“For in every adult there dwells the child that was,
and in every child there lies the adult that will be.”
-John Connolly, The Book of Lost Things
NephMadness is pleased to see the return of the Pediatric Nephrology Region in 2018. Although a young region, the teams in this region have endurance. Many kidney disorders diagnosed in childhood persist into adulthood and have serious consequences not only on kidney health, but on cardiovascular health as well. The identification, treatment, and prevention of pediatric kidney disorders is so important that World Kidney Day chose this topic as their theme in 2016. Pediatric chronic kidney disease (CKD) differs from CKD in adults in that it is predominantly caused by congenital anomalies of the kidney and urinary tract (CAKUT) and glomerulonephritis rather than the more typical adult diseases of diabetes and hypertension (see table below). The Pediatric Region plays in a whole different league. Welcome to our house.
Selection Committee Member for the Pediatric Nephrology Region:
Dr. Rheault is an Associate Professor of Pediatrics in the Division of Nephrology at the University of Minnesota Masonic Children’s Hospital. She conducts clinical research in Alport syndrome and pediatric glomerular disease treatment and outcomes. Follow her @rheault_m.
Competitors for the Pediatric Nephrology Region
Genes in CAKUT vs Environment in CAKUT
This matchup is a classic nature versus nurture battle. CAKUT occur in around 1 in 500 newborns and these are some of the most common developmental anomalies identified on prenatal ultrasound. A wide spectrum of abnormalities falls under this umbrella term that includes hydronephrosis, hypoplasia, dysplasia, vesicoureteral reflux (VUR), ureteropelvic junction (UPJ) obstruction, duplication anomalies, ectopic kidneys, posterior urethral valves, complete kidney agenesis, and others. The ultimate kidney phenotype depends on where and when in kidney development something goes wrong. Is genetics guiding this process? Is the environment in which organogenesis is happening responsible?
Regardless of which team “wins,” children with CAKUT are surviving infancy and thriving into adulthood due to medical advances. Although ~25% of children with bilateral disease will require renal replacement therapy (RRT) in the first 2 decades of life, the remainder survive to transition to adult providers. In fact, the median age at initiation of RRT for patients with CAKUT was 31 years in an ERA-EDTA registry study. No matter if you are an adult or pediatric nephrologist, these are disorders that you should be well aware of.
Kidney development is complicated. Structures form, involute, and signal to each other in a highly choreographed manner to form three separate kidney structures including the pronephros, mesonephros, and metanephros, the final functional kidney that we all know and love. Understanding these steps is vital in appreciating the role genes and environment play in disrupting them.
The pronephros, consisting of simple tubules, forms at 3 weeks’ gestation and has completely involuted by the 4th week. Although nonfunctional, if this structure doesn’t form, it results in kidney agenesis.
The mesonephros originates at the caudal end of the regressing pronephros. The mesonephros consists of a glomerulus with well-developed proximal and distal tubules that drain into the mesonephric (Wolffian) duct. By the end of the 2nd month, the cranially located glomeruli and tubules have degenerated. In the male, some of the caudal tubules and mesonephric duct remain; however, these disappear in the female.
The ureteric bud is an outgrowth of the mesonephric duct that invades the metanephric mesenchyme in the 5th week of gestation to initiate formation of the metanephros. As the ureteric bud invades, it dilates to form the primitive renal pelvis and undergoes its first division to form the future major calyces. These continue to subdivide in response to signaling from the metanephric mesenchyme until they form all of the minor calyces and 1-3 million mature collecting tubules. The ureteric bud isn’t just important for the development of the collecting system, however. Signaling from the tips of the branching ureteric bud induces condensation of metanephric mesenchyme and formation of a renal vesicle.
The renal vesicle undergoes several phases of development including the comma and S-shaped body and eventually forms the glomerulus and proximal and distal tubules. The first glomeruli are present at ~9 weeks’ gestation. Due to branching, the increase in number of nephrons is exponential during the 2nd and early 3rd trimester until the completion of kidney development at ~32-36 weeks of gestation. Fetal urine is a major contributor to amniotic fluid by 16-20 weeks’ gestation, around the time of a typical first routine prenatal ultrasound.
