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Preview: Nephrology Dialysis Transplantation - current issue

Nephrology Dialysis Transplantation - current issue



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Pro: STOP immunosuppression in IgA nephropathy?

2016-11-02T00:05:41-07:00

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest a 6-month course of corticosteroids (CS) for IgA nephropathy (IgAN) patients with persistent proteinuria ≥1 g/day despite 3–6 months of renin–angiotensin system (RAS) blockers and glomerular filtration rate (GFR) >50 mL/min/1.73 m2. In December 2015, Rauen et al. (N Engl J Med 2015; 373: 2225–2236) published an article entitled ‘Intensive supportive care plus immunosuppression in IgA nephropathy’ (STOP-IgAN), which presented results from 379 IgAN patients from 32 nephrology centres in Germany. During a run-in phase of 6 months, patients received supportive care therapy including RAS blockers, dietary counselling, advice to stop smoking and avoid nephrotoxic drugs, and statins if required. After 6 months, 177 patients with proteinuria >0.75 g/day (non-responder patients) were randomized to either receive continued supportive care or supportive care plus immunosuppression (monotherapy with CS or combined therapy with three immunosuppressants). The authors reported that, after 36 months of observation, the addition of immunosuppressants to ongoing comprehensive supportive care was not beneficial in IgAN patients with moderate proteinuria and chronic kidney disease stages 1–3. These conclusions are questionable for several reasons: (i) studies on time-average proteinuria have shown that beneficial effects on renal survival, not evident after 36 months, emerge over the course of longer observation periods; (ii) supportive care in the STOP-IgAN study resulted in a small loss of renal function during the 36 months of observation (annual decrease in the estimated GFR of 1.6 mL/min/1.73 m2), but was unable to reduce proteinuria below 1 g/day; in contrast, 6 months of steroid therapy lowered proteinuria below 1 g/day; and (iii) the lack of any assessment of the histological data does not allow the importance of the morphological lesions on renal survival and therapy effects to be monitored. Further evaluation with a longer follow-up period is needed to obtain more reliable answers than the weak evidence of this study.




Opponent's comments

2016-11-02T00:05:41-07:00




Con: STOP immunosuppression in IgA nephropathy

2016-11-02T00:05:41-07:00

A comprehensive supportive therapy approach constitutes the mainstay treatment of IgA nephropathy (IgAN) patients. In our recent Supportive versus immunosuppressive Therapy Of Progressive IgA Nephropathy (STOP-IgAN) trial, we systematically selected for patients at high risk of a progressive disease course and evaluated the effect of immunosuppression, combined with supportive care, on renal end points in these patients. There was a higher rate of full clinical remission and transient proteinuria reduction in immunosuppressed patients. However, deterioration of renal function (i.e. number of patients with an estimated glomerular filtration rate (eGFR) decrease of at least 15 mL/min over the 3-year trial phase) was remarkably slow in both groups, compared with previous studies, and was not slowed further by adding immunosuppression to supportive care. Here, we address several concerns raised on the design and interpretation of our trial. In our randomized patients, we confirmed a lower baseline proteinuria to be predictive of clinical remission in IgAN. However, the observed transient drop in proteinuria in the immunosuppressed patients did not translate into an improved overall renal outcome in these patients. Although longer follow-up would be desirable, there was not even a trend for the eGFR course to diverge between our two treatment arms during the trial phase. Finally, it is important to note that we excluded specific infrequent patient groups during our run-in phase. Therefore, IgAN patients with a rapidly progressing course and those with persistent proteinuria >3.5 g/day would require further evaluation regarding potential benefits of immunosuppressive therapies.




Opponent's comments

2016-11-02T00:05:41-07:00




Moderator's view: Treatment of IgA nephropathy--getting comfortable with uncertainty

2016-11-02T00:05:41-07:00

A Polar Views discussion by Pozzi and Rauen et al. on the interpretation and clinical application of the recently published Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) trial has elucidated important points concerning potential strengths and weaknesses of this landmark randomized trial. This critical examination of the impact of steroid monotherapy or steroid plus an immunosuppressive (IS) agent compared with ‘supportive’ therapy with inhibitors of the renin–angiotensin system (RAS) has enhanced our appreciation of the importance of rigorous application of titrated RAS inhibition in high-risk patients with persistent proteinuria >0.75 g/day. At the same time, it brings a new level of uncertainty concerning the overall value and risk of steroid or steroid plus IS therapy in patients failing such ‘supportive' therapy. Some of these uncertainties revolve on issues of study design, such as the duration of follow-up, participant stratification (particularly underlying pathology) and dosing regimens. It is hoped that additional trials, better methods of patient selection, improved surrogate end points and safer regimens will lead to less uncertainty over the best treatment practices. On balance, the STOP-IgAN trial raises some key concerns about the merits of steroid alone or steroid plus IS therapy for selected subjects with IgAN, but it does not by itself close the door on the utility of steroid monotherapy in subjects with high-risk IgAN, even as it further degrades the value of steroid plus IS, at least with sequential cyclophosphamide and azathioprine.




