01/12
BJ BANTAO Journal
Editor-in-Chief
Official Publication of the BANTAO Association Incorporating Proceedings of the BANTAO Association
Associate Editors Skopje
Goce Spasovski
Mustafa Arici Nada Dimkovic Dimitrios Goumenos Nikolina Basic-Jukic
Editores Emeriti Varna Skopje Belgrade Athens Izmir
Dimitr Nenov Momir Polenakovic Ljubica Djukanovic Charalambos Stathakis Ali Basci
Ankara Belgrade Patra Zagreb
Deputy Editors Veselin Nenov Adrian Covic
Varna Iasi
Editorial Board Aydin Turkmen Alketa Koroshi Amira Peco Antic Biljana Stojmirovic Boriana Kiperova Cengiz Utas Daniela Monova Dimitrios Memmos Dimitris Tsakiris Ekrem Erek Evgueniy Vazelov Fehmi Akcicek Fevzi Ersoy Georgios Vergoulas Gordana Peruncic-Pekovic Gultekin Suleymanlar Halima Resic Igor Mitic Jadranka Buturovic-Ponikvar Jelka Masin Spasovska John Boletis Kamil Serdengecti Kenan Ates
Istanbul Tirana Belgrade Belgrade Sofija Kayseri Sofia Thessaloniki Thessaloniki Istanbul Sofija Izmir Antalya Thessaloniki Belgrade Antalya Sarajevo Novi Sad Ljubljana Skopje Athens Istanbul Ankara
Katica Zafirovska Ladislava Grcevska Liliana Garneata Kostas Siamopoulos Marko Malovrh Milan Radovic Myftar Barbullushi Olivera Stojceva Taneva Paul Gusbeth-Tatomir Petar Kes Rade Naumovic Rafael Ponikvar Sanja Simic-Ogrizovic Sanjin Racki Serhan Tuglular Sevgi Mir Tekin Akpolat Velibor Tasic Vidosava Nesic Vidojko Djordjevic Visnja Lezaic Vladislav Stefanovic Mahmut Ilker Yilmaz
Skopje Skopje Bucharest Ioannina Ljubljana Belgrade Tirana Skopje Iasi Zagreb Belgrade Ljubljana Belgrade Rijeka Istanbul Izmir Samsun Skopje Belgrade Nis Belgrade Nis Ankara
International Advisory Board Andrzej Wiecek Claudio Ponticelli Carmine Zoccali David Goldsmith Dimitrios Oreopoulos Francesco Locatelli Horst Klinkmann John Feehally Jorg Vienken
Poland Italy Italy UK Canada Italy Germany UK Germany
Published by: Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs Printing: BANTAO, 2012
Jorge Cannata Jurgen Floege Marc De Broe Markus Ketteler Mohamed Daha Norbert Lameire Raymond Vanholder Rosanna Coppo Ziad Massy
Spain Germany Belgium Germany Netherlands Belgium Belgium Italy France
Contents I. Editorial Comments Developmental Programming –Importance For Nephrologists Sanja Simic-Ogrizovic…………………………………………………………………………………
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II. Review Articles Calcineurin Inhibitor Nephropathy-Can we prevent the histological damage? Michael J. Mihatsc……………………………………………………………………………………..
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Primary Vascular Access: How can we do better? Marko Malovrh………………………………………………………………………………………...
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III. Original Articles Immunohistochemical Study of the Inflammatory Infiltrate and the Proliferative Index in the Tubulointerstitium in Human Glomerulonephritides Gordana Petrushevska, Slavica Kostadinova-Kunovska, Rubens Jovanovic, Ladislava Grcevska, Jelka Masin-Spasovska, Goce Spasovski and Momir Polenakovic …………………………………
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Epidemiology and Treatment of End Stage Renal Disease (ESRD) Patients in Kosovo in 2010 Ymer Elezi, Bejtush Zylfiu, Blerta Rugova, Venera Hasanxhekaj, Ibrahim Rrudhani, Njazi Gashi and Erblin Elezi………………………………………………………………………………………
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Predictive Value of Rifle Criteria on Renal Function Recovery of Patients with Septic and Non-Septic Acute Kidney Injury Aida Hamzic-Mehmedbasic, Senija Rasic, Sukrija Zvizdic, Alma Muslimovic, Damir Rebic and Amila Mehmedovic……………………………………………………………………………………
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Evaluation of the Metabolic Syndrome in Obese Patients on Hemodialysis Amela Beciragic, Halima Resic, Nejra Prohic, Fahrudin Masnic and Nihad Kukavica………………
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Rate and Causative Flora of the Peritoneal Infections in Patients Treated by Peritoneal Dialysis (Pd) in "Aleksandrovska" University Hospital, Sofia, Bulgaria Evgueniy Vazelov……………………………………………………………………………………...
