Measured and Estimated Glomerular Filtration Rate to Evaluate Rapid Progression and Changes over Time in Autosomal Polycystic Kidney Disease: Potential Impact on Therapeutic Decision-Making.

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (-3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.

Increased expression of SCARF genes favoring SARS-CoV-2 infection in key target organs in CKD.

Background: Chronic kidney disease (CKD), especially diabetic CKD, is the condition that most increases the risk of lethal coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the underlying molecular mechanisms are unclear. SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) regulate coronavirus cell entry and/or replication. We hypothesized that CKD may alter the expression of SCARF genes. Methods: A literature search identified 34 SCARF genes of which we selected 21 involved in interactions between SARS-CoV/SARS-CoV-2 and host cells, and assessed their mRNA expression in target tissues of COVID-19 (kidneys, lungs, aorta and heart) in mice with adenine-induced CKD. Results: Twenty genes were differentially expressed in at least one organ in mice with CKD. For 15 genes, the differential expression would be expected to favor SARS-CoV-2 infection and/or severity. Of these 15 genes, 13 were differentially expressed in the kidney and 8 were validated in human CKD kidney transcriptomics datasets, including those for the most common cause of CKD, diabetic nephropathy. Two genes reported to protect from SARS-CoV-2 were downregulated in at least two non-kidney target organs: Ifitm3 encoding interferon-induced transmembrane protein 3 (IFITM3) in lung and Ly6e encoding lymphocyte antigen 6 family member 6 (LY6E) in aorta. Conclusion: CKD, including diabetic CKD, is associated with the differential expression of multiple SCARF genes in target organs of COVID-19, some of which may sensitize to SARS-CoV-2 infection. This information may facilitate developing therapeutic strategies aimed at decreasing COVID-19 severity in patients with CKD.

Autosomal dominant polycystic kidney disease in young adults.

Background: The clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD) usually appear in adulthood, however pediatric series report a high morbidity. The objective of the study was to analyze the clinical characteristics of ADPKD in young adults. Methods: Family history, hypertension, albuminuria, estimated glomerular filtration rate (eGFR) and imaging tests were examined in 346 young adults (18-30 years old) out of 2521 patients in the Spanish ADPKD registry (REPQRAD). A literature review searched for reports on hypertension in series with more than 50 young (age <30 years) ADPKD patients. Results: The mean age of this young adult cohort was 25.24 (SD 3.72) years. The mean age at diagnosis of hypertension was 21.15 (SD 4.62) years, while in the overall REPQRAD population was aged 37.6 years. The prevalence of hypertension was 28.03% and increased with age (18-24 years, 16.8%; 25-30 years, 36.8%). Although prevalence was lower in women than in men, the age at onset of hypertension (21 years) was similar in both sexes. Mean eGFR was 108 (SD 21) mL/min/1.73 m2, 38.0% had liver cysts and 3.45% of those studied had intracranial aneurysms. In multivariate analyses, hematuria episodes and kidney length were independent predictors of hypertension (area under the curve 0.75). The prevalence of hypertension in 22 pediatric cohorts was 20%-40%, but no literature reports on hypertension in young ADPKD adults were found. Conclusions: Young adults present non-negligible ADPKD-related morbidity. This supports the need for a thorough assessment of young adults at risk of ADPKD that allows early diagnosis and treatment of hypertension.

The association of urinary epidermal growth factors with ADPKD disease severity and progression.

