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doi:10.1111/jpc.12812
REVIEW ARTICLE
Paediatric nephrology: The last 50 years Joshua Y Kausman1,2 and Harley R Powell1 1
Department of Nephrology, Royal childrens Hospital, and 2Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
Abstract: In 1965, the specialty of paediatric nephrology was in its infancy. Following the development of a landmark collaborative research study, the International Study of Kidney Disease in Childhood in the mid-1960s, the first specialist societies were formed: the European Society of Pediatric Nephrology in 1967 and the American Society of Pediatric Nephrology in 1969. The extraordinary improvements in care delivered to children with kidney disease over the past 50 years are too broad to cover in any one paper. They traverse the spectrum of diagnosis, classification, therapeutics, social well-being and transition to adult care. We have selected four case scenarios to highlight these changes in key areas of paediatric nephrology: post-streptococcal glomerulonephritis, nephrotic syndrome, haemolytic uraemic syndrome and neonatal dialysis and childhood transplantation. Key words:
glomerulonephritis; haemolytic-uraemic; syndrome; nephrotic syndrome.
Post-Streptococcal Glomerulonephritis (PSGN) Jasmine is 7 years old and presents with 3 days of macroscopic haematuria and oedema, 2 weeks after a throat infection. Blood pressure is elevated at 140/100, and her urine output has decreased in the last 24 h. In 1965, a hypertensive patient with acute nephritis and severe oliguric renal failure would be treated with electrolyte and fluid restriction and with the few available antihypertensive medications (methyldopa and reserpine), with a course of penicillin and, if necessary, with a short period on peritoneal dialysis. Many patients experienced hypertensive fitting. In the 1970s, papers reported that plasma renin levels were low in acute nephritis, suggesting that fluid overload was primarily responsible for the hypertension.1 Treatment with frusemide was introduced, and it was shown that the degree of hypertension was directly proportional to the amount of fluid overload as measured by the weight lost in the subsequent diuresis.2 In 2015, Jasmine would still receive supportive care, but the judicious use of frusemide with salt and fluid restriction would dramatically reduce her risk of hypertensive encephalopathy and very few patients need dialysis today. During the last 50 years, there has been a substantial decline in the incidence of PSGN in most developed countries and most now are pharyngitis-associated.3–6 On the contrary, the majority of PSGN world-wide occurs in developing countries, Correspondence: Dr J. Y. Kausman, Royal Childrens Hospital, Department of Nephrology, Flemington Road, Parkville, Melbourne, Vic. 3052, Australia. Fax: +61 3 9345 5611; email: [email protected] Conflict of interest: The authors declare they have no knowledge of any conflict of interest. Accepted for publication 7 May 2014.
where pyoderma-associated cases predominate as they did 50 years ago. This discordance is thought to largely relate to hygiene and access to antibiotics, with the incidence in certain communities such as indigenous Australians about 50 times the incidence in the non-indigenous population.7 More importantly, a direct link has been demonstrated between high endemic rates of PSGN in this community and subsequent development of chronic kidney disease in adulthood.8 In 2015, it is our responsibility that every child has equal access to basic health care; rates of PSGN will be a good barometer of our success in meeting this goal.
