Testicular function in males with infantile nephropathic cystinosis.

STUDY QUESTION: Do males with the rare lysosomal storage disease infantile nephropathic cystinosis (INC) have a chance of biological fatherhood? SUMMARY ANSWER: Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval from the centre of the testes providing additional opportunities for fatherhood. WHAT IS KNOWN ALREADY: Biallelic mutations in the cystinosin (CTNS) gene in INC cause dysfunction in cystine transport across lysosomal membranes and cystine accumulation throughout the body. Spontaneous paternity in cystinosis has not been described, despite the availability of cysteamine treatment. Azoospermia has been diagnosed in small case series of males with INC. ART using ICSI requires few spermatozoa, either from semen or extracted surgically from the testes of azoospermic men. However, there is limited evidence to suggest this could be successful in INC. STUDY DESIGN, SIZE, DURATION: In this prospective cohort study performed between 2018 and 2019, we performed a cross-sectional investigation of 18 male patients with INC to delineate endocrine and spermatogenic testicular function. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum hormone levels, semen samples (according to World Health Organization 2010 standards), and testicular ultrasound images were analysed in 18 male patients aged 15.4-40.5 years. Surgical sperm extraction was performed in two, and their testicular biopsies were investigated by light and electron microscopy. Past adherence to cysteamine treatment was assessed from medical record information, using a composite scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: Adherence to cysteamine treatment was high in most patients. Testicular volumes and testosterone levels were in the normal ranges, with the exception of two and three older patients, respectively. Serum LH levels were above the normal range in all subjects aged ≥20 years. FSH levels were elevated in all but four males: three with spermatozoa in semen and one adolescent. Inhibin B levels were shown to be lower in older men. Testicular ultrasound revealed signs of obstruction in 67% of patients. Reduced fructose and zinc seminal markers were found in 33%, including two patients with azoospermia who underwent successful surgical sperm retrieval. Histology identified fully preserved spermatogenesis in the centre of their testes, but also tubular atrophy and lysosomal overload in Sertoli and Leydig cells of the testicular periphery. LIMITATIONS, REASONS FOR CAUTION: Limitations of this study are the small number of assessed patients and the heterogeneity of their dysfunction in cystine transport across lysosomal membranes. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that testicular degeneration in cystinosis results from the lysosomal overload of Sertoli and Leydig cells of the testicular periphery, and that this can possibly be delayed, but not prevented, by good adherence to cysteamine treatment. Endocrine testicular function in INC may remain compensated until the fourth decade of life; however, azoospermia may occur during adolescence. Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval providing additional opportunities for biological fatherhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Cystinosis Foundation Germany. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: n/a.

Phosphate wasting disorders in adults.

A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments.

Uremia-related vascular calcification: more than apatite deposition.

In the present study, we characterized and compared the mineral phase deposited in the aortic wall of two different frequently used chronic renal failure rat models of vascular calcification. Vascular calcification was induced in rats by either a 4-week adenine treatment followed by a 10-week high-phosphate diet or 5/6 nephrectomy followed by 6 weeks of 0.25 microg/kg/day calcitriol treatment and a high-phosphate diet. Multi-element mapping for calcium and phosphate together with mineral identification was performed on several regions of aortic sections by means of synchrotron X-ray-mu-fluorescence and diffraction. Bulk calcium and magnesium content of the aorta was assessed using flame atomic absorption spectrometry. Based on the diffraction data the Von Kossa-positive precipitate in the aortic regions (N=38) could be classified into three groups: (1) amorphous precipitate (absence of any diffraction peak pattern, N=12); (2) apatite (N=16); (3) a combination of apatite and magnesium-containing whitlockite (N=10). The occurrence of these precipitates differed significantly between the two models. Furthermore, the combination of apatite and whitlockite was exclusively found in the calcitriol-treated animals. These data indicate that in adenine/phosphate-induced uremia-related vascular calcification, apatite is the main component of the mineral phase. The presence of magnesium-containing whitlockite found in addition to apatite in the vitamin D-treated rats, has to be seen in view of the well-known vitamin D-stimulated gastrointestinal absorption of magnesium.

"Periodic fever" without fever: two cases of non-febrile TRAPS with mutations in the TNFRSF1A gene presenting with episodes of inflammation or monosymptomatic amyloidosis.