BACKGROUND: The epidermal growth factor receptor (EGFR) pathway is involved in kidney tissue repair and growth. Preclinical interventional data and scarce human data have suggested a role for this pathway in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD), while other data have suggested that its activation is causally linked to repair of damaged kidney tissue. We hypothesize that urinary EGFR ligands, as a reflection of EGFR activity, are associated with kidney function decline in ADPKD in the context of tissue repair following injury, and as the disease progresses as a sign of insufficient repair. METHODS: In the present study, we measured the EGFR ligands, EGF and heparin binding-EGF (HB-EGF), in 24-h urine samples of 301 ADPKD patients and 72 age- and sex-matched living kidney donors to dissect the role of the EGFR pathway in ADPKD. During a median follow-up of 2.5 years, the association of urinary EGFR ligand excretion with annual change in estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume in ADPKD patients was analyzed using mixed-models methods, and the expression of three closely related EGFR family receptors in ADPKD kidney tissue was investigated by immunohistochemistry. Additionally, the effect of reducing renal mass (after kidney donation), was assessed to investigate whether urinary EGF matches this reduction and thus reflects the amount of remaining healthy kidney tissue. RESULTS: At baseline, urinary HB-EGF did not differ between ADPKD patients and healthy controls (P = .6), whereas a lower urinary EGF excretion was observed in ADPKD patients [18.6 (11.8-27.8)] compared with healthy controls [51.0 (34.9-65.4) µg/24 h, P < .001]. Urinary EGF was positively associated with baseline eGFR (R = 0.54, P < .001) and a lower EGF was strongly associated with a more rapid GFR decline, even when adjusted for ADPKD severity markers (ß = 1.96, P < .001), whereas HB-EGF was not. Expression of the EGFR, but not other EGFR-related receptors, was observed in renal cysts but was absent in non-ADPKD kidney tissue. Finally, unilateral nephrectomy resulted in a decrease of 46.4 (-63.3 to -17.6) % in urinary EGF excretion, alongside a decrease of 35.2 ± 7.2% in eGFR and 36.8 ± 6.9% in measured GFR (mGFR), whereas maximal mGFR (measured after dopamine induced hyperperfusion) decreased by 46.1 ± 7.8% (all P < .001). CONCLUSIONS: Our data suggest that lower urinary EGF excretion may be a valuable novel predictor for kidney function decline in patients with ADPKD.

Sodium zirconium cyclosilicate and metabolic acidosis: Potential mechanisms and clinical consequences.

Metabolic acidosis is frequent in chronic kidney disease (CKD) and is associated with accelerated progression of CKD, hypercatabolism, bone disease, hyperkalemia, and mortality. Clinical guidelines recommend a target serum bicarbonate ≥ 22 mmol/L, but metabolic acidosis frequently remains undiagnosed and untreated. Sodium zirconium cyclosilicate (SZC) binds potassium in the gut and is approved to treat hyperkalemia. In clinical trials with a primary endpoint of serum potassium, SZC increased serum bicarbonate, thus treating CKD-associated metabolic acidosis. The increase in serum bicarbonate was larger in patients with more severe pre-existent metabolic acidosis, was associated to decreased serum urea and was maintained for over a year of SZC therapy. SZC also decreased serum urea and increased serum bicarbonate after switching from a potassium-binding resin in normokalemic individuals. Mechanistically, these findings are consistent with SZC binding the ammonium ion (NH4+) generated from urea by gut microbial urease, preventing its absorption and, thus, preventing the liver regeneration of urea and promoting the fecal excretion of H+. This mechanism of action may potentially result in benefits dependent on corrected metabolic acidosis (e.g., improved well-being, decreased catabolism, improved CKD mineral bone disorder, better control of serum phosphate, slower progression of CKD) and dependent on lower urea levels, such as decreased protein carbamylation. A roadmap is provided to guide research into the mechanisms and clinical consequences of the impact of SZC on serum bicarbonate and urate.

Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on kidney replacement therapy (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression.

Gain-of-function TLR7 and loss-of-function A20 gene variants identify a novel pathway for Mendelian lupus and lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic and inflammatory autoimmune disease of unknown origin that may cause kidney disease, i.e. lupus nephritis (LN). Within a wider trend towards an expanding field of genetic causes of kidney disease, two recent reports have emphasized the role of Mendelian autoimmune disorders in causing LN both in children and in young adults. Loss-of-function (LOF) variants of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and gain of function (GOF) variants of Toll-like receptor 7 (TLR7) cause SLE and LN, respectively. Interestingly, both genes regulate the same signaling route, as A20, the protein encoded by TNFAIP3, inhibits nuclear factor ĸB (NF-ĸB) activation while TLR7 promoted NF-ĸB activation. Moreover, TNFAIP3 and TLR7 variants are relatively frequent, potentially contributing to polygenic risk for LN. Finally, they both may be expressed by kidney cells, potentially contributing to the severity of kidney injury in persons who have already developed autoimmunity. The fact that both genes regulate the same pathway may lead to novel therapeutic approaches targeting the shared molecular pathway.