Nephrotic Syndrome Johnny is 5 years old and presents with classic nephrotic syndrome following an upper respiratory infection. In 1965, it was well recognised that this condition responded extremely well to oral corticosteroids in the majority of cases. The cause was unknown so blood tests would show the low albumin and normal blood urea, urine with heavy proteinuria and a renal biopsy, which generally showed minimal change disease. However, the ideal way to use steroids was unknown and varied between a few pulses of intravenous methylprednisolone, daily treatment for several months or steroids being given only on days with heavy proteinuria and omitted as soon as proteinuria resolved. The International Study of Kidney Disease in Children (ISKDC)9,10 was actively recruiting patients across Europe and Northern America to determine the ideal duration of steroid medication. As many as 50% of children would have frequent relapses so these would be treated with repeated doses of oral steroids, causing a heavy burden of side effects. If there was no response to steroids, the child would have few therapeutic options and would likely progress to renal failure and/or die. Cyclophosphamide, developed in the 1950s, was found to reduce the number of relapses in very frequent relapsers.11
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
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Paediatric nephrology – the last 50 years
JY Kausman and HR Powell
In 2015, Johnny would have the nephrotic syndrome confirmed and would then commence oral steroids. We now know that extending the course of steroids beyond 3 months reduces the relapse rate by as much as 30%, but we are still gathering data on the ideal dose and duration some 50 years after the findings of the ISKDC.12 He would not have a renal biopsy as the findings are less relevant than his response to steroids. However, if he failed to respond to 4 weeks of steroids or had a family history of nephrotic syndrome, he would have further diagnostic testing. Nephrotic syndrome is one area of medicine profoundly affected by the molecular understanding of the nephron and specifically the podocyte and the slit-pores. In 1998, Trygvasson’s group discovered that a gene mutation in nephrin, a protein specific to the slit diaphragm of the visceral podocyte, was the basis of the congenital nephrotic syndrome commonly seen in Finland.13 This triggered several studies on the podocyte and revealed a number of gene mutations that cause nephrotic syndrome.14 Most importantly, this explained many infantile and familial cases and almost none respond to immunosuppression. This is critically important in the most difficult group of patients with steroid-resistant nephrotic syndrome (SRNS). Rather than subject them to prolonged courses of heavy immunosuppression, they would be weaned off once the gene mutation was discovered. There may be a risk of progression to end-stage kidney disease, but the risk of disease recurrence posttransplant would be negligible, making them excellent transplant candidates. On the other hand, the child with SRNS and no identifiable mutation may have up to 50% risk of disease recurrence post-transplant and graft loss without rapid control with heavy immunosuppression. Another notable development is in the armamentarium of therapeutic options. Not only do we have prednisolone and cyclophosphamide, but for the frequent relapsers with steroid side effects or SRNS, we now have other agents including cyclosporine, tacrolimus, mycophenolate mofetil, vincristine, levamisole and most recently, rituximab.15 Rituximab in particular is emerging as a very promising agent for steroiddependent children requiring multiple immunosuppressants to partially maintain remission. Many such cases are successfully treated with rituximab and allow them to stop all other immunosuppressants. It is hoped this is the start of a more tailored therapeutic approach, but further research is required to get a clear understanding of the molecular/immunological basis of this classical childhood kidney disease.
Haemolytic Uraemic Syndrome (HUS) Rachael is 4 months old and presents with anaemia, thrombocytopenia, red cell fragmentation and acute renal failure (ARF). There was no clear history of bloody diarrhoea, but at 4 months, her bowel actions may have been a bit loose. She is diagnosed with HUS. In 1965, the situation would be quite tenuous for Rachael. There would be no option of haemodialysis and emerging ‘paediatric nephrologists’ were learning the technique of peritoneal dialysis. This involved the use of stiff, straight catheters that were hard to secure in the abdomen, very prone to infection and only an option for a maximum of a few weeks. Unless Rachael’s 2
blood pressure could be controlled, anaemia corrected and ARF managed conservatively, there would be a high chance of Rachael dying. It would take until 1983 for the commonest cause of HUS, shigatoxin, to be identified.16 If Rachael were to present in the 1990s, she would still be diagnosed with HUS and managed supportively, but this would include peritoneal dialysis, or haemodialysis if necessary. This would be expected as a short-term treatment with a high chance of success, providing the ARF resolved with return of native renal function. Mortality of a patient due to the ARF would now be reduced from over 90% to 2–3%.17 However, in 1990, if Rachael did not recover renal function, her prospects on long-term dialysis would be poor and she would be too small for renal transplant. It would be likely her parents would be counselled against further active treatment. In 