BACKGROUND: Tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS) is caused by dominant mutations in the TNFRSF1A gene. In typical cases TRAPS begins early in childhood and is characterised by high and remittent fever over a period of 1-4 weeks or longer, accompanied by systemic and local inflammation. CASE REPORTS: Patient 1 presented with recurrent episodes of weakness, migrating myalgias, arthralgias, exanthema, and chest pain lasting for 1-4 weeks, but without any fever over an initial period of 4 years at least. Diagnosis of TRAPS was confirmed by the heterozygous mutation Y20H in TNFRSF1A. Patient 2, a 23 year old woman never had any symptoms indicative of TRAPS. Genetic evaluation of all members of her family with a TRAPS index patient disclosed the T50M mutation in TNFRSF1A. A medical check up showed proteinuria, and renal biopsy disclosed AA amyloidosis. CONCLUSIONS: TRAPS associated mutations can induce considerable inflammation that is not necessarily accompanied by fever. Even monosymptomatic severe amyloidosis can occur in these patients. Genetic counselling and appropriate management to prevent or mitigate amyloidosis may be necessary.

Long-term treatment with growth hormone in short children with nephropathic cystinosis.

OBJECTIVE: The objective was to assess the efficacy and safety of growth hormone (GH) treatment in severely growth retarded children with nephropathic cystinosis during conservative treatment and during renal replacement therapy. STUDY DESIGN: The design was an open-labeled prospective trial with a run-in period of 1 year. RESULTS: A total of 74 children with cystinosis (age 3.0 to 18 years) were treated with GH over a mean period of 3.1 years (range 1 to 10 years); 52 patients were receiving conservative treatment (mean age 7.1 years), 7 were receiving dialysis (12.5 years), and 15 had received a renal transplant (14.8 years). The mean standardized height (SD score) was -4.0 in the conservative treatment group, -4.4 in the dialysis group, and -4.9 in the renal transplant group. During the first treatment year, height velocity doubled in the conservative treatment group, increased by 80% in the dialysis group, and increased by 45% in renal transplant group. Within 3 years the height SD score increased by +1.6 (P <.001) in prepubertal patients receiving conservative treatment, and percentile parallel growth was maintained thereafter. These effects of GH were less expressed in peripubertal patients receiving renal replacement therapy. No major side effects were observed. CONCLUSION: Long-term GH treatment is safe and effective in young children with nephropathic cystinosis. GH treatment should be started early in the course of the disease if adequate nutrition and cysteamine treatment do not prevent growth retardation.

Long-term outcome of paediatric patients with hereditary tubular disorders.

BACKGROUND: An increasing number of children with hereditary tubular disorders (HTD) reach adult life due to diagnostic and therapeutic advances which results in growing need to manage these patients by adult centres. Data on the prevalence and the late clinical problems of these patients are limited. METHODS: We observed 177 paediatric patients with isolated or complex HTD between 1969 and 1994. The median age at the time of diagnosis was 3 (range 0-18) years and the median observation period 10 (range 1-43) years. The long-term outcomes with respect to renal function, bone disease, and body growth were analyzed. RESULTS: The prevalence of HTD was 3.2% of all patients observed in our renal unit and 14% of those patients with chronic renal failure and/ or end-stage renal disease. The three most frequent disorders observed were nephropathic cystinosis (n = 34), X-linked hypophosphataemic rickets (n = 26), and idiopathic hypercalciuria (n = 17). At the last observation, 12% of the patients with isolated HTD and 30% of those with complex HTD had developed preterminal chronic renal failure; end-stage renal disease was observed in 5 and 25%, respectively (p < 0.001). Progressive disease occurred mainly in patients having cystinosis, primary hyperoxaluria, the syndrome of hypomagnesaemia/hypercalciuria, primary Fanconi syndrome, Fanconi-Bickel syndrome, and methylmalonic aciduria. Nephrocalcinosis was found in 42%, urolithiasis in 14%, bone deformities and/or fractures in 28%, and other extrarenal alterations in 29% of all patients. The median body height at last observation was 2.0 SD below the normal mean (range from -10.4 to +2. 6), and the adult height was subnormal in 48% of 67 grown-up patients. Growth retardation was more severe in complex than in isolated HTD. The mortality decreased from 17% in 1969-1981 to 12% in 1982-1994. CONCLUSION: Although HTD are rare nephropathies, their frequently progressive course associated with extrarenal complications requires the attention of nephrologists beyond the paediatric age.