Who killed Bruce Lee? The hyponatraemia hypothesis.

Bruce Lee brought attention to martial arts in the Western world and popularized the quote 'Be water, my friend'. Lee died at the age of 32 years in Hong Kong on 20 July 1973, under mysterious circumstances. The cause of death is unknown, although numerous hypotheses have been proposed, from assassination by gangsters to the more recent suggestion in 2018 that he died from heatstroke. The necropsy showed cerebral oedema. A prior episode was diagnosed as cerebral oedema 2 months earlier. We now propose, based on an analysis of publicly available information, that the cause of death was cerebral oedema due to hyponatraemia. In other words, we propose that the kidney's inability to excrete excess water killed Bruce Lee. In this regard, Lee had multiple risk factors for hyponatraemia that may have included high chronic fluid intake, factors that acutely increase thirst (marijuana) and factors that decrease the ability of the kidneys to excrete water by either promoting secretion of antidiuretic hormone (ADH) or interfering with water excretion mechanisms in kidney tubules: prescription drugs (diuretics, non-steroidal anti-inflammatory drugs, opioids, antiepileptic drugs), alcohol, chronic low solute intake, a past history of acute kidney injury and exercise.

Documento de consenso de poliquistosis renal autosómica dominante del grupo de trabajo de enfermedades hereditarias de la Sociedad Española de Nefrología. Revisión 2020 / Consensus document on autosomal dominant polycystic kindey disease from the Spanish Working Group on Inherited Kindey Diseases. Review 2020

La poliquistosis renal autosómica dominante (PQRAD) es la causa más frecuente de nefropatía genética y representa entre el 6 y el 10% de los pacientes en terapia de reemplazo renal (TRR).Muy pocos ensayos prospectivos, aleatorizados o estudios clínicos abordan el diagnóstico y el tratamiento de este trastorno relativamente frecuente. No hay guías clínicas disponibles hasta la fecha. Este es un documento de consenso revisada de la versión anterior del 2014, que presenta las recomendaciones del Grupo de Trabajo Español de Enfermedades Renales Hereditarias, acordadas tras la búsqueda bibliográfica y discusiones. Los niveles de evidencia en su mayoría son C y D según el Centro de Medicina Basada en Evidencia (Universidad de Oxford). Las recomendaciones se relacionan, entre otros temas, con el uso de diagnóstico por imágenes y genético, el manejo de la hipertensión, el dolor, las infecciones y el sangrado quístico, la afectación extrarrenal, incluida la enfermedad poliquística hepática y los aneurismas craneales, el manejo de la enfermedad renal crónica y el TRR, así como el seguimiento de niños con PQRAD. Se proporcionan recomendaciones sobre terapias específicas para la PQRAD, así como la recomendación para evaluar la rápida progresión. (AU)

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6–10% of patients on kidney replacement therapy (KRT).Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression. (AU)

The mysterious death of the beer drinking champ: potential role for hyperacute water loading and acute hyponatremia.

Hyponatremia is acute when present for <48 h. Most cases of acute hyponatremia involve both excess free water intake and an at least partial urinary free water excretion defect. By contrast, hyperacute water intoxication may result from a large excess electrolyte-free water intake in such a short time that properly working urinary free water excretion mechanisms cannot cope. A hyperacute decrease in serum sodium may lead to death before medical intervention takes place. Well-documented cases have been published in the military medicine literature. In addition, news reports suggest the existence of cases of voluntary ingestion of excess free water by non-psychiatric individuals usually during 'dare' activities. Education of the public is required to prevent harm from these high-risk activities. Adequate training of emergency medical units may prevent lethal outcomes. Spanish media reported the case of a male who died following his triumph in a 20-min beer drinking contest. 'From a heart attack. Man dies after drinking six litres of beer in a contest' ran the news. We now review the physiology underlying hyperacute water intoxication and discuss the potential contribution of hyperacute water loading and acute hyponatremia to the demise of this patient.

Growth differentiation factor-15 preserves Klotho expression in acute kidney injury and kidney fibrosis.