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The Relationship Between Cardiac Valve Calcification and Abdominal Aortic Calcification in Peritoneal Dialysis Patients Saimir Seferi, Merita Rroji, Eriola Likaj, Majlinda Cafka, Nereida Spahia, Myftar Barbullushi, and Nestor Thereska………………………………………………………………………………………..
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IV. Case Report Emphysematous Pyelonephrıtıs in a Dıabetıc Patıent with Kidney Stone Kemal Magden, Utku Erdem Soyaltın, Gursel Yıldız, Cihan Celik and Ender Hur…………………..
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Phenytoin-Related DRESS Syndrome in a Hemodialysis Patient Georgios Vlachopanos ………………………………………………………………………………...
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V. In Memoriam A Tribute to Charalambos Stathakis John Boletis, Dimitrios Goumenos, Momir Polenakovic and Goce Spasovski…………...………………
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BANTAO Journal 2012; 10 (1): 1-5
BJ BANTAO Journal Editorial Comment
Developmental Programming –Importance for Nephrologists Sanja Simic-Ogrizovic1,2 1
Clinic of Nephrology, Clinical Center of Serbia, Belgrade, 2School of Medicine, Belgrade University, Belgrade, Serbia
Introduction
Animal models
The term "developmental programming" means the concept that many adult conditions or disease can have origins traced back to fetal and early postnatal life. Namely, developmental programming is the response by the developing mammalian organism to a specific challenge during a critical fetal time that alters the route of organ and tissue development with resulting persistent effects on the phenotype. Mammals pass more biological milestones before birth than any other time later in their lives. Each individual's phenotype is influenced by the developmental environment as much as by their genes [1]. The developmental origin of the disease hypothesis was first proposed by Barker and Osmond in The Lancet in 1986 [2]. This study was followed later by some human epidemiological and numerous animal investigations involving fetal undernutrition and/or low birth weight (LBW) and associated epigenetic influences in the development of common chronic diseases, such as hypertension, kidney disease, cardiovascular disease, liver disease, diabetes, and other metabolic abnormalities [3]. The two major topics of interest to nephrologists-hypertension and chronic kidney disease (CKD), commonly exist together and in everyday nephrological practice it is well known that the influence of one upon the other is difficult to elucidate. Moreover, hypertension is the numbertwo cause of end-stage renal disease (ESRD) after diabetes in the United States and Western countries. It is also a comorbid condition in approximately 61-66% of patients with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m 2 [4]. In a historical article Brenner and Chertow [5] hypothesized that retardation of renal development, as occurs in individuals of low birth weight (LBW), gives rise to increased postnatal risks for systemic and glomerular hypertension, as well as an enhanced risk of expression of renal disease. The mechanisms involved in developmental programming and hypertension include nutrition, oxidative stress and inflammation, glucocorticoids, transgenerational programmming and epigenetic changes. This review article will try to converge the mechanisms involved in developmental programming for the nephrologist population through animal studies.
With the aim of finding out how fetal insults result in hypertension and chronic kidney disease, investigators have used animal models, primarily experiments performed in rats and sheep that mimic the adverse events occuring in some pregnant women, such as maternal malnutrition, prenatal administration of glucocorticoids and uteroplacental insufficiency [6,7]. The most interesting experiments concerned: a) possible pathways of maternal malnutrition and glucocorticoids leading to prenatal programming; b) timing of adverse effects; c) sex differences in response to an adverse maternal event; d) nephron number, renal sodium transport, RAS and renal nerves in mechanisms causing hypertension and kidney disease by fetal programming; e) effect of the postnatal environment on glomerular number and blood pressure. a. Possible pathways of maternal malnutrition and glucocorticoids leading to prenatal programming The fetus is protected from the relatively high concentration of maternal glucocorticoids by placental 11β-hydroxysteroid dehydrogenase type 2 (11β-hsd -2) that converts physiological maternal glucocorticoids to inactive metabolites. Rats fed a low-protein diet during pregnancy had lower placental 11β-hsd-2 activity [8-10]. Also dexamethasone can cause similar insults as dietary protein deprivation, because it is able to cross the placenta intact and is a poor substrate for 11β-hsd-2. In humans, placental 11β-hsd-2 activity was shown not to change substantively during gestation but was significantly reduced in placentas of small-for-gestationalage infants [11]. In an elegant experiment Langley-Evans [12] showed that exposure to a maternal low-protein diet in utero programmed hypertension in the offspring and the data are consistent with the hypothesis that corticosteroids of maternal origin play a role in this programming effect. b. Timing of adverse effects Depending on the timing and severity, each of these insults is associated with small-for-gestational weight infants. However, Moritz et al. [13] recently pointed out that prenatal
________________________ Correspondence to: Sanja Simic-Ogrizovic, Clinic of Nephrology, Clinical Center of Serbia, Pasterova 2,
11 000 Belgrade, Serbia; Phone: +381 64 167 58 25; E-mail:
[email protected]
2
