REVIEW URRENT C OPINION
Therapies for polycystic kidney disease John J. Bissler
Purpose of review All polycystic diseases of the kidney exhibit tubular or saccular cysts. The cysts can either be open to the tubule or isolated sacs that have lost their connections. Polycystic kidney diseases derived from different genetic mutations share basic mechanisms of cytogenesis, formation, and progressive enlargement, involving a cellular organelle called the primary cilium. Given the mechanistic commonalities, this review will focus on the therapeutic approaches currently available or under development that likely apply to all inherited renal cystic diseases. Recent findings Recent advances in clinical trials and preclinical experiments have illuminated common signaling pathway involvement. Summary Avoidance of nephrotoxic drugs or radio-contrast and maintaining normal BMI are routine preventive measures. Limiting the intake of calories, salt, and protein, together with increased intake of fruits, vegetables, and water are dietary treatments that should be started early in the course of the disease. Potential pharmacological treatments targeting cyst initiation and progression are on the horizon. Keywords chronic kidney disease, polycystic kidney disease, primary cilia, renal cyst
INTRODUCTION Inherited renal cystic diseases were initially grouped together based upon their pathological appearance – that they all contained a renal cyst. This structure, derived from the tubule, can either be a dilatation of the tubule, such as seen in autosomal recessive polycystic disease, or a saccular structure that has lost its connections with the tubule, such as in autosomal dominant polycystic kidney disease. More recent studies have revealed that inherited renal cystic diseases share an association with a sensory cellular organelle, called the primary cilia – a topic covered earlier in this volume of Current Opinion in Pediatrics (Katherine Dell’s review). The current review integrates both basic science and clinical trial results to refine treatment considerations for pediatric renal cystic disease. While current treatment of pediatric renal cystic disease is limited to symptomatic care, new understanding of the signaling pathways of the tubular cell offer therapeutic lifestyle changes and elude to possible pharmacological interventions in the near future. These ‘cystogenic’ signaling pathways include calcium, sonic hedgehog, Wnt, and notch signaling pathways described in other reviews in this volume. Leveraging these disease initiation and progression-related pathways offers a unique
pediatric opportunity to modify disease and hopefully prolong renal function.
CURRENT PRACTICE The hallmarks of the current treatment include hypertension control and avoiding nephrotoxic insults. Hypertension can occur in infants and small children with renal cystic disease, including those with autosomal dominant polycystic kidney disease. Blood pressure should be controlled to the level considered average for age, sex, and size. Hypertension in the child with renal cystic disease indicates that the cysts are damaging the Division of Nephrology, Department of Pediatrics, St Jude Children’s Research Hospital, University of Tennessee Health Science Center, Children’s Foundation Research Center, Memphis, Tennessee, USA Correspondence to John J. Bissler, MD, FedEx Chair of Excellence, Professor and Chief, Division of Nephrology, LeBonheur Children’s Hospital and Department of Pediatrics, Director of the Tuberous Sclerosis Center of Excellence, Medical Director of Nephrology, St Jude Children’s Research Hospital, University of Tennessee Health Science Center, Children’s Foundation Research Center, 50 N. Dunlap, Suite 528R WPT, Memphis, TN 38103, USA. Tel: +1 901 287 4825; fax: +1 901 287 4589; e-mail: [email protected] Curr Opin Pediatr 2015, 27:227–232 DOI:10.1097/MOP.0000000000000202
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KEY POINTS Clinical trials and bench research have changed the approach towards the child with polycystic kidney disease.
hyperlordotic posture to maintain balance. Such back pain can be improved by prescribing exercises to strengthen the abdominal core musculature and consciously altering posture.
Lifestyle changes are an important part of caring for a child with a polycystic kidney disease.
CELL BIOLOGY AND SIGNALING PATHWAYS OF RENAL CYSTIC DISEASE
New therapies are on the horizon.
All inherited renal cystic diseases are characterized by fluid-filled cysts that can be microscopic, or macroscopic. By distorting the sophisticated countercurrent multiplier in the renal medulla, small and large cysts can render the concentrating mechanism dysfunctional. The macroscopic structures, at least in part, compromise renal function, compressing the surrounding renal parenchyma [1]. The fusiform dilation of the collecting ducts in autosomal recessive polycystic disease alters the flow dynamics of blood, lymph, and urine, compromising the countercurrent amplification of the interstitial solutes for generating a maximally concentrated urine. Although renal cystic diseases were initially grouped by the observation of the pathology and subsequently by inheritance, another commonality is emerging. Most inherited renal cystic diseases have gene products that are associated with a cellsignaling organelle called the primary cilia, which arises from the basal body. The complex activities of the basal body range from critical extracellular sensing functions of the primary cilia, to chromosomal segregation during mitosis. Adding another layer of complexity to the renal cystic diseases is the simple fact that renal cyst development can be initiated as early as fetal development and can progress to cause end-stage renal disease during the midlife years of an individual, or, in the other extreme, disturb fetal development so that postnatal renal function is not possible [2]. As discussed earlier in this volume of Current Opinion in Pediatrics, cytogenesis appears to be associated with perturbed signal integration of calcium, cyclic adenosine monophosphate, hedgehog, Wnt, notch, and mechanosensation. These pathways may be required, but may not always be sufficient for cystogenesis, and their role differs depending on the initial system perturbation. The stage of a cyst is an important aspect when one considers therapeutic interventions. Although a cyst is most often thought of as a static entity – a fluid-filled structure surrounded by a single layer of cells – the reality is more complex than that. A cyst can maintain continuity with the tubule, as in autosomal recessive polycystic kidney disease (ARPKD), or lose this connection as in autosomal dominant polycystic kidney disease (ADPKD). A cyst can occur as an early pediatric life event (e.g.