Growth differentiation factor-15 (GDF15) is a member of the GDF subfamily with potential kidney protective functions. Here, we explored the impact of GDF15 on the expression of the kidney protective factor Klotho in models of acute kidney injury and kidney fibrosis in mice. GDF15 was the most upregulated GDF family gene in experimental toxic acute kidney injury and in kidney fibrosis transcriptomics. GDF15 function was explored in toxic acute kidney injury in genetically modified mice and following treatment with GDF15. Gdf15-deficient mice developed more severe toxic acute kidney injury (folic acid or cisplatin) while GDF15 overexpression or GDF15 administration were protective. Kidney expression of Klotho was more severely depressed in Gdf15-deficient mice and was preserved by GDF15 overexpression or GDF15 treatment. Moreover, increased plasma calcitriol levels inversely correlated with kidney Klotho across models with diverse levels of GDF15 availability. Kidney fibrosis induced by unilateral ureteral obstruction was more severe in Gdf15-deficient mice while GDF15 overexpression decreased kidney injury and preserved Klotho expression. GDF15 increased Klotho expression in vivo in healthy mice, in cultured tubular cells, and prevented Klotho downregulation by inflammatory factors in tubular cells by preventing transcription factor NF-ĸB activation. Thus, spontaneous increased kidney expression of endogenous GDF15 is not enough to prevent kidney injury, but further increments in GDF15 are kidney protecting and preserve expression of the kidney protective factor Klotho within the kidney in acute and chronic settings.

Autosomal dominant polycystic kidney disease: possibly the least silent cause of chronic kidney disease.

Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but it remains infrequently and inconsistently measured across countries, studies and trials. The study by El-Damanawi et al. integrated a network of ADPKD expert clinicians, pain specialists, researchers and patient representatives from the national UK PKD charity, with the aim of addressing the lack of validated ADPKD-specific pain assessment tools (APATs). The APAT designed by the authors included several pain measurement tools and was tested in ADPKD patients, although further validation through assessment in larger cohorts is needed. Establishing a standardized instrument for pain measurement will ensure that pain is measured and reported in a consistent way to inform decision-making and identify effective interventions aimed at managing pain and minimizing the impact pain has on patients with ADPKD. In this context, the APAT established by the authors is to be warmly welcomed.

Milestones of Precision Medicine: An Innovative, Multidisciplinary Overview.

Although the concept of precision medicine, in which healthcare is tailored to the molecular and clinical characteristics of each individual, is not new, its implementation in clinical practice has been heterogenous. In some medical specialties, precision medicine has gone from being just a promise to a reality that achieves better patient outcomes. This is a fact if we consider, for example, the great advances made in the genetic diagnosis and subsequent treatment of countless hereditary diseases, such as cystic fibrosis, which have improved the life expectancy of many of the affected children. In the field of oncology, the development of targeted therapies has prolonged the survival of patients with breast, lung, colorectal, melanoma, and hematological malignancies. In other disciplines, clinical milestones are perhaps less well known, but no less important. The current challenge is to expand and generalize the use of technologies that are central to precision medicine, such as massively parallel sequencing, to improve the management (prevention and treatment) of complex conditions such as cardiovascular, kidney, or autoimmune diseases. This process requires investment in specialized expertise, multidisciplinary collaboration, and the nationwide organization of genetic laboratories for diagnosis of specific diseases.

TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. METHODS: To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. RESULTS: Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-κB pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. CONCLUSIONS: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.

Phosphate, Microbiota and CKD.

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.

Urinary Growth Differentiation Factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease.