2015, the situation may be better, but is also more complicated as our knowledge and therapeutic options have grown. With respect to diagnosis, even the terminology has changed. Rachael would be diagnosed with acute kidney injury (AKI) due to thrombotic microangiopathy, likely HUS, and we would rapidly be able to identify shigatoxin if present. However, at her age, there would be consideration that this may be atypical HUS (aHUS). In 1998, Dr Goodship’s laboratory in the UK identified a mutation in complement factor H (CFH) as a cause of aHUS18 and subsequently it has become evident that defects in the complement regulatory pathway underlie the majority of cases of aHUS.19,20 This has important implications: a high risk of recurrence and progression to endstage kidney disease (ESKD) or death, up to 80% recurrence post-transplant with graft loss and finally the implications for family members who may share the mutation. From an acute management perspective, Rachael could be offered peritoneal dialysis, haemodialysis or haemofiltration with a high chance of success in controlling the AKI. If renal recovery did not occur, she would be maintained on peritoneal dialysis if she did not require vascular access for other reasons (see below). Initial therapy for controlling aHUS has depended on plasma infusion or plasma exchange, which has variable results and would be challenging due to need for vascular access in a small infant. Even with this intensive therapy as many as 2/3 of patients with aHUS due to CFH mutations will progress to ESKD or die in the first year after the initial presentation. A detailed molecular understanding of the role played by the alternative complement pathway in aHUS has led to the development of novel therapies such as eculizumab, which offers hope for an effective treatment for this disease.21 A great challenge in 2015 remains the early diagnosis, including gene mutation analysis, of rare conditions such as aHUS and funding for expensive therapies such as eculizumab.22
Neonatal Dialysis and Childhood Transplantation Rohan was born at term weighing 2.8 kg and has poor urine output and respiratory distress. On the first day after birth, his oxygen requirement is dramatically increasing and imaging shows severe bilateral hydronephrosis and a thick-walled
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
JY Kausman and HR Powell
bladder. Serum creatinine increases rapidly over the first 48 h to 500 μmol/l. He has a presumptive diagnosis of posterior urethral valves with pulmonary hypoplasia. In 1965, Rohan would be managed conservatively and palliated. His anatomy would be identified by micturating cystourethrogram (MCU), but his upper tracts would need retrograde pyelography, as ultrasound was not yet available. Ventilation in this setting would exceed the technological capabilities, but even if he did survive the first week, there would be no facility for long term dialysis of a neonate. In 1990, Rohan would be ventilated and may survive this period of respiratory distress with the advances in neonatal intensive care expertise. If so, the respiratory component would no longer present significant long-term risks. However, the oliguric renal failure would be at the very limits of contemporary medical care. If relief by catheterisation/vesicostomy/ nephrostomy was unsuccessful, any attempt to provide dialysis would be regarded as extraordinary or even experimental care. Due to the burden of providing chronic dialysis, the low chance of success and the high morbidity, the consensus opinion among paediatric nephrologists in this era would be for conservative management with palliation, in the best interests of the child and the family. In most circumstances this would follow a medical discussion independent of the family and the parents would be informed of the decision. In 2015, the situation would be quite different, likely from beginning to end. The diagnosis would almost certainly be made antenatally by ultrasound. The parents would be well informed by a fetal diagnostic specialist unit with nephrology and urology input and the pregnancy closely monitored. Termination of pregnancy would be considered, although some centres may consider vesico-amniotic shunting. If Rohan survived to birth, he would be rapidly stabilised and ventilated, catheterised and optimal fluid management provided for control of his oliguria. The formal diagnosis would be made by MCU, and valve ablation performed cystoscopically could be offered without the need for vesicostomy or nephrostomies. As above, if Rohan’s respiratory status stabilised, a discussion would be held with the parents regarding the relative merits of palliative care or intervention with dialysis. Even, with marked improvements in peritoneal dialysis, this is still a difficult and risky road in a 2.8 kg oligo-anuric neonate. However, the current consensus of paediatric nephrologists would be to offer this and in reality, most parents opt for the therapy once presented with any prospect of their child’s longterm survival. The ideal outcome would be to achieve a weight of 10 kg and have a pre-emptive transplant from a member of the family. However, this may take up to 2 years in the context of an infant with dialysis-associated complications, poor feeding and failure to thrive. Chronic dialysis of an infant was rarely if ever practised prior to the 1980s, whereas this has become increasingly accepted in the last three decades with a 67% survival after 10 years of dialysis (a 32-fold increased mortality risk compared with healthy infants).23 Although the first paediatric kidney transplant was performed in 1954, soon after the first adult transplants, children faced high rates of complications, particularly due to graft thrombosis. This was often due to the unanticipated relative hypoperfusion of an adult donor kidney anastomosed to a small child’s