microvasculature and anatomic configurations within the kidneys, even in those children with normal estimated glomerular filtration rates (GFRs). The altered renal anatomy in renal cystic disease can also disrupt the urine concentrating capacity, and this feature puts the child at considerable risk for dehydration and enuresis. Currently, parents are instructed to have a scale and to measure the child’s weight the moment they wonder if their child is getting ill. Sometimes parents can detect an illness even before the child complains or is symptomatic. Should illness ensue, such as gastroenteritis, the parents can again weigh the child before phoning their physician, so the percentage dehydration can be weight-based, and the physician should know not to use the patient’s urine output as an index of dehydration. The same concentration defect can also make patients or their families frustrated by prolonged nocturnal enuresis. This can be significantly improved by explaining that this is the natural course of events, and by sharing with the family the issues of urine concentration capacity. Such reassurance and strategies such as a wetting alarm can be very helpful, while drugs like 1-desamino-8D-arginine vasopressin (desmopressin) are strongly discouraged because of their potential to accelerate cyst growth. Likewise, families should be counseled about solute load, such as excess meat or salt intake, which increases osmolar clearance and forces water loss. Parents need to be aware of solute effects on urine volume when urine cannot be maximally concentrated. The effects cause endogenous antidiuretic hormone to be secreted and potentially can accelerate cyst growth. Children with very large kidneys sometime complain of flank pain. The reasons for such pain can be multiple. The onset of acute severe pain may be caused by a hemorrhage or, less likely, an infection in a cyst or surrounding tissue. If infection is strongly suspected, sometimes a PET study can help detect the infected cyst because of the glucose utilization by the leukocytes. Chronic pain often is due to the large kidney mass disturbing the patient’s center of balance, forcing a lordotic or even 228
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Therapies for polycystic kidney disease Bissler
ARPKD) or later in childhood (e.g. nephronophthisis), or in midlife (e.g. ADPKD). Cysts, depending on their size, can also have different appearances on ultrasound. This frustrating aspect of cytogenesis occurs because, by ultrasound, small cysts can appear as echo-dense structures that later develop an echo-lucent center. This contradictory finding serves as an introduction into cyst growth. To simplify the discussion, one can assume the cyst to be a sphere so that the relationship between cyst volume and surface area can be put into perspective. The equation for the fluid volume of a cyst, V, is as follows: V ¼ 4pr 3 3 and the equation for the single cellular surface area, (SA), is as follows:
M, 10 wks
F, 10 wks
M, 20 wks
F, 20 wks
AVP +/+
AVP +/–
AVP –/–
(c) Male AVP –/– Male AVP –/– +dDAVP Female AVP –/–
SA ¼ 4pr 2 ; Then, simple substitution reveals the relationship between the volume (V) and the surface area SA as follows: V¼
(a)
SAr 3
Up to a point, the fluid volume of a cyst is less compared to the cellular proliferation, but after that point, the volume begins to exceed, and in fact far exceeds, the surface area (when r>>3). This relationship is important when one considers the best surrogate maker for cystic disease in renal cystic burden [3]. For macrocystic disease, the rate of cyst growth is more a function of fluid accumulation than it is of cysts’ cellular proliferation. The different contributions of cellular proliferation and fluid secretion can be better appreciated in preclinical and clinical trial results. Therapies under development may have the potential to cure or greatly assuage polycystic disease if administered early enough. For example, completely interrupting vasopressin signaling completely normalizes renal histology in a murine model of ARPKD (Fig. 1) [4 ]. Initial studies using murine models of renal cystic disease clearly demonstrated a beneficial effect of mammalian target of rapamycin (mTOR)C1 inhibitors [5,6]. These studies use an experimental approach that could be considered preventive. The animals developed significant cystic disease at a young age, and they received either drug or vehicle over a period of time, starting from when they were not yet adult animals. The group that received active drug had much less cystic disease compared to the control group animals. The mTORC1 inhibitor effect clearly was beneficial as it decreased the cystic &&
Female AVP –/– +dDAVP Male AVP +/+
Male AVP +/+ +dDAVP
Female AVP +/+ Female AVP +/+ +dDAVP
FIGURE 1. (a) Representative hematoxylin and eosin-stained kidney sections from 10 and 20-week-old male and female PCK AVPþ/þ, PCK AVPþ/, and PCK AVP/ rats. PCK AVP/ kidneys exhibit nearly complete protection from cystic disease. (b) Hematoxylin and eosin-stained kidney sections from male and female PCK AVP/ and PCK AVPþ/þ rats (n ¼ 4 for each genotype and sex) treated continuously with dDAVP (10 ng/h/100 g body weight) or vehicle alone between 12 and 20 weeks of age. The administration of dDAVP recovered the cystic phenotype of the PCK AVP/ and aggravated the cystic disease of the PCK AVPþ/þ rats. This figure is reproduced with permission from Wang et al. [4 ]. AVP, arginine vasopressin; dDAVP, 1-desamino-8-D-arginine vasopressin (desmopressin); PCK, polycystic kidney.
