The primary hyperoxalurias Hoppe, Bernd; Beck, Bodo B.; Milliner, Dawn S.
Kidney international,
06/2009, Letnik:
75, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The primary hyperoxalurias (PHs) are rare disorders of glyoxylate metabolism in which specific hepatic enzyme deficiencies result in overproduction of oxalate. Due to the resulting severe ...hyperoxaluria, recurrent urolithiasis or progressive nephrocalcinosis are principal manifestations. End stage renal failure frequently occurs and is followed by systemic oxalate deposition along with its devastating effects. Due to the lack of familiarity with PHs and their heterogeneous clinical expressions, the diagnosis is often delayed until there is advanced disease. In recent years, improvements in medical management have been associated with better patient outcomes. Although there are several therapeutic options that can help prevent early kidney failure, the only curative treatment to date is combined liver–kidney transplantation in patients with type I PH. Promising areas of investigation are being identified. Knowledge of the spectrum of disease expression, early diagnosis, and initiation of treatment before renal failure are essential to realize a benefit for patients.
Background
RMND1
is a nuclear gene needed for proper function of mitochondria. A pathogenic gene will cause multiple oxidative phosphorylation defects. A renal phenotype consisting of hyponatremia, ...hyperkalemia, and acidosis is frequently reported, previously considered to be due to aldosterone insensitivity.
Methods
Clinical features and pathophysiology of three patients will be reported. DNA of these patients was subjected to exome screening.
Results
In the first family, one pathogenic heterozygous and one highly probable heterozygous mutation were detected. In the second family, a homozygous pathogenic mutation was present. The electrolyte disbalance was not due to aldosterone insensitivity but to low plasma aldosterone concentration, a consequence of low plasma renin activity. This disbalance can be treated. In all three patients, the kidney function declined. In the first family, both children suffered from an unexplained arterial thrombosis with dire consequences.
Conclusions
Hyporeninemic hypoaldosteronism is the mechanism causing the electrolyte disbalance reported in patients with
RMND1
mutations, and can be treated.
Primary hyperoxaluria type I (PH I) is caused by deficiency of the liver-specific enzyme alanine-glyoxylate:aminotransferase (AGT). Many mutations are known to perturb AGT protein folding. Vitamin B6 ...(B6) is the only specific drug available for treatment. Although B6 has been used for >40 years, controlled data on B6 efficacy are lacking. Therefore, this study investigated the absolute and relative change of urinary oxalate (Uox) excretion under increasing dosages of B6, the first prospective trial to do so.
B6 response was studied in 12 patients (7 male patients) with genetically confirmed PH I (3 Gly170Arg homozygous, 5 compound Gly170Arg and/or Phe152Ile heterozygous, and 4 negative for Gly170Arg and/or Phe152Ile mutations) and noncompromised renal function. Efficacy was defined as a 30% relative reduction in Uox excretion. B6 was administered orally starting at 5 mg/kg body weight per day and given in increments of 5 mg/kg every 6 weeks, up to a final dosage of 20 mg/kg per day at week 24. Uox and serum B6 levels were measured every 6 weeks.
Mean relative Uox reduction was 25.5%. Uox declined from 2.09±0.55 (mean±SD) at baseline to 1.52±0.60 mmol/1.73 m(2) per day (P=0.01) at week 24. Serum B6 levels increased from 22.5±8.7 to 1217±776 ng/ml (P<0.001). Six patients showed a ≥30% relative reduction of Uox at week 24.
This first prospective trial confirmed B6 efficacy in 50% of patients (three of three homozygous, one of five heterozygous, and two of four patients negative for the Gly170Arg and/or Phe152Ile mutations). Interestingly, no complete biochemical remission was observed, even in the homozygous Gly170Arg study participants. Future trials are necessary to learn more about genotype-related B6 response and B6 metabolism.
Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the ...subsequent storage of oxalate can cause life-threatening systemic disease. Diagnosis of PH is often delayed or missed owing to its rarity, variable clinical expression and other diagnostic challenges. Management of patients with PH and kidney failure is also extremely challenging. However, in the past few years, several new developments, including new outcome data from patients with infantile oxalosis, from transplanted patients with type 1 PH (PH1) and from patients with the rarer PH types 2 and 3, have emerged. In addition, two promising therapies based on RNA interference have been introduced. These developments warrant an update of existing guidelines on PH, based on new evidence and on a broad consensus. In response to this need, a consensus development core group, comprising (paediatric) nephrologists, (paediatric) urologists, biochemists and geneticists from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), formulated and graded statements relating to the management of PH on the basis of existing evidence. Consensus was reached following review of the recommendations by representatives of OxalEurope, ESPN, ERKNet and ERA, resulting in 48 practical statements relating to the diagnosis and management of PH, including consideration of conventional therapy (conservative therapy, dialysis and transplantation), new therapies and recommendations for patient follow-up.
