Introduction

Pediatricians are usually on the alert for autosomal recessive polycystic kidney disease (ARPKD) in the rare newborn with massively enlarged kidneys. Although much more common than ARPKD, in children, asymptomatic autosomal dominant PKD (ADPKD) usually goes unrecognized until renal cysts are inadvertently discovered in an imaging study or because hypertension, hematuria or abdominal pain calls attention to the kidneys. ADPKD, the most common monogenetic disorder that leads to end-stage renal disease (ESRD), does not usually become clinically evident until the third or fourth decade of life. Cysts develop bilaterally, primarily in collecting duct segments and expand relentlessly, ultimately leading to massively enlarged kidneys, the clinical hallmark of this condition [1] (Fig. 1).

Fig. 1
figure 1

Cysts are the hallmark of polycystic kidney disease (PKD). Three men with massive renal enlargement due to autosomal dominant PKD (ADPKD) are shown. Bottom right Surgical specimen with a length of 51 cm and filled with cysts of widely different sizes containing urine-like fluid or blood

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Although a human kidney contains approximately one million nephrons, cysts develop in only a relatively small fraction of them; nonetheless, these “renegade” nephrons ultimately lead to the destruction of functioning parenchyma and to ESRD. Evidence is mounting that renal injury commences with the formation of the first cyst. In ARPKD patients cyst formation begins in utero without question; however, the medical world has been slow to recognize that fetal cyst formation is also an important feature of ADPKD [2]. Consequently, it is appropriate to alert pediatric physicians that they will be treating young patients with ADPKD in the years ahead. In this brief review, I address the pathogenesis of cyst formation, the mechanisms by which these tumor-like growths cause renal failure and the prospects for imminent treatment of the condition.

Pathogenesis

Mutations in PKD1, the most common and the most severe dominantly inherited genotype, will be the principal cystic disorder discussed in this review. PKD2 and the much rarer ARPKD and NPHP (nephronopthisis) ciliopathies share many pathogenetic features of cyst formation and growth in common with PKD1; those will be noted as well.

Cyst formation

Every cell in the kidney carries a copy of the mutated PKD1 gene; yet cysts appear to develop primarily in relatively few tubules, principally collecting ducts [3]. Polycystin-1, the protein product of PKD1, is developmentally regulated and has a role in establishing and maintaining a mature tubule phenotype and in injury repair [4, 5].

The allele inherited from the normal parent usually produces sufficient polycystin-1 to hold tubule cell proliferation in check in most patients. In a few cells, somatic mutations or biochemically mediated changes render the normal allele incompetent, and polycystin-1 levels fall below a threshold necessary to prevent cell proliferation. These troubled cells become highly susceptible to growth factors, such as vasopressin, that provoke mitogenesis and endless replication, causing mural cells to extend the tubule wall to form ectatic lesions [6, 7] (Fig. 2). Upstream urine flows into the nascent cyst and assists in further expansion. Most of the expanding cysts eventually separate from the parent tubule to form an isolated sac of fluid. In these solitary cysts, mural proliferation continues, and fluid enters secondary to cyclic AMP-stimulated, chloride-dependent NaCl secretion and osmotically driven water transport [8]. A small fraction of the collecting duct cysts appear to maintain contact with the afferent parent tubule [9, 10].

Fig. 2
figure 2

Pathogenesis of cyst formation and growth. In a single tubule cell bearing a germ-line mutation of PKD1 or PKD2, a second “hit”, shown here as a somatic mutation, renders the cell PKD1 or PKD2 recessive. In the presence of progression factors, including vasopressin, cell proliferation is stimulated, and the increased mural area forms an ectatic bulge into the interstitium. With further enlargement, the cyst separates from the parent tubule to create an isolated sac and a blocked tubule. Salt is pumped into the cyst via a chloride-dependent secretion mechanism stimulated by vasopressin, and water follows osmotically. The original tubule undergoes atrophy and apoptosis. PKD1, PKD2 Polycystic kidney disease type 1, type 2 genes

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Cysts have local and distant effects

As these benign tumors infiltrate into neighboring parenchyma, cyst expansion is accompanied by extensive remodeling of the extracellular basement membranes surrounding them as well as adjacent interstitium. Cysts can block the flow of urine in the tubule they form in and block urine flow in adjacent tubules by compression [11]. The blockage of urine flow by a downstream cyst causes separation of the glomerulus from the attached proximal tubule, leaving an atubular glomerulus [12–14].