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burden and preserved renal function in the treated animals. Because these findings were so positive, there was hope that mTORC1 inhibitors may be therapeutic in the most common renal cystic disease –ADPKD. These clinical trials used similar endpoints, specifically renal volume and renal function. In a 2-year, double-blind trial, 433 patients with ADPKD were randomly assigned to receive either placebo or the mTOR inhibitor everolimus (NCT00414440). The authors concluded that everolimus slowed the increase in total kidney volume of patients with ADPKD, but did not slow the progression of renal impairment [7]. In a second 18-month openlabel, randomized controlled trial using sirolimus, considering the rate of growth as an endpoint, 100 adult patients were randomly assigned to receive either sirolimus (2 mg daily) or standard care (NCT00346918). All patients had an estimated creatinine clearance of at least 70 ml/min. These authors concluded that sirolimus did not halt polycystic kidney growth [8]. Although there are several differences in these two studies, including duration, number of patients, and even some patient characteristics, both studies used adult patients and failed to show a beneficial effect on renal function. The kidney is not uniquely resistant to mTORC1 inhibitors, as these drugs have been demonstrated to be effective in renal cell carcinoma [9], and the renal angiomyolipomata associated with tuberous sclerosis complex [10,11] and are US Food and Drug Administration (FDA)-approved for adults with these proliferative diseases. Newer agents and a different patient population earlier in disease may reveal a different outcome. Cyst growth is also modifiable by interfering with fluid secretion. Specifically, interfering with antidiuretic hormone signaling has been identified to be an effective method to alter the renal cystic phenotype. In murine models of polycystic disease, either blocking the V2 receptor signaling or increasing fluid intake resulted in a lessoning of the renal cystic disease phenotype [4 ,12 ,13]. Likewise, this was demonstrated to be effective in a human trial (ClinicalTrials.gov number, NCT00428948). This phase 3, multicenter, double-blind, placebocontrolled, 3-year trial, conducted in patients with ADPKD and a total kidney volume equal to or greater than 750 ml, randomized patients aged 18–50 years of age to tolvaptan, a V2-receptor antagonist, or placebo [14]. The primary outcome was the annual rate of change in the total kidney volume, whereas secondary endpoints included a composite of time to progression that was defined as worsening kidney function, kidney pain, hypertension, and albuminuria and rate of kidney-function decline. &&
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&
The increase in total kidney volume in the treatment group was 2.8% per year, whereas it was 5.5% per year in the placebo group. The treatment group exhibited a slower rate of renal function decline. There were fewer ADPKD-related adverse events in the tolvaptan group, but this was offset by more events related to excess excretion of free water and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate in the patients treated with tolvaptan (23%) versus the control group (14%). The authors concluded that tolvaptan slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD, but was associated with a higher discontinuation rate, owing to adverse events. The involvement of the renin–angiotensin system in the context of blood pressure is well established. Renal tubular cells also express angiotensin type I receptors [15] and these can be important for renal development [16]. Aggressive intervention in the renin–angiotensin system has significant merit in ADPKD. Early, aggressive blood pressure control slowed progression of cystic disease. A double-blind, placebo-controlled trial randomly assigned 558 hypertensive participants with ADPKD with similar characteristics to the tolvaptan trial to either a standard blood pressure target (120/70 to 130/ 80 mmHg) or a low blood pressure target (95/60 to 110/75 mmHg) (ClinicalTrials.gov number, NCT00283686). These patients were also randomly assigned to an angiotensin-converting enzyme inhibitor (lisinopril) and an angiotensin-receptor blocker (telmisartan), or lisinopril and placebo. Using a similar primary outcome as above, the annual percentage change in the total kidney was significantly lower in the low-blood pressure group than in the standard-blood pressure group, without significant differences between the lisinopril–telmisartan group and the lisinopril–placebo group. The authors concluded that in early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume compared to the lisinopril alone, though rigorous blood pressure control was associated with a slower increase in total kidney volume, better preserved estimated GFR, greater decline in the left ventricular mass index, and greater reduction in urinary albumin excretion as compared with standard blood pressure control [17,18].
TIMING, DISEASE STAGE, AND IMPLICATIONS FOR TREATMENT To introduce the possible treatments of polycystic kidney disease, it is useful to consider the different factors that are involved in cystogenesis as a Volume 27 Number 2 April 2015
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Therapies for polycystic kidney disease Bissler
Disease stage
Initiation
Treatment goal
Progression
Prevention
Targeted therapy
Tissue disease Tissue/cyst therapy
D
D
+
PK
Disease activity
CK
Pro lif e
et ecr
rat
ion
S
ion
CystKidney • Vascular • Inflammation • Other
Time
FIGURE 2. Disease activity as a function of time. Different disease activities can be broken up into different stages. Intervention during these different stages would be aimed at different goals. CKD, chronic kidney disease; PKD, polycystic kidney disease.