insults can result in programming a reduced nephron number and renal dysfunction in later life independent of LBW. From this point of view the question of the timing of the prenatal insult arises, which can determine programmed changes that affect the kidney. Woods et al. [14] found a reduction in glomerular number and elevated blood pressure in adult male offspring of pregnant rats that were fed a low-protein diet in the second half but not in the first half of pregnancy. They concluded that the window of sensitivity of adult blood pressure to prenatal protein restricttion falls within the period of nephrogenesis in the rat. On the other hand glucocorticoids are often administered to pregnant women to accelerate fetal lung maturation and studies in vitro have shown that dexamethasone inhibited branching morphogenesis and reduced glomerular number when added to media of day 14.5 and day 15.5 embryonic rat metanephrons [15]. In an elegant animal experiment Ortiz et al. [16], showed that prenatal dexamethasone resulted in hypertension and a reduction in nephron number in adult offspring of pregnant rats when administered daily on days 15 and 16 or 17 and 18 of gestation but not before or after this time. Nephrogenesis in the rat occurs during the last third of gestation and continues for a few days after delivery. It is obvious that the period of active nephrogenesis is the point when the kidney is most susceptible to injury, resulting in a reduction in nephron number and programming for hypertension in the adult offspring. c. Sex differences in response to an adverse maternal event In an animal study prenatal insults were found to affect males and females differently. In the previous mentioned study where dexamethasone was administered on days 14 and 15 of gestation, Oritz et al. [16] concluded that both male and female rats develop increased blood pressure with severe prenatal insults. However, milder maternal insults either affect only males or have only a transient effect on blood pressure in females. Other studies also showed that in response to moderate protein restriction during gestation in the rat, a reduction in nephron number associated with hypertension is observed only in male offspring [17] and that only male offspring exhibit vascular dysfunction in response to fetal hypoxia [18]. Therefore, the relative protection of females and the vulnerability of males to prenatal insults is probably associated with estrogen and testosterone. d. Nephron number, renal sodium transport, RAS and renal nerves in the mechanism of hypertension and kidney disease by fetal programming It is well known that the kidney is extremely sensitive to the effects of an adverse environment during critical windows of early development. In humans LBW is directly associated with oligonephronia [19] and the famous Brenner hypothesis [5,20,21] concerned infants with a small number of nephrons at birth who developed an impaired ability to excrete sodium leading to systemic and glomerular hypertension and eventually to glomerular sclerosis and impaired
Developmental programming in nephrology
renal function. This has been demonstrated in most animal models of prenatal programming [16,22-24,] and also in clinical studies [19,25]. Nephron loss occuring in response to fetal insult is probably due to alterations in the expression of genes and growth factors critical for proper nephrogenesis [26]. Furthermore, as already pointed out, timing of the insult during development is critical for nephron balance. However in some animal models there is a no association between a reduction in nephron number and the development of hypertension [27]. Moreover, some of them demonstrate that compensatory hyperfiltration occurs in response to the reduction in nephron number leading to preservation of glomerular filtration rate [28]. Thus, a reduction in nephron number may not be a key mechanism in the developmental programming of hypertension but may be critical for the increased susceptibility to renal injury and disease observed in response to fetal insult [29]. On the other hand there is significant evidence that prenatal insults program increases in renal tubular sodium transport. In the animal models of Betratam et al. [9] adult rats whose dams were fed a low-protein diet or administered prenatal glucocorticoids had an increase in renal Na/ K-ATPase mRNA loads. In another experiment Manning et al. [30] demonstrated increases in renal bumetanide-sensitive cotransporter (BSC2) and thiazide-sensitive cotransporter (TSC) but not the the apical proximal tubule Na/H exchanger-3 (NHE3), or any of the epithelial sodium channel (ENaC) subunits in offspring of females that had received restricted dietary protein compared with controls. Sodium transport via ENaC in the distal convoluted tubule and collecting tubule is regulated by aldosterone. Glucocorticoids bind to the mineralocorticoid receptor with equal affinity to aldosterone but are prevented from having an effect because 11β-hsd 2 in the distal nephron converts cortisol to cortisone in humans and corticosterone to inactive 11-dehydrocorticosterone in the rat. Renal mRNA expression of 11β-hsd 2 was lower in adult rat kidneys that had undergone a prenatal insult than in controls [9]. Therefore, while whole kidney ENaC protein loads may not differ between controls and rats with prenatal insults, there still may be increased surface ENaC expression leading to higher rates of sodium absorption. Thus, critical alterations in the morphology and pathophysiology of the kidney occur in response to fetal insult. Developmental programmming of renal structure and function leads to marked changes in the renal pressure-natriuresis relationship resulting in salt-sensitive hypertension associated with diminished resistance to renal injury and disease. However, the mechanism by which the fetal environment programs sensitivity and an increased susceptibility to renal injury remains unknown and may involve either intrinsic or extrinsic renal mechanisms or both [7]. The renin-angiotensin system plays a fundamental role in nephrogenesis [31,32], in body fluid balance through systemic and intrarenal action of angiotensin and is also an importmant regulator of arterial pressure [33,34]. Pregnant women treated with an ACE inhibitor during the first trimester are at increased risk of having children with central nervous system and cardiovascular disorders [35], while ACE administered after the first trimester resulted in se-
