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The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol [1]. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Background Fumaric acid esters (FAEs) are used to treat chronic plaque psoriasis. Fumarate is a crucial component of the Krebs cycle and mitochondrial function. Proximal tubule cells have high energy demands and rely on aerobic respiration. Proximal tubular dysfunction can cause renal Fanconi syndrome and acute kidney injury. We sought to better understand the mechanism for this in the context of FAE therapy. Methods We describe a case series of 10 patients with FAE-associated Fanconi syndrome. Patients were diagnosed and managed at a tertiary renal tubular disorder clinic, with examination of serum and urine biochemistry. Five patients had a renal biopsy with examination of the specimens by electron microscopy. Results The median age was 36.5 years [interquartile range (IQR) 32.25–54.25]. The median dose of FAE was 720 mg/day (IQR 390–720). There was low molecular weight proteinuria: the median urinary retinol-binding protein (RBP) at presentation was 8385 μg/mL (IQR 2793–14 600) and the RBP:creatinine ratio was 710 (IQR 390–2415). All patients had hyperphosphaturia [median fractional excretion of phosphate 24.2% (IQR 20.8–26.9), normal range Conclusions We document for the first time that FAE-associated renal Fanconi syndrome is associated with mitochondrial damage visible on electron microscopy. This effect may be ameliorated by antagonism of the organic anion transporter with probenecid.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.

Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson’s marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.

BackgroundDistinguishing patients with the inherited salt-losing tubulopathies (SLT), Gitelman or Bartter syndrome (GS or BS) from wildtype (WT) patients who purge is difficult. We decided to identify clinical/biochemical characteristics which correctly classify SLT.Methods66 patients with possible SLT were recruited to a prospective observational cohort study at the UCL Renal Tubular Clinic (London). 31 datapoints were recorded on each patient. All patients were genotyped for pathogenic mutations in genes which cause SLT; 39 patients had pathogenic variants in genes causing SLT. We obtained similar datasets from cohorts in Taipei and Kobe; the combined dataset comprised 419 patients, 291 had genetically confirmed SLT. London and Taipei datasets were combined to train machine learning (ML) algorithms. These were then tested on the Kobe dataset to determine the best biochemical predictors of genetic confirmation of SLT.ResultsSingle biochemical variables (e.g. plasma renin) were significantly, but inconsistently different between SLT and WT, in the London and combined cohorts.A decision table algorithm using serum bicarbonate and urinary sodium excretion (FENa) achieved a classification accuracy of 74%. A simpler algorithm based on the FECl achieved a classification accuracy of 61%. This was superior to all of the single biochemical variables identified previously.

BACKGROUND Sodium intake is correlated with the development of hypertension. Guyton’s principals suggest that the 24-hour urinary sodium excretion reflects sodium ingestion over the same period. 24-hour urine collections are arduous to collect, so many centers use spot urinary measurements instead. We compared spot to matched 24-hour urinary electrolyte measurements. METHODS We examined 419 hypertensive patients from the UCL Complex Hypertension Clinic. 77 had matched and complete 24-hour and spot urinary and serum biochemistry to examine. We compared the spot and 24-hour urinary; sodium concentration, Na/Cr ratio, FENa, Kawasaki and Tanaka estimated sodium excretion as well as the potassium concentration, K/Cr ratio, Kawasaki and Tanaka potassium excretion. RESULTS Our cohort was 58% male and the median age was 41 years. The 24-hour and spot Na concentrations correlated moderately (r = 0.4633, P < 0.0001). The 24-hour and spot Na/creatinine ratios correlated weakly (r = 0.2625, P = 0.0194). The 24-hour and spot FENa results showed a weak negative correlation (r = −0.222, P = ns). The 24-hour sodium excretion and the Kawasaki-derived spot urine sodium excretion correlated moderately (r = 0.3118, P = 0.0052). All Bland–Altman analyses showed poor agreement. The 24-hour and spot potassium concentrations correlated very poorly (r = 0.1158, P = ns). The 24-hour and spot urinary K/creatinine ratios correlated weakly (r = 0.47, P ≤ 0.0001). 24-hour and Kawasaki and Tanaka estimated potassium excretions correlated much better (r = 0.58, P < 0.0001). CONCLUSIONS Spot urinary measurements of sodium give a very poor understanding of the natriuresis occurring over the same 24-hour period. The Kawasaki and Tanaka estimations of the 24-hour sodium excretion showed a much lower correlation than previously reported.