function of time (Fig. 2). Considering the disease activity over time, there is the disease phase that is dominated by cellular proliferation. This phase would be particularly vulnerable to antiproliferative agents like mTORC1 inhibitors. For such drugs to be optimally beneficial, the time of proliferation would be limited, and thus avoid possible lifelong therapy. In this way, the treatment could be conceptualized as being preventive. A possible example could be found in the polycystic variety of tuberous sclerosis complex in which the disease is identified in utero, but develops into severe cystic disease over the first year or two of life. Such mTROC1 studies will soon be initiated. The goal will be to interfere with the proliferative phase of cystogenesis for a limited time and in that way act as a preventive therapy. Drugs that can affect both cellular proliferation and fluid secretion would be optimally beneficial for the phase of cyst growth that is dominated by fluid secretion. This was clearly demonstrated by the tolvaptan preclinical work and clinical trial. This kind of treatment would truly be targeted therapy aimed at halting disease progression. Therapy during the obvious cystic stage of disease will be more complex, because this stage also involves a final common pathway of chronic kidney disease and scaring that greatly complicate treatment, because two disease processes are at play. Therapy would need to address not only the polycystic renal disease, but also the renal response.
RECOMMENDATIONS FOR THERAPY OF POLYCYSTIC KIDNEY DISEASES The current recommendations for the treatment of patients with polycystic kidney disease continue to
mandate the prevention of harm, but now have additional potential ways to improve the long-term renal function [19 ]. Recommendations for the diagnosis and management of ARPKD are available and were created by experts in the associated fields during a consensus guideline development conference [20]. Furthermore, the convergence from pathological observations of cysts [21] to an association with a cellular organelle, the primary cilium, suggests that there may be several final common pathways involved which can be additional aspects of a general therapy. Considering the clinical and preclinical data, additional recommendations to be considered include the following: &&
(1) Patients should be counseled to attain and maintain an appropriate BMI. (2) Diet, calories, protein, salt, fruits, and vegetables, fluid and lifestyle changes will need to be adopted by the family. (3) Avoid nonsteroidal anti-inflammatory drugs, radio-contrast, and other known nephrotoxic drugs. (4) Patients should be encouraged to think of water as a required therapy that must be taken and on a schedule. Preclinical studies and the tolvaptan trial establish vasopressin as a target that should be kept at the lowest levels. (5) A blood pressure target of 110/80 or less in adults or below the 70th percentile for height and age is rational. (6) Although inconvenient at the beginning, these therapeutic interventions are well tolerated and hold the prospect of slowing disease progression.
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CONCLUSION Pediatric renal cystic diseases have many genetic causes. While there are potential treatments on the horizon, there are new recommendations as to lifestyle that potentially may have a large impact on slowing disease initiation or progression. Patient and family education and early referral to a pediatric nephrologist for blood pressure and disease control may offer a better outcome. Acknowledgements The author would like to thank Jared Grantham for his constructive critique and help preparing this manuscript. Financial support and sponsorship Funding from: NIH, PKD Foundation, LAM Foundation, TS Alliance, Wyeth, and Novartis. Conflicts of interest Dr Bissler has received honoraria from Up To Date, and Novartis Pharmaceuticals. He also has received grant support from Novartis Pharmaceuticals and the Department of Defense.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney disease. Nature Rev Nephrol 2011; 7:556–566. 2. Tran PV, Sharma M, Li X, Calvet JP. Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis? Birth Defects Res C Embryo Today 2014; 102:159–173. 3. Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol 2008; 3:1197–1204.
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4. Wang X, Wu Y, Ward CJ, et al. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 2008; 19:102–108. Good evidence for vasopressin involvement in renal cystic disease. 5. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 2005; 16:46–51. 6. Shillingford JM, Murcia NS, Larson CH, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A 2006; 103:5466–5471. 7. Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363:830–840. 8. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363:820–829. 9. Chan H-Y, Grossman AB, Bukowski RM. Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. Adv Ther 2010; 27:495– 511. 10. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebocontrolled trial. Lancet 2013; 381:817–824. 11. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358:140–151. 12. Gattone VH, Maser RL, Tian C, et al. Developmental expression of urine & concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev Genet 1999; 24:309–318. Classic article about vasopressin and cystic disease. 13. Nagao S, Nishii K, Katsuyama M, et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol 2006; 17:2220–2227. 14. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367:2407–2418. 15. Wilson BA, Marshall AC, Alzayadneh EM, Chappell MC. The ins and outs of angiotensin processing within the kidney. Am J Physiol Regul Integr Comp Physiol 2014; 307:R487–R489. 16. Gubler M-C. Renal tubular dysgenesis. Pediatr Nephrol 2014; 29:51–59. 17. Schrier RW, Abebe KZ, Perrone RD, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med 2014; 371:2255–2266; doi: 10.1056/NEJMoa1402685. [Epub ahead of print] 18. Torres VE, Abebe KZ, Chapman AB, et al. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med 2014; 371:2267–2276; doi: 10.1056/NEJMoa1402686. [Epub ahead of print] 19. Grantham JJ. Rationale for early treatment of polycystic kidney disease. && Pediatr Nephrol 2014; doi: 10.1007/s00467-014-2882-8. [Epub ahead of print] An excellent study supporting earlier lifestyle changes. 20. Guay-Woodford LM, Bissler JJ, Braun MC, et al. Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease: report of an international conference. J Pediatr 2014; 165:611–617. 21. Bissler JJ, Dixon BP. A mechanistic approach to inherited polycystic kidney disease. Pediatr Nephrol 2005; 20:558–566.
