Diagnosis Cystinosis #1

00:00:00: Welcome to Crystal Clear.

00:00:02: In this podcast, we share knowledge and experiences around cystinosis To help make living with this chronic disease a little more manageable And a bit easier in everyday life.

00:00:13: We're glad you are here today.

00:00:16: Today will look at how varied and nonspecific the first symptoms of cystinoses can be From failure-to-thrive Meaning when child doesn't develop properly Too excessive thirst Frequent urination electrolyte losses, and signs of Fanconi syndrome.

00:00:34: We'll explain how the diagnosis is ultimately confirmed— what it means for affected children, siblings and families —and what daily life looks like after diagnosis including therapeutic challenges such as nutrition medication and fluid intake?

00:00:49: we will address medical facts and answer first burning questions What does the diagnosis mean to families And How do they find their way through those difficult months?

00:01:02: I'm delighted to welcome Dr.

00:01:04: Elka Vool, she is a specialist in Pediatrics and Adolescent Medicine And a senior physician In the section of pediatric nephrology at Heidelberg University Hospital.

00:01:15: Doctor Vool how are children with cystinosis typically identified?

00:01:19: The challenges that Children With Cystinosis often present with very non-specific symptoms.

00:01:26: Most commonly it's failure to thrive.

00:01:29: The children have no appetite There're feeding difficulties They vomit frequently, or on the other hand they drink very large amounts which usually leads to a reduced sense of hunger.

00:01:40: And the children need frequent nappy changes.

00:01:43: These are symptoms that bring parents to pediatrician.

00:01:46: Further diagnostic workup often reveals that the children have a lot sugar in their urine Or protein and that they're losing salts through urine For example potassium calcium phosphate magnesium.

00:01:59: Further investigation can then show that this salt loss is coming from the kidneys losing too much salt, protein and sugar.

00:02:06: This is called Fanconi syndrome—a malfunction of their renal tubules —the fine collecting ducts in which cystinosis causes to little of these vital substances to be reabsorbed after they have been filtered into the tubules.

00:02:20: The hallmark for this so-called renal fanconi symptom is primarily the loss of electrolytes, blood salts as well as glucose and protein And this is the leading symptom, especially present in young children.

00:02:32: It's not at all uncommon for patients to be referred with a suspected diagnosis of diabetes because The Children Drink A Lot and the urine dipstick shows positive result.

00:02:40: for sugar.

00:02:41: only further investigation to reveal that blood glucose completely normal and it is infact a Symptom Of Fanconi Syndrome and Cystinosis.

00:02:48: How can a suspected Diagnosis Be Confirmed?

00:02:53: What Tests Are Used To Establish The Diagnoses?

00:02:56: The most reliable method is molecular genetic testing, and this is already possible prenatally.

00:03:03: Meaning that if there are already affected children or other family members.

00:03:07: the condition can be identified very early.

00:03:10: In infants –or slightly older-children–the intraleucocytic cysteine concentration can be measured—that is, the cystein level —is determined in white blood cells through a blood test.

00:03:21: Cysteine deposits in the cornea of eye also detected.

00:03:25: However, this is only a reliable diagnostic tool after the second year of life.

00:03:31: In infants, this finding may still be negative meaning that an ophthalmological examination does not rule out the disease.

00:03:38: What does diagnosis mean for siblings and parents' wish to have further children?

00:03:44: Since it's hereditary condition in case with so-called autosomal recessive inheritance The parent themselves has no symptoms but each carries one affected copy of the gene and passes one copy on to each child.

00:03:58: When you look at possible combinations, there is a twenty-five percent probability for each subsequent pregnancy that the child will have cystinosis because it receives the effected gene from both parents.

00:04:09: There's a fifty percent probability that a child will be carrier having received the effecting gene copy form one parent And a twenty five percent probably that both healthy genes are passed in and the child completely healthy.

00:04:21: If there are already affected siblings, prenatal diagnosis is possible in a subsequent pregnancy through chorionic villa sampling or amniocentesis.

00:04:29: A placental examination of the newborn —or molecular genetic testing— can also confirm the diagnosis.