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S. Simic-Ogrizovic
vere renal damage leading to anuria and oligohydramnios [36]. In an animal model where rats received an AT blocker during the time when nephrogenesis was still occurring, had a reduced nephron number as well as a lower glomerular filtration rate, impaired renal concentrating ability and increased blood pressure compared with controls [37]. In another animal study maternal dietary protein deprivation resulted in offspring with lower renal renin mRNA, renal AT1-receptor protein, mRNA abundance and renal angiotensin II levels, but higher AT2-receptor mRNA levels [38-40]. Nevertheless, there are conflicting data concerning the association of plasma levels of angiotensin II with blood pressure. Thus, it could be concluded that prenatal insults probably result in renal injury by disturbing the renin-angiotensin system, but it is unlikely that RAS plays the primary role in generating or mediating the hypertension seen in neonates or adults that were small for gestational age. Changes in renal sympathetic nerve activation have constant effects on natriuresis leading to long term alterations in blood pressure [41] but whether the sympathetic nervous system contributes to hypertension in LBW is controversial [42]. However, Johansson et al. [43] showed that elevations in circulating levels of catecholamines were greater in LBW children relative to their normal birth weight counterparts. Some animal studies demonstrated that chronic hypoxia during fetal development programmed by placental insufficiency [44,45] or fetal exposure to glucocorticoids [46] leads to sympathetic hyperinnervation. Increased sympathetic flow may be followed by upregulation of renal sodium transporters, increased sodium reabsorption, and hypertension [46]. Furthermore, in the experimental model of hypertension programmed by gestational malnutrition of Playdes et al. [47], expression of angiotensin II receptors was elevated in the low-protein offspring in regions of the brain critical for cardiovascular regulation. They pointed out a critical role for central angiotensin II in the etiology of programmed hypertension. Consequently, the pathogenesis of programmed hypertension may involve central activation of the RAS that leads to an increase in renal sympathetic nerve activity which in turn up-regulates sodium reabsorption resulting in hypertension. Several animal studies [16,49,50] have demonstrated that a prenatal insult in rats results in pups that develop progressive renal injury over time. Thus, Oritz et al. [16] found that, subsequent to administration of dexamethasone on days 15 and 16 of gestation, the offspring exhibited renal interstitial fibrosis, tubular atrophy, and glomerular sclerosis at 8 months of age. e. Effect of the postnatal environment on glomerular number and blood pressure As mentioned before nephrogenesis continues in humans until 34-36 weeks gestation, so premature human neonates born before this time still have new nephrons forming after birth. Also in rats, nephrogenesis continues for a few days after delivery. The postnatal environment can have a negative impact on renal development and may program changes in blood pressure. Recent evidence shows that postnatal nutrition and drugs can modulate prenatal program-
mming of hypertension as well as the number of glomeruli. Schreuder et al. [51] demonstrated that postnatal food restriction in the rat is associated with growth retardation, with a 25% reduction in nephron number and a concomitant increase in glomerular volume compared with controls. On the other hand Yzydorczyk et al. [52] verified that neonatal oxygen exposure in rats leads to cardiovascular and renal alterations in adulthood. These findings have relevance to premature human neonates kept in a neonatal intensive care unit where, even under the best circumstances, neonates are not in an environment comparable to the intrauterine one. It also interesting that perinatal caloric excess can be harmful as well. Boubred et al. [53] showed that rats fed excess milk gained more weight and both males and females had significantly more glomeruli than the control offspring. Nonetheless, male offspring that were overfed had higher blood pressure at 2 months, proteinuria at 12 months and glomerulosclerosis at 22 months of age. Regarding preventive measurements, the experimental study of Manning et al. [54] is very important. They demonstrated that administration of either a low-salt diet or an ACE inhibitor to offspring of mothers fed a low-protein diet at the time of weaning for 3 weeks prevented the development of hypertension. Blood pressure remained at control levels even though the low-salt diet and enalapril were discontinued weeks before the final measurement. Thus, there are critical times during postnatal development where one can potentially intervene and prevent hypertension. Whether this is true in humans has not yet been determined. Lastly, all mentioned animal studies have revealed that prenatal programming of hypertension and renal injury is not definitive and can be adjust by postnatal environment. Conclusions In conclusion, in the last decade the structural and physiological alterations involved in the complex mechanisms of fetal programming were almost elucidated through numerous animal studies and some of them are pointed in this article. However, associations between hypertension and kidney injury in adults and events that occur in the early fetal milieu are need to be definitive approved in humans. Conflict of interest statement. None declared.