Midkine, a heparin-binding growth factor, and its roles in atherogenesis and inflammatory kidney diseases

2016-11-02T00:05:41-07:00

The heparin-binding protein midkine is a potent growth factor with emerging roles in numerous inflammatory diseases. Beyond its characterization in embryogenesis and organ development, ample insights into its function have been collected from experimental disease models using knockout animals or knockdown intervention strategies. Here a comprehensive overview on midkine and its functions in atherogenesis and kidney diseases is provided. Molecular clues to key signalling pathways (Akt, ERK, HIF1α) and key events in atherosclerotic vessels link midkine expression with vascular smooth muscle proliferation and (neo)angiogenesis. In acute and chronic kidney diseases, midkine expression is upregulated in tubular as well as endothelial cells. Experimental disease models that mimic diabetic nephropathy and/or immunologic glomerular damage indicate dichotomous midkine activities, with cytoprotective as well as injurious effects. This review also pinpoints the commonalities of the disease models. An understanding of the underlying molecular events will be required in order to design a targeted intervention into cardiovascular or renal diseases as well as inflammatory processes.




Sex hormones in women with kidney disease

2016-11-02T00:05:41-07:00

Menstrual disorders, infertility and premature menopause are common but often underrecognized phenomena among women with chronic kidney disease. Hypothalamic, rather than ovarian dysfunction, may be the cause of the abnormal reproductive milieu, which can be at least partially reversed by kidney transplantation and increased intensity of hemodialysis. Endogenous sex hormones, and specifically estradiol, appear to be renoprotective in women, although the effects of exogenous estradiol (as an oral contraceptive and postmenopausal hormone therapy) on kidney function are more controversial. Treatment with postmenopausal hormone therapy in women with end-stage kidney disease (ESKD) has been associated with improved quality of life, bone health and markers of cardiovascular risk, as well as an increased risk of arteriovenous access thrombosis. The selective estrogen receptor modulator raloxifene has been associated with both a decreased fracture risk as well as renoprotection in women with kidney disease. Young women with ESKD are more likely to die from infection or develop malignancy, suggesting an immunomodulatory role of estrogen. Whether the premature menopause commonly observed in female patients with kidney disease results in increased cardiovascular morbidity and mortality is unknown, although preliminary studies have suggested a possible therapeutic role for manipulation of the sex hormone milieu to mitigate risk in this population. Large, prospective, randomized studies examining the role of sex hormones in women with kidney disease are required to address the question.




Should chronic metabolic acidosis be treated in older people with chronic kidney disease?

2016-11-02T00:05:41-07:00

Metabolic acidosis is common in advanced chronic kidney disease and has been associated with a range of physiological derangements of importance to the health of older people. These include associations with skeletal muscle weakness, cardiovascular risk factors, and bone and mineral disorders that may lead to fragility fractures. Although metabolic acidosis is associated with accelerated decline in kidney function, end-stage renal failure is a much less common outcome in older, frail patients than cardiovascular death. Correction of metabolic acidosis using bicarbonate therapy is commonly employed, but the existing evidence is insufficient to know whether such therapy is of net benefit to older people. Bicarbonate is bulky and awkward to take, may impose additional sodium load with effects on fluid retention and blood pressure, and may cause gastrointestinal side effects. Trial data to date suggest potential benefits of bicarbonate therapy on progression of renal disease and nutrition, but trials have not as yet been published examining the effect of bicarbonate therapy across a range of domains relevant to the health of older people. Fortunately, a number of trials are now underway that should allow us to ascertain whether bicarbonate therapy can improve physical function, quality of life, and vascular, bone and kidney health in older people, and hence decide whether any benefits seen outweigh adverse effects and additional treatment burden in this vulnerable group of patients.




Genetic testing in steroid-resistant nephrotic syndrome: when and how?

2016-11-02T00:05:41-07:00

Steroid-resistant nephrotic syndrome (SRNS) represents the second most frequent cause of chronic kidney disease in the first three decades of life. It manifests histologically as focal segmental glomerulosclerosis (FSGS) and carries a 33% risk of relapse in a renal transplant. No efficient treatment exists. Identification of single-gene (monogenic) causes of SRNS has moved the glomerular epithelial cell (podocyte) to the center of its pathogenesis. Recently, mutations in >30 recessive or dominant genes were identified as causing monogenic forms of SRNS, thereby revealing the encoded proteins as essential for glomerular function. These findings helped define protein interaction complexes and functional pathways that could be targeted for treatment of SRNS. Very recently, it was discovered that in the surprisingly high fraction of ~30% of all individuals who manifest with SRNS before 25 years of age, a causative mutation can be detected in one of the ~30 different SRNS-causing genes. These findings revealed that SRNS and FSGS are not single disease entities but rather are part of a spectrum of distinct diseases with an identifiable genetic etiology. Mutation analysis should be offered to all individuals who manifest with SRNS before the age of 25 years, because (i) it will provide the patient and families with an unequivocal cause-based diagnosis, (ii) it may uncover a form of SRNS that is amenable to treatment (e.g. coenzyme Q10), (iii) it may allow avoidance of a renal biopsy procedure, (iv) it will further unravel the puzzle of pathogenic pathways of SRNS and (v) it will permit personalized treatment options for SRNS, based on genetic causation in way of ‘precision medicine’.




