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Anna Lindgren,1,2 Erik Fjellstedt,2,3 Anders Christensson2,3 1Department of Nephrology, Skåne University Hospital, Lund, Sweden; 2Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; 3Department of Nephrology, Skåne University Hospital, Malmö, SwedenCorrespondence: Anna LindgrenDepartment of Clinical Sciences Malmö, Lund University, SUS Malmö, Jan Waldenströms Gata 15, Malmö SE-205 02, SwedenTel +46-46-171698Fax +46-40-337052Email Anna.Lindgren@med.lu.sePurpose: Conventional hemodialysis (HD) treatment has an acceptable removal of small uremic molecules, but so-called “middle molecules” in the range of 0.5– 60 kDa are poorly cleared with HD compared to a native kidney, which may contribute to morbidity in the dialysis population. Hemodiafiltration (HDF) has a better removal of middle molecules compared to HD but is technically demanding and requires well-functioning dialysis access. The newly introduced medium cutoff (MCO) filters have been developed to enhance middle molecule clearance in HD-mode. The aim of this study was to compare reduction ratios (RRs) of molecules with different molecular weights (0.06– 150 kDa) during dialysis with MCO dialyzer (used in HD-mode) compared to online-hemodiafiltration (ol-HDF) treatment with a conventional high-flux dialyzer.Patients and Methods: This is a prospective controlled single-center cross-over study, including 16 patients in Malmö, Sweden. All patients had ongoing post-dilution ol-HDF treatment before the study. The study compared reduction ratios of small-, middle-, and large-sized molecules during a single 4h dialysis treatment with post-dilution ol-HDF (Polyflux 210H) to a 4h dialysis treatment with MCO dialyzer (Theranova 500) in HD-mode. Between treatments, the patients had a washout period of at least two weeks of their ordinary HDF treatment to reach their ordinary steady state.Results: ol-HDF had significantly higher RR for cystatin C (13 kDa), compared to MCO (RR 68.1 vs 65.8, p=0.003), during a 4h dialysis treatment (mean convection volume of 24.5 L for HDF, and mean Qb of 324 mL/min for HDF and 323 mL/min for MCO). There was no significant difference in the RR for other middle molecules, or for smaller or larger molecules.Conclusion: Overall, the RRs were comparable for ol-HDF and MCO-HD. There was a slightly higher RR of cystatin C (a small middle molecule) for HDF compared to MCO but no difference in other measured molecules.Keywords: chronic hemodialysis, dialysis, hemodiafiltration, hemodialysis, MCO, uremic toxins

Background: Glomerulonephritis clusters in families. However, infections are common inducers of glomerulonephritis and may also cluster in families. Studies of adoptees and their biological and adoptive parents may disentangle genetic from environmental causes of familial clustering. This is the first adoption study aimed to estimate the genetic contribution to the familial transmission of glomerulonephritis., Materials and Methods: We performed a family study for Swedish-born adoptees (born 1945-2000) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the Hospital Inpatient Register for the period 1964-2012 and the Hospital Outpatient Register for 2001-2012. Odds ratio (OR) for glomerulonephritis was determined for adoptees with a biological parent with glomerulonephritis compared with adoptees without an affected biological parent. Similarly, the OR for glomerulonephritis was also determined in adoptees with an affected adoptive parent compared with adoptees without an affected adoptive parent. Heritability was estimated to be twice the observed tetrachoric correlation among adoptees and biological parents, under the assumption that only additive genetic factors contribute to the similarity between biological parents and adoptees., Results: The OR for glomerulonephritis was 4.08 in adoptees (95% confidence interval [CI] 1.79-9.27, P-value = 0.001) of biological parents diagnosed with glomerulonephritis. The OR for glomerulonephritis was 1.67 in adoptees (95% CI 0.53-5.26, P-value = 0.380) of adoptive parents diagnosed with glomerulonephritis. The heritability was 48%., Conclusion: Family history of glomerulonephritis in a biological parent is a risk factor for glomerulonephritis. The present study indicates that genetic factors play an important role in the aetiology of glomerulonephritis., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Background/aims: The heritability of end-stage renal disease (ESRD) among adoptees has not been examined so far. By studying adoptees and their biological and adoptive parents, it is possible to differentiate between the genetic causes and environmental causes of familial aggregation. This nationwide study aimed to disentangle the genetic and shared environmental contribution to the familial transmission of ESRD., Methods: We performed a family study for Swedish-born adoptees (born between 1945 until 1995) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the National Patient Registry for the period 1964-2012. ESRD was defined as patients in active uremic care, that is, chronic dialysis or kidney transplantation. OR for ESRD was determined for adoptees with an affected biological parent with ESRD compared with adoptees without a biological parent with ESRD. The OR for ESRD was also calculated in adoptees with an adoptive parent with ESRD compared with adoptees with an adoptive parent without ESRD. Moreover, heritability for ESRD was estimated with Falconer's regression., Results: A total of 111 adoptees, 463 adoptive parents, and 397 biological parents were affected by ESRD. The OR for ESRD was 6.41 in adoptees (95% CI 2.96-13.89) of biological parents diagnosed with ESRD. The OR for ESRD was 2.40 in adoptees (95% CI 0.76-7.60) of adoptive parents diagnosed with ESRD. The heritability of ESRD was 59.5 ± 18.2%., Conclusion: The family history of ESRD in a biological parent is an important risk factor for ESRD. The high heritability indicates that genetic factors play an important role in understanding the etiology of ESRD., (© 2017 S. Karger AG, Basel.)