The genesis of atubular glomeruli has been elegantly explicated in a series of studies in mice with unilateral ureteral obstruction [15–19]. The complete cessation of urine flow leads to injury and thinning of the glomerular junction with proximal convoluted tubules, followed by separation of the tubule from the glomerulus in association with atrophy, apoptosis, inflammation and fibrosis. As parenchyma disappears, this process eventually produces a large, fluid-filled renal pelvis surrounded by a fibrotic shell of tissue.

A similar process appears to be at play in ADPKD when cysts in downstream tubule segments appear to block filtration by upstream glomeruli [12]. The local effect of cysts is to disrupt flow in the tubule segment they form in as well as in adjacent blood vessels, lymphatics and tubules [11, 20]. The renal interstitium is invaded by abnormal numbers of monocytic cells and macrophages, and apoptotic cells appear within the cyst epithelium and in adjacent renal tubules. Cysts developing in inner medullary and papillary collecting ducts have the potential to destroy the function of hundreds—if not thousands—of upstream nephrons that ordinarily drain into the tubule arcade served by the cystic collecting duct [11]. This magnification effect of collecting duct cysts may help to explain how substantial damage to proximal tubules and glomeruli can be found in the absence of adjacent cysts in the cortex, as well as provide an explanation for how a relatively small number of cysts can lead to widespread nephron destruction.

Patterns of cyst and kidney enlargement

The biology of cyst formation and expansion has been elucidated in in vitro studies of renal epithelial cells grown in three-dimensional cultures [6, 21]. When individual renal tubule cells were suspended in a collagen matrix, they divided repeatedly to form a continuous mono-layered epithelium similar to the intact cyst illustrated in Fig. 2. Individual cysts in culture derived from a clonal stock grow at different rates, indicating that intrinsic factors within individual cells probably determine the baseline rate of cell proliferation. Cyst growth is also influenced by extrinsic factors. For example, cysts derived from collecting ducts bearing AVP-V2 receptors are stimulated to enlarge by the antidiuretic hormone, arginine vasopressin (AVP), through the intermediacy of cyclic AMP [8]. In addition, AVP stimulates chloride-dependent fluid secretion into isolated cysts, filling the potential lumen space created by the expanding epithelial wall [22, 23]. Epidermal growth factor and insulin-like growth factor can be counted among the many autocrine and paracrine substances that also promote cell proliferation [24, 25].

The pattern of individual cyst growth in vitro is exponential, reflecting the logarithmic increase in the number of cells within the continuous epithelium comprising individual cysts [21, 26]. Cysts, therefore, are benign tumors that grow relentlessly, but at variable rates depending on intrinsic and extrinsic factors.

Patterns of cyst and kidney enlargement in humans

The Consortium for the Radiologic Imaging Study of PKD (CRISP) is a long-term longitudinal study of ADPKD progression in adult volunteers with well-preserved glomerular filtration rate (GFR) at enrollment [26, 27]. This study disclosed that: (1) total kidney volume (TKV) and total cyst volume (TCV) increased year after year in the vast majority of volunteers; (2) cysts accounted for the increase in total kidney volume; (3) kidney and cyst volume increased annually in an exponential pattern of change, a signature rate for individual subjects; (4) both cystic kidneys enlarged at approximately the same annual rate within an individual; however, between individual volunteers, kidneys enlarged at annual rates ranging from approximately 0.0 to >15 % (median 5.3 %/year); (5) cysts within PKD1 and PKD2 kidneys grew at about the same rate; however, kidneys harboring PKD1 mutations enlarged faster than those with PKD2 mutations because they contained more cysts. Cysts form in utero, expand continuously and are joined by new cysts, supporting similar growth rates over a lifetime. The patterns of total kidney growth captured in magnetic resonance imaging (MRI) and computed tomography (CT) scans are an important tool to physicians for evaluating prognosis in individual subjects (Fig. 3). A single determination of TKV gives insight into how fast the disease is progressing when viewed against age-related normal TKV. Sequential TKV measurements made a few years apart can provide a more accurate determination of the kidney growth rate and can be used to estimate kidney volumes in the years ahead.