Paediatric nephrology – the last 50 years
vessels and small total blood volume. This was addressed with improved pre-transplant hydration, but immunosuppression was still very limited using azathioprine and prednisolone, and success depended on close tissue matching. Graft survival was as poor as 50% at 1 year.24 By the 1990s, rejection rates and graft survival had improved dramatically, thanks to the introduction of cyclosporine with graft survival 75–85% at 1 year. More potent immunosuppressive agents were on the horizon, particularly tacrolimus and mycophenolate mofetil.25 In 2015, kidney transplantation is evolving into a sub-specialty of its own due to the complexity of immunophenotyping, immunosuppression and approaches to overcoming barriers to transplantation. The latter has been necessitated through the imbalance of a growing breadth of patients eligible for transplant and a shortage of deceased donor organs. New strategies have been developed to widen the donor pool. In paired kidney exchange, a recipient with an incompatible, healthy live-donor can be entered into a national database and matched to a compatible pair. The pairs can then swap donor kidneys, facilitating the benefits of a live-donor transplant. The first national programme was developed in the Netherlands in 200426 and similar programmes now operate in most developed countries.27 Other approaches are careful use of ABO-incompatible transplants28 and selective desensitisation for patients with high donor-specific HLA antibodies. So in 2015, by about 2 years of age, we would expect Rohan to be fit for transplant and ideally a parent or grandparent would be fully worked up to allow a successful live-related transplant. Up to 60% of paediatric transplants come from livedonors, and this provides the best long-term prognosis with graft survival at 5 years now 75–80%, as compared with approximately 65% for a deceased donor transplant.29
Conclusion The last 50 years have seen enormous changes in the knowledge and care available for children with diseases of the kidneys and urinary tract. Paediatric nephrology has become a sub-specialty with national and international societies encouraging collaborative approaches to clinical practice, education and research. Each of the areas touched on in this paper is worthy of multiple dedicated reviews to do justice to the advances over the last half-century. However, the stark reality we have tried to highlight is the different outcomes these four children would face today as you sit down to read this compared with the day this journal was first published. Jasmine would have a brief stay in hospital treated with frusemide instead of possible hypertensive seizures with need for dialysis; Johnny could escape terrible steroid-induced osteoporosis and stunted growth; Rachael’s dialysis and therapy for HUS would give her a chance of survival possibly with normal kidney function; and Rohan’s dialysis and kidney transplant would mean he too would not perish.
References 1 Powell HR, Rotenberg E, Williams AL, McCredie DA. Plasma renin activity in acute poststreptococcal glomerulonephritis and the haemolytic-uraemic syndrome. Arch. Dis. Child. 1974; 49: 802–7.
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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JY Kausman and HR Powell
2 Powell HR, McCredie DA, Rotenberg E. Response to frusemide in acute renal failure: dissociation of renin and diuretic responses. Clin. Nephrol. 1980; 14: 55–9. 3 Eison TM, Ault BH, Jones DP, Chesney RW, Wyatt RJ. Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis. Pediatr. Nephrol. 2011; 26: 165–80. 4 Zhang Y, Shen Y, Feld LG, Stapleton FB. Changing pattern of glomerular disease at Beijing Children’s Hospital. Clin. Pediatr. (Phila) 1994; 33: 542–7. 5 Yap HK, Chia KS, Murugasu B et al. Acute glomerulonephritis – changing patterns in Singapore children. Pediatr. Nephrol. 1990; 4: 482–4. 6 Berrios X, Lagomarsino E, Solar E, Sandoval G, Guzman B, Riedel I. Post-streptococcal acute glomerulonephritis in Chile – 20 years of experience. Pediatr. Nephrol. 2004; 19: 306–12. 7 Marshall CS, Cheng AC, Markey PG et al. Acute post-streptococcal glomerulonephritis in the Northern Territory of Australia: a review of 16 years data and comparison with the literature. Am. J. Trop. Med. Hyg. 2011; 85: 703–10. 8 Hoy WE, White AV, Dowling A et al. Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life. Kidney Int. 2012; 81: 1026–32. 9 International Study of Kidney Disease in Children. Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int. 1981; 20: 765–71. 10 Abramowicz M, Barnett HL, Edelmann CM Jr et al. Controlled trial of azathioprine in children with nephrotic syndrome. A report for the international study of kidney disease in children. Lancet 1970; 1: 959–61. 11 Arbeitsgemeinschaft für Pädiatrische Nephrologie. Effect of cytotoxic drugs in frequently relapsing nephrotic syndrome with and without steroid dependence. N. Engl. J. Med. 1982; 306: 451–4. 12 Lombel RM, Gipson DS, Hodson EM. Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr. Nephrol. 2013; 28: 415–26. 13 Kestila M, Lenkkeri U, Mannikko M et al. Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Mol. Cell 1998; 1: 575–82. 14 Rood IM, Deegens JK, Wetzels JF. Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice. Nephrol. Dial. Transplant. 2012; 27: 882–90.