Innate immunity in CKD-associated vascular diseases

2016-11-02T00:05:42-07:00

Chronic kidney disease (CKD) is associated with an increased risk for cardiovascular events. Therefore, the activation of the innate immune system plays an important role. In contrast to the adaptive immunity, unspecific recognition of conserved endogenous and exogenous structures by pattern recognition receptors (PRRs) represents a key feature of the innate immunity. Of these PRRs, Toll-like receptors (TLRs) as well as the inflammasome complex have been documented to be involved in the pathogenesis of cardiovascular diseases (CVDs). They are not only expressed in leukocytes but also in a variety of cell types such as endothelial cells or fibroblasts. While activation of TLRs on the cell surface leads to nuclear factor B-dependent expression of pro-inflammatory mediators, the inflammasome is a cytosolic multimeric protein complex, which cleaves cytokines such as interleukin-1β into their biologically active forms. Several endogenous ligands for these PRRs have been identified as contributing to the development of a CKD-specific pro-inflammatory microenvironment. Notably, activation of TLRs as well as the inflammasome is associated with arterial hypertension, formation of atherosclerotic vascular lesions and vascular calcification. However, detailed molecular mechanisms on how the innate immune system contributes to CKD-associated CVDs are as yet poorly understood. Currently, several agents modulating the activation of the innate immune system are the focus of cardiovascular research. Large clinical studies will provide further information on the therapeutic applicability of these substances to reduce cardiovascular morbidity and mortality in the general population. Further trials including patients with CKD will be necessary to assess their effects on CKD-associated CVD.







Resveratrol delays polycystic kidney disease progression through attenuation of nuclear factor {kappa}B-induced inflammation

2016-11-02T00:05:42-07:00

Background

Inflammation plays an important role in polycystic kidney disease (PKD). The current study aimed to examine the efficacy of the anti-inflammatory compound resveratrol in PKD and to investigate its underlying mechanism of action.

Methods

Male Han:SPRD (Cy/+) rats with PKD were treated with 200 mg/kg/day resveratrol or vehicle by gavage for 5 weeks. Human autosomal dominant (AD) PKD cells, three-dimensional (3D) Madin-Darby canine kidney cells and zebrafish were treated with various concentrations of resveratrol or the nuclear factor B (NF-B) inhibitor QNZ.

Results

Resveratrol treatment reduced blood urea nitrogen levels and creatinine levels by 20 and 24%, respectively, and decreased two-kidney/total body weight ratio by 15% and cyst volume density by 24% in Cy/+ rats. The proliferation index and the macrophage infiltration index were reduced by 40 and 43%, respectively, in resveratrol-treated cystic kidneys. Resveratrol reduced the levels of the pro-inflammatory factors monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and complement factor B (CFB) in Cy/+ rat kidneys in parallel with the decreased activity of NF-B (p50/p65). The activation of NF-B and its correlation with pro-inflammatory factor expression were confirmed in human ADPKD cells and kidney tissues. Resveratrol and QNZ inhibited the expression of MCP-1, TNF-α and CFB and reduced NF-B activity in ADPKD cells. Moreover, NF-B blockage minimized the inhibition of inflammatory factor production by resveratrol treatment. Furthermore, resveratrol or QNZ inhibited cyst formation in the 3D cyst and zebrafish models.

Conclusions

The NF-B signaling pathway is activated and partly responsible for inflammation in polycystic kidney tissues. Targeting inflammation through resveratrol could be a new strategy for PKD treatment in the future.




Impact of individual intravenous iron preparations on the differentiation of monocytes towards macrophages and dendritic cells

2016-11-02T00:05:42-07:00

Background

Treatment of iron deficiency with intravenous (i.v.) iron is a first-line strategy to improve anaemia of chronic kidney disease. Previous in vitro experiments demonstrated that different i.v. iron preparations inhibit differentiation of haematopoietic stem cells to monocytes, but their effect on monocyte differentiation to macrophages and mature dendritic cells (mDCs) has not been assessed. We investigated substance-specific effects of iron sucrose (IS), sodium ferric gluconate (SFG), ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) on monocytic differentiation to M1/M2 macrophages and mDCs.

Methods

Via flow cytometry and microRNA (miRNA) expression analysis, we morphologically and functionally characterized monocyte differentiation to M1/M2 macrophages and mDCs after monocyte stimulation with IS, SFG, FCM and IIM (0.133, 0.266 and 0.533 mg/mL, respectively). To assess potential clinical implications, we compared monocytic phagocytosis capacity in dialysis patients who received either 500 mg IS or IIM.

