Post-Transplant Bone Disease in Kidney Transplant Recipients: Diagnosis and Management.

Kidney transplantation is the preferred gold standard modality of treatment for kidney failure. Bone disease after kidney transplantation is highly prevalent in patients living with a kidney transplant and is associated with high rates of hip fractures. Fractures are associated with increased healthcare costs, morbidity and mortality. Post-transplant bone disease (PTBD) includes renal osteodystrophy, osteoporosis, osteonecrosis and bone fractures. PTBD is complex as it encompasses pre-existing chronic kidney disease-mineral bone disease and compounding factors after transplantation, including the use of immunosuppression and the development of de novo bone disease. After transplantation, the persistence of secondary and tertiary hyperparathyroidism, renal osteodystrophy, relative vitamin D deficiency and high levels of fibroblast growth factor-23 contribute to post-transplant bone disease. Risk assessment includes identifying both general risk factors and kidney-specific risk factors. Diagnosis is complex as the gold standard bone biopsy with double-tetracycline labelling to diagnose the PTBD subtype is not always readily available. Therefore, alternative diagnostic tools may be used to aid its diagnosis. Both non-pharmacological and pharmacological therapy can be employed to treat PTBD. In this review, we will discuss pathophysiology, risk assessment, diagnosis and management strategies to manage PTBD after kidney transplantation.

Burden of chronic kidney disease and rapid decline in renal function among adults attending a hospital-based diabetes center in Northern Europe.

INTRODUCTION: This study aimed to determine the prevalence of diabetic kidney disease (DKD) and rapid renal function decline and to identify indices associated with this decline among adults attending a diabetes center in Northern Europe. RESEARCH DESIGN AND METHODS: This is a retrospective cohort study of 4606 patients who attended a diabetes center in Ireland between June 2012 and December 2016. Definition/staging of chronic kidney disease used the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 classification based on data from the most recently attended appointment. Relevant longitudinal trends and variabilities were derived from serial records prior to index visit. Rapid renal function decline was defined based on per cent and absolute rates of estimated glomerular filtration rate (eGFR) change. Multiple linear regression was used to explore the relationships between explanatory variables and per cent eGFR change. RESULTS: 42.0% (total), 23.4% (type 1 diabetes), 47.9% (type 2 diabetes) and 32.6% (other diabetes) had DKD. Rapid decline based on per cent change was more frequent in type 2 than in type 1 diabetes (32.8% vs 14.0%, p<0.001). Indices independently associated with rapid eGFR decline included older age, greater number of antihypertensives, higher log-normalized urine albumin to creatinine ratio (LNuACR), serum alkaline phosphatase, thyroid stimulating hormone, variability in systolic blood pressure and variability in LNuACR, lower glycated hemoglobin, high-density lipoprotein cholesterol and diastolic blood pressure, and lack of ACE inhibitor/angiotensin receptor blocker prescription. CONCLUSIONS: DKD (using the KDIGO 2012 classification) and rapid eGFR decline were highly prevalent among adults attending a hospital-based diabetes clinic in a predominantly Caucasian Northern European country. The burden was greater for adults with type 2 diabetes. Expected as well as potentially novel clinical predictors were identified.

Pilot Randomized Controlled Trial of a Standard Versus a Modified Low-Phosphorus Diet in Hemodialysis Patients.

INTRODUCTION: The standard low-phosphorus diet restricts pulses, nuts, and whole grains and other high phosphorus foods to control hyperphosphatemia. We conducted a randomized controlled trial to evaluate the effectiveness, safety, and tolerability of the modified diet, which introduced some pulses and nuts, increased the use of whole grains, increased focus on the avoidance of phosphate additives, and introduced the prescription of low-biological-value protein such as bread. METHODS: We conducted a multicenter, pragmatic, parallel-arm, open-label, randomized controlled trial of modified versus standard diet in 74 adults on hemodialysis with hyperphosphatemia over 1 month. Biochemistry was assessed using monthly laboratory tests. Dietary intake was assessed using a 2-day record of weighed intake of food, and tolerability was assessed using a patient questionnaire. RESULTS: There was no significant difference in the change in serum phosphate between the standard and modified diets. Although total dietary phosphorus intake was similar, phytate-bound phosphorus, found in pulses, nuts, and whole grains, was significantly higher in the modified diet (P < 0.001). Dietary fiber intake was also significantly higher (P < 0.003), as was the percentage of patients reporting an increase in bowel movements while following the modified diet (P = 0.008). There was no significant difference in the change in serum potassium or in reported protein intake between the 2 diets. Both diets were similarly well tolerated. CONCLUSION: The modified low phosphorus diet was well tolerated and was associated with similar phosphate and potassium control but with a wider food choice and greater fiber intake than the standard diet.

Influence of Referral to a Combined Diabetology and Nephrology Clinic on Renal Functional Trends and Metabolic Parameters in Adults With Diabetic Kidney Disease.

OBJECTIVE: To examine the impact of a diabetes renal clinic (DRC) on renal functional and metabolic indices in adults who have diabetes mellitus (DM) and chronic kidney disease (CKD). PATIENTS AND METHODS: All patients evaluated at a DRC in a single tertiary referral center from January 1, 2008, to December 31, 2012, were identified. Serial renal and metabolic indices from January 1, 2004, to December 31, 2014, were recorded, and trends over time were analyzed by linear mixed-effects models. RESULTS: A total of 200 patients who had DM and CKD were identified and subdivided into 3 categories based on presumptive CKD etiology: 43 (21.5%) with type 1 DM (T1D) only, 127 (63.5%) with type 2 DM (T2D) only, and 30 (15.0%) with DM and an additional CKD etiology. Average annual absolute (mL/min per body surface area per year) and percentage (%/year) changes, respectively, in Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate before vs after first DRC attendance were: -1.59 vs -3.10 (P=.31) and -1.22 vs -9.39 (P=.06) for T