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15 Greenbaum LA, Benndorf R, Smoyer WE. Childhood nephrotic syndrome – current and future therapies. Nat. Rev. Nephrol. 2012; 8: 445–58. 16 Karmali MA, Steele BT, Petric M, Lim C. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools. Lancet 1983; 1: 619–20. 17 Noris M, Remuzzi G. Hemolytic uremic syndrome. J. Am. Soc. Nephrol. 2005; 16: 1035–50. 18 Warwicker P, Goodship TH, Donne RL et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 1998; 53: 836–44. 19 Barbour T, Johnson S, Cohney S, Hughes P. Thrombotic microangiopathy and associated renal disorders. Nephrol. Dial. Transplant. 2012; 27: 2673–85. 20 Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat. Rev. Nephrol. 2012; 8: 622–33. 21 Legendre CM, Licht C, Muus P et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 2013; 368: 2169–81. 22 Isaacs D. Ethical dilemmas about orphan drugs for orphan diseases. J. Paediatr. Child Health 2014; 50: 333–4. 23 McDonald SP, Craig JC. Long-term survival of children with end-stage renal disease. N. Engl. J. Med. 2004; 350: 2654–62. 24 Shapiro R, Sarwal MM. Pediatric kidney transplantation. Pediatr. Clin. North Am. 2010; 57: 393–400, table of contents. 25 Halloran PF. Immunosuppressive drugs for kidney transplantation. N. Engl. J. Med. 2004; 351: 2715–29. 26 de Klerk M, Keizer KM, Claas FH, Witvliet M, Haase-Kromwijk BJ, Weimar W. The Dutch national living donor kidney exchange program. Am. J. Transplant. 2005; 5: 2302–5. 27 Ferrari P, Woodroffe C, Christiansen FT. Paired kidney donations to expand the living donor pool: the Western Australian experience. Med. J. Aust. 2009; 190: 700–3. 28 Flint SM, Walker RG, Hogan C et al. Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression. Am. J. Transplant. 2011; 11: 1016–24. 29 Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). The 35th Annual ANZDATA Report. Chapter 11 Paediatric Report. (2012). Available from: www.anzdata.org.au/v1/report_2012 .html [accessed 12 December 2014].
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
doi:10.1111/jpc.12812
REVIEW ARTICLE
Paediatric nephrology: The last 50 years Joshua Y Kausman1,2 and Harley R Powell1 1
Department of Nephrology, Royal childrens Hospital, and 2Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
Abstract: In 1965, the specialty of paediatric nephrology was in its infancy. Following the development of a landmark collaborative research study, the International Study of Kidney Disease in Childhood in the mid-1960s, the first specialist societies were formed: the European Society of Pediatric Nephrology in 1967 and the American Society of Pediatric Nephrology in 1969. The extraordinary improvements in care delivered to children with kidney disease over the past 50 years are too broad to cover in any one paper. They traverse the spectrum of diagnosis, classification, therapeutics, social well-being and transition to adult care. We have selected four case scenarios to highlight these changes in key areas of paediatric nephrology: post-streptococcal glomerulonephritis, nephrotic syndrome, haemolytic uraemic syndrome and neonatal dialysis and childhood transplantation. Key words:
glomerulonephritis; haemolytic-uraemic; syndrome; nephrotic syndrome.
Post-Streptococcal Glomerulonephritis (PSGN) Jasmine is 7 years old and presents with 3 days of macroscopic haematuria and oedema, 2 weeks after a throat infection. Blood pressure is elevated at 140/100, and her urine output has decreased in the last 24 h. In 1965, a hypertensive patient with acute nephritis and severe oliguric renal failure would be treated with electrolyte and fluid restriction and with the few available antihypertensive medications (methyldopa and reserpine), with a course of penicillin and, if necessary, with a short period on peritoneal dialysis. Many patients experienced hypertensive fitting. In the 1970s, papers reported that plasma renin levels were low in acute nephritis, suggesting that fluid overload was primarily responsible for the hypertension.1 Treatment with frusemide was introduced, and it was shown that the degree of hypertension was directly proportional to the amount of fluid overload as measured by the weight lost in the subsequent diuresis.2 In 2015, Jasmine would still receive supportive care, but the judicious use of frusemide with salt and fluid restriction would dramatically reduce her risk of hypertensive encephalopathy and very few patients need dialysis today. During the last 50 years, there has been a substantial decline in the incidence of PSGN in most developed countries and most now are pharyngitis-associated.3–6 On the contrary, the majority of PSGN world-wide occurs in developing countries, Correspondence: Dr J. Y. Kausman, Royal Childrens Hospital, Department of Nephrology, Flemington Road, Parkville, Melbourne, Vic. 3052, Australia. Fax: +61 3 9345 5611; email: [email protected] Conflict of interest: The authors declare they have no knowledge of any conflict of interest. Accepted for publication 7 May 2014.