&&
Volume 27 Number 2 April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Therapies for polycystic kidney disease John J. Bissler
Purpose of review All polycystic diseases of the kidney exhibit tubular or saccular cysts. The cysts can either be open to the tubule or isolated sacs that have lost their connections. Polycystic kidney diseases derived from different genetic mutations share basic mechanisms of cytogenesis, formation, and progressive enlargement, involving a cellular organelle called the primary cilium. Given the mechanistic commonalities, this review will focus on the therapeutic approaches currently available or under development that likely apply to all inherited renal cystic diseases. Recent findings Recent advances in clinical trials and preclinical experiments have illuminated common signaling pathway involvement. Summary Avoidance of nephrotoxic drugs or radio-contrast and maintaining normal BMI are routine preventive measures. Limiting the intake of calories, salt, and protein, together with increased intake of fruits, vegetables, and water are dietary treatments that should be started early in the course of the disease. Potential pharmacological treatments targeting cyst initiation and progression are on the horizon. Keywords chronic kidney disease, polycystic kidney disease, primary cilia, renal cyst
INTRODUCTION Inherited renal cystic diseases were initially grouped together based upon their pathological appearance – that they all contained a renal cyst. This structure, derived from the tubule, can either be a dilatation of the tubule, such as seen in autosomal recessive polycystic disease, or a saccular structure that has lost its connections with the tubule, such as in autosomal dominant polycystic kidney disease. More recent studies have revealed that inherited renal cystic diseases share an association with a sensory cellular organelle, called the primary cilia – a topic covered earlier in this volume of Current Opinion in Pediatrics (Katherine Dell’s review). The current review integrates both basic science and clinical trial results to refine treatment considerations for pediatric renal cystic disease. While current treatment of pediatric renal cystic disease is limited to symptomatic care, new understanding of the signaling pathways of the tubular cell offer therapeutic lifestyle changes and elude to possible pharmacological interventions in the near future. These ‘cystogenic’ signaling pathways include calcium, sonic hedgehog, Wnt, and notch signaling pathways described in other reviews in this volume. Leveraging these disease initiation and progression-related pathways offers a unique
pediatric opportunity to modify disease and hopefully prolong renal function.
CURRENT PRACTICE The hallmarks of the current treatment include hypertension control and avoiding nephrotoxic insults. Hypertension can occur in infants and small children with renal cystic disease, including those with autosomal dominant polycystic kidney disease. Blood pressure should be controlled to the level considered average for age, sex, and size. Hypertension in the child with renal cystic disease indicates that the cysts are damaging the Division of Nephrology, Department of Pediatrics, St Jude Children’s Research Hospital, University of Tennessee Health Science Center, Children’s Foundation Research Center, Memphis, Tennessee, USA Correspondence to John J. Bissler, MD, FedEx Chair of Excellence, Professor and Chief, Division of Nephrology, LeBonheur Children’s Hospital and Department of Pediatrics, Director of the Tuberous Sclerosis Center of Excellence, Medical Director of Nephrology, St Jude Children’s Research Hospital, University of Tennessee Health Science Center, Children’s Foundation Research Center, 50 N. Dunlap, Suite 528R WPT, Memphis, TN 38103, USA. Tel: +1 901 287 4825; fax: +1 901 287 4589; e-mail: [email protected] Curr Opin Pediatr 2015, 27:227–232 DOI:10.1097/MOP.0000000000000202
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Nephrology
KEY POINTS Clinical trials and bench research have changed the approach towards the child with polycystic kidney disease.
hyperlordotic posture to maintain balance. Such back pain can be improved by prescribing exercises to strengthen the abdominal core musculature and consciously altering posture.
Lifestyle changes are an important part of caring for a child with a polycystic kidney disease.
CELL BIOLOGY AND SIGNALING PATHWAYS OF RENAL CYSTIC DISEASE
New therapies are on the horizon.
All inherited renal cystic diseases are characterized by fluid-filled cysts that can be microscopic, or macroscopic. By distorting the sophisticated countercurrent multiplier in the renal medulla, small and large cysts can render the concentrating mechanism dysfunctional. The macroscopic structures, at least in part, compromise renal function, compressing the surrounding renal parenchyma [1]. The fusiform dilation of the collecting ducts in autosomal recessive polycystic disease alters the flow dynamics of blood, lymph, and urine, compromising the countercurrent amplification of the interstitial solutes for generating a maximally concentrated urine. Although renal cystic diseases were initially grouped by the observation of the pathology and subsequently by inheritance, another commonality is emerging. Most inherited renal cystic diseases have gene products that are associated with a cellsignaling organelle called the primary cilia, which arises from the basal body. The complex activities of the basal body range from critical extracellular sensing functions of the primary cilia, to chromosomal segregation during mitosis. Adding another layer of complexity to the renal cystic diseases is the simple fact that renal cyst development can be initiated as early as fetal development and can progress to cause end-stage renal disease during the midlife years of an individual, or, in the other extreme, disturb fetal development so that postnatal renal function is not possible [2]. As discussed earlier in this volume of Current Opinion in Pediatrics, cytogenesis appears to be associated with perturbed signal integration of calcium, cyclic adenosine monophosphate, hedgehog, Wnt, notch, and mechanosensation. These pathways may be required, but may not always be sufficient for cystogenesis, and their role differs depending on the initial system perturbation. The stage of a cyst is an important aspect when one considers therapeutic interventions. Although a cyst is most often thought of as a static entity – a fluid-filled structure surrounded by a single layer of cells – the reality is more complex than that. A cyst can maintain continuity with the tubule, as in autosomal recessive polycystic kidney disease (ARPKD), or lose this connection as in autosomal dominant polycystic kidney disease (ADPKD). A cyst can occur as an early pediatric life event (e.g.