Results

Phenotypically, IS and SFG dysregulated the expression of macrophage (e.g. CD40, CD163) and mDC (e.g. CD1c, CD141) surface markers. Functionally, IS and SFG impaired macrophage phagocytosis capacity. Phenotypic and functional alterations were less pronounced with FCM, and virtually absent with IIM. In miRNA expression analysis of mDCs, IS dysregulated miRNAs such as miR-146b-5p and miR-155-5p, which are linked to Toll-like receptor and mitogen-activated protein kinase signalling pathways. In vivo, IS reduced monocytic phagocytosis capacity within 1 h after infusion, while IIM did not.

Conclusions

This study demonstrates that less stable i.v. iron preparations specifically affect monocyte differentiation towards macrophages and mDCs.




A simple care bundle for use in acute kidney injury: a propensity score-matched cohort study

2016-11-02T00:05:42-07:00

Background

Consensus guidelines for acute kidney injury (AKI) have recommended prompt treatment including attention to fluid balance, drug dosing and avoidance of nephrotoxins. These simple measures can be incorporated in a care bundle to facilitate early implementation. The objective of this study was to assess the effect of compliance with the AKI care bundle (AKI-CB) on in-hospital case–fatality and AKI progression.

Methods

In this larger, propensity score-matched cohort of multifactorial AKI, we examined the impact of compliance with an AKI-CB in 3717 consecutive episodes of AKI in 3518 patients between 1 August 2013 and 31 January 2015. Propensity score matching was performed to match 939 AKI events where the AKI-CB was completed with 1823 AKI events where AKI-CB was not completed.

Results

The AKI-CB was completed in 25.6% of patients within 24 h. The unadjusted case–fatality was higher when the AKI-CB was not completed versus when the AKI-CB was completed (24.4 versus 20.4%, P = 0.017). In multivariable analysis, AKI-CB completion within 24 h was associated with lower odds for in-hospital death [odds ratio (OR): 0.76; 95% confidence interval (95% CI): 0.62–0.92]. Increasing age (OR: 1.04; 95% CI: 1.03–1.05), hospital-acquired AKI (OR: 1.28; 95% CI: 1.04–1.58), AKI stage 2 (OR: 1.91; 95% CI: 1.53–2.39) and increasing Charlson's comorbidity index (CCI) [OR: 3.31 (95% CI: 2.37–4.64) for CCI of more than 5 compared with zero] had higher odds for death, whereas AKI during elective admission was associated with lower odds for death (OR: 0.29; 95% CI: 0.16–0.52). Progression to higher AKI stages was lower when the AKI-CB was completed (4.2 versus 6.7%, P = 0.02).

Conclusions

Compliance with an AKI-CB was associated with lower mortality and reduced progression of AKI to higher stages. The AKI-CB is simple and inexpensive, and could therefore be applied in all healthcare settings to improve outcomes.




Atherosclerotic renal artery stenosis is associated with elevated cell cycle arrest markers related to reduced renal blood flow and postcontrast hypoxia

2016-11-02T00:05:42-07:00

Background

Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow (RBF), ultimately leading to kidney hypoxia and inflammation. Insulin-like growth factor binding protein-7 (IGFBP-7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) are biomarkers of cell cycle arrest, often increased in ischemic conditions and predictive of acute kidney injury (AKI). This study sought to examine the relationships between renal vein levels of IGFBP-7, TIMP-2, reductions in RBF and postcontrast hypoxia as measured by blood oxygen level–dependent (BOLD) magnetic resonance imaging.

Methods

Renal vein levels of IGFBP-7 and TIMP-2 were obtained in an ARAS cohort (n= 29) scheduled for renal artery stenting and essential hypertensive (EH) healthy controls (n = 32). Cortical and medullary RBFs were measured by multidetector computed tomography (CT) immediately before renal artery stenting and 3 months later. BOLD imaging was performed before and 3 months after stenting in all patients, and a subgroup (N = 12) underwent repeat BOLD imaging 24 h after CT/stenting to examine postcontrast/procedure levels of hypoxia.

Results

Preintervention IGFBP-7 and TIMP-2 levels were elevated in ARAS compared with EH (18.5 ± 2.0 versus 15.7 ± 1.5 and 97.4 ± 23.1 versus 62.7 ± 9.2 ng/mL, respectively; P< 0.0001); baseline IGFBP-7 correlated inversely with hypoxia developing 24 h after contrast injection (r = –0.73, P< 0.0001) and with prestent cortical blood flow (r = –0.59, P= 0.004).

Conclusion

These data demonstrate elevated IGFBP-7 and TIMP-2 levels in ARAS as a function of the degree of reduced RBF. Elevated baseline IGFBP-7 levels were associated with protection against postimaging hypoxia, consistent with ‘ischemic preconditioning’. Despite contrast injection and stenting, AKI in these high-risk ARAS subjects with elevated IGFBP-7/TIMP-2 was rare and did not affect long-term kidney function.