The proximal tubule is responsible for reclaiming water, phosphates and amino acids from the tubular filtrate. There are genetic defects in both phosphate and amino acid transporters leading to nephrolithiasis. This review also explores genetic defects in regulators of phosphate and calcium transport in this nephron segment that lead to stone formation.

Renal risk stratification in systemic immunoglobulin light-chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein 4 (uRBP), a low molecular weight tubular protein and highly sensitive marker of PTD, was prospectively measured in 285 newly diagnosed, untreated patients with systemic AL amyloidosis between August 2017 to August 2018. At diagnosis, the uRBP/creatinine ratio (uRBPCR) correlated with serum creatinine (r = 0·618, P 30 ml/min/1.73 m2 [HR 4·11, (95% CI 1·45-11·65); P = 0·008] and those who failed to achieve a deep haematological response to chemotherapy within 3 months of diagnosis [HR 6·72, (95% CI 1·83-24·74); P = 0·004], and also predicted renal progression [HR 1·91, (95% CI 1·18-3·07); P = 0·008]. Elevated uRBPCR indicates PTD and predicts renal outcomes independently of eGFR, uPCR and clonal response in systemic AL amyloidosis. The role of uRBPCR as a novel prognostic biomarker merits further study, particularly in monoclonal gammopathies of renal significance.

Renal involvement in primary Sjögren’s syndrome (pSS) was first described in the 1960s, with reports of acquired defects in tubular function, in the setting of lymphocytic tubulointerstitial inflammation. Renal involvement in pSS is common, but is frequently undiagnosed due to its covert nature. It may manifest either as epithelial disease causing tubulointerstitial nephritis, or as an immune-complex glomerulopathy. Tubulointerstitial inflammation leads to acquired defects in tubular function, which may occur at multiple nephron segments. Treatment protocols lack evidence from randomized trials, and involve immunosuppression targeting B- and T-cells, which mediate both interstitial and glomerular disease to varying extents. In this chapter, we review the prevalence of renal involvement in pSS and its clinical manifestations, likely pathogenesis, and treatment.

Síndrome de Bartter; Hipokalièmia heretada; Tubulopatia perdedora de sal Síndrome de Bartter; Hipopotasemia hereditaria; Tubulopatía perdedora de sal Bartter syndrome; Inherited hypokalemia; Salt-losing tubulopathy Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care.

The Gitelman and Bartter syndromes (GS and BS, respectively) are characterized by the constellation of hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemic hyperaldosteronism, low to normal blood pressure and juxtaglomerular apparatus hypertrophy. These are due to pathogenic variants in the genes that encode the thiazide-sensitive sodium–chloride cotransporter NCC (SLC12A3) in the distal convoluted tubule or transporters involved in sodium chloride reabsorption in the loop of Henle. ‘Pseudo-Bartter syndrome’ (PBS) is caused by extrarenal or acquired renal salt losses and shares the same plasma electrolyte profile and acid–base disturbances, making the distinction from the genetic forms very challenging. PBS has various etiologies, including diuretic and laxative abuse, self-induced vomiting and the side effects of some antimicrobials. Additionally, congenital chloride diarrhea, cystic fibrosis, Pendred syndrome and chloride-deficient diet can manifest as PBS. In this review we focus on factitious PBS secondary to diuretic abuse, laxative abuse or self-induced vomiting, whereby we point out some clinical and laboratory clues to help clinicians make the correct diagnosis.