Fig. 3
figure 3

Prognosis of autosomal dominant polycystic kidney disease (ADPKD) as revealed by kidney volume. Over a lifetime, polycystic kidneys enlarge at a relatively constant rate in individual patients; however, the enlargement rates may vary widely among different patients. This hypothetical chart illustrates four cases with renal growth rates of 2.5, 5.0, 10.0 and 20.0 % per year. Note that the growth curves have an exponential shape, and thus would be straight lines on a semi-logarithmic grid. Total kidney volume is factored by height to reduce the differences between men and women. Each curve starts at a nominal kidney volume for an 18 year-old patient determined in the Consortium for the Radiologic Imaging Study of PKD. The dashed horizontal line is taken from Chapman et al. [60] and defines the threshold, above which a patient can expect to reach Kidney Disease Outcomes Quality Initiative stage 3 chronic kidney disease within 8 years

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MRI studies in children with PKD1 mutations have revealed the same kidney growth features as those in adults, and the exponential pattern of enlargement was more rapid than could be attributed to maturation alone [28]. Accurate measurements of TKV are currently available only in the research setting; in addition, kidney enlargement may be difficult to quantify in young children. Consequently, in this patient group total cyst count may be a clearer indicator of future outcome, although studies confirming this notion remain to be done. While MRI can detect cysts as small as 2 mm in diameter, as many as 60-fold more hidden cysts may exist below this detection threshold [29]. High-performance ultrasound is useful for detecting cysts >5 mm in diameter but is of limited value for judging prognosis in patients with relatively few cysts above the detection limit.

There is growing consensus among nephrologists specializing in PKD that for patients with chronic kidney disease (CKD) stages 1 and 2, kidney size provides the clearest view of disease aggressiveness among the techniques currently available.

Determinants of kidney enlargement

Intrinsic elements set the basal rate of cell proliferation within individual renal tubules and cysts, and extrinsic factors modify that rate. Vasopressin is a potent extrinsic factor known to circulate in blood, but diet and anthropomorphic factors are important as well [30].

Vasopressin

In preclinical studies of rodents with spontaneous and imposed renal cystic disease, the administration of AVP V2-receptor blockers slowed cyst and kidney growth, as well as the rise in blood urea nitrogen (BUN) [31–33]. These studies identified vasopressin as a variable extrinsic factor with the capacity to stimulate renal enlargement and reduce GFR. Extra water intake sufficient to lower urine osmolality persistently accomplished the same thing in PCK rats (Pkhd1 -/-), the orthologue of ARPKD [34]. Moreover, crossing Brattleboro (AVP -/-) and PCK rats generated animals with PKD and varying amounts of AVP [35]. Double null animals (Pkhd1 -/-:AVP -/-) were born without cysts and did not develop them until DDAVP (1-deamino-8-D-arginine vasopressin; desmopressin acetate) was administered continuously by mini-pump beginning at age 12 weeks. This seminal study provides strong proof that vasopressin is essential for the formation and the growth of collecting duct cysts.

The absence of renal cysts in PCK rats lacking vasopressin indicates that collecting duct receptors for other adenylyl cyclase receptors (adenosine, β-adrenergic agonists, secretin, prostaglandin E2) do not play significant roles in generating collecting duct cysts [36]. Although tyrosine kinase-activated growth factors increased the growth rate in established cysts, they do not seem to be involved in collecting duct cyst formation in PCK.

In the PCK rat, it is generally agreed that every collecting duct cell bears two mutated Pkhd1 genes; consequently, the failure of these kidneys to generate cysts in the absence of vasopressin suggests that a “third hit” is required for a cyst to form. Vasopressin apparently satisfies that need. Since vasopressin circulates continuously in anti-diuretic terrestrial mammals, it is especially important in diseases richly endowed with distal tubule and collecting duct cysts.