Treatment of congenital nephrotic syndrome (CNS) and steroid-resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in ...SRNS that affect the renal podocyte. In the era of high-throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease.
Cross-sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50-178). Genotyping was performed systematically in all patients.
The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA-induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy.
The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients.
Understanding podocyte-specific responses to injury at a systems level is difficult because injury leads to podocyte loss or an increase of extracellular matrix, altering glomerular cellular ...composition. Finding a window into early podocyte injury might help identify molecular pathways involved in the podocyte stress response.
We developed an approach to apply proteome analysis to very small samples of purified podocyte fractions. To examine podocytes in early disease states in FSGS mouse models, we used podocyte fractions isolated from individual mice after chemical induction of glomerular disease (with Doxorubicin or LPS). We also applied single-glomerular proteome analysis to tissue from patients with FSGS.
Transcriptome and proteome analysis of glomeruli from patients with FSGS revealed an underrepresentation of podocyte-specific genes and proteins in late-stage disease. Proteome analysis of purified podocyte fractions from FSGS mouse models showed an early stress response that includes perturbations of metabolic, mechanical, and proteostasis proteins. Additional analysis revealed a high correlation between the amount of proteinuria and expression levels of the mechanosensor protein Filamin-B. Increased expression of Filamin-B in podocytes in biopsy samples from patients with FSGS, in single glomeruli from proteinuric rats, and in podocytes undergoing mechanical stress suggests that this protein has a role in detrimental stress responses. In
, nephrocytes with reduced filamin homolog Cher displayed altered filtration capacity, but exhibited no change in slit diaphragm structure.
We identified conserved mechanisms of the podocyte stress response through ultrasensitive proteome analysis of human glomerular FSGS tissue and purified native mouse podocytes during early disease stages. This approach enables systematic comparisons of large-scale proteomics data and phenotype-to-protein correlation.
Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria ...type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.
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Primary hyperoxaluria type 1 displays a heterogeneous phenotype, likely to be affected by genetic and non-genetic factors, including timeliness of diagnosis and quality of care. As previous ...genotype-phenotype studies were hampered by limited patient numbers the European OxalEurope Consortium was constituted. This preliminary retrospective report is based on 526 patients of which 410 have the AGXT genotype defined. We grouped mutations by the predicted effect as null, missense leading to mistargeting (G170R), and other missense, and analyzed their phenotypic correlations. Median age of end-stage renal disease increased from 9.9 for 88 homozygous null patients, 11.5 for 42 heterozygous null/missense, 16.9 for 116 homozygous missense patients, 25.1 for 61 G170R/null patients, 31.2 for 32 G170R/missense patients, and 33.9 years for 71 homozygous G170R patients. The outcome of some recurrent missense mutations (p.I244T, p.F152I, p.M195R, p.D201E, p.S81L, p.R36C) and an unprecedented number of G170R homozygotes is described in detail. Diagnosis is still delayed and actions aimed at increasing awareness of primary hyperoxaluria type 1 are recommended. Thus, in addition to G170R, other causative mutations are associated with later onset of end-stage renal disease. The OxalEurope registry will provide necessary tools for characterizing those genetic and non-genetic factors through a combination of genetic, functional, and biostatistical approaches.
Angiotensin-converting enzyme inhibitors (ACEis) have evolved as a first-line therapy for delaying end-stage renal failure (ESRF) in Alport syndrome (AS). The present study tested the hypothesis of a ...superior nephroprotective potential of an early ACEi intervention, examining a cohort with the COL4A5 missense variant p.(Gly624Asp).
In this observational cohort study (NCT02378805), 114 individuals with the identical gene variant were explored for age at ESRF and life expectancy in correlation with treatment as endpoints.
All 13 untreated hemizygous patients developed ESRF (mean age 48.9 ± 13.7 years), as did 3 very late treated hemizygotes (51.7 ± 4.2 years), with a mean life expectancy of 59.2 ± 9.6 years. All 28 earlier-treated estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 hemizygous patients were still alive and still had not reached ESRF. Therapy minimized the annual loss of their GFR, similar to the annual loss in healthy individuals. Of 65 heterozygotes, 4 untreated individuals developed ESRF at an age of 53.3 ± 20.7 years. None of the treated heterozygous females developed ESRF.
For the first time, this study shows that in AS, early therapy in individuals with missense variants might have the potential to delay renal failure for their lifetime and thus to improve life expectancy and quality of life without the need for renal replacement therapy. Some treated patients have reached their retirement age with still-functioning kidneys, whereas their untreated relatives have reached ESRF at the same or a younger age. Thus, in children with glomerular haematuria, early testing for Alport-related gene variants could lead to timely nephroprotective intervention.
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