Primary care physicians perceived barriers, facilitators and strategies to enhance conservative care for older adults with chronic kidney disease: a qualitative descriptive study

2016-11-02T00:05:42-07:00

Background

Although primary care physicians (PCPs) are often responsible for the routine care of older adults with chronic kidney disease (CKD), there is a paucity of evidence regarding their perspectives and practice of conservative (non-dialysis) care. We undertook a qualitative study to describe barriers, facilitators and strategies to enhance conservative, non-dialysis, CKD care by PCPs in the community.

Methods

Semi-structured telephone and face-to-face interviews were conducted with PCPs from Alberta, Canada. Participants were identified using a snowball sampling strategy and purposively sampled based on sex, age and rural/urban location of clinical practice. Eligible participants had managed at least one patient ≥75 years with Stage 5 CKD (estimated glomerular filtration rate <15 mL/min/1.73 m2, not on dialysis) in the prior year. Participant recruitment ceased when data saturation was reached. Transcripts were analyzed thematically using conventional content analysis.

Results

In total, 27 PCPs were interviewed. The majority were male (15/27), were aged 40–60 years (15/27) and had practiced in primary care for >20 years (14/27). Perceived barriers to conservative CKD care included: managing expectations of kidney failure for patients and their families; dealing with the complexity of medical management of patients requiring conservative care; and challenges associated with managing patients jointly with specialists. Factors that facilitated conservative CKD care included: establishing patient/family expectations early; preserving continuity of care; and utilizing a multidisciplinary team approach. Suggested strategies for improving conservative care included having: direct telephone access to clinicians familiar with conservative care; treatment decision aids for patients and their families; and a conservative care clinical pathway to guide management.

Conclusions

PCPs identified important barriers and facilitators to conservative care for their older patients with Stage 5 CKD. Further investigation of potential strategies that address barriers and enable facilitators is required to improve the quality of conservative care for older adults in the community.




Selective screening for distal renal tubular acidosis in recurrent kidney stone formers: initial experience and comparison of the simultaneous furosemide and fludrocortisone test with the short ammonium chloride test

2016-11-02T00:05:42-07:00

Background

Distal renal tubular acidosis (dRTA) is associated with renal stone disease, and it often needs to be considered and excluded in some recurrent calcium kidney stone formers (KSFs). However, a diagnosis of dRTA, especially when ‘incomplete’, can be missed and needs to be confirmed by a urinary acidification (UA) test. The gold standard reference test is still the short ammonium chloride (NH4Cl) test, but it is limited by gastrointestinal side effects and occasionally failure to ingest sufficient NH4Cl. For this reason, the furosemide plus fludrocortisone (F+F) test has been proposed as an easier and better-tolerated screening test. The aim of the present study was to assess the usefulness of the F+F test as a clinical screening tool for dRTA in a renal stone clinic.

Methods

We studied 124 patients retrospectively in whom incomplete dRTA was suspected: 71 had kidney stones only, 9 had nephrocalcinosis only and 44 had both. A total of 158 UA tests were performed: 124 F+F and 34 NH4Cl; both tests were completed in 34 patients.

Results

The mean age was 45.4 ± 15 years, and 49% of patients were male. The prevalence of complete and incomplete dRTAs was 7 and 13.7%, respectively. Of the 34 patients tested using both tests, 17 (50%) were abnormal and 4 (12%) were normal. Thirteen (39%) patients were abnormal by F+F, but normal by NH4Cl [sensitivity 100% (95% CI 80–100), specificity 24% (95% CI 7–50), positive predictive value 57% (95% CI 37–75), negative predictive value 100% (95% CI 40–100)].

Conclusions

The F+F test is characterized by an excellent sensitivity and negative predictive value, and the diagnosis of incomplete dRTA can be excluded reliably in a patient who acidifies their urine normally with this test. However, its lack of specificity is a drawback, and if there is any doubt, an abnormal F+F test may need to be confirmed by a follow-up NH4Cl test. Ideally, a prospective blinded study in unselected KSFs is needed to accurately assess the reliability of the F+F test in diagnosing, rather than excluding, dRTA.




Development and initial validation of prescribing quality indicators for patients with chronic kidney disease

2016-11-02T00:05:42-07:00

Background

Quality assessment is a key element for improving the quality of care. Currently, a comprehensive indicator set for measuring the quality of medication treatment in patients with chronic kidney disease (CKD) is lacking. Our aim was to develop and validate a set of prescribing quality indicators (PQIs) for CKD care, and to test the feasibility of applying this set in practice.

Methods

Potential indicators were based on clinical practice guidelines and evaluated using the RAND/UCLA Appropriateness Method. This is a structured process in which an expert panel assesses the validity of the indicators. Feasibility was tested in a Dutch primary care database including >4500 diabetes patients with CKD.