References 1. 2.
3.
4.
Nijland MJ, Ford SP, Nathanielsz PW. Prenatal origins of adult disease. Curr Opin Obstet Gynecol 2008; 20(2): 132-138. Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986; 1:1077-1081. Nistala,R, Hayden M, DeMarco, et al. Prenatal Programming and Epigenetics in the Genesis of the Cardiorenal Syndrome. Cardiorenal Med 2011; 1(4): 243-254. U.S. Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage RenalDisease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2010.
4
5.
6.
7. 8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Developmental programming in nephrology
Brenner BM, Chertow GM. Congenital oligonephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis 1994; 23 (2): 171-175. Baum M. Role of the kidney in the prenatal and early postnatal programming of hypertension. Am J Physiol Renal Physiol 2010; 298: F235-F247. Nuyt AM, Alexander B. Developmental programming and hypertension. Curr Opin Nephrol Hypertens 2009; 18(2): 144-152. Benediktsson R, Lindsay RS, Noble J, et al. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 1993; 41: 339-341. Bertram C, Trowern AR, Copin N, et al. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11β-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 2001; 142: 2841-2853. Langley-Evans SC, Phillips GJ, Benediktsson R, et al. Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 1996; 17: 169-172. Kajantie E, Dunkel L, Turpeinen U, et al. Placental 11_hydroxysteroid dehydrogenase-2 and fetal cortisol/cortisone shuttle in small preterm infants. J Clin Endocrinol Metab 2003; 88: 493-500. Langley-Evans SC. Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. J Hypertens 1997; 15: 537-544. Moritz KM, Singh RR, Probyn ME, Denton KM. Developmental programming of a reduced nephron endowment: more than just a baby’s birth weight. Am J Physiol Renal Physiol 2009; 296: F1-F9. Woods LL, Weeks DA, Rasch R. Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Int 2004; 65: 1339-1348. Singh RR, Moritz KM, Bertram JF, Cullen-McEwen LA. Effects of dexamethasone exposure on rat metanephric development: in vitro and in vivo studies. Am J Physiol Renal Physiol 2003; 293: F548-F554. Ortiz LA, Quan A, Zarzar F, et al. Prenatal dexamethasone programs hypertension and renal injury in the rat. Hypertension 2003; 41: 328-334. Ozaki T, Nishina H, Hanson MA, Poston L. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol 2001; 530: 141-152. Hemmings DG, Williams SJ, Davidge ST. Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy. Am J Physiol Heart Circ Physiol 2005; 289: H674-H682. Hoy WE, Hughson MD, Bertram JF, et al. Nephron number, hypertension, renal disease, and renal failure. J Am Soc Nephrol 2005; 16: 2557-2564. Brenner BM, Chertow GM. Congenital oligonephropathy: an inborn cause of adult hypertension and progressive renal injury? Curr Opin Nephrol Hypertens 1993; 2: 691-695. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens 1988; 1: 335-347. Celsi G, Kistner A, Aizman R, et al. Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring. Pediatr Res 1998; 44: 317-322. Wintour EM, Moritz KM, Johnson K, et al. Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol 2003; 549: 929-935.
