Nephropathic Cystinosis in Adolescents and Adults Figure 3: Histological Findings in Late-onset Nephropathic Cystinosis A C
B
D
Panel A: light microscopy (trichrome light green x 100) showing focal tubulo-interstitial lesions with mild interstitial fibrosis, tubular atrophy and focal arteriolar thickening. Panel B: light microscopy (trichrome light green x 200) showing focal segmental glomerulosclerosis on one glomerulus. Panel C: electron microscopy (x 5,000) showing alterations in distal tubules without cystine crystals, and dilatation and atrophy of distal tubules. Panel D: electron microscopy (x 5,000) showing effacement of foot processes along the glomerular basement membrane.
Thus renal disease progression cannot be accurately predicted from the rate of progression in affected relatives.
The ‘benign’ ocular form seen in adults is usually differentiated from late-onset nephropathic cystinosis.26
Our findings challenge this
distinction. Indeed, one female patient aged 59 had typical corneal deposits and high free cystine granulocyte content, with little or no renal involvement (no proteinuria, borderline glomerular filtration rate of 59 ml/min per 1.73 m2, no renal biopsy carried out), whereas her brother had reached ESRD at the age of 28 years. These observations suggest that environmental and/or modifier genes may influence renal disease progression in patients with late-onset cystinosis.
There are several possible reasons for the slow progression of renal disease in patients with late-onset cystinosis. ‘Mild’ mutations are usually found in these patients, often preserving some transport activity of cystine out of lysosomes. The renal toxicity of cystine depends on events downstream from the lysosomes. These pathophysiological steps may modulate the severity of the disease, and some polymorphisms in the genes controlling these steps may modify the clinical expression of the disease.
EUROPEAN NEPHROLOGY
Thoene et al. in a family with intermediate cystinosis, whereas renal progression was remarkably similar in two further patients from another family.23
The possibilities for treating late-onset cystinosis depend on the putative mechanisms responsible for renal disease progression. Oral cysteamine can be considered to deplete cystine from lysosomes. However, its efficacy against renal damage in late-onset forms is unknown. Cysteamine may also be useful for preventing or reversing cystine deposition in other organs. Inhibitors of the renin–angiotensin system should be administered to reduce proteinuria and prevent focal segmental glomerulosclerosis. Progress in the treatment of cystinosis depends on the development of new compounds designed to prevent the accumulation of cystine in lysosomes, and on improvements in our understanding of the successive steps leading from the primary lysosomal event to cell damage.
Conclusions
Cystinosis provides a good example of a ‘paediatric’ disease with a spectrum extending its management into adult medicine.
A small number of studies from Europe and the US have shown consistent improvements in the renal and extra-renal complications of cystinosis in cysteamine-treated patients over the past 20 years. The importance of early diagnosis in order to initiate cysteamine treatment as soon as possible has been clearly demonstrated. Early oral cysteamine therapy slows the deterioration of renal function.
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