Results

An initial list of 22 PQIs was assessed by 12 experts. After changing 10 PQIs, adding 2 and rejecting 8, a final list of 16 indicators was accepted by the expert panel as valid. These PQIs focused on the treatment of hypertension, albuminuria, mineral and bone disorder, statin prescribing and possible unsafe medication. The indicators were successfully applied to measure treatment quality in the primary care database, but for some indicators the number of eligible patients was too small for reliable calculation. Results showed that there was room for improvement in the treatment quality of this population.

Conclusions

We developed a set of 16 PQIs for measuring the quality of treatment in CKD patients, which had sufficient content and face validity as well as operational feasibility. These PQIs can be used to point out priority areas for improvement.




Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial

2016-11-02T00:05:42-07:00

Background

The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical ‘albuminuria events’ may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable.

Methods

Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR).

Results

Baseline median (interquartile range) ACR was 3.2 (1.7–7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus –0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure –1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR.

Conclusions

In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.




Association between low birth weight and childhood-onset chronic kidney disease in Japan: a combined analysis of a nationwide survey for paediatric chronic kidney disease and the National Vital Statistics Report

2016-11-02T00:05:42-07:00

Background

Although numerous epidemiological surveys performed across several continents and ethnic groups have linked low birth weight (LBW) to increased risk of chronic kidney disease (CKD) in adulthood, the effects of birth weight and prematurity on development of CKD in childhood have not been clearly established.

Methods

Data on sex, LBW incidence and gestational age were compared between paediatric CKD cases and a control group. Paediatric CKD cases were obtained from a nationwide survey conducted by the Pediatric CKD Study Group in Japan. The population attributable fraction was calculated to evaluate the effects of reducing the prevalence of LBW infants (LBWI).

Results

Of 447 individuals born between 1993 and 2010 that fulfilled the eligibility criteria, birth weight data were obtained for 381 (85.2%) (231 boys and 150 girls), 106 (27.8%) of whom were LBWI. The proportion of LBWI in the general population during the same period was much lower (8.6%). Therefore, the risk ratio (RR) for paediatric CKD was significantly higher in the LBW group [crude RR: 4.10; 95% confidence interval (CI) 3.62–5.01], and the overall impact on paediatric CKD for removal of LBW amounted to 21.1% (95% CI 16.0–26.1%). In addition, 82 patients (21.9%) with paediatric CKD were born prematurely (before 37 weeks of gestation), and as with LBW, a strong correlation was observed between prematurity and CKD (RR: 4.73; 95% CI 3.91–5.73).

Conclusions

Both birth weight and gestational age were strongly associated with childhood-onset CKD in this study.




Lipoprotein(a) concentrations, apolipoprotein(a) isoforms and clinical endpoints in haemodialysis patients with type 2 diabetes mellitus: results from the 4D Study

2016-11-02T00:05:42-07:00

Background

High lipoprotein(a) [Lp(a)] concentrations and low molecular weight (LMW) apolipoprotein(a) [apo(a)] isoforms are associated with cardiovascular disease and mortality in the general population. We examined the association of both with all-cause mortality and cardiovascular endpoints in haemodialysis patients with diabetes mellitus.

Methods

This is a post hoc analysis of the prospective 4D Study (German Diabetes Dialysis Study) that evaluated atorvastatin compared with placebo in 1255 haemodialysis patients with type 2 diabetes mellitus (median follow-up 4 years). The association of natural logarithm-transformed Lp(a) concentrations (increment one unit) and apo(a) isoforms with outcomes was analysed by Cox proportional hazards regression. The influence of age (median 66 years) was evaluated by stratified survival analyses.

Results

The median baseline Lp(a) concentration was 11.5 mg/dL (IQR 5.0–41.8). A quarter of patients had at least one LMW apo(a) isoform. Increased Lp(a) concentrations were associated with all-cause mortality in the total group [hazard ratio (HR) 1.09 (95% CI 1.03–1.16), P = 0.004]. LMW apo(a) isoforms were only associated with all-cause mortality in patients ≤ 66 years [HR 1.38 (95% CI 1.05–1.80), P = 0.02]. The strongest association for Lp(a) concentrations and LMW apo(a) isoforms was found for death due to infection in patients ≤ 66 years [HR 1.39 (95% CI 1.14–1.71), P = 0.001; HR 2.17 (95% CI 1.26–3.75), P = 0.005]. Lp(a) concentrations were also associated with fatal stroke in patients ≤66 years of age [HR 1.54 (95% CI 1.05–2.24), P = 0.03]. Neither Lp(a) nor LMW apo(a) isoforms were associated with other atherosclerosis-related events.

Conclusions

High Lp(a) concentrations and LMW apo(a) isoforms are risk predictors for all-cause mortality and death due to infection in haemodialysis patients with diabetes mellitus. These associations are modified by age.