00:04:35: It's important however that families always seek genetic counseling if disease risk is known.

00:04:41: Pre-implantation Genetic Diagnosis is an option allowing families to ensure they do not have an effected child.

00:04:47: This service however isn't currently covered by health insurance.

00:04:51: What can the family expect after the diagnosis?

00:04:54: what challenges will they face?

00:04:56: First and foremost, The Family has to come to terms with a diagnosis of cystinosis.

00:05:01: It is rare congenital metabolic disorder And current treatment options means lifelong medical therapy.

00:05:09: From broader perspective it's multi-system disease in which not only the kidneys but also other organs are affected.

00:05:16: But it also has very practical consequences because the medication often needs to be given at very frequent intervals, sometimes every two hours around the clock.

00:05:26: Medications must also be given a night.

00:05:28: children need adequate fluid intake and may require tube feeding due to high fluid intake required And Because The Kidneys Cannot Concentrate Urine Causing Children To Excrete Very Large Amounts.

00:05:40: Nappy Changes Are More Frequent And Nighttime Rest Is Significantly Disrupted.

00:05:44: It takes time for families to develop a routine, to adjust the daily schedule and children properly tolerate medication.

00:05:52: It can be very, VERY exhausting but it does get better over time!

00:05:57: It should also said that medications administered especially electrolytes are often infusion solutions because no suitable tablet form is available for infants.

00:06:07: And these electrolyte solutions taste unpleasant – salty, soapy, bitter… often very metallic.

00:06:13: that alone makes administration a challenge.

00:06:16: Sistineamine therapy plays a key role in the treatment of cystinosis and will be discussed in detail, but what additional medications does it need?

00:06:29: because of kidney involvement?

00:06:31: Just to treat the kidney involvement alone several medications are required.

00:06:36: Electrolyte supplementation itself involves many different substances.

00:06:41: It's essentially a modular system.

00:06:44: Patients need supplementation tailored to their individual needs because there is no one-size fits all approach.

00:06:51: The treatment is adjusted based on laboratory values.

00:06:54: the focus is primarily on replacing the electrolyte sodium, potassium calcium phosphate and magnesium.

00:07:03: Lab tests are done ,the childs requirements are estimated prescriptions are issued And then follow up checks are carried out.

00:07:11: You don't need to aim for the upper or middle range of normal.

00:07:14: It is sufficient if values are in lower-normal range—that alone can already require four, five different solutions just to normalize blood salts!

00:07:23: In addition, the blood becomes acidic due to loss bicarbonate through kidneys — a condition called metabolic acidosis which must also be corrected.

00:07:33: Metabolic acidoses have negative impact on metabolism growth and many other bodily functions.

00:07:40: Patients are therefore also supplemented with so-called alkali, which can be bicarbonate, citrate or a mixture of both.

00:07:47: Bicarbonates also taste quite unpleasant — soapy— and children often reluctant to take it.

00:07:54: For older children or adults tablets could eventually be prescribed but this is not yet possible for young people.

00:08:00: in these cases a gastric tube is considered as an option.

00:08:04: usually this is a peg tube a tube placed into the stomach through which medications can be administered.

00:08:10: Nutrition and fluids can also be given this way, it ensures both medication delivery and adequate nutrition and hydration for the child.

00:08:18: however from many parents deciding to go with a peg-tube is very significant step.

00:08:23: Why Is That?

00:08:25: Many parents feel on one hand that represents failure they are unable feed their child or provide adequate nutrition themselves.

00:08:35: Some also worry that if meal times are no longer the same, The interaction with family or child will suffer.

00:08:43: And of course there is always psychological aspect—the body image.

00:08:47: when suddenly a tube in stomach.

00:08:50: That's something that puts some parents off.

00:08:53: In end however it often a tremendous relief Especially for night time medication and fluid administration When the child does not have to be woken up everytime but can receive everything through the tube while continuing to sleep.

00:09:06: Or there is option of attaching a continuous drip overnight, solution of electrolytes and tea delivered via pump providing child with fluids and electrolytes continuously throughout night.

00:09:19: So that ensures everything fluid intake nutrition electrolyte and alkali supplementation medication administration.