Treatment with recombinant human growth hormone in short children with nephropathic cystinosis: no evidence for increased deterioration rate of renal function. The European Study Group on Growth Hormone Treatment in Short Children with Nephropathic Cystinosis.

To evaluate the effect of long-term treatment with recombinant human GH (rhGH) on renal function in short children with nephropathic cystinosis with and without concomitant cysteamine treatment, 36 growth-retarded children with nephropathic cystinosis (age 7.3+/-2.7 y; creatinine clearance [C(CR)] 50+/-27 mL (min x 1.73 m2)(-1) were treated with 1 IU rhGH/kg/wk for up to 5 y. The rise in serum creatinine before and during rhGH treatment was compared with that in a historical control group of cystinotic patients. The effect of concomitant cysteamine treatment on the evolution of renal function before and after the start of rhGH was evaluated separately in patients without (group A) and with cysteamine treatment (group B). The decline of C(CR) was also compared with that in noncystinotic patients with chronic renal failure with and without rhGH treatment. At study entry, serum creatinine values in group A were similar to those in the historical controls, whereas group B had significantly lower serum creatinine values. Treatment with rhGH did not accelerate the rise in creatinine independently of cysteamine treatment. There were no significant differences in the mean decline of C(CR) per year in cystinotic compared with noncystinotic patients with chronic renal failure with or without rhGH treatment. rhGH therapy for up to 5 y does not accelerate the deterioration of renal function. This justifies the continuation of controlled studies of rhGH treatment in these patients. The study also provides further evidence that cysteamine therapy reduces the progression of renal failure in children with cystinosis.

The clinical spectrum of shunt nephritis.

BACKGROUND: Shunt nephritis is an immune-complex-mediated glomerulonephritis (GN) associated with chronically infected ventriculoatrial shunts inserted for treatment of hydrocephalus. METHODS: Six patients aged 5-22 years with shunt nephritis are reported who have been observed between 1971 and 1994. The clinical course and long-term outcome are analysed in relation to the time of diagnosis and renal histopathology. RESULTS: The time of diagnosis of shunt nephritis ranged from 0.3 to 4.5 years after the last shunt operation. Diagnosis was delayed up to 1.5 years after the first clinical manifestations. All patients had signs of infection, i.e. recurrent fever, hepatosplenomegaly, anaemia, and cerebral symptoms. Renal manifestations consisted of haematuria (macroscopic in 3 patients), proteinuria (heavy in 5), renal insufficiency (4) and hypertension (2). Decreased C3 levels, cryoglobulins, and antinuclear factors were frequent. Cultures of blood and cerebrospinal fluid provided growth mainly of S. epidermidis. Renal biopsy revealed endocapillary GN (1), membranoproliferative GN (1) and endocapillary/extracapillary GN with crescents (2). All patients received antibiotics i.v. Complete recovery was observed in three of four patients in whom the shunt was totally removed, supported by transient external drainage of cerebrospinal fluid, and followed by placement of a ventriculoperitoneal shunt. One child with delayed diagnosis, presenting with a serum creatinine of 3.2 mg/dl, hypertension, and severe scarring on renal biopsy, rapidly progressed to irreversible ESRD within 5 months. Two patients without and only partial removal of the shunt died subsequently from sepsis. CONCLUSIONS: The renal outcome of shunt nephritis is good if early diagnosis and treatment is provided including i.v. antibiotics and total removal of the infected shunt. The possible progression to ESRD requires frequent nephrological monitoring of patients with ventriculoatrial shunts.

Body growth in primary de Toni-Debré-Fanconi syndrome.

Body growth in nine children with primary de Toni-Debré-Fanconi syndrome was followed from birth to adolescence or adult life. At the time of diagnosis, corresponding to the start of treatment, the median age was 2.3 (range 0.4-13.9) years and height standard deviation score (SDS) was always decreased (median -3.5, range -6.8 to -2.1). Despite continuous electrolyte and bicarbonate supplementation only four patients showed a slight improvement in growth. At the time of the last observation at the age of 17.2 (4.5-20.1) years median height was -4.7 (-5.9 to -1.8) SDS. The median difference between height at last observation and target height was -4.5 SDS. Final height (n = 5) ranged between -1.8 and -5.5 (median -4.3) SDS. The pubertal growth spurt was absent in two children. Metabolic acidosis was identified as a significant growth-retarding factor. Mean serial blood bicarbonate levels and height SDS at the last observation were correlated (r = -0.87, P < 0.01). No correlation was observed between last height SDS and the degree of hypokalemia, hypophosphatemia, or hypercalciuria. In conclusion, patients with primary de Toni-Debré-Fanconi-syndrome present severe growth failure at the time of diagnosis which persists into adult life. Supportive therapy is frequently unable to prevent further loss of relative height.