Dietary and anthropomorphic determinants

Excess salt excretion, excess urea excretion, large body surface area and low plasma high-density lipoprotein (HDL) levels are risk factors associated with large kidneys and reduced GFR levels [30, 37]. Although molecular linkages between these factors and renal cyst enlargement have not been established, a common sense diet prescription that controls these factors would seem to be a reasonable foundation upon which to add targeted molecular therapy.

Additional cyst growth-promoting agonists

Epidermal growth factor activates the mitogen-activated protein-kinase (MAP-kinase) pathway to increase cyst growth in a variety of cystic disorders [24, 25]. Periostin, a protein first identified in bone, is also expressed in colon tumors and in ADPKD cysts [38, 39]. Periostin promotes cell growth and kidney enlargement. Monocyte chemotactic growth factor 1 (MCP-1) is also synthesized in cysts and fosters the proliferation of mural cells [40–42]. It is unlikely that these substances cause cysts to form; however evidence indicates that they have the potential to stimulate the growth of established cysts.

Disease presentation in children and adults

Cysts may be sentinels of occult renal injury

The prevalence of solitary renal cysts (Bosniak stage 1) in “normal” people increases with age. Solitary cysts are generally considered to be innocent bystanders of the aging process. As they grow slowly [2, 43], lesions visible by conventional radiologic imaging would likely have formed in renal tubules many years before discovery. Looking at solitary cysts with fresh eyes, Al-Said et al. [44] and Rule et al. [45] associated cysts with the later development of renal dysfunction, raising the strong possibility that stage 1 cysts reflect past renal injuries. Once formed, the anatomic distortion of expanding cysts adds further injury by disrupting the artful arrangement of tubules, blood vessels and lymphatics. It is not unreasonable to suppose that in cystic disorders, renal injury begins with the formation of the first cyst.

Signs and symptoms of renal injury

Children are often the first to experience the injuries to renal parenchyma caused by cysts. Renal size is a notorious sign of injury in children with ARPKD. In children at risk for ADPKD, blood pressure above the 95th percentile of normal is occasionally found in the absence of renal symptoms [46–49]. Hypertensive children with ADPKD have larger kidneys containing more cysts than normotensive patients with few cysts and relatively small kidneys.

Upper abdominal and back pain is a common symptom in those patients with ADPKD [50]. The specific cause of pain frequently goes unrecognized unless it occurs in association with hematuria or urinary tract infection. Gross hematuria from cyst rupture following abdominal trauma is not uncommon in children and adults. Hypertension and hematuria, but not pain, are associated with increased kidney volume [50, 51].

Long-term impact of cysts on renal function

Space-occupying cysts mimic the local expansion of benign solid tumors. Effects on single nephron function probably begin in utero where cyst formation starts in most patients with ARPKD and ADPKD. Fetal renal cysts grow many times faster than those in the post-partum environment [2]. The severity of the disease in newborns depends on how many cysts formed in utero. The vast majority of babies carrying a single mutated PKD gene will, on physical examination, have apparently normal-sized kidneys. In rare cases where the baby exhibits large numbers of renal cysts, the disease may be confused with ARPKD or bilateral Wilms tumor.

Urine concentrating capacity

The anatomically complex counter-current multiplier system that generates maximally concentrated urine is an early victim of medullary cyst formation. The expansion of cysts upsets the highly organized circulation of blood, lymph and urine in the counter-current arrangement of blood capillaries and tubules. A diminished capacity to maximally concentrate urine osmolality is occasionally seen in children and may precede reductions in the GFR in patients of all ages [52–54]. Impaired concentrating capacity is a common feature in older patients with various degrees of renal insufficiency [55].

Renal blood flow

The CRISP study revealed that renal blood flow diminishes before the GFR declines [56]. Cortical cysts apparently distort the renal microvasculature and promote the release of renin followed by the formation of angiotensin II and the constriction of glomerular efferent arterioles [57, 58]. This process increases renal vascular resistance and decreases renal blood flow while raising intra-glomerular capillary filtration pressure, thereby easing GFR toward the normal range.