where pyoderma-associated cases predominate as they did 50 years ago. This discordance is thought to largely relate to hygiene and access to antibiotics, with the incidence in certain communities such as indigenous Australians about 50 times the incidence in the non-indigenous population.7 More importantly, a direct link has been demonstrated between high endemic rates of PSGN in this community and subsequent development of chronic kidney disease in adulthood.8 In 2015, it is our responsibility that every child has equal access to basic health care; rates of PSGN will be a good barometer of our success in meeting this goal.
Nephrotic Syndrome Johnny is 5 years old and presents with classic nephrotic syndrome following an upper respiratory infection. In 1965, it was well recognised that this condition responded extremely well to oral corticosteroids in the majority of cases. The cause was unknown so blood tests would show the low albumin and normal blood urea, urine with heavy proteinuria and a renal biopsy, which generally showed minimal change disease. However, the ideal way to use steroids was unknown and varied between a few pulses of intravenous methylprednisolone, daily treatment for several months or steroids being given only on days with heavy proteinuria and omitted as soon as proteinuria resolved. The International Study of Kidney Disease in Children (ISKDC)9,10 was actively recruiting patients across Europe and Northern America to determine the ideal duration of steroid medication. As many as 50% of children would have frequent relapses so these would be treated with repeated doses of oral steroids, causing a heavy burden of side effects. If there was no response to steroids, the child would have few therapeutic options and would likely progress to renal failure and/or die. Cyclophosphamide, developed in the 1950s, was found to reduce the number of relapses in very frequent relapsers.11
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
1
Paediatric nephrology – the last 50 years
JY Kausman and HR Powell
In 2015, Johnny would have the nephrotic syndrome confirmed and would then commence oral steroids. We now know that extending the course of steroids beyond 3 months reduces the relapse rate by as much as 30%, but we are still gathering data on the ideal dose and duration some 50 years after the findings of the ISKDC.12 He would not have a renal biopsy as the findings are less relevant than his response to steroids. However, if he failed to respond to 4 weeks of steroids or had a family history of nephrotic syndrome, he would have further diagnostic testing. Nephrotic syndrome is one area of medicine profoundly affected by the molecular understanding of the nephron and specifically the podocyte and the slit-pores. In 1998, Trygvasson’s group discovered that a gene mutation in nephrin, a protein specific to the slit diaphragm of the visceral podocyte, was the basis of the congenital nephrotic syndrome commonly seen in Finland.13 This triggered several studies on the podocyte and revealed a number of gene mutations that cause nephrotic syndrome.14 Most importantly, this explained many infantile and familial cases and almost none respond to immunosuppression. This is critically important in the most difficult group of patients with steroid-resistant nephrotic syndrome (SRNS). Rather than subject them to prolonged courses of heavy immunosuppression, they would be weaned off once the gene mutation was discovered. There may be a risk of progression to end-stage kidney disease, but the risk of disease recurrence posttransplant would be negligible, making them excellent transplant candidates. On the other hand, the child with SRNS and no identifiable mutation may have up to 50% risk of disease recurrence post-transplant and graft loss without rapid control with heavy immunosuppression. Another notable development is in the armamentarium of therapeutic options. Not only do we have prednisolone and cyclophosphamide, but for the frequent relapsers with steroid side effects or SRNS, we now have other agents including cyclosporine, tacrolimus, mycophenolate mofetil, vincristine, levamisole and most recently, rituximab.15 Rituximab in particular is emerging as a very promising agent for steroiddependent children requiring multiple immunosuppressants to partially maintain remission. Many such cases are successfully treated with rituximab and allow them to stop all other immunosuppressants. It is hoped this is the start of a more tailored therapeutic approach, but further research is required to get a clear understanding of the molecular/immunological basis of this classical childhood kidney disease.
