How genomics reclassifies diseases : the case of Alport syndrome

Altres ajuts: The author's research is funded by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (FEDER) funds, RETIC REDINREN RD16/0009 FIS FEDER FUNDS.In this issue, Matthews et al. provide a comprehensive review of published cohorts with heterozygous pathogenic variants in COL4A3 or COL4A4, documenting the wide spectrum of the disease. Due to the extreme phenotypes that patients with heterozygous pathogenic variants in COL4A3 or COL4A4 may show, the disease has been referred to in a variety of ways, including 'autosomal dominant Alport syndrome', 'thin basement membrane disease', 'thin basement membrane nephropathy', 'familial benign hematuria' and 'carriers of autosomal dominant Alport syndrome'. This confusion over terminology has prevented nephrologists from being sufficiently aware of the relevance of the entity. Nowadays, however, next-generation sequencing facilitates the diagnosis and it is becoming a relatively frequent finding in haematuric-proteinuric nephropathies of unknown origin, even in non-familial cases. There is a need to raise awareness among nephrologists about the disease in order to improve diagnosis and provide better management for these patients

Recent advances in the clinical management of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic systemic disorder causing the development of renal and hepatic cysts and decline in renal function. It affects around 1 in 1,000 live births. Early hypertension and progressive renal failure due to massive enlargement of cysts and fibrosis are hallmarks of the disease. This article reviews recent advances in ADPKD and focuses mainly on diagnosis, management, and prediction of the course of the disease

Fabry disease : the many faces of a single disorder

In 1898, two dermatologists, William Anderson in England and Johannes Fabry in Germany, separately described a disease characterized by skin lesions, known as angiokera-tomas. This issue contains two reports of Fabry disease (FD) patients presenting with proteinuric chronic kidney disease (CKD) but lacking angiokeratomas [1,2]. These cases illustrate the phenotypic heterogeneity of the disease in females [1] and FD variants [2],theroleof genetic diagnosis [1] and renal biopsy [2] and recent advances in pathophysiology [1]. FD is caused by deficient activity of alpha-galactosidase A (α-GalA) due to mutations in the X-chromosome GLA gene, leading to accumulation of neutral glycolipids and eventual tissue injury and organ dysfunction [3]. In classical FD males, α-GalA activity is absent or nearly absent and there is an early onset of acroparesthesias, angiokeratoma and hypohydrosis followed by life-threatening cardiac, central nervous system and kidney disease leading to end-stage renal disease (ESRD) at a mean age of 40 year

Dietary Aspects and Drug-Related Side Effects in Autosomal Dominant Polycystic Kidney Disease Progression

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease. In the absence of targeted therapies, it invariably progresses to advanced chronic kidney disease. To date, the only approved treatment is tolvaptan, a vasopressin V2 receptor antagonist that has been demonstrated to reduce cyst growth and attenuate the decline in kidney function. However, it has various side effects, the most frequent of which is aquaresis, leading to a significant discontinuation rate. The strategies proposed to combat aquaresis include the use of thiazides or metformin and a reduction in the dietary osmotic load. Beyond the prescription of tolvaptan, which is limited to those with a rapid and progressive decline in kidney function, dietary interventions have been suggested to protect against disease progression. Moderate sodium restriction, moderate protein intake (up to 0.8 g/kg/day), avoidance of being overweight, and increased water consumption are recommended in ADPKD guidelines, though all with low-grade evidence. The aim of the present review is to critically summarize the evidence on the effect of dietary modification on ADPKD and to offer some strategies to mitigate the adverse aquaretic effects of tolvaptan

Renal replacement therapy in ADPKD patients : a 25-year survey based on the Catalan registry

Background: Some 7-10% of patients on replacement renal therapy (RRT) are receiving it because of autosomal dominant polycystic kidney disease (ADPKD). The age at initiation of RRT is expected to increase over time. Methods: Clinical data of 1,586 patients (7.9%) with ADPKD and 18,447 (92.1%) patients with other nephropathies were analysed from 1984 through 2009 (1984-1991, 1992-1999 and 2000-2009). Results: The age at initiation of RRT remained stable over the three periods in the ADPKD group (56.7 ± 10.9 (mean ± SD) vs 57.5 ± 12.1 vs 57.8 ± 13.3 years), whereas it increased significantly in the non-ADPKD group (from 54.8 ± 16.8 to 63.9 ± 16.3 years, p < 0.001). The ratio of males to females was higher for non-ADPKD than for ADPKD patients (1.6-1.8 vs 1.1-1.2). The prevalence of diabetes was significantly lower in the ADPKD group (6.76% vs 11.89%, p < 0.001), as were most of the co-morbidities studied, with the exception of hypertension. The survival rate of the ADPKD patients on RRT was higher than that of the non-ADPKD patients (p < 0.001). Conclusions: Over time neither changes in age nor alterations in male to female ratio have occurred among ADPKD patients who have started RRT, probably because of the impact of unmodifiable genetic factors in the absence of a specific treatment

Genetic kidney diseases as an underrecognized cause of chronic kidney disease : the key role of international registry reports

