Addressing gaps in patient care in rare inherited disorders: the role of the nephrologist – Organised by CHIESI FARMACEUTICI S.P.A.

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Transition from paediatric to adult care

David Cassiman, Belgium

Over the last 15 years, a steady increase in the number of children and adults with metabolic diseases has been observed. As David Cassiman, Leuven, Belgium, pointed out at a symposium organized by Chiesi Farmaceutici S.p.A. at the 2021 ERA-EDTA Congress, there are two types of adult patients: Former paediatric patients who have grown up with such diseases, and adults newly diagnosed with inborn errors of metabolism in adulthood. The first group is growing in size due to better pre- and post-natal diagnosis and better symptomatic or specific treatments. Many orphan drugs have been developed, and there are many patients who have been transplanted in childhood (e.g. bone marrow transplantation, liver transplantation, kidney or heart transplantation). They survive childhood, outgrow paediatric care and are transferred to the care of internists.

“A challenge we face when treating these patients that have outgrown paediatric care is the fact that there is a lack of scientific data on long-term outcomes and survival”, commented Cassiman. “They might be cured for one aspect of the disease, but previously unknown features of the disease occur later on.” Furthermore, these patients also develop “normal” aging issues and comorbidities such as hypertension, cancers, prostrate problems, diabetes, cardiac diseases, etc., or drug-related issues such as alcohol and smoking.

New problems also arise on reaching adulthood: these can involve social, financial and professional aspects, as well as sexuality, fertility and family planning. Many patients are lower-skilled or only partly skilled or have received a lower level of education compared to the general population in the same region, thus giving rise to specific economical and social issues.

“Our population has its own specific social and professional issues”, explained David Cassiman, “but what we see on the adult care side is that there is often a lack of structure and a lack of ‘dedicated’ specialists. According to this expert in the field, there is liable to be a discontinuity in care provision, especially after a patient outgrows paediatric care, which unfortunately is around the very vulnerable period when patients are supposed to develop autonomy. “To bridge this gap, we need to take action!”

A special transition program for cystinosis patients has been initiated in Leuven: If the patient is 12 or 13 years of age, a metabolic internist joins the paediatric nephrologist every three months. The patient is seen jointly, and a metabolic team takes over after he or she has grown out of paediatric care. Apart from doctors, the team also consists of dieticians, psychologists and social assistants and can provide the patient with holistic support. The nephrologist plays an important role in this team – cystinosis patients are liable to develop many complications in adulthood, some due to the cystinosis itself, but patients also suffer from the ‘common’ complications of transplantation, immunosuppressive treatment and kidney disease.

Managing multidisciplinary care in adult cystinosis patients

Aude Servais, France

As Aude Servais, Paris, France, pointed out, 55% of patients living with cystinosis are adults nowadays. Disease progression leads to kidney failure, diabetes, myopathy, hypothyroidism, hypogonadism, and central nervous system deterioration. In the study conducted by Brodin-Sartorius and colleagues, the first complication was ESRD at a mean age of 11.1. Hypothyroidism and diabetes usually develop after that, with neuromuscular disorders and strokes occurring in the second decade.

But there is hope: The same study group showed that 5% of patients, with a median age of 20.9 years (15.7–27.2), all treated before 2.5 years of age, had not developed any complications at all. Registry data have shown that cysteamine given before the age of five reduces the incidence of long-term renal and extra-renal complications – this is why the continuation of cysteamine treatment also in patients treated by dialysis or transplantation is strongly recommended.

However, adherence also plays a powerful role, of course. Only 50% of the adult patients take their medication strictly according to the prescription, which is a problem, because adherence is directly associated with renal survival. Compliant patients reach ESKD significantly later than the non-compliant. It has been shown that, for each year of good cystine depletion, one year of preserved renal function is gained.

Early treatment pays off in many respects: Starting treatment before the age of five is associated with a significant delay in the occurrence of hypothyroidism. Even the incidence of diabetes can be suspended with consequent and early treatment. Cystine accumulates in the beta cells of the islets of Langerhans, with massive crystal deposits in the pancreas and complete architectural disorganisation, and treatment clearly slows this pathogenesis.

As Aude Servais emphasized, it is important to monitor cystinosis patients regularly for diabetes mellitus, especially in transplant patients, and for hypothyroidism. Annual laboratory tests for adults include thyroid function tests as well as fasting blood glucose. Haemoglobin A1c (HbA1c) tests are also recommended.

Cystine deposition in muscles may also cause progressive distal myopathy – and here again, it has been shown that starting therapy early, before the patient is five years of age, is associated with a significant delay in the occurrence of neuromuscular disorders.