24. Wlodek ME, Westcott K, Siebel AL, et al. Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats. Kidney Int 2008; 74: 187-195. 25. Mackenzie HS, Lawler EV, Brenner BM. Congenital oligonephropathy: The fetal flaw in essential hypertension? Kidney Int (Suppl) 1996; 55: S30-S34. 26. Abdel-Hakeem AK, Henry TQ, Magee TR, et al. Mechanisms of impaired nephrogenesis with fetal growth restriction: altered renal transcription and growth factor expression. Am J Obstet Gynecol 2008; 199: 252-257. 27. Wlodek ME, Mibus A, Tan A, et al. Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat. J Am Soc Nephrol 2007; 18: 1688-1696. 28. Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein restriction suppresses thenewborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res 2001; 49: 460-467. 29. Ojeda NB, Grigore D, Alexander BT. Developmental programming of hypertension: insight from animal models of nutritional manipulation. Hypertension 2008; 52: 44-50. 30. Manning J, Beutler K, Knepper MA, Vehaskari VM. Upregulation of renal BSC1 and TSC in prenatally programmed hypertension. Am J Physiol Renal Physiol 2002; 283: F202-F206. 31. Friberg P, Sundelin B, Bohman SO, et al. Renin-angiotensin system in neonatal rats-induction of a renal abnormality in response to aceinhibition or angiotensin-ii antagonism. Kidney Int 1994; 45: 485-492. 32. Guron G, Friberg P. An intact renin-angiotensin system is a prerequisit for normal renal development. J Hypertens 2000; 18: 123-137. 33. Hall JE, Guyton AC, and Mizelle HL. Role of the renin-angiotensin system in control of sodium excretion and arterial pressure. Acta Physiol Scand Suppl 1990; 591: 48-62. 34. Carey RM and Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003; 24: 261-271. 35. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443-2451. 36. Tabacova S, Little R, Tsong Y, et al. Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment. Pharmacoepidemiol Drug Saf 2003; 12: 633-646. 37. Woods LL, Rasch R. Perinatal ANG II programs adult blood pressure, glomerular number, and renal function in rats. Am J Physiol Regul Integr Comp Physiol 1998; 275: R1593-R1599. 38. Vehaskari VM, Stewart T, Lafont D, et al. Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am J Physiol Renal Physiol 2004; 287: F262-F267. 39. Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res 2001; 49: 460-467. 40. Woods LL, Ingelfinger JR, Rasch R. Modest maternal protein restriction fails to program adult hypertension in female rats. Am J Physiol Regul Integr Comp Physiol 2005; 289: R1131-R1136. 41. Lohmeier TE. The sympathetic nervous system and longterm blood pressure regulation. Am J Hypertens 2001; 14: 147S-154S. 42. Weitz G, Deckert P, Heindl S, et al. Evidence for lower sympathetic nerve activity in young adults with low birth weight. J Hypertens 2003; 21: 943-950.
S. Simic-Ogrizovic
43. Johansson S, Norman M, Legnevall L, et al. Increased catecholamines and heart rate in children with low birth weight: perinatal contributions to sympathoadrenal overactivity. J Intern Med 2007; 261: 480-487. 44. Tintu AN, Noble FA, Rouwet EV. Hypoxia disturbs fetal hemodynamics and growth. Endothelium 2007; 14: 353-360. 45. Alexander BT, Hendon AE, Ferril G, Dwyer TM. Renal denervation abolishes hypertension in lowbirth-weight offspring from pregnant rats with reduced uterine perfusion. Hypertension 2005; 45: 754-758. 46. Dagan A, Kwon HM, Dwarakanath V, Baum M. Effect of renal denervation on prenatal programming of hypertension and renal tubular transporter abundance. Am J Physiol Renal Physiol 2008; 295: F29-F34. 47. Pladys P, Lahaie I, Cambonie G, et al. Role of brain and peripheral angiotensin II in hypertension and altered arterial baroreflex programmed during fetal fife in rat. Pediatr Res 2004; 55: 1042-1049. 48. Alexander BT. Fetal programming of hypertension. Am J Physiol Regul Integr Comp Physiol 2006; 290: R1-R10.
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49. Lucas SRR, Miraglia SM, Gil FZ, Coimbra TM. Intrauterine food restriction as a determinant of nephrosclerosis. Am J Kidney Dis 2001; 37: 467-476. 50. Regina S, Lucas R, Miraglia SM, et al. Intrauterine food restriction as a determinant of nephrosclerosis. Am J Kidney Dis 2001; 37: 467–476. 51. Schreuder MF, Nyengaard JR, Remmers F, et al. Postnatal food restriction in the rat as a model for a low nephron endowment. Am J Physiol Renal Physiol 2006; 291: F1104-F1107. 52. Yzydorczyk C, Comte B, Cambonie G, et al. Neonatal oxygen exposure in rats leads to cardiovascular and renal alterations in adulthood. Hypertension 2008; 52: 889-895. 53. Boubred F, Buffat C, Feuerstein JM, et al. Effects of early postnatal hypernutrition on nephron number and long-term renal function and structure in rats. Am J Physiol Renal Physiol 2007; 293: F1944-F1949. 54. Manning J, Vehaskari VM. Postnatal modulation of prenatally programmed hypertension by dietary Na and ACE inhibition. Am J Physiol Regul Integr Comp Physiol 2005; 288: R80-R84.