microvasculature and anatomic configurations within the kidneys, even in those children with normal estimated glomerular filtration rates (GFRs). The altered renal anatomy in renal cystic disease can also disrupt the urine concentrating capacity, and this feature puts the child at considerable risk for dehydration and enuresis. Currently, parents are instructed to have a scale and to measure the child’s weight the moment they wonder if their child is getting ill. Sometimes parents can detect an illness even before the child complains or is symptomatic. Should illness ensue, such as gastroenteritis, the parents can again weigh the child before phoning their physician, so the percentage dehydration can be weight-based, and the physician should know not to use the patient’s urine output as an index of dehydration. The same concentration defect can also make patients or their families frustrated by prolonged nocturnal enuresis. This can be significantly improved by explaining that this is the natural course of events, and by sharing with the family the issues of urine concentration capacity. Such reassurance and strategies such as a wetting alarm can be very helpful, while drugs like 1-desamino-8D-arginine vasopressin (desmopressin) are strongly discouraged because of their potential to accelerate cyst growth. Likewise, families should be counseled about solute load, such as excess meat or salt intake, which increases osmolar clearance and forces water loss. Parents need to be aware of solute effects on urine volume when urine cannot be maximally concentrated. The effects cause endogenous antidiuretic hormone to be secreted and potentially can accelerate cyst growth. Children with very large kidneys sometime complain of flank pain. The reasons for such pain can be multiple. The onset of acute severe pain may be caused by a hemorrhage or, less likely, an infection in a cyst or surrounding tissue. If infection is strongly suspected, sometimes a PET study can help detect the infected cyst because of the glucose utilization by the leukocytes. Chronic pain often is due to the large kidney mass disturbing the patient’s center of balance, forcing a lordotic or even 228
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Therapies for polycystic kidney disease Bissler
ARPKD) or later in childhood (e.g. nephronophthisis), or in midlife (e.g. ADPKD). Cysts, depending on their size, can also have different appearances on ultrasound. This frustrating aspect of cytogenesis occurs because, by ultrasound, small cysts can appear as echo-dense structures that later develop an echo-lucent center. This contradictory finding serves as an introduction into cyst growth. To simplify the discussion, one can assume the cyst to be a sphere so that the relationship between cyst volume and surface area can be put into perspective. The equation for the fluid volume of a cyst, V, is as follows: V ¼ 4pr 3 3 and the equation for the single cellular surface area, (SA), is as follows:
M, 10 wks
F, 10 wks
M, 20 wks
F, 20 wks
AVP +/+
AVP +/–
AVP –/–
(c) Male AVP –/– Male AVP –/– +dDAVP Female AVP –/–
SA ¼ 4pr 2 ; Then, simple substitution reveals the relationship between the volume (V) and the surface area SA as follows: V¼
(a)
SAr 3
Up to a point, the fluid volume of a cyst is less compared to the cellular proliferation, but after that point, the volume begins to exceed, and in fact far exceeds, the surface area (when r>>3). This relationship is important when one considers the best surrogate maker for cystic disease in renal cystic burden [3]. For macrocystic disease, the rate of cyst growth is more a function of fluid accumulation than it is of cysts’ cellular proliferation. The different contributions of cellular proliferation and fluid secretion can be better appreciated in preclinical and clinical trial results. Therapies under development may have the potential to cure or greatly assuage polycystic disease if administered early enough. For example, completely interrupting vasopressin signaling completely normalizes renal histology in a murine model of ARPKD (Fig. 1) [4 ]. Initial studies using murine models of renal cystic disease clearly demonstrated a beneficial effect of mammalian target of rapamycin (mTOR)C1 inhibitors [5,6]. These studies use an experimental approach that could be considered preventive. The animals developed significant cystic disease at a young age, and they received either drug or vehicle over a period of time, starting from when they were not yet adult animals. The group that received active drug had much less cystic disease compared to the control group animals. The mTORC1 inhibitor effect clearly was beneficial as it decreased the cystic &&
Female AVP –/– +dDAVP Male AVP +/+
Male AVP +/+ +dDAVP
Female AVP +/+ Female AVP +/+ +dDAVP
FIGURE 1. (a) Representative hematoxylin and eosin-stained kidney sections from 10 and 20-week-old male and female PCK AVPþ/þ, PCK AVPþ/, and PCK AVP/ rats. PCK AVP/ kidneys exhibit nearly complete protection from cystic disease. (b) Hematoxylin and eosin-stained kidney sections from male and female PCK AVP/ and PCK AVPþ/þ rats (n ¼ 4 for each genotype and sex) treated continuously with dDAVP (10 ng/h/100 g body weight) or vehicle alone between 12 and 20 weeks of age. The administration of dDAVP recovered the cystic phenotype of the PCK AVP/ and aggravated the cystic disease of the PCK AVPþ/þ rats. This figure is reproduced with permission from Wang et al. [4 ]. AVP, arginine vasopressin; dDAVP, 1-desamino-8-D-arginine vasopressin (desmopressin); PCK, polycystic kidney.