Glomerular filtration

Declining GFR is secondary to the brutish effects of cysts on blood and urine flow within polycystic kidneys. The blockage of urine flow by a downstream cyst diminishes the function of one or more upstream glomeruli. While the loss of glomeruli may begin in utero or in childhood, in most patients it proceeds at a relatively slow pace that does not lead to renal failure for five or six decades. Exceptions to this pattern are seen infrequently in children born with grossly enlarged kidneys filled with innumerable cysts leading to ESRD in childhood or as young adults. On the other end of the age scale, patients with mutations in PKD2 develop ESRD about 16 years later than those with PKD1 [59].

The number of cysts that develop is an important determinant of when ESRD may be encountered [27]. Those with PKD2 mutations at any given age have about one-half as many cysts as those with PKD1 mutations. This finding supports the view that cysts are responsible for the development of ESRD.

Most individuals with ADPKD have normal or mildly decreased GFR (KDOQI stages 1–2) for several decades (Fig. 4). Unfortunately, this good function is a façade. Unknown to the patient or the physician, parenchyma is progressively destroyed by cysts during the apparently peaceful early years. The damage to glomerular filtration is hidden from detection owing to hyperfiltration and hypertrophy of unaffected residual nephrons, thereby keeping the GFR within a normal range (Fig. 4). The anatomic damage can be seen on MR images and CT scans, two diagnostic modalities which are commonly used to evaluate these patients. GFR, widely regarded as the “Gold Standard” for assessing renal disease severity, has the value of a base metal in the early stages of chronic, progressive diseases.

Fig. 4
figure 4

Decline of glomerular filtration rate (GFR) in autosomal dominant polycystic kidney disease (ADPKD). Hypothetical chart of GFR in relation to the severity of cystic disease (insets magnetic resonance imaging scans). Great parenchymal damage has occurred before the GFR begins to decline. The GFR is maintained for several decades by compensatory glomerular hyperfiltration and tubule hypertrophy. Towards end-stage renal failure, this compensation also fails and GFR declines. Thick horizontal lines at bottom of graph signify the best ages to start preventive treatments that block cyst formation and cyst growth before irreversible damage is done. Preventive agents will have diminished effectiveness after the GFR has declined; drugs that combat inflammation and fibrosis may have temporizing effects

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Risk factors favoring the development of ESRD in ADPKD include genotype, TKV, urine sodium excretion, urine osmolar excretion, loss of maximal urine concentration capacity, plasma HDL, hypertension, hematuria and multiple pregnancies [27, 37, 51, 60]. These symptoms, signs and abnormal laboratory tests often precede elevations in the serum concentration of creatinine and serve as biomarkers of renal injury and diminished function. The decrease in GFR is gradual for several years before accelerating to approximately 4–6 mL/min/1.73 m2/year up tol death, dialysis or renal transplantation interventions [61].

Perspectives on treatment

In the light of evidence that parenchymal destruction occurs under the cover of compensated GFR values, it would appear that the best chance for preserving long-term renal function is to begin treatment as early as possible. The types of treatment currently fall into three general categories: supportive, imminent, and future.

Supportive treatment

Diet

In the CRISP study daily intakes of salt, protein and calories were associated with worsening kidney volumes and renal function. Reasonable limits should be placed on each of these risk factors. The TEMPO (Tolvaptan Efficacy and Safety in Management of ADPKD) and its outcomes study demonstrated that blocking AVP would reduce the increase in TKV and slow the decline in GFR. Plasma AVP levels can be lowered in patients by increasing water intake throughout the day. Increased water intake appears to have a medicinal effect in those with progressive renal diseases [62].