BANTAO Journal 2012; 10 (1): 6-10
BJ BANTAO Journal Review Article
Calcineurin Inhibitor Nephropathy - Can we prevent the histological damage? Michael J. Mihatsch Institute for Pathology, University Hospital Basel, Basel, Switzerland Abstract The morphological aspects of calcineurin inhibitor (cyclosporine, tacrolimus, CNI) nephrotoxicicity are briefly reviewed. The most important lesion of CNI-toxicity is the arteriolopathy. CNI-arteriolopathy is characterized by nodular protein deposits, which replace smooth muscle cells of the media in the arterioles. In case of severe involvement of the arterioles the vessels may be completely occluded, which results in glomerular and tubulo-interstitial damage. Statistical analysis shows a CNI driven pattern of renal lesions: CNI-arteriolopathy is highly correlated with CNI-glomerulopathy, focal segmental glomerulosclerosis, obsolescent glomeruli, tubular atrophy and interstitial fibrosis accompanied by sparse interstitial cellular infiltrates (CNI-nephropathy). CNI-therapy per se results in vasoconstriction of the afferent arterioles, which may cause a slight serum creatinine increase (functional toxicity). Superimposed on functional toxicity, morphological toxicity may cause a further increase in serum creatinine, due to progressive nephron loss, which reflects in part the structural damage. Today, severe Cyclosporine (CSA)-arteriolopathy occurs late (years) after transplantation. Until the year 2000, one third of biopsies showed CSA-arteriolopathy, thereafter the prevalence decreased, probably due to a strict low dose therapy and more effective co-medication. The findings suggest that, in case of any unexplained serum creatinine increase in Tx-recipients at any time after transplantation, a biopsy should be performed to eventually identify CNI-related lesions. These may require dose reduction of CNI or switch of therapy to other potent drugs. The greatest threat for the kidney transplant is still rejection and not CNI-toxicity. Keywords: calcineurin toxicity, chronic allograft nephropathy tubular atrophy, interstitial fibrosis
___________________________________________ Introduction The introduction of Cyclosporine A (CSA) marked the start
of an epic success story in renal transplantation (Tx): the survival rates of renal transplants soared rapidly; severe rejection reactions and other complications fell conspicuously. However, "chaque medaille a son revers". With the introduction of calcineurin inhibitors (cyclosporine, tacrolimus (CNI)), clinicians were confronted with this "revers" i.e. nephrotoxicity. Over the last decades, clinicians have learnt both to take advantage of the superior immunosuppressive power of CNI and to minimize the side effects. The nephrotoxicity of CNI has been reviewed many times and the morphological and functional consequences of CNItherapy became standard textbook knowledge [1-4]. In the following, I will give a brief overview with special reference to the prevalence of CNI-nephropathy in recent years. Classification, clinical and morphological findings in CNI-toxicity Calcineurin inhibitor toxicity may be classified into two major groups (Figure 1): A) Functional toxicity and B) Morphological toxicity (Toxic tubulopathy and Microangiopathy with or without tubulo-interstitial fibrosis). These different forms of toxicity have been reported in patients with kidney, liver, heart, and bone marrow transplants, as well as in patients with autoimmune diseases. Functional toxicity Functional changes due to CNI encompass renal side effects that are not associated with distinct morphologic renal lesions and that can already be seen at therapeutic trough levels and doses. Most patients develop functional changes at therapeutic dose levels, characterized by a slight increase in the serum creatinine, a decreased glomerular filtration rate and variable signs of tubular dysfunction. At high doses and trough levels, morphological toxicitythat is, tubulopathy and/or microangiopathy and their sequelae-may be superimposed on functional changes. Whereas functional changes and tubulopathy are reversible, microangiopathy may result in irreversible renal damage.