Still confused? Here’s a ~10 minute YouTube tutorial to get you up to speed.
Genes in CAKUT
At the time I completed my fellowship in the early 2000s, we didn’t understand a lot about the genetic underpinnings of CAKUT. We recognized that some (VUR for example) tended to run in families and that after having one pregnancy with CAKUT there was a higher likelihood in a subsequent pregnancy. One of the earliest genes identified to cause bilateral renal agenesis was RET, a receptor for GDNF.
GDNF is secreted by metanephric mesenchyme and signals to the RET receptor on the tip of the ureteric bud. Absence of this signaling leads to failure of nephron development. Recently, mutations in GREB1L, a coactivator for the RET receptor, were also found to cause renal agenesis. With the introduction of chromosomal microarrays and next-generation sequencing (NGS, see NephMadness 2015 coverage), more than 40 genomic disorders (copy number variants and deletions) and 50 individual genes have been implicated in CAKUT, with more being published seemingly every month.
Genomic disorders caused by deletions in 22q11.2, 17q12, 16p11.2, and 1q21.1, among others, account for ~3.5% of CAKUT and often have additional extrarenal manifestations including neurodevelopmental and cardiac phenotypes. For example, deletion in 17q12 (including the HNF1B gene) causes the renal cysts and diabetes syndrome. Single-gene causes of CAKUT, both isolated and syndromic, account for ~10% of CAKUT:
Mutations in EYA1, SIX1, and SIX5, transcription factors that regulate GDNF expression in the metanephric mesenchyme, are associated with brachio-oto-renal syndrome. At the other end of the genitourinary tract, mutations in TNXB (encoding the extracellular matrix glycoprotein tenascin XB) cause primary VUR. Tenascin XB is expressed in the uroepithelial lining of the ureterovesical junction (UVJ) and it is hypothesized that this protein is important in the generation of tensile forces that close the UVJ during voiding. Interestingly, mutations in TNXB also cause the joint hypermobility variant of Ehlers-Danlos syndrome. New patient with VUR? Ask them if they are “double-jointed” and you just may save yourself the cost of genetic testing!
Genetic testing can provide answers to the “why” question that so many families have when faced with a diagnosis of CAKUT. In addition, a specific genetic diagnosis can lead to individualized recommendations for screening for extrarenal manifestations that may be present. Which patients with CAKUT should be offered genetic testing and which genes should be tested? Most experts recommend offering chromosomal microarrays as first-line testing for individuals with CAKUT as part of multiple congenital anomaly syndrome and this approach may be reasonable for isolated CAKUT as well. If microarray studies are negative, then NGS gene panels or whole-exome sequencing can identify a culprit in 5%-10% of patients. Although a young team, this Nephmadness competitor has been coming on strong and is clear to be a major player in the future.
Environment in CAKUT
So what if all 23 chromosomal pairs fall perfectly into place with all 20,000 or so genes intact? You’re home free, right? Of course not. There are still many places where this process can go wrong and it does. Nephrogenesis continues through the 36th week of gestation, however almost 1 in 10 infants in the US are born before the 37th week of gestation, accounting for ~382,000 infants per year.
On a global scale, over 15 million preterm births occur each year. Prematurity leads to the arrest of nephron development and renal hypoplasia although some nephron development may continue after birth. Unfortunately, while premature infants are trying to form a few last nephrons after birth, they are exposed to nephrotoxic medications in the course of their care that may further disrupt this process.
Maternal factors can also increase the risk for CAKUT. Maternal pregestational diabetes increases the risk of CAKUT possibly by interfering with ureteric bud branching. Maternal obesity has also been associated with CAKUT; however, the etiology is unclear. With the increasing prevalence of diabetes and obesity around the world, this is going to be an increasingly difficult team to beat.