Introduction Anion exchanger 1 (AE1) (SLC4A1 gene product) is a membrane protein expressed in both kidney and red blood cells (RBCs): it exchanges extracellular bicarbonate (HCO3–) for intracellular chloride (Cl–) and participates in acid−base homeostasis. AE1 mutations in kidney α-intercalated cells can lead to distal renal tubular acidosis (dRTA). In RBC, AE1 (known as band 3) is also implicated in membrane stability: deletions can cause South Asian ovalocytosis (SAO). Methods We retrospectively collected clinical and biological data from patients harboring dRTA due to a SLC4A1 mutation and analyzed HCO3– and Cl– transports (by stopped-flow spectrophotometry) and expression (by flow cytometry, fluorescence activated cell sorting, and Coomassie blue staining) in RBCs, as well as RBC membrane stability (ektacytometry). Results Fifteen patients were included. All experience nephrolithiasis and/or nephrocalcinosis, 2 had SAO and dRTA (dRTA SAO+), 13 dominant dRTA (dRTA SAO−). The latter did not exert specific RBC membrane anomalies. Both HCO3– and Cl– transports were lower in patients with dRTA SAO+ than in those with dRTA SAO− or controls. Using 3 different extracellular probes, we report a decreased expression (by 52%, P < 0.05) in dRTA SAO+ patients by fluorescence activated cell sorting, whereas total amount of protein was not affected. Conclusion Band 3 transport function and expression in RBCs from dRTA SAO− patients is normal. However, in SAO RBCs, impaired conformation of AE1/band 3 corresponds to an impaired function. Thus, the driver of acid−base defect during dominant dRTA is probably an impaired membrane expression., Graphical abstract

Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT). Forty-seven genotyped SLT patients (with Bartter, Gitelman or EAST Syndromes) are recruited. Clinical features of dysregulated immunity are recorded with a standardised questionnaire and immunological investigations of IL-17 responsiveness undertaken. The effects of altering extracellular ionic concentrations on immune responses are then assessed. Patients are hypokalaemic and hypomagnesaemic, with reduced interstitial sodium stores determined by 23Na-magnetic resonance imaging. SLT patients report increased mucosal infections and allergic disease compared to age-matched controls. Aligned with their clinical phenotype, SLT patients have an increased ratio of Th2:Th17 cells. SLT Th17 and Tc17 polarisation is reduced in vitro, yet STAT1 and STAT3 phosphorylation and calcium flux following T cell activation are unaffected. In control cells, the addition of extracellular sodium (+40 mM), potassium (+2 mM), or magnesium (+1 mM) reduces Th2:Th17 ratio and augments Th17 polarisation. Our results thus show that the ionic environment typical in SLT impairs IL-17 immunity, but the intracellular pathways that mediate salt-driven Th17 polarisation are intact and in vitro IL-17 responses can be reinvigorated by increasing extracellular sodium concentration. Whether better correction of extracellular ions can rescue the immunophenotype in vivo in SLT patients remains unknown., Salt levels in culture affect the polarisation of Th17 cells, which normally protect the host from fungal and bacterial infections. Here, the authors study patients with salt-losing tubulopathies (SLT) to find that, while Th17 immunity is dampened in SLT patients, their Th17-inducing signaling pathways are intact and can be reinvigorated by exogenous salt.

Salt intake as part of a western diet currently exceeds recommended limits, and the small amount found in the natural diet enjoyed by our Paleolithic ancestors. Excess salt is associated with the development of hypertension and cardiovascular disease, but other adverse effects of excess salt intake are beginning to be recognized, including the development of autoimmune and inflammatory disease. Over the last decade there has been an increasing body of evidence demonstrating that salt affects multiple components of both the innate and adaptive immune systems. In this review we outline the recent laboratory, animal and human data, highlighting the effect of salt on immunity, with a particular focus on the relevance to inflammatory kidney disease.

This article explores the effects of CKD and end-stage kidney disease on magnesium balance. In CKD, there is decreased glomerular filtration of magnesium. Decreased tubular reabsorption can compensate to a degree, but once CKD stage 4 is reached there is a tendency toward hypermagnesemia. In dialysis, magnesium balance is dependent on the constituents of the dialysate that the blood is exposed to. The concentration of dialysate magnesium is just one of the factors that need to be considered. During transplantation, there are particular effects of immunosuppressants that can affect the magnesium balance and need to be considered by the clinician.