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burden and preserved renal function in the treated animals. Because these findings were so positive, there was hope that mTORC1 inhibitors may be therapeutic in the most common renal cystic disease –ADPKD. These clinical trials used similar endpoints, specifically renal volume and renal function. In a 2-year, double-blind trial, 433 patients with ADPKD were randomly assigned to receive either placebo or the mTOR inhibitor everolimus (NCT00414440). The authors concluded that everolimus slowed the increase in total kidney volume of patients with ADPKD, but did not slow the progression of renal impairment [7]. In a second 18-month openlabel, randomized controlled trial using sirolimus, considering the rate of growth as an endpoint, 100 adult patients were randomly assigned to receive either sirolimus (2 mg daily) or standard care (NCT00346918). All patients had an estimated creatinine clearance of at least 70 ml/min. These authors concluded that sirolimus did not halt polycystic kidney growth [8]. Although there are several differences in these two studies, including duration, number of patients, and even some patient characteristics, both studies used adult patients and failed to show a beneficial effect on renal function. The kidney is not uniquely resistant to mTORC1 inhibitors, as these drugs have been demonstrated to be effective in renal cell carcinoma [9], and the renal angiomyolipomata associated with tuberous sclerosis complex [10,11] and are US Food and Drug Administration (FDA)-approved for adults with these proliferative diseases. Newer agents and a different patient population earlier in disease may reveal a different outcome. Cyst growth is also modifiable by interfering with fluid secretion. Specifically, interfering with antidiuretic hormone signaling has been identified to be an effective method to alter the renal cystic phenotype. In murine models of polycystic disease, either blocking the V2 receptor signaling or increasing fluid intake resulted in a lessoning of the renal cystic disease phenotype [4 ,12 ,13]. Likewise, this was demonstrated to be effective in a human trial (ClinicalTrials.gov number, NCT00428948). This phase 3, multicenter, double-blind, placebocontrolled, 3-year trial, conducted in patients with ADPKD and a total kidney volume equal to or greater than 750 ml, randomized patients aged 18–50 years of age to tolvaptan, a V2-receptor antagonist, or placebo [14]. The primary outcome was the annual rate of change in the total kidney volume, whereas secondary endpoints included a composite of time to progression that was defined as worsening kidney function, kidney pain, hypertension, and albuminuria and rate of kidney-function decline. &&
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&
The increase in total kidney volume in the treatment group was 2.8% per year, whereas it was 5.5% per year in the placebo group. The treatment group exhibited a slower rate of renal function decline. There were fewer ADPKD-related adverse events in the tolvaptan group, but this was offset by more events related to excess excretion of free water and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate in the patients treated with tolvaptan (23%) versus the control group (14%). The authors concluded that tolvaptan slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD, but was associated with a higher discontinuation rate, owing to adverse events. The involvement of the renin–angiotensin system in the context of blood pressure is well established. Renal tubular cells also express angiotensin type I receptors [15] and these can be important for renal development [16]. Aggressive intervention in the renin–angiotensin system has significant merit in ADPKD. Early, aggressive blood pressure control slowed progression of cystic disease. A double-blind, placebo-controlled trial randomly assigned 558 hypertensive participants with ADPKD with similar characteristics to the tolvaptan trial to either a standard blood pressure target (120/70 to 130/ 80 mmHg) or a low blood pressure target (95/60 to 110/75 mmHg) (ClinicalTrials.gov number, NCT00283686). These patients were also randomly assigned to an angiotensin-converting enzyme inhibitor (lisinopril) and an angiotensin-receptor blocker (telmisartan), or lisinopril and placebo. Using a similar primary outcome as above, the annual percentage change in the total kidney was significantly lower in the low-blood pressure group than in the standard-blood pressure group, without significant differences between the lisinopril–telmisartan group and the lisinopril–placebo group. The authors concluded that in early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume compared to the lisinopril alone, though rigorous blood pressure control was associated with a slower increase in total kidney volume, better preserved estimated GFR, greater decline in the left ventricular mass index, and greater reduction in urinary albumin excretion as compared with standard blood pressure control [17,18].
TIMING, DISEASE STAGE, AND IMPLICATIONS FOR TREATMENT To introduce the possible treatments of polycystic kidney disease, it is useful to consider the different factors that are involved in cystogenesis as a Volume 27 Number 2 April 2015
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Therapies for polycystic kidney disease Bissler
Disease stage
Initiation
Treatment goal
Progression
Prevention
Targeted therapy
Tissue disease Tissue/cyst therapy
D
D
+
PK
Disease activity
CK
Pro lif e
et ecr
rat
ion
S
ion
CystKidney • Vascular • Inflammation • Other
Time
FIGURE 2. Disease activity as a function of time. Different disease activities can be broken up into different stages. Intervention during these different stages would be aimed at different goals. CKD, chronic kidney disease; PKD, polycystic kidney disease.