Hypertension

It is generally agreed that children at risk for ADPKD should be screened for hypertension. Not uncommonly, blood pressure is elevated above the 95th percentile of normal (prevailing pediatric guidelines) in otherwise asymptomatic children. The long-term potential for cardiovascular damage due to hypertension makes therapy an important consideration when elevated blood pressures are first recognized. These patients tend to suffer from sodium overload and have sodium-sensitive hypertension. The cysts cause increased amounts of renin and angiotensin II to be produced within the kidneys, leading to reduced renal blood flow, glomerular hyperfiltration and elevated blood pressure. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are usually sufficient to control blood pressure when administered with a salt-restricted diet. However, they must be used cautiously in females of child-bearing age given their teratogenic potential.

Currently, diagnosing ADPKD is not recommended in asymptomatic children until definitive therapies are available. Diagnosis carries both psychosocial risks and affects insurability. In children who manifest clear-cut signs and symptoms of ADPKD, diagnosis is unavoidable. Undiagnosed children and adults at risk who do not wish to be tested should at the very minimum be encouraged to follow a PKD management program.

Imminent treatment

Preclinical studies have demonstrated the likelihood that several drugs may slow or prevent the formation of cysts and cyst enlargement. The key word here is “prevent” since no studies have demonstrated that nephrons destroyed by cysts can regenerate. Consequently, to maximize long-term gain it will be important to administer drugs before extensive damage has occurred.

As noted above, the GFR can be exceedingly misleading as a marker for the degree of underlying parenchymal damage. Consequently, a surrogate marker of progression was developed to enable clinical trials in the early stages of ADPKD when GFR is in the normal range. Cyst formation and expansion is an unambiguous manifestation of disease progression. When cysts enlarge they increase total kidney volume. MR and CT image scans can be used to determine both total cyst and total kidney volume, as well as the rates of change in these parameters, can be determined on MR images and CT scans [26, 63].

Chapman et al. [60] performed MRI on an annual basis on dozens of ADPKD subjects with initial GFR values characteristic of CKD stages 1–2 and found a strong association between the initial TKV adjusted for height (htTKV) and the propensity of GFR to decline (Fig. 3). More specifically, a baseline htTKV exceeding 600 mL/m height predicted progression to KDOQI CKD stage 3 within 8 years. This longitudinal study confirms several previous cross-sectional analyses associating kidney volume and renal insufficiency [64].

In double-blind, randomized trials of m-TOR inhibitors, everolimus decreased the rate of increase in TKV but had no effect on eGFR, whereas sirolimus had no effect on TKV or renal function [65, 66]. The failure of these studies to demonstrate efficacy was possibly related to the lower blood levels of these drugs compared to those achieved in animal studies; yet, blood levels were high enough to elicit a wide range of side effects.

TEMPO was a double-blind trial involving ADPKD patients with creatinine clearances of ≥60 mL/min and had the aim of determining the effects of tolvaptan, an inhibitor of AVP-V2 receptors on ascending limbs, distal tubules and collecting ducts, the primary sites of cyst formation and growth, on TKV and eGFR [67]. Tolvaptan administered to ADPKD patients for 3 years significantly reduced the rate of increase in TKV (−48 %) and slowed the rate of eGFR decrease (−26 %). However, the Food and Drug Administration, concerned about the potential for liver toxicity and what they considered a small effect size, chose not to grant registration pending further analysis and study. The drug has been approved for use in ADPKD patients in Japan. In the meantime, the proof of principle established by TEMPO has encouraged nephrologists working in this field to recommend increased water intake by ADPKD patients, distributed throughout the day in amounts sufficient to reduce plasma AVP levels and lower urine osmolality to or slightly below isothenuria [62, 68, 69].

In ADPKD, hepatic cyst growth is also dependent on cyclic AMP. Since liver cysts bear no AVP-V2 receptors, a strategy to block adenylyl cyclase has been tested. Somatostatin inhibits adenylyl cyclase and reduces cyclic AMP levels in renal and hepatic cysts in experimental animals. Three small clinical trials have shown beneficial effects of the somatostatin analogues octreotide and lanreotide on liver and kidney volumes in patients with symptomatic cystic disease of the liver [70–72]. While these initial results are promising and further support a role for cyclic AMP in the promotion of cyst growth, larger trials of longer duration will be needed before somatostatin analogues can be recommended for general use.