BACKGROUND: Growth Differentiation Factor-15 (GDF15) is a member of the TGF-ß superfamily. Increased serum GDF15 has been associated with increased risk of chronic kidney disease (CKD) progression. However, no prior studies have addressed the significance of urinary GDF15 in adult CKD. METHODS: We measured serum and urinary GDF15 in a prospective cohort of 84 patients who underwent kidney biopsy and assessed their association with outcomes (survival, kidney replacement therapy) during a follow-up of 29 ± 17 months. RESULTS: There was a statistically significant correlation between serum and urine GDF15 values. However, while serum GDF15 values increased with decreasing glomerular filtration rate, urinary GDF15 did not. Immunohistochemistry located kidney GDF15 expression mainly in tubular cells, and kidney GDF15 staining correlated with urinary GDF15 values. Urine GDF15 was significantly higher in patients with a histologic diagnosis of diabetic nephropathy than in diabetic patients without diabetic nephropathy. This was not the case for serum GDF15. Both serum and urine GDF15 were negatively associated with patient survival in multivariate models. However, when both urine and serum GDF15 were present in the model, lower urine GDF15 predicted patient survival [B coefficient (SEM) - 0.395 (0.182) p 0.03], and higher urine GDF15 predicted a composite of mortality or kidney replacement therapy [0.191 (0.06) p 0.002], while serum GDF15 was not predictive. Decision tree analysis yielded similar results. The area under the curve (AUC) of the receiver operating curve (ROC) for urine GDF15 as a predictor of mortality was 0.95 (95% CI 0.89-1.00, p < 0.001). CONCLUSIONS: In conclusion, urinary GDF15 is associated with kidney histology patterns, mortality and the need for renal replacement therapy (RRT) in CKD patients who underwent a kidney biopsy.

Urine proteomics for prediction of disease progression in patients with IgA nephropathy.

BACKGROUND: Risk of kidney function decline in immunoglobulin A (IgA) nephropathy (IgAN) is significant and may not be predicted by available clinical and histological tools. To serve this unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts rapid disease progression in IgAN, thus enabling a personalized risk stratification. METHODS: In this multicentre study, urine samples were collected in 209 patients with biopsy-proven IgAN. Progression was defined by tertiles of the annual change of estimated glomerular filtration rate (eGFR) during follow-up. Urine samples were analysed using capillary electrophoresis coupled mass spectrometry. The area under the receiver operating characteristic curve (AUC) was used to evaluate the risk prediction models. RESULTS: Of the 209 patients, 64% were male. Mean age was 42 years, mean eGFR was 63 mL/min/1.73 m2 and median proteinuria was 1.2 g/day. We identified 237 urine peptides showing significant difference in abundance according to the tertile of eGFR change. These included fragments of apolipoprotein C-III, alpha-1 antitrypsin, different collagens, fibrinogen alpha and beta, titin, haemoglobin subunits, sodium/potassium-transporting ATPase subunit gamma, uromodulin, mucin-2, fractalkine, polymeric Ig receptor and insulin. An algorithm based on these protein fragments (IgAN237) showed a significant added value for the prediction of IgAN progression [AUC 0.89; 95% confidence interval (CI) 0.83-0.95], as compared with the clinical parameters (age, gender, proteinuria, eGFR and mean arterial pressure) alone (0.72; 95% CI 0.64-0.81). CONCLUSIONS: A urinary peptide classifier predicts progressive loss of kidney function in patients with IgAN significantly better than clinical parameters alone.

Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease.

Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) and statins may not be protective in advanced CKD. The reasons for the limited efficacy of statins in advanced CKD are unclear, but statins may increase plasma levels of the highly atherogenic molecule lipoprotein(a), also termed Lp(a), as well as PCSK9 (protein convertase subtilisin/kexin type 9) levels. Lp(a) has also been linked to calcific aortic stenosis, which is common in CKD. Moreover, circulating Lp(a) levels increase in nephrotic syndrome with declining renal function and are highest in patients on peritoneal dialysis. Thus, the recent publication of the Phase 2 randomized controlled trial of pelacarsen [also termed AKCEA-APO(a)-LRx and TQJ230], a hepatocyte-directed antisense oligonucleotide targeting the LPA gene messenger RNA, in persons with CVD should be good news for nephrologists. Pelacarsen safely and dose-dependently decreased Lp(a) levels by 35-80% and a Phase 3 trial [Lp(a)HORIZON, NCT04023552] is planned to run from 2020 to 2024. Unfortunately, patients with estimated glomerular filtration rate <60 mL/min or urinary albumin:creatinine ratio >100 mg/g were excluded from Phase 2 trials and those with 'significant kidney disease' will be excluded from the Phase 3 trial. Optimized exclusion criteria for Lp(a)HORIZON would provide insights into the role of Lp(a) in CVD in CKD patients.