Intrauterine growth retardation and low birth weight, either caused by maternal protein-calorie malnutrition or placental insufficiency, also are risk factors for CAKUT. Maternal medication exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers interfere with ureteric bud branching and leads to renal agenesis or dysplasia when exposure occurs during the second half of pregnancy. Additional teratogenic drugs may include NSAIDS, glucocorticoids, mycophenolate mofetil, alcohol, and cocaine. Finally, maternal vitamin A deficiency leads to decreased expression of retinoic acid, which regulates a number of genes responsible for kidney development. While not a clinical problem in the US, vitamin A deficiency was found in 15.3% of pregnant women in developing countries by the World Health Organization. Since changing your genes (maybe with CRISPR-Cas9) is likely to be an intervention for the distant future, this team includes a number of modifiable risk factors that make it one to watch.
GN Diagnosis in Pediatrics vs HTN Diagnosis in Pediatrics
Glomerular disease and hypertension are the bread and butter of pediatric nephrology practice. You can’t get through a clinic without seeing at least one patient with each of these disorders. Treatment is often very different from adults with the same diseases and may not be entirely evidenced based. Glomerular disease is a team made up from all superstars. These are the Michael Jordan and Lebron James of the nephrology world that are exciting and make everyone stop what they are doing to watch. Hypertension, on the other hand, is all about playing defense. This is a team that’s in it for the long haul. This matchup is one for the ages.
GN Diagnosis in Pediatrics
Primary glomerular diseases account for ~21.8% of pediatric ESKD in the US, almost the same as CAKUT (22%), so don’t sell this team short. Glomerular disorders in childhood can present with either a nephrotic or nephritic picture. In children who present with nephrotic syndrome and undergo biopsy, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are most commonly diagnosed, with membranous and membranoproliferative glomerulonephritis (MPGN) only rarely identified. Nephritic presentations more likely represent IgA nephropathy/IgA vasculitis or lupus nephritis, with only rare cases of ANCA-associated glomerulonephritis.
One of the most important players on this team is nephrotic syndrome. The incidence of nephrotic syndrome is 2-7 per 100,000 children. Much of our knowledge about childhood nephrotic syndrome comes from a seminal study in the 1960s and 70s known as the International Study of Kidney Disease in Children (ISKDC). This paragon of collaborative research in pediatric nephrology enrolled children at their initial presentation with nephrotic syndrome and performed a kidney biopsy on everyone. That’s right, everyone gets a biopsy. What they found changed practice to this day. Steroid responsiveness (i.e., remission within 6 weeks of high-dose steroid) was seen in 78% of all children and was predictive of MCD on histopathology. 93.7% of steroid-sensitive children ≤6 years of age and 85.7% of steroid-sensitive children between 7-16 years of age demonstrated MCD on kidney biopsy.
Since then, we skip the biopsy and assume that kids with nephrotic syndrome will be steroid sensitive and have MCD until proven otherwise. Biopsies are triggered by older age (>12 years or so), steroid resistance, or in some cases frequently relapsing disease where second-line therapies are being considered. This is in contrast to adults who generally receive a biopsy on presentation with nephrotic syndrome.
If diagnosed with MCD, they receive the KDIGO-recommended prolonged treatment with high-dose steroids for up to 16 weeks. ~40-50% of steroid-sensitive children have frequently relapsing or steroid-dependent disease, leading to a host of steroid side effects including short stature, obesity, increased risk of fractures, hypertension, acne, and behavior problems. In these children, steroid-sparing medications are recommended by KDIGO, including cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil, levamisole (non-US), and rituximab. Each of these immunosuppressive drugs has their own set of risks and side effects. A visit to discuss treatment options can easily run an hour or more. This team has a close relationship with the coach.
What are the long-term cardiovascular risks of glomerular disorders in childhood? Are there risks of having a cholesterol of 600 for weeks at a time several times per year, as may be common in children with frequently relapsing MCD? Long-term studies are lacking, so we don’t know. In the Chronic Kidney Disease in Children (CKiD) study, children with glomerular disease and CKD (median GFR of 48 mL/min/1.73 m2) have a higher rate of anemia (43%) and dyslipidemia (56%) compared to children with nonglomerular disease. Rates of obesity and hypertension are also high in children with glomerular disease, sometimes related to steroids and other medications. This team is not only a contender in #NephMadness, but may be entering the #CardioMadness competition as well.