function of time (Fig. 2). Considering the disease activity over time, there is the disease phase that is dominated by cellular proliferation. This phase would be particularly vulnerable to antiproliferative agents like mTORC1 inhibitors. For such drugs to be optimally beneficial, the time of proliferation would be limited, and thus avoid possible lifelong therapy. In this way, the treatment could be conceptualized as being preventive. A possible example could be found in the polycystic variety of tuberous sclerosis complex in which the disease is identified in utero, but develops into severe cystic disease over the first year or two of life. Such mTROC1 studies will soon be initiated. The goal will be to interfere with the proliferative phase of cystogenesis for a limited time and in that way act as a preventive therapy. Drugs that can affect both cellular proliferation and fluid secretion would be optimally beneficial for the phase of cyst growth that is dominated by fluid secretion. This was clearly demonstrated by the tolvaptan preclinical work and clinical trial. This kind of treatment would truly be targeted therapy aimed at halting disease progression. Therapy during the obvious cystic stage of disease will be more complex, because this stage also involves a final common pathway of chronic kidney disease and scaring that greatly complicate treatment, because two disease processes are at play. Therapy would need to address not only the polycystic renal disease, but also the renal response.
RECOMMENDATIONS FOR THERAPY OF POLYCYSTIC KIDNEY DISEASES The current recommendations for the treatment of patients with polycystic kidney disease continue to
mandate the prevention of harm, but now have additional potential ways to improve the long-term renal function [19 ]. Recommendations for the diagnosis and management of ARPKD are available and were created by experts in the associated fields during a consensus guideline development conference [20]. Furthermore, the convergence from pathological observations of cysts [21] to an association with a cellular organelle, the primary cilium, suggests that there may be several final common pathways involved which can be additional aspects of a general therapy. Considering the clinical and preclinical data, additional recommendations to be considered include the following: &&
(1) Patients should be counseled to attain and maintain an appropriate BMI. (2) Diet, calories, protein, salt, fruits, and vegetables, fluid and lifestyle changes will need to be adopted by the family. (3) Avoid nonsteroidal anti-inflammatory drugs, radio-contrast, and other known nephrotoxic drugs. (4) Patients should be encouraged to think of water as a required therapy that must be taken and on a schedule. Preclinical studies and the tolvaptan trial establish vasopressin as a target that should be kept at the lowest levels. (5) A blood pressure target of 110/80 or less in adults or below the 70th percentile for height and age is rational. (6) Although inconvenient at the beginning, these therapeutic interventions are well tolerated and hold the prospect of slowing disease progression.
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CONCLUSION Pediatric renal cystic diseases have many genetic causes. While there are potential treatments on the horizon, there are new recommendations as to lifestyle that potentially may have a large impact on slowing disease initiation or progression. Patient and family education and early referral to a pediatric nephrologist for blood pressure and disease control may offer a better outcome. Acknowledgements The author would like to thank Jared Grantham for his constructive critique and help preparing this manuscript. Financial support and sponsorship Funding from: NIH, PKD Foundation, LAM Foundation, TS Alliance, Wyeth, and Novartis. Conflicts of interest Dr Bissler has received honoraria from Up To Date, and Novartis Pharmaceuticals. He also has received grant support from Novartis Pharmaceuticals and the Department of Defense.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney disease. Nature Rev Nephrol 2011; 7:556–566. 2. Tran PV, Sharma M, Li X, Calvet JP. Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis? Birth Defects Res C Embryo Today 2014; 102:159–173. 3. Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol 2008; 3:1197–1204.
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4. Wang X, Wu Y, Ward CJ, et al. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 2008; 19:102–108. Good evidence for vasopressin involvement in renal cystic disease. 5. Tao Y, Kim J, Schrier RW, Edelstein CL. Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease. J Am Soc Nephrol 2005; 16:46–51. 6. Shillingford JM, Murcia NS, Larson CH, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci U S A 2006; 103:5466–5471. 7. Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363:830–840. 8. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363:820–829. 9. Chan H-Y, Grossman AB, Bukowski RM. Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. Adv Ther 2010; 27:495– 511. 10. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebocontrolled trial. Lancet 2013; 381:817–824. 11. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358:140–151. 12. Gattone VH, Maser RL, Tian C, et al. Developmental expression of urine & concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev Genet 1999; 24:309–318. Classic article about vasopressin and cystic disease. 13. Nagao S, Nishii K, Katsuyama M, et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol 2006; 17:2220–2227. 14. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367:2407–2418. 15. Wilson BA, Marshall AC, Alzayadneh EM, Chappell MC. The ins and outs of angiotensin processing within the kidney. Am J Physiol Regul Integr Comp Physiol 2014; 307:R487–R489. 16. Gubler M-C. Renal tubular dysgenesis. Pediatr Nephrol 2014; 29:51–59. 17. Schrier RW, Abebe KZ, Perrone RD, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med 2014; 371:2255–2266; doi: 10.1056/NEJMoa1402685. [Epub ahead of print] 18. Torres VE, Abebe KZ, Chapman AB, et al. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med 2014; 371:2267–2276; doi: 10.1056/NEJMoa1402686. [Epub ahead of print] 19. Grantham JJ. Rationale for early treatment of polycystic kidney disease. && Pediatr Nephrol 2014; doi: 10.1007/s00467-014-2882-8. [Epub ahead of print] An excellent study supporting earlier lifestyle changes. 20. Guay-Woodford LM, Bissler JJ, Braun MC, et al. Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease: report of an international conference. J Pediatr 2014; 165:611–617. 21. Bissler JJ, Dixon BP. A mechanistic approach to inherited polycystic kidney disease. Pediatr Nephrol 2005; 20:558–566.
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