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

International audience; Hereditary tubulopathies are rare diseases with unknown prevalence in adults. Often diagnosed in childhood, hereditary tubulopathies can nevertheless be evoked in adults. Precise diagnosis can be difficult or delayed due to insidious development of symptoms, comorbidities and polypharmacy. Here we evaluated the diagnostic value of a specific panel of known genes implicated in tubulopathies in adult patients and compared to our data obtained in children. To do this we analyzed 1033 non-related adult patients of which 744 had a clinical diagnosis of tubulopathy and 289 had a diagnosis of familial hypercalcemia with hypocalciuria recruited by three European reference centers. Three-quarters of our tubulopathies cohort included individuals with clinical suspicion of Gitelman syndrome, kidney hypophosphatemia and kidney tubular acidosis. We detected pathogenic variants in 26 different genes confirming a genetic diagnosis of tubulopathy in 29% of cases. In 16 cases (2.1%) the genetic testing changed the clinical diagnosis. The diagnosis of familial hypercalcemia with hypocalciuria was confirmed in 12% of cases. Thus, our work demonstrates the genetic origin of tubulopathies in one out of three adult patients, half of the rate observed in children. Hence, establishing a precise diagnosis is crucial for patients, in order to guide care, to survey and prevent chronic complications, and for genetic counselling. At the same time, this work enhances our understanding of complex phenotypes and enriches the database with the causal variants described.

Hypertension is the most important modifiable risk factor for death worldwide. Finding novel model mechanisms for blood-pressure (BP) regulation is an important goal and Mendelian syndromes have been very helpful in that regard. Pseudohypoparathyroidism type 1B (PHP1B) is an example in which affected individuals are invariably hypertensive for unknown reasons. We encountered a 48 year-old woman with severe, five-drug-resistant, hypertension. Her father and two aunts were also severely hypertensive. Her two young sons have developed drug-dependent hypertension before age 20 years. We measured 24-h ambulatory blood pressure and excluded all known secondary causes. However, the proband’s sons and their grandfather have the PHP1B phenotype, while our index patient and her two hypertensive aunts do not. The blood pressure phenotype in this pedigree suggested autosomal dominant inheritance. The Syntaxin 16 (STX16) gene encodes a snare protein and mutations cause PHP1B. Mutated STX16 causes methylation defects of Guanine Nucleotide Binding Protein, Alpha Stimulating (GNAS), a G protein regulator. Since GNAS is an imprinted gene, only inheritance from the mother causes the PHP1B phenotype. Subsequently, we sequenced STX16 in our kindred. We found a heterozygous deletion involving exons 5 and 6. We were also able to show complete loss of methylation in GNAS exon 1A. All hypertensive persons in our kindred have the STX16 mutation and are hypertensive. However, only those with maternal inheritance show the PHP1B phenotype. The methylation target region influenced by STX16 encompasses 7 genes. Our candidate is endothelin-3 encoded by EDN3 . Our data separate the hypertension-PHP1B phenotypes. We imply separate mechanisms are involved. We suggest new targets of blood pressure-raising relevance.

In physiological conditions, circulating iron can be filtered by the glomerulus and is almost completely reabsorbed by the tubular epithelium to prevent urinary iron wasting. Increased urinary iron concentrations have been associated with renal injury. However, it is not clear whether increased urinary iron concentrations in patients are the result of increased glomerular iron filtration and/or insufficient tubular iron reabsorption and if these processes contribute to renal injury. We measured plasma and urine iron parameters and urinary tubular injury markers in healthy human subjects ( n = 20), patients with systemic iron overload ( n = 20), and patients with renal tubular dysfunction ( n = 18). Urinary iron excretion parameters were increased in both patients with systemic iron overload and tubular dysfunction, whereas plasma iron parameters were only increased in patients with systemic iron overload. In patients with systemic iron overload, increased urinary iron levels were associated with elevated circulating iron, as indicated by transferrin saturation (TSAT), and increased body iron, as suggested by plasma ferritin concentrations. In patients with tubular dysfunction, enhanced urinary iron and transferrin excretion were associated with distal tubular injury as indicated by increased urinary glutathione S-transferase pi 1-1 (GSTP1-1) excretion. In systemic iron overload, elevated urinary iron and transferrin levels were associated with increased injury to proximal tubules, indicated by increased urinary kidney injury marker 1 (KIM-1) excretion. Our explorative study demonstrates that both glomerular filtration of elevated plasma iron levels and insufficient tubular iron reabsorption could increase urinary iron excretion and cause renal injury.