A novel COL4A1 frameshift mutation in familial kidney disease: the importance of the C-terminal NC1 domain of type IV collagen

2016-11-02T00:05:42-07:00

Background

Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts.

Methods

We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses.

Results

We identified a novel frameshift mutation, c.4611_4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the C-terminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested.

Conclusions

Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated with HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the α1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans.




Pregnancy in dialysis patients in the new millennium: a systematic review and meta-regression analysis correlating dialysis schedules and pregnancy outcomes

2016-11-02T00:05:42-07:00

Background

Advances have been made in the management of pregnancies in women receiving dialysis; however, single-centre studies and small numbers of cases have so far precluded a clear definition of the relationship between dialysis schedules and pregnancy outcomes. The aim of the present systematic review was to analyse the relationship between dialysis schedule and pregnancy outcomes in pregnancies in chronic dialysis in the new millennium.

Methods

Medline–PubMed, Embase and the Cochrane library were searched (1 January 2000–31 December 2014: MESH, Emtree, free terms on pregnancy and dialysis). A separate analysis was performed for case series (more than five cases) and case reports. Meta-regression was performed in case series dealing with the larger subset of haemodialysis (HD) patients; case reports were analysed separately [according to peritoneal dialysis (PD) versus HD; conception before or during dialysis].

Results

We obtained 190 full texts and 25 congress abstracts from 2048 references. We selected 101 full papers and 25 abstracts (36 series; 90 case reports), for a total of 681 pregnancies in 647 patients. In the case series (574 pregnancies in 543 patients), preterm delivery was extremely frequent (83%). Meta-regression analysis showed a relationship between hours of dialysis per week in HD and preterm delivery, and was significant for preterm deliveries (<37 gestational weeks: P = 0.044; r2 = 0.22) and for small for gestational age (SGA) (P = 0.017; r2 = 0.54). SGA was closely associated with the number of dialysis sessions per week (P = 0.003; r2 = 0.84). Case report analysis suggests a lower incidence of SGA on HD versus PD (31 versus 66.7%; P = 0.015). No evidence of an increased risk of congenital abnormality was found in the retrieved papers.

Conclusions

Data on pregnancy on dialysis are heterogeneous but rapidly accumulating; the main determinant of outcomes on HD is the dialysis schedule. The differences between PD and HD should be further analysed.




Solute solver 'what if module for modeling urea kinetics

2016-11-02T00:05:42-07:00

Background

The publicly available Solute Solver module allows calculation of a variety of two-pool urea kinetic measures of dialysis adequacy using pre- and postdialysis plasma urea and estimated dialyzer clearance or estimated urea distribution volumes as inputs. However, the existing program does not have a ‘what if’ module, which would estimate the plasma urea values as well as commonly used measures of hemodialysis adequacy for a patient with a given urea distribution volume and urea nitrogen generation rate dialyzed according to a particular dialysis schedule.

Methods

Conventional variable extracellular volume 2-pool urea kinetic equations were used.

Results

A javascript-HTML Web form was created that can be used on any personal computer equipped with internet browsing software, to compute commonly used Kt/V-based measures of hemodialysis adequacy for patients with differing amounts of residual kidney function and following a variety of treatment schedules.

Conclusions

The completed Web form calculator may be particularly useful in computing equivalent continuous clearances for incremental hemodialysis strategies.




Impact of the Banff 2013 classification on the diagnosis of suspicious versus conclusive late antibody-mediated rejection in allografts without acute dysfunction

2016-11-02T00:05:42-07:00

Background

The Banff classification is used worldwide to characterize pathological findings in renal allograft biopsies. During the 11th Banff meeting, relevant changes were introduced in the diagnostic criteria for Category 2 antibody-mediated rejection (ABMR). Here, we assess the effect of these changes on the diagnosis of late chronic ABMR.

Methods

Seventy-three indication renal graft biopsies (chronic dysfunction, proteinuria and/or the presence of de novo donor-specific antibodies) from 68 kidney transplant recipients initially classified following the Banff 2009 criteria were reviewed and reclassified as per the new Banff 2013 criteria.

Results

The diagnostic category changed in 18% of the study biopsies with Banff 2013. The reclassification mainly involved Category 2 cases, from which 23.5% of the biopsies from older patients with worse graft function were overlooked by Banff 2009. ABMR was ruled out in 13% of cases under the Banff 2009 criteria. A significant number of the study samples were conclusively diagnosed as ABMR (40% as per Banff 2009 and 74% as per Banff 2013; P = 0.006), because of the inclusion of microvascular inflammation and the acceptance of some ultrastructural diagnostic criteria. However, when following the criteria of the new classification, samples with histological signs of chronic ABMR, in which human leucocyte antigen donor-specific antibodies are not detected or ultrastructural studies are not performed, may be inadequately characterized.

Conclusions

The Banff 2013 classification helps in making a diagnosis of late ABMR, identifying cases, decreasing the percentage of suspected ABMR and making more conclusive diagnoses.