Effect of growth hormone treatment on pubertal growth in a boy with cystinosis and growth failure after renal transplantation.

Recombinant human growth hormone (rhGH) has proven effective in improving growth in short prepubertal children with chronic renal failure (CRF) before and after renal transplantation. However, its effect in pubertal patients is still doubtful. We report the case of a boy with nephropathic cystinosis and persistent growth failure despite successful renal transplantation who was treated with rhGH (30 i.u./m2 body surface area/week sc) from early puberty up to final height.

A morphometric filter improves the diagnostic value of morphometric analyses of frozen histopathological sections from mammary tumours.

Frozen sections of 202 consecutive breast tumour cases were analyzed by morphometric quantitation of nuclear features. Nuclei were selected at random. Conventional light microscope examination of the paraffin-embedded specimens revealed 144 cases of cancer and 56 benign tumours. Using multivariate discriminant analysis of morphometric features, all but two of the benign cases and 79% of the malignant tumours were correctly classified. When a morphometrically based dynamic filter set to exclude 'non-diagnostic' nuclei was used, the correctly classified malignant cases rose to 86% Morphometry is a fast, reproducible and efficient method that can be used in conjunction with the histomorphological diagnosis of mammary frozen sections. The combination of systematic sampling and an objective dynamic filter may be a powerful approach to quantitative analyses of tumours from other sites. However, it is also likely that efficiency can be improved by combining nuclear morphometric features with structural, histochemical and molecular biological data. The combination of traditional histomorphological examination with quantitative information may well increase the diagnostic accuracy in individual patients.

Growth hormone induced rise in glomerular filtration rate is not obliterated by angiotensin-converting enzyme inhibitors.

In 8 healthy normotensive probands with normal glomerular filtration rate, the effect of recombinant human growth hormone (rhGH) on inulin clearance (Cin) was examined in an open study with intraindividual crossover with or without enalapril pretreatment (20 mg/day). rhGH was administered by subcutaneous injection (4.5 U twice daly) for 3 days. On the following day Cin was measured with an enzymatic steady state infusion technique. Systemic hemodynamics and potential metabolic effects of rhGH, i.e., inulin-like growth factors I and II, somatomedin-binding protein, glucagon, C peptide, amino acid pattern, etc., were monitored. On controlled dietary intake of protein, the median Cin rose 72 h after start of rhGh administration from 114 (range 91-158) to 135 (108-167) ml/min/1.73 m2 without enalapril pretreatment (p less than 0.01) and from 111 (88-153) to 131 (100-173 ml/min/1.73 m2 with enalapril pretreatment (p less than 0.02). The results confirm that (1) rhGH increases Cin to a similar extent as extractive GH and (2) further demonstrate that this action is not obliterated by blocking the circulating converting enzyme.

The acute effect of growth hormone on GFR is obliterated in chronic renal failure.

Recombinant human growth hormone (rhGH) has become available for treatment of growth failure in uremic children. Since GH raises the glomerular filtration rate (GFR) in healthy individuals, there has been concern that treatment with rhGH, by its action on glomerular hemodynamics, may adversely affect the progression of renal failure. To further address this issue, inulin clearance (enzymatic steady-state infusion technique) was measured in 7 healthy normotensive adult volunteers and 7 patients with chronic renal failure from glomerular or non-glomerular causes. Subjects were given 4.5 U bid of rhGH by s.c. injection for 3 days. In volunteers, a significant increase in Cin was noted 72 h after start of rhGH administration from 120 ml/min/1.73 m2 (range 91-158) to 133 (108-167) (p less than 0.02). In contrast, no significant increase in Cin was noted in patients with chronic renal failure (baseline Cin 21 ml/min/1.73 m2, 15-32; after rhGH 22 ml/min/1.73 m2, 15-32) despite pronounced effects of GH on S-cholesterol and urea excretion rate. The results show that stimulation of GFR by short-term administration of rhGH is obliterated in chronic renal failure.