Objective: Familial risks of glomerulonephritis (acute, chronic and unspecified glomerulonephritis) have not been studied. This study aims to determine the familial risks of glomerulonephritis., Methods: Individuals born from1932 onwards diagnosed with glomerulonephritis (acute [n = 7011], chronic [n = 10,242] and unspecified glomerulonephritis [n = 5762]) were included. The familial risk (Standardized incidence ratio = SIR) was calculated for individuals whose parents/full-siblings were diagnosed with glomerulonephritis compared to those whose parents/full-siblings were not. The procedure was repeated for spouses. Familial concordant risk (same disease in proband and exposed relative) and discordant risk (different disease in proband and exposed relative) of glomerulonephritis were determined., Results: Familial concordant risks (parents/full-sibling history) were: SIR = 3.57 (95% confidence interval, 2.77-4.53) for acute glomerulonephritis, SIR = 3.84 (3.37-4.36) for chronic glomerulonephritis and SIR = 3.75 (2.85-4.83) for unspecified glomerulonephritis. High familial risks were observed if two or more relatives were affected; the SIR was 209.83 (150.51-284.87) in individuals with at least one affected parent as well as one full-sibling. The spouse risk was only moderately increased (SIR = 1.53, 1.33-1.75)., Conclusions: Family history of glomerulonephritis is a strong predictor for glomerulonephritis, and is a potentially useful tool in clinical risk assessment. Our data emphasize the contribution of familial factors to the glomerulonephritis burden in the community. Key Messages The familial risks (full-sibling/parent history) of glomerulonephritis (acute, chronic and unspecified glomerulonephritis) have not been determined previously. The familial risks of glomerulonephritis were increased among individuals with family history of acute, chronic or unspecified glomerulonephritis. The familial risks of glomerulonephritis were slightly increased among spouses indicating a modest non-genetic contribution. Very high familial risks were observed in multiplex families, i.e. with one or more affected first-degree relatives.

Background/aims: Chronic kidney disease (CKD) is common in the general population, may lead to end-stage renal disease, and is most frequently found among males. Familial clustering of kidney diseases has been observed. We aimed to study a potential association between the family history of myocardial infarction (MI) and renal dysfunction., Methods: 22,297 males and 10,828 females, aged 33-60 years, from a population-based cohort study were studied. Estimated glomerular filtration rate (eGFR) was assessed by the CKD-EPI creatinine equation. Every participant filled in a self-administered questionnaire including family history. Heredity for MI was defined as mother or father having had MI and/or died from MI, and/or brother or sister having had MI. Binary logistic regression and multiple linear regression were used in the analyses., Results: Multiple linear regression revealed a significantly increased risk of renal dysfunction in those with a positive heredity for MI (the whole cohort p = 0.01, males p = 0.000, females p = 0.169). Binary logistic regression showed that males with heredity for MI with a mean age of 43 years have a 2 times higher risk (p = 0.02) of belonging to the group with GFR <45 ml/min/1.73 m(2) compared to those without heredity. For the whole cohort the increased risk was 1.6 times (p = 0.07). There was no significant association for females (p = 0.88)., Conclusion: These findings demonstrate that a familial burden of MI is associated with renal dysfunction, in men, already in middle age. Genetic variants may underlie predisposition to CKD in those with heredity for MI.

Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine ( p<0.01) as well as of arginine, lysine and ornithine ( p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine ( p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.

Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas nontype I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.

Cystinuria is an autosomal recessive disorder that affects luminal transport of cystine and dibasic amino acids in the kidneys and the small intestine. Three subtypes of cystinuria can be defined biochemically, and the classical form (type I) has been associated with mutations in the amino acid transporter gene SLC3A1. The mutations detected in SLC3A1 tend to be population specific and have not been previously investigated in Sweden. We have screened the entire coding sequence and the intron/exon boundaries of the SLC3A1 gene in 53 cystinuria patients by means of single strand conformation polymorphism (SSCP) and DNA sequencing. We identified 12 novel mutations (a 2 bp deletion, one splice site mutation, and 10 missense mutations) and detected another three mutations that were previously reported. Five polymorphisms were also identified, four of which were formerly described. The most frequent mutation in this study was the previously reported M467T and it was also detected in the normal population with an allelic frequency of 0.5%. Thirty-seven patients were homozygous for mutations in the SLC3A1 gene and another seven were heterozygous which implies that other genes may be involved in cystinuria. Future investigation of the non-type I cystinuria gene SLC7A9 may complement our results but recent studies also suggest the presence of other potential disease genes., (Copyright 2001 Wiley-Liss, Inc.)

Based on previous observations of the diurnal variation of urinary cystine excretion, the use of separate day and night urine collections was proposed. To improve the medical treatment of patients with cystinuria, this strategy was performed to guide the fluid intake and the administration of SH compounds (tiopronin, D-penicillamine, and MESNA).Twenty-six patients (19 treated with SH compounds and seven with alkalinization and hydration only) were followed during two 3.5-year periods. During Period 1, 24-h urine was collected and during Period 2, separate day and night urine was collected. There were 56 episodes of high urinary cystine supersaturation (> 1,200 micromol/l) during Period 2, 47% of which would have evaded detection with 24-h urine analysis. In comparison with Period 1, the urinary cystine concentration was lower (P < 0.05), and the urinary volume was higher (P < 0.05) during Period 2. Patients treated with tiopronin had reduced cystine excretion (P < 0.05) and at the end of Period 2, an increased dose of tiopronin, reflecting a more aggressive treatment. Furthermore, a reduced number of stone episodes and need of active stone removal (P < 0.05) was noted in the whole group of patients. Analyses of separate day and night urine samples can be used advantageously to reveal episodes of high supersaturation with cystine not detected in 24-h urine samples. Such a procedure might be useful for optimizing the treatment of patients with cystinuria.

For many years, urine alkalinization has been one of the cornerstones in the treatment of homozygous cystinuria. Because of the relationship found between the excretion of urinary sodium and cystine, potassium citrate has emerged as the preferred sodium-free alkalizing agent. To evaluate the usefulness of potassium citrate for urine alkalization in cystinuric patients, sodium bicarbonate and potassium citrate were compared in 14 patients (10 on tiopronin treatment and four without treatment with sulfhydryl compounds). The study started with 1 week without the use of any alkalizing agents (Period 0) followed by 2 weeks with sodium bicarbonate (Period 1) and 2 weeks with potassium citrate (Period 2). Urinary pH, volume, excretion of sodium, potassium, citrate and free cystine, as well as the plasma potassium concentration, were recorded. Potassium citrate was shown to be effective as an alkalizing agent and, in this respect, not significantly different from sodium bicarbonate. Even though a normal diet was used, a significant increase in urinary sodium excretion was observed with sodium bicarbonate (Period 1). Urinary potassium and citrate excretion increased with potassium citrate (Period 2). A significant correlation was found between urinary sodium and cystine in the tio-pronin-treated patients. No significant differences in cystine excretion were recorded in Periods 0, 1 and 2. Plasma potassium was significantly higher during Period 2, but only one patient developed a mild hyperkalemia (5.0 mmol/l). The use of potassium citrate for urine alkalization in homozygous cystinuria is effective and can be recommended in the absence of severe renal impairment.