Urinary angiotensinogen excretion parallels albumin excretion, which is not the case for renin, while renin's precursor, prorenin, is undetectable in urine. We hypothesized that renin and prorenin, given their smaller size, are filtered through the glomerulus in larger amounts than albumin and angiotensinogen, and that differences in excretion rate are because of a difference in reabsorption in the proximal tubule. To address this, we determined the glomerular sieving coefficient of renin and prorenin and measured urinary renin/ prorenin 1) after inducing prorenin in Cyp1a1Ren2 rats and 2) in patients with Dent disease or Lowe syndrome, disorders characterized by defective proximal tubular reabsorption. Glomerular sieving coefficients followed molecular size ( renin> prorenin> albumin). The induction of prorenin in rats resulted in a > 300- fold increase in plasma prorenin and doubling of blood pressure but did not lead to the appearance of prorenin in urine. It did cause parallel rises in urinary renin and albumin, which losartan but not hydralazine prevented. Defective proximal tubular reabsorption increased urinary renin and albumin 20- to 40- fold, and allowed prorenin detection in urine, at similar to 50% of its levels in plasma. Taken together, these data indicate that circulating renin and prorenin are filtered into urine in larger amounts than albumin. All 3 proteins are subsequently reabsorbed in the proximal tubule. For prorenin, such reabsorption is similar to 100%. Minimal variation in tubular reabsorption ( in the order of a few %) is sufficient to explain why urinary renin and albumin excretion do not correlate. Urinary renin does not reflect prorenin that is converted to renin in tubular fluid.

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATMaggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

Gitelman syndrome is caused by inactivating mutations of the gene that encodes the renal sodium/chloride cotransporter (NCC; encoded by SLC12A3), resulting in hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Renal salt wasting commonly provokes mild hypotension. The paucity of previous kidney transplants from donors with known tubulopathies suggests that such conditions may be considered contraindications to donation. A 76-year-old man received a live unrelated kidney transplant from a donor with known Gitelman syndrome secondary to a pathogenic mutation of SLC12A3. Immediate graft function preceded the emergence of the Gitelman syndrome biochemical phenotype and blood pressure subsequently improved. The recipient developed unexpected hyponatremia. Potential causes are discussed, including the possibility that it paralleled the physiologic changes seen in the high-volume state of thiazide-induced hyponatremia. Transplanted kidneys are subject to nephrotoxicity from the use of calcineurin inhibitors. Acquired Gitelman syndrome may confer a potential long-term advantage to the recipient through both improved blood pressure control and protection against the calcineurin inhibitor–induced side-effect profile caused by NCC overactivation. Both the donor and recipient remain well. In conclusion, Gitelman syndrome need not preclude kidney donation and transference of the phenotype may have benefits for the recipient.

The clinical diagnosis of inherited renal tubulopathies can be challenging as they are rare and characterized by significant phenotypic variability. Advances in sequencing technologies facilitate the establishment of a molecular diagnosis. Therefore, we determined the diagnostic yield of a next generation sequencing panel assessing relevant disease genes in children followed through three national networks with a clinical diagnosis of a renal tubulopathy. DNA was amplified with a kit provided by the European Consortium for High-Throughput Research in Rare Kidney Diseases with nine multiplex PCR reactions. This kit produced 571 amplicons covering 37 genes associated with tubulopathies followed by massive parallel sequencing and bioinformatic interpretation. Identified mutations were confirmed by Sanger sequencing. Overall, 384 index patients and 16 siblings were assessed. Most common clinical diagnoses were 174 patients with Bartter/Gitelman syndrome and 76 with distal renal tubular acidosis. A total of 269 different variants were identified in 27 genes, of which 95 variants were considered likely, 136 definitely pathogenic and 100 had not been described at annotation. These mutations established a genetic diagnosis in 245 of the index patients. Genetic testing changed the clinical diagnosis in 16 cases and provided insights into the phenotypic spectrum of the respective disorders. Our results demonstrate a high diagnostic yield of genetic testing in children with a clinical diagnosis of a renal tubulopathy, consistent with a predominantly genetic etiology in known disease genes. Thus, genetic testing helped establish a definitive diagnosis in almost two-thirds of patients thereby informing prognosis, management and genetic counseling.