00:09:29: for the kidneys in particular It is very important that cysteamine is started as early as possible and taken regularly.

00:09:38: There are at least small case series suggesting that very early cysteamine therapy could even prevent this tubulopathy altogether, And at the very least it can significantly delay progression to chronic kidney failure which may develop over time.

00:09:52: What other medications play a role?

00:09:55: In cases of severe uncontrolled vancone syndrome endomethacin can be prescribed.

00:10:01: This is a medication that slightly reduces the filtration of urine, proteins and other salts in the kidney thereby reducing fluid and electrolyte losses.

00:10:11: However caution is needed to avoid combining it with other medications or medications affecting the renin angiotensin system like ACE inhibitors, or angiotensen receptor blockers which are also commonly used in kidney disease and hypertension.

00:10:30: The combined effect on filtration can increase the risk of side effects and may lead to reduced kidney perfusion and a worsening of kidney function.

00:10:38: these are also medications that often need to be discontinued as kidney functions declines further.

00:10:44: Renin Angiotensin System Inhibitors ACE inhibitors and angiotensin receptor blockers are recommended in other kidney diseases because they can slow the progression of kidney failure.

00:10:54: However, they're not generally recommended in cystinosis though there may be appropriate in individual cases.

00:11:00: for example when patients have high blood pressure that is always an individual decision.

00:11:05: similarly SGLT-II inhibitors now standard therapy for chronic kidney disease in adults lack sufficient data in cystinosis so no treatment recommendation.

00:11:15: Since phosphate is also lost through the kidneys and phancony syndrome, it must of course be replaced.

00:11:21: Phosphate and calcium play a major role in bone metabolism—and vitamin D is often low!

00:11:26: There's therefore ALSO a recommendation to correct mineral metabolism as best as possible —to ensure patients remain physically active... ...and ideally receive physiotherapy.

00:11:36: Growth hormone therapy is an option.

00:11:38: The key point is that in cystinosis the losses of salt, electrolytes and bicarbonate need to be compensated as well as possible so blood levels remain within normal range.

00:11:48: Only then can a child thrive or develop normally.

00:11:51: Systamine therapy itself sometimes causes problems such stomach pain or gastritis.

00:11:56: In some patients proton pump inhibitors are beneficial and other medications are better tolerated.

00:12:04: You've already mentioned kidneys.

00:12:06: How does the disease progress with regard to the kidneys?

00:12:10: The first severely affected organ.

00:12:12: When should families expect kidney failure, and what happens

00:12:16: then?".

00:12:17: The first sign of kidney involvement is this tubulopathy—the collecting ducts are altered in their function by cysteine deposits causing the children to lose electrolytes and bicarbonate.

00:12:29: At this stage however... ...The Kidney's detoxification function usually still completely normal Before cysteamine existed, that was in the early nineteen eighties.

00:12:39: Untreated children showed a relatively rapid deterioration of kidney function and typically reached dialysis between the ages of eight to nine.

00:12:48: Thanks to early cysteamine therapy this has fortunately shifted considerably.

00:12:53: Today patients have a chance get through at least childhood and adolescence without renal replacement therapy though many still require it in early adulthood.

00:13:02: Once kidney function drops below a critical threshold, roughly fifteen to twenty percent of the healthy kidneys' function renal replacement therapy should be planned.

00:13:12: This includes transplantation, dialysis and potentially preemptive transplant.

00:13:18: The management of chronic kidney disease.

00:13:20: in cystinosis patients should follow current guidelines for chronic kidney conditions.

00:13:25: Could

00:13:25: I as parent donate a kidney?

00:13:28: That would actually ideal because preemptive kidney transplantation, that is, transplantation before dialysis becomes necessary.

00:13:37: Is medically the best option?

00:13:39: Living kidney donation is possible.

00:13:42: in cystinosis.

00:13:43: both parents can donate provided the tissue characteristics and blood type are compatible.

00:13:49: being a carrier but not affected by the disease is not a problem.

00:13:53: if a living donation is not possible which could happen with other risk factors present Then hemodialysis or peritoneal dialysis should be started.

00:14:03: This follows current guidelines, and patients must then be listed with Euro transplant for a deceased donor kidney.

00:14:09: When children are listed with Eurotransplant the median waiting time is approximately two years For older adolescents Or adults that Is those over eighteen.

00:14:19: The Waiting Time is unfortunately significantly longer As they enter the adult waiting list And it can Be around eight Years before an organ becomes available.

00:14:28: Can we say anything about how long a newly transplanted kidney survives?

00:14:33: Looking at the overall data, The median graft survival for kidneys from living donors is approximately fifteen years.

00:14:41: Meaning that after fifteen years around fifty percent of transplanted kidneys are still functioning.

00:14:47: For deceased donor kidneys it's slightly worse At around twelve years.

00:14:51: However Data specifically for systemisous patients show that after twelve years, approximately eighty-five percent of transplanted kidneys are still functioning.

00:15:01: That is significantly better than in other kidney seizes.

00:15:04: so graft survival and cystinosis is actually above average.

00:15:08: Is the transplanted kidney also affected by disease?

00:15:12: No The cells on the transplanted kidney aren't affected.

00:15:17: Sistine transport functions normally and no new cysteine deposits develop.

00:15:23: Does cysteamine therapy need to be continued after kidney transplantation?

00:15:29: Yes, it is a systemic disease... ...and all other organs remain at risk from cystein deposits.

00:15:36: Therefore, cysteined depleting therapy with cysteamine must continue even after transplantation.

00:15:44: Based on current knowledge this remains lifelong therapy.

00:15:48: What happens to the patient's own kidneys during transplantation?

00:15:52: If the native kidneys are not causing any problems, they do NOT need to be removed.

00:15:57: However if at the time of transplantation there is still severe phancony syndrome with significant fluid loss protein loss and frequently disturbed blood salts then consideration should be given to whether the patient might benefit from removal of the native kidneys, as this would eliminate these disruptive factors that can also negatively affect transplant function.

00:16:19: What follow-up checks are recommended with regard to the kidneys?

00:16:24: It is important to check kidney function regularly every two months for young children, every two to three months for older children.

00:16:32: This includes looking at protein excretion blood electrolytes, and a blood gas analysis.

00:16:38: Unfortunately this is often not something the general pediatrician can do so it would need to take place at a specialist outpatient clinic.

00:16:46: there It could be assessed how well condition is controlled whether medication sufficient or anything needs adjusted.

00:16:54: growth development also needed to monitor regularly.

00:16:58: therapy should optimized accordingly.

00:17:00: in addition kidney ultrasound performed once year to check that there is no urinary obstruction, also due the high fluid volumes.

00:17:08: Dr.

00:17:09: Vuhl how did you come work in the field of cystinosis?

00:17:13: When I started working i was given opportunity take on a study on growth hormone therapy and within it were specific component looking at growth hormone therapies.

00:17:24: children with cystinoses.

00:17:26: It's European project involving eighty patients.

00:17:30: That Is How I Came To Cystinosis.

00:17:32: I also started co-managing the cystinosis patients being treated at our clinic, and the topic has stayed with me ever since.

00:17:41: Dr.

00:17:41: Elcavul, specialist in Pediatrics & Adolescent Medicine, senior physician of Pediatric Nephrology at Heidelberg University Hospital.

00:17:51: Thank you so much!

00:17:53: To briefly summarize key points around diagnosis, recognize early symptoms Non-specific complaints such as failure to thrive, increased thirst and frequent nappy changes can be early signs of cystinosis and should be investigated promptly.

00:18:08: Early diagnosis through molecular genetic testing or detection of cysteine in cells on the cornea significantly improves the prognosis.

00:18:17: Cystinosis affects many organs and is hereditary.

00:18:21: affected families should absolutely seek genetic counseling.

00:18:25: As kidney function declines, kidney transplantation including living donation offers an important and successful treatment option with above-average graft survival.

00:18:35: Thank you for listening!

00:18:36: If you'd like to learn more the Cystinosis Foundation offers further podcast episodes in videos that provide helpful information and support for everyday life with Cystinosus.

00:18:46: Do take a look And see you next episode.