________________________ Correspondence to: Michael J. Mihatsch, Institute for Pathology, University Hospital Basel,
Schonbeinstrasse 40, CH-4031 Basel; Phone: +41 61 3287872; Fax: +41 61 2652230
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M.J. Mihatsch
Calcineurin Inhibitor Toxicity
tubular changes
tubular dysfunction
tubulopathy (proximal tubule)
common but reversible
seldom but reversible
vascular changes
vascular dysfunction
common but reversible
vasculopathy (afferent arteriole)
seldom and irreversible
Fig. 1. Classification of CNI-nephrotoxicity
Morphological Toxicity The morphologic changes seen in tubulopathy include isometric tubular vacuolization, inclusion bodies in tubular epithelial cells (corresponding to giant mitochondria), and microcalcification. Today, the only characteristic feature of tubulopathy is isometric vacuolization (Figire 2). Tubulopathy may develop and vanish quickly, without leaving behind any morphological damage. Tubulopathy is not accompanied by any specific tubular dysfunction and may be considered as a morphological indicator of too high trough levels of CNI for the kidney (also termed "acute CNI-toxicity").
hy) and upstream into arteries, close to where they branch into arterioles. Intimal fibrosis in arteries is quite common in patients with severe and longstanding CNI-microangiopathy.
Fig. 3. Early CNI-arteriolopathy
Fig. 2. Isometric vacuolization as seen in proximal tubules
Far more important than tubulopathy is microangiopathy, with or without tubulo-interstitial lesions (also termed "chronic CNI-toxicity"). CNI-microangiopathy (arteriolopathy) predominates in the peripheral vascular tree mainly the arterioles (afferent vessels). The vascular lesions sometimes extend downstream into the glomerulus (CNI-glomerulopat-
Typical CNI-arteriolopathy is characterized by circular nodular protein deposits which permeate the arteriolar wall, replace necrotic smooth muscle cells and may narrow or even occlude the vascular lumen (Figure 3, 4). Often, the protein deposits are arranged in a pattern resembling a pearl necklace. The protein deposits consist of IgM or complement (C3, C1q, C5b-9), or both. Fibrin is not uncommon and accompanied, in some cases, by fibrin thrombi in glomeruli and/or arterioles in the light microscope (Figure 5). CNI-arteriolopathy is rather similar to severe arteriolar hyalinosis, as seen in hypertension (Figure 6). However in ordinary arteriolar hyalinosis, the protein deposits are found underneath the endothelium and not in the media. Interestingly, typical CNI-arteriolopathy may regress after stopping or reducing the dose of CNI.This is usually the case as long as no circular involvement of the arteriole is present. With severe circular involvement, the arteriole may become completely scarred.
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Fig. 4. Severe CNI-arteriolopathy with circular protein deposits (red) in the vessel wall positive for IgM by immunofluorescence (green)
Fig. 5. Full blown picture of "thrombotic microangiopathy" with complete necrosis of the vessel wall and fibrin thrombi following CNI-therapy
The second feature of CNI-microangiopathy is CNI-glomerulopathy. The morphology of CNI-glomerulopathy is highly variable, ranging from fibrin thrombi in the beginning, to proliferative lesions mainly at the vascular pole of the glomerulus and segmental focal glomerulosclerosis. CNI-microangiopathy is often accompanied by tubulo-interstitial lesions. Irregular foci or stripes of tubular atrophy accompanied by fibrosis are observed in the renal cortex (Figure 7). The atrophic tubules exhibit mostly thickened basement membranes. A sparse mononuclear cell infiltrate is often seen in the fibrotic area, not only in patients with kidney transplants, but also in those with autoimmune disease without primary renal involvement. Glomerular changes, mainly completely obsolescent glomeruli, are usually not prominent but become more common in patients with advanced interstitial fibrosis and tubular atrophy. Hand in hand with progressive glomerular obsolescence, an increase in the glomerular cross sectional area of the remaining patent glomeruli (hypertrophy) is found. Statistical evaluation of 4,500 unselected renal biopsies of CSA-treated patients reveal a CNI-driven pattern of injury in he kidney. CNI-arteriolopathy is closely correlated (p
+
and Glomerulopathy % cases
60
40
% cases 61.7
CIN-Glompath.
27.5 40 31.7 20
26.4 20 7.1 4.5
0
0 Score 0
0 Score 1
Score 2
CNI- arteriolopathy
Score 3
0
1
CNI- glomerulopathy (Score)
Fig. 9. Severity of CNI-arteriolopathy and time to first biopsy
2
10
Calcineurin Inhibitor Nephropathy
The severity of the glomerulopathy (Figure 10) depends closely on the severity of the arteriolopathy. In the case of mild or moderate arteriolopathy, less than 5% of biopsies reveal a glomerulopathy, which is seen in severe cases in contrast in more than 25%. This means that an unclear, late rise in creatinine after transplantation, eventually accompanied by proteinuria, should prompt us to consider whether a CSA arteriolopathy/glomerulopathy is present. CIN- arteriolopathy and Morphological Sequelae %
frequency of arteriolopathy fell to 19%, that of glomerulopathy to around 2.5%. This reduction was certainly connected with the shorter observation period (in the earlier periods >5 years, between 2000-2004