Epidemiology and management of hypertension in paediatric and young adult kidney transplant recipients in The Netherlands

2016-11-02T00:05:42-07:00

Introduction

Hypertension in kidney transplant recipients (KTRs) is a risk factor for cardiovascular mortality and graft loss. Data on the prevalence of hypertension and uncontrolled hypertension (uHT) in paediatric and young adult KTRs are scarce. Also, it is unknown whether ‘transition’ (the transfer from paediatric to adult care) influences control of hypertension. We assessed the prevalence of hypertension and uHT among Dutch paediatric and young adult KTRs and analysed the effects of transition. Additionally, we made an inventory of variations in treatment policies in Dutch transplant centres.

Methods

Cross-sectional and longitudinal national data from living KTRs ≤30 years of age (≥1-year post-transplant, eGFR >20 mL/min) were extracted from the ‘RICH Q’ database, which comprises information about all Dutch KTRs <19 years of age, and the Netherlands Organ Transplant Registry database for adult KTRs (≥18–30 years of age). We used both upper-limit blood pressure (BP) thresholds for treatment according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. uHT was defined as a BP above the threshold. A questionnaire on treatment policies was sent to paediatric and adult nephrologists at eight Dutch transplant centres.

Results

Hypertension and uHT were more prevalent in young adult KTRs (86.4 and 75.8%) than in paediatric KTRs (62.7 and 38.3%) according to the KDIGO definition. Time after transplantation was comparable between these groups. Longitudinal analysis showed no evidence of effect of transition on systolic BP or prevalence of uHT. Policies vary considerably between and within centres on the definition of hypertension, BP measurement and antihypertensive treatment.

Conclusion

Average BP in KTRs increases continuously with age between 6 and 30 years. Young adult KTRs have significantly more uHT than paediatric KTRs according to KDIGO guidelines. Transition does not influence the prevalence of uHT.




Pregnancy outcomes after kidney graft in Italy: are the changes over time the result of different therapies or of different policies? A nationwide survey (1978-2013)

2016-11-02T00:05:42-07:00

Background Kidney transplantation is the treatment of choice to restore fertility to women on renal replacement therapy. Over time, immunosuppressive, support therapies and approaches towards high-risk pregnancies have changed. The aim of this study was to analyse maternal–foetal outcomes in two cohorts of transplanted women who delivered a live-born baby in Italy in 1978–2013, dichotomized into delivery before and after January 2000. Methods A survey involving all the Italian transplant centres was carried out, gathering data on all pregnancies recorded since the start of activity at each centre; the estimated nationwide coverage was 75%. Data on cause of ESRD, dialysis, living/cadaveric transplantation, drug therapy, comorbidity, and the main maternal–foetal outcomes were recorded and reviewed. Data were compared with a low-risk cohort of pregnancies from two large Italian centres (2000–14; Torino and Cagliari Observational Study cohort). Results The database consists of 222 pregnancies with live-born babies after transplantation (83 before 2000 and 139 in 2000–13; 68 and 121 with baseline and birth data, respectively), and 1418 low-risk controls. The age of the patients significantly increased over time (1978–99: age 30.7 ± 3.7 versus 34.1 ± 3.7 in 2000–13; P < 0.001). Azathioprine, steroids and cyclosporine A were the main drugs employed in the first time period, while tacrolimus emerged in the second. The prevalence of early preterm babies increased from 13.4% in the first to 27.1% in the second period (P = 0.049), while late-preterm babies non-significantly decreased (38.8 versus 33.1%), thus leaving the prevalence of all preterm babies almost unchanged (52.2 and 60.2%; P = 0.372). Babies below the 5th percentile decreased over time (22.2 versus 9.6%; P = 0.036). In spite of high prematurity rates, no neonatal deaths occurred after 2000. The results in kidney transplant patients are significantly different from controls both considering all cases [preterm delivery: 57.3 versus 6.3%; early preterm: 22.2 versus 0.9%; small for gestational age (SGA): 14 versus 4.5%; P < 0.001] and considering only transplant patients with normal kidney function [preterm delivery: 35 versus 6.3%; early preterm: 10 versus 0.9%; SGA: 23.7 versus 4.5% (P < 0.001); risks increase across CKD stages]. Kidney function remained stable in most of the patients up to 6 months after delivery. Multiple regression analysis performed on the transplant cohort highlights a higher risk of preterm delivery in later CKD stages, an increase in preterm delivery and a decrease in SGA across periods. Conclusions Pregnancy after transplantation has a higher risk of adverse outcomes compared with the general population. Over time, the incidence of SGA babies decreased while the incidence of ‘early preterm’ babies increased. Although acknowledging the differences in therapy (cyclosporine versus tacrolimus) and in maternal age (significantly increased), the decrease in SGA and the increase in prematurity may be explained by an obstetric policy favouring earlier delivery against the risk of foetal growth restriction. [...]



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2016-11-02T00:05:42-07:00