to sodium transport (driven passively by the electrical gradient) and around 75% of filtered potassium is reabsorbed by the proximal convoluted tubule. The proximal straight tubule may secrete some potassium into the urine, and this secretion can be upregulated significantly in

as glucose, chloride, sodium, phosphate, urea, uric acid, creatinine and potassium.

inherited tubular disorders which may cause hypokalemia.

**2. Renal tubular handling of potassium 2.1 Glomerular filtration and proximal tubule** 

**1. Introduction** 

hypertension.