Lovastatin was shown to slow disease progression in a rodent model of ADPKD, presumably by inhibiting ras protein in cyst epithelial cells [73, 74]. In a recent controlled trial, an HMG-CoA reductase inhibitor, pravastatin, slowed kidney growth and preserved kidney function in children with ADPKD [75]. Further confirmation is needed in children and adults before lipid-lowering agents can be recommended for general use in the treatment of ADPKD.

Future treatment

The new drug “pipeline” is nearly bursting at the seams. The PKD Foundation (www.pkdcure.org/research/clinical-trials) and National Institutes of Health (www.clinicaltrials.gov) websites list special diets, water prescriptions, new somatostatin analogues, radio-frequency ablation, bosutinib (tyrosine kinase inhibitor), KD019 (protein kinase inhibitor), triptolide (calcium agonist), spironolactone (anti-fibrotic natriuretic) and modifications of tolvaptan. As these pilot studies and randomized controlled clinical trials mature, we can expect to see additional progress toward finding a treatment or group of treatments that slow or stop cyst formation and cyst growth. Actually curing PKD is within the realm of possibility, as shown convincingly and dramatically by the study in PCK rats that stopped cyst formation in its tracks [35].

New agents showing efficacy in pre-clinical animal testing include insulin-sensitizing agents used in the treatment of type 2 diabetes mellitus, a peroxisome proliferator-activated receptor-gamma agonist, an inhibitor of MCP-1, nicotinamide, and a Smac-mimetic that promotes apoptosis.

It is important to develop drugs targeted for specific molecular processes in cystic kidneys. Patients will be using drugs like these for decades, and the risk of unintended consequences will likely be higher for agents that have widespread effects. It stands to reason that drugs targeting cyst formation and cyst growth will be more efficacious if administered very early in the disease (Figs. 3 and 4), whereas anti-fibrosis and blood vessel protective agents will likely be efficacious at later stages.

Recommendations for current treatment

Autosomal dominant polycystic kidney disease is with patients for a lifetime, and treatments must take that fact into consideration. Unacceptable lifestyle changes will go unheeded, and medications with annoying or serious side effects will likely go unused, especially in the early stages of the disease, since no direct benefit will be noticed by the patient. Until curative treatment becomes available, careful and repeated education on the potential long-term benefits of diet and fluid therapy should be woven into the daily routine and maintained for a lifetime.

Diet

ADPKD patients, like those with juvenile diabetes mellitus, will benefit by adopting healthy lifestyles as early as possible. Physicians can advise ADPKD families with small children at risk to serve everyone at the table the same choice of food in amounts appropriate to maintain a body mass index at 20–25 kg/m2, while increasing the daily intake of fluids throughout the day by approximately 3 L for adults, proportionately less for children [69]. It is important for children to have constant access to water, especially when playing out-of-doors on hot summer days. The excretion of highly concentrated urine should be avoided. Beverages containing caffeine should be used in moderation or avoided altogether. Salt intake of ≤90 mmol/day (corresponding to ≤5 g of sodium chloride and ≤2 g of sodium), protein intake of approximately 1.0 g/kg/day, extra portions of fruits and vegetables and 30 min of exercise five times a week round out the program for adults and can be adjusted for children of different ages.

Compliance with this program is a lifetime commitment, but would tolerate an occasional “steak or pizza” holiday without untoward effects. “All things in moderation” is a good slogan for families dealing with ARPKD or ADPKD.

Hypertension

Limiting dietary salt is an essential underpinning of antihypertensive therapy in ADPKD. ACE inhibitors or ARBs will usually meet a goal of keeping blood pressure at <140/90 mmHg. Pressures lower than this are usually well tolerated by ADPKD patients but whether renal outcomes are better remains to be determined. The HALT-PKD trial ends in 2014 and should shed some light on this question [30, 76].

Lipids

HMGCoA-reductase inhibitors should be added to the regimen in those with elevated plasma LDL-cholesterol. In a recent clinical trial, pravastatin slowed the growth of cysts in children with ADPKD [75]; although highly suggestive, the evidence is not strong enough to warrant widespread use.