Background Sjogren´s syndrome (SS) is an autoimmune rheumatic disease that is characterised by decreased exocrine gland function and frequent ocular symptoms associated with eye dryness. Significantly, dry eyes can lead to corneal abrasions, infection, ulceration, chronic scarring and, in severe cases, perforation. The available conventional therapies have limited efficacy and there are no biologic therapies licensed for use in SS patients. Materials and methods A literature search of PubMed (MEDLINE) and EMBASE electronic data bases was performed covering the period from January 1994 to September 2014. Evidence was graded in categories I–IV and a treatment algorithm, comprising first line, second line and rescue therapies for ocular dryness associated with SS was proposed. It is based on the current evidence of efficacy of different therapies and explores their link with the pathogenesis of ocular dryness associated with SS. Results Recent developments in the understanding of the pathogenesis of SS provided evidence that the ocular dryness is associated with pathologic infiltration and dysfunction of the lacrimal glands and changes in the tear composition, together with abnormalities involving the neurosecreting circuits. There is good evidence for the efficacy of topical artificial tears, antiinflammatories and Cyclosporine, and oral Pilocarpine and Cevimeline in controlling the symptoms of ocular dryness associated with SS. Conclusions Conventional DMARDs are not particularly effective in addressing the symptoms of ocular dryness associated with SS, despite being commonly prescribed for other SS manifestations. Emerging evidence suggests that B cell and co-stimulatory targeted therapy may play a role in the future.

SS is a prevalent and underdiagnosed systemic disease that primarily affects epithelial tissue. It may affect renal function either as epithelial disease causing tubulointerstitial nephritis or as an immune complex-mediated glomerulopathy. These lesions may cause a variety of clinical features, both overt and occult. The epithelial disease is mediated by B and T cells, notably the Th17 subtype. We review the prevalence of renal SS, its presentation, likely pathogenesis and treatment.

Objective.To investigate the perception and willingness of rheumatology patients to participate in clinical trials. No previous similar studies are available.Methods.We conducted a cross-sectional survey of rheumatology patients using a questionnaire, which comprised 2 demographic questions, two 5-point Likert opinion questions, 19 true/false/unsure knowledge questions, and 1 open question addressing what would help the participant to gain a better understanding about clinical trials.Results.Eighty-five patients returned the questionnaires (response rate 84.1%). The mean number of correct answers to the 19 knowledge questions was 10.5 ± 2.87. Patients with higher versus lower levels of education had significantly higher knowledge scores (mean correct answers 59.4 ± 13.1 vs 39.8 ± 20.4, p = 0.013). They also expressed greater willingness to take part in research (87.5% vs 48.2%, p < 0.001). The patients who agreed to participate in research provided significantly more correct answers (59.4 ± 15.3% vs 47.7 ± 27.2%, p = 0.032). Poor disease control as the main reason to join a clinical trial correlated well with patients’ previous participation in research (r = 0.71; p < 0.05) and the lack of understanding of research principles (defined as less than 50% correct answers to the knowledge questions) correlated with the lack of willingness to participate in clinical trials (r = 0.72; p < 0.05).Conclusion.The results of our study revealed that patients lack information about clinical trials (the correct response rate was only slightly above 50%), and that they had a moderate willingness to take part in clinical trials. The need for educational programs about clinical research was highlighted by the participants to the survey.