Haemolytic Uraemic Syndrome (HUS) Rachael is 4 months old and presents with anaemia, thrombocytopenia, red cell fragmentation and acute renal failure (ARF). There was no clear history of bloody diarrhoea, but at 4 months, her bowel actions may have been a bit loose. She is diagnosed with HUS. In 1965, the situation would be quite tenuous for Rachael. There would be no option of haemodialysis and emerging ‘paediatric nephrologists’ were learning the technique of peritoneal dialysis. This involved the use of stiff, straight catheters that were hard to secure in the abdomen, very prone to infection and only an option for a maximum of a few weeks. Unless Rachael’s 2
blood pressure could be controlled, anaemia corrected and ARF managed conservatively, there would be a high chance of Rachael dying. It would take until 1983 for the commonest cause of HUS, shigatoxin, to be identified.16 If Rachael were to present in the 1990s, she would still be diagnosed with HUS and managed supportively, but this would include peritoneal dialysis, or haemodialysis if necessary. This would be expected as a short-term treatment with a high chance of success, providing the ARF resolved with return of native renal function. Mortality of a patient due to the ARF would now be reduced from over 90% to 2–3%.17 However, in 1990, if Rachael did not recover renal function, her prospects on long-term dialysis would be poor and she would be too small for renal transplant. It would be likely her parents would be counselled against further active treatment. In 2015, the situation may be better, but is also more complicated as our knowledge and therapeutic options have grown. With respect to diagnosis, even the terminology has changed. Rachael would be diagnosed with acute kidney injury (AKI) due to thrombotic microangiopathy, likely HUS, and we would rapidly be able to identify shigatoxin if present. However, at her age, there would be consideration that this may be atypical HUS (aHUS). In 1998, Dr Goodship’s laboratory in the UK identified a mutation in complement factor H (CFH) as a cause of aHUS18 and subsequently it has become evident that defects in the complement regulatory pathway underlie the majority of cases of aHUS.19,20 This has important implications: a high risk of recurrence and progression to endstage kidney disease (ESKD) or death, up to 80% recurrence post-transplant with graft loss and finally the implications for family members who may share the mutation. From an acute management perspective, Rachael could be offered peritoneal dialysis, haemodialysis or haemofiltration with a high chance of success in controlling the AKI. If renal recovery did not occur, she would be maintained on peritoneal dialysis if she did not require vascular access for other reasons (see below). Initial therapy for controlling aHUS has depended on plasma infusion or plasma exchange, which has variable results and would be challenging due to need for vascular access in a small infant. Even with this intensive therapy as many as 2/3 of patients with aHUS due to CFH mutations will progress to ESKD or die in the first year after the initial presentation. A detailed molecular understanding of the role played by the alternative complement pathway in aHUS has led to the development of novel therapies such as eculizumab, which offers hope for an effective treatment for this disease.21 A great challenge in 2015 remains the early diagnosis, including gene mutation analysis, of rare conditions such as aHUS and funding for expensive therapies such as eculizumab.22
Neonatal Dialysis and Childhood Transplantation Rohan was born at term weighing 2.8 kg and has poor urine output and respiratory distress. On the first day after birth, his oxygen requirement is dramatically increasing and imaging shows severe bilateral hydronephrosis and a thick-walled
Journal of Paediatrics and Child Health (2014) © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
JY Kausman and HR Powell
bladder. Serum creatinine increases rapidly over the first 48 h to 500 μmol/l. He has a presumptive diagnosis of posterior urethral valves with pulmonary hypoplasia. In 1965, Rohan would be managed conservatively and palliated. His anatomy would be identified by micturating cystourethrogram (MCU), but his upper tracts would need retrograde pyelography, as ultrasound was not yet available. Ventilation in this setting would exceed the technological capabilities, but even if he did survive the first week, there would be no facility for long term dialysis of a neonate. In 1990, Rohan would be ventilated and may survive this period of respiratory distress with the advances in neonatal intensive care expertise. If so, the respiratory component would no longer present significant long-term risks. However, the oliguric renal failure would be at the very limits of contemporary medical care. If relief by catheterisation/vesicostomy/ nephrostomy was unsuccessful, any attempt to provide dialysis would be regarded as extraordinary or even experimental care. Due to the burden of providing chronic dialysis, the low chance of success and the high morbidity, the consensus opinion among paediatric nephrologists in this era would be for conservative management with palliation, in the best interests