Inherited kidney diseases (IKDs) are among the leading causes of early-onset chronic kidney disease (CKD) and are responsible for at least 10-15% of cases of kidney replacement therapy (KRT) in adults. Paediatric nephrologists are very aware of the high prevalence of IKDs among their patients, but this is not the case for adult nephrologists. Recent publications have demonstrated that monogenic diseases account for a significant percentage of adult cases of CKD. A substantial number of these patients have received a non-specific/incorrect diagnosis or a diagnosis of CKD of unknown aetiology, which precludes correct treatment, follow-up and genetic counselling. There are a number of reasons why genetic kidney diseases are difficult to diagnose in adulthood: (i) adult nephrologists, in general, are not knowledgeable about IKDs; (ii) existence of atypical phenotypes; (iii) genetic testing is not universally available; (iv) family history is not always available or may be negative; (v) lack of knowledge of various genotype-phenotype relationships and (vi) conflicting interpretation of the pathogenicity of many sequence variants. Registries can contribute to visualize the burden of IKDs by regularly grouping all IKDs in their annual reports, as is done for glomerulonephritis or interstitial diseases, rather than reporting only cystic disease and hiding other IKDs under labels such as 'miscellaneous' or 'other'. Any effort to reduce the percentage of patients needing KRT with a diagnosis of 'nephropathy of unknown etiology' or an unspecific/incorrect diagnosis should be encouraged as a step towards precision nephrology. Genetic testing may be of value in this context but should not be used indiscriminately, but rather on the basis of a deep knowledge of IKDs

Hypertension in autosomal-dominant polycystic kidney disease (ADPKD)

Cardiovascular (CV) complications are the major cause of death in autosomal-dominant polycystic kidney disease (ADPKD) patients. Hypertension is common in these patients even before the onset of renal insufficiency. Blood pressure (BP) elevation is a key factor in patient outcome, mainly owing to the high prevalence of target organ damage together with a poor renal prognosis when BP is increased. Many factors have been implicated in the pathogenesis of hypertension, including the renin-angiotensin-aldosterone system (RAAS) stimulation. Polycystin deficiency may also contribute to hypertension because of its potential role in regulating the vascular tone. Early diagnosis and treatment of hypertension improve the CV and renal complications of this population. Ambulatory BP monitoring is recommended for prompt diagnosis of hypertension. CV risk assessment is mandatory. Even though a nonpharmacological approach should not be neglected, RAAS inhibitors are the cornerstone of hypertension treatment. Calcium channel blockers (CCBs) should be avoided unless resistant hypertension is present. The BP should be <140/90 mmHg in all ADPKD patients and a more intensive control (<135/85 mmHg) should be pursued as soon as microalbuminuria or left ventricle hypertrophy is present

Why do we keep ignoring sex in kidney disease?

Disparity; Pharmacokinetics; WomenDisparidad; Farmacocinética; MujeresDisparitat; Farmacocinètica; DonesThroughout the history of nephrology, little attention has been paid to the sex and gender differences in kidney disease. This lack of awareness prevents optimal diagnosis and management of kidney disease. In today's world of precision medicine, it is imperative to appreciate the differential factors regarding gender and kidney disease. This editorial summarizes the up-to-date literature regarding sex and gender differences in kidney disease and considers areas where knowledge is incomplete and where further research is needed. We address sex-specific effects on chronic kidney disease epidemiology; risks of dialysis underdosing and medication overdosing in women; unexplained loss of female sex advantage in life expectancy during dialysis, and impact of sex on diagnosis and management of genetic kidney disease. We also aim to highlight the impact of gender on kidney health and raise awareness of disparities that may be faced by women, and transgender and gender-diverse persons when a male-model approach is used by healthcare systems. By understanding the link between sex and kidney disease, kidney specialists can improve the care and outcomes of their patients. In addition, research on this topic can inform the development of targeted prevention and intervention strategies that address the specific needs and risk factors of different populations

Rare diseases, rare presentations : recognizing atypical inherited kidney disease phenotypes in the age of genomics

Altres ajuts: Fundación Renal Íñigo Álvarez de Toledo (FRIAT)A significant percentage of adults (10%) and children (20%) on renal replacement therapy have an inherited kidney disease (IKD). The new genomic era, ushered in by the next generation sequencing techniques, has contributed to the identification of new genes and facilitated the genetic diagnosis of the highly heterogeneous IKDs. Consequently, it has also allowed the reclassification of diseases and has broadened the phenotypic spectrum of many classical IKDs. Various genetic, epigenetic and environmental factors may explain 'atypical' phenotypes. In this article, we examine different mechanisms that may contribute to phenotypic variability and also provide case examples that illustrate them. The aim of the article is to raise awareness, among nephrologists and geneticists, of rare presentations that IKDs may show, to facilitate diagnosis

MYH9-related disease : it does exist, may be more frequent than you think and requires specific therapy

Altres ajuts: Sources of support: FIS/Fondos FEDER (REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. Salary support: ISCIII Rio Hortega to M.V.P.-G.In this issue of ckj, Tabibzadeh et al. report one of the largest series of patients with MYH9 mutations and kidney disease. The cardinal manifestation of MYH9-related disease is thrombocytopenia with giant platelets. The population frequency of pathogenic MYH9 mutations may be at least 1 in 20 000. The literature abounds in misdiagnosed cases treated for idiopathic thrombocytopenic purpura with immune suppressants and even splenectomy. Additional manifestations include neurosensorial deafness and proteinuric and hematuric progressive kidney disease (at some point, it was called Alport syndrome with macrothrombocytopenia), leucocyte inclusions, cataracts and liver enzyme abnormalities, resulting in different names for different manifestation combinations (MATINS, May-Hegglin anomaly, Fechtner, Epstein and Sebastian syndromes, and deafness AD 17). The penetrance and severity of kidney disease are very variable, which may obscure the autosomal dominant inheritance. A correct diagnosis will both preclude unnecessary and potentially dangerous therapeutic interventions and allow genetic counselling and adequate treatment. Morphological erythrocyte, granulocyte and platelet abnormalities may allow the future development of high-throughput screening techniques adapted to clinical peripheral blood flow cytometers