Hypertension Diagnosis in Pediatrics
Blood pressure starts out low in the newborn and rises with age and height until it reaches adult values in the teen years. Pediatric nephrologists don’t have the luxury of arguing about a single blood pressure definition of hypertension, we get to argue about hundreds of them. In the absence of outcome data, we have used the normative distribution of blood pressure to define hypertension in children as >95th percentile compared to children of the same age and height and “elevated blood pressure” as >90th percentile. In the most recently published American Academy of Pediatrics blood pressure guidelines, the normal values were adjusted down slightly across the board after obese children were removed from the normative calculations. Around 3.5% of children and adolescents have hypertension and this is one of the most common reasons for referral to the pediatric nephrology clinic.
The first challenge in the clinic is to ensure that the blood pressure readings are accurate. Anyone who has tried to take a blood pressure on a screaming toddler can attest that whatever number you heard may not reflect the actual blood pressure. Best practices including ensuring the correct cuff size through arm measurements, allowing quiet time in the room prior to measurement, taking blood pressures in the right arm, and judicious use of child family life staff. In older children, ambulatory blood pressure monitoring is recommended. Normal values are available for children >120 cm (~7 years old).
Once hypertension is confirmed, we try to figure out why. The younger a child the more likely we will find a secondary cause of hypertension; however, primary or essential hypertension remains the most common diagnosis in childhood. Detailed recommendations for diagnostic evaluation for children with confirmed hypertension are laid out in the recent guidelines. In brief, limited evaluation is recommended for children over 6 years of age who have a family history of hypertension, obesity, and no clear signs or symptoms of secondary hypertension.
Unfortunately, obesity is common in children, affecting ~17% of the population in the US, and strongly correlates with hypertension. The screening evaluation for secondary hypertension should include urinalysis, chemistry panel, lipid profile, and kidney ultrasound if <6 years of age or if kidney function is abnormal. For children under 6 years, kidney parenchymal disease and structural abnormalities account for 34%-79% of secondary hypertension. Careful history and physical exam can identify other screening targets for secondary hypertension such as café-au-lait spots as a sign of neurofibromatosis or tonsillar hypertrophy that may be a sign of sleep apnea.
Similar to treatment of adult hypertension, lifestyle interventions—including DASH diet, weight loss, and increased physical activity—are recommended for all children with hypertension and elevated blood pressure. Children who remain hypertensive after these interventions or who are symptomatic, have stage II hypertension, or have CKD or diabetes should be started on pharmacologic therapy with a target blood pressure of <90the percentile. Choice of agent should be individualized.
Why do we care about hypertension in children? Most of them don’t have any symptoms and don’t feel any different if they skip their meds for a few days. Unfortunately, children with high blood pressure grow up to be adults with high blood pressure. In the Childhood Determinants of Adult Health study, children with blood pressure >90th percentile had a 35% increased risk of elevated blood pressure or hypertension in adulthood. Children with hypertension also demonstrate increased intermediate markers of cardiovascular disease including increased LV mass, carotid intimal media thickness, and pulse wave velocity. By putting in a little effort early to diagnose and treat childhood hypertension, a lifetime of cardiovascular disease risk can be minimized. From a potential health system impact standpoint, this team has a clear leg up on the competition.
– Post written by Michelle Rheault (@rheault_m)
How to Claim CME
US-based physicians can earn 1.0 CME credit for reading this region. Please register/log in at the NKF PERC portal. Click on “Continue,” click on the “Pediatrics Region,” then click on “Continue” to access the evaluation. You’ll need to click on “Continue” again to complete the evaluation, after which you can claim 1.0 credit and print your certificate. The CME activity will expire on June 15th, 2018.