of the child and the family. In most circumstances this would follow a medical discussion independent of the family and the parents would be informed of the decision. In 2015, the situation would be quite different, likely from beginning to end. The diagnosis would almost certainly be made antenatally by ultrasound. The parents would be well informed by a fetal diagnostic specialist unit with nephrology and urology input and the pregnancy closely monitored. Termination of pregnancy would be considered, although some centres may consider vesico-amniotic shunting. If Rohan survived to birth, he would be rapidly stabilised and ventilated, catheterised and optimal fluid management provided for control of his oliguria. The formal diagnosis would be made by MCU, and valve ablation performed cystoscopically could be offered without the need for vesicostomy or nephrostomies. As above, if Rohan’s respiratory status stabilised, a discussion would be held with the parents regarding the relative merits of palliative care or intervention with dialysis. Even, with marked improvements in peritoneal dialysis, this is still a difficult and risky road in a 2.8 kg oligo-anuric neonate. However, the current consensus of paediatric nephrologists would be to offer this and in reality, most parents opt for the therapy once presented with any prospect of their child’s longterm survival. The ideal outcome would be to achieve a weight of 10 kg and have a pre-emptive transplant from a member of the family. However, this may take up to 2 years in the context of an infant with dialysis-associated complications, poor feeding and failure to thrive. Chronic dialysis of an infant was rarely if ever practised prior to the 1980s, whereas this has become increasingly accepted in the last three decades with a 67% survival after 10 years of dialysis (a 32-fold increased mortality risk compared with healthy infants).23 Although the first paediatric kidney transplant was performed in 1954, soon after the first adult transplants, children faced high rates of complications, particularly due to graft thrombosis. This was often due to the unanticipated relative hypoperfusion of an adult donor kidney anastomosed to a small child’s
Paediatric nephrology – the last 50 years
vessels and small total blood volume. This was addressed with improved pre-transplant hydration, but immunosuppression was still very limited using azathioprine and prednisolone, and success depended on close tissue matching. Graft survival was as poor as 50% at 1 year.24 By the 1990s, rejection rates and graft survival had improved dramatically, thanks to the introduction of cyclosporine with graft survival 75–85% at 1 year. More potent immunosuppressive agents were on the horizon, particularly tacrolimus and mycophenolate mofetil.25 In 2015, kidney transplantation is evolving into a sub-specialty of its own due to the complexity of immunophenotyping, immunosuppression and approaches to overcoming barriers to transplantation. The latter has been necessitated through the imbalance of a growing breadth of patients eligible for transplant and a shortage of deceased donor organs. New strategies have been developed to widen the donor pool. In paired kidney exchange, a recipient with an incompatible, healthy live-donor can be entered into a national database and matched to a compatible pair. The pairs can then swap donor kidneys, facilitating the benefits of a live-donor transplant. The first national programme was developed in the Netherlands in 200426 and similar programmes now operate in most developed countries.27 Other approaches are careful use of ABO-incompatible transplants28 and selective desensitisation for patients with high donor-specific HLA antibodies. So in 2015, by about 2 years of age, we would expect Rohan to be fit for transplant and ideally a parent or grandparent would be fully worked up to allow a successful live-related transplant. Up to 60% of paediatric transplants come from livedonors, and this provides the best long-term prognosis with graft survival at 5 years now 75–80%, as compared with approximately 65% for a deceased donor transplant.29
Conclusion The last 50 years have seen enormous changes in the knowledge and care available for children with diseases of the kidneys and urinary tract. Paediatric nephrology has become a sub-specialty with national and international societies encouraging collaborative approaches to clinical practice, education and research. Each of the areas touched on in this paper is worthy of multiple dedicated reviews to do justice to the advances over the last half-century. However, the stark reality we have tried to highlight is the different outcomes these four children would face today as you sit down to read this compared with the day this journal was first published. Jasmine would have a brief stay in hospital treated with frusemide instead of possible hypertensive seizures with need for dialysis; Johnny could escape terrible steroid-induced osteoporosis and stunted growth; Rachael’s dialysis and therapy for HUS would give her a chance of survival possibly with normal kidney function; and Rohan’s dialysis and kidney transplant would mean he too would not perish.
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