Central neurological complications may also develop. These can be of two types: On the one hand, there is ‘cystinosis encephalopathy’ with cerebellar signs and/or motor difficulties, decrease of oral expression and motor coordination difficulties. On the other hand, stroke-like episodes involving coma, hemiplegia or milder symptoms can be observed. Patients may also develop mild neurocognitive abnormalities, e.g. specific impairments in the processing of visual information, relative weakness in visual motor, visual spatial and visual memory skills, which might be the reason why the disease is often associated with academic difficulties, primarily in arithmetic. Aude Servais pointed out the importance of conducting a Micro-Randomized Trial (MRT) and involving neurology colleagues if there are any complaints of headache, symptoms of bradykinesia, stroke or potential dementia.

The illness also has a socio-psychological dimension: Male patients suffer from primary hypogonadism, which often is a psychological burden and has impacts on quality of life. Testosterone treatment allows puberty but does not prevent infertility. Pregnancy in women with cystinosis involves many challenges. Pre-pregnancy planning and treatment in a renal obstetric clinic with expertise in complex pregnancies is essential.

Aude Servais concluded that the spectrum of the disease has extended from a renal disease of childhood to a multisystem adult disease. The Clinical Decision Support Programme (CDSP) was set up for that reason in order to provide guidance to specialist and non-specialist clinicians in their daily clinical practice when treating adolescent and adult patients with cystinosis. The aim is to extend existing guidance with practical advice and strategies that address the requirements and management of adolescents and adults living with multi-organ effects of cystinosis.

The role of the nephrologist in Fabry care: from early diagnosis to therapeutic goals

Christine Kurschat, Germany

Fabry disease is a lysosomal storage disease and an X-linked inherited disorder. It is a mutation in the GLA gene, which codes for the α-galactosidase A enzyme, and results in translation of a malfunctioning protein and the accumulation of sphingolipids in all cells of the human body. The disease is often characterized by angiokeratoma. The disease affects other organ systems as well: The GI tract (diarrhoea, cramps), the ear and eye (hearing loss, cornea verticillate), the cardio-vascular system (cardiac arrhythmia, LVH), the central nervous system (early strokes) and the kidneys (renal insufficiency, dialysis). Nowadays, with therapies available, patients die mainly from cardiovascular complications. The delay in diagnosis is significant. Studies have shown that the time between the onset of symptoms and diagnosis is 13.7 years in male patients and as much as 16.3 years in females.

What role do nephrologists play when kidneys are involved? Their job should primarily be to diagnose the disease at an early stage. Proteinuria and/or albuminuria are one of the earliest signs of organ damage in Fabry patients. They are signs of podocyte damage because sphingolipids accumulate in such cells. As Christine Kuscheid pointed out, the process of accumulation starts very early on in the disease. The next important step is early therapy. Christine Kuscheid referred to a European consensus paper that summarizes the current state of the art.

In classically affected males, therapy is at least recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but therapy may be considered in patients aged 16 or more without organ involvement and classical mutations. This is because the disease will lead to organ damage, so a preventive strategy can be considered. A different strategy is recommended for women. As they have two X-chromosomes, one never knows whether the healthy chromosome may compensate for the diseased chromosome. In classically affected females, treatment should therefore be started when organ involvement has been diagnosed, but not before.

Another important message Christine Kurscheid emphasized was that treatment should always be continued on dialysis or after renal transplantation. As she pointed out, Fabry disease is a systemic disease, and the therapy also protects the vessels and the heart, even if the patient is on renal replacement therapy.

Two types of treatment are currently available: Enzyme replacement (available since 2001, must be infused every other week) and Chaperone therapy (an oral therapy available since 2016). It has been shown that enzyme replacement therapy significantly decreases pathogenic Gb3 deposition in the kidney, but clearance is never complete and not all patients respond very well. “In most patients we can slow the decline of renal function, but we cannot stop it.” Chaperone therapy also significantly decreases Gb3 deposition in podocytes and slows progression, but it cannot halt it completely. Moreover, it works in only about a third of patients, with success depending strongly on amenable mutations.

“There are still unmet needs in our patients”, Christine Kurscheid concluded. “It is very important to develop new therapies that can cure the patients and that can help patients who do not respond well to the therapies we have.”

Further reading

Brodin-Sartorius A et al. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults Kidney Int 2012;81:179-189

Gahl WA et al. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med 2007;147(4):242-250

Ariceta G et al. Cysteamine (Cystagon®) adherence in patients with cystinosis in Spain: successful in children and a challenge in adolescents and adults. Nephrol Dial Transplant 2015; 30:457-480

Biegstraaten M et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis 2015; 10: 36

Germain et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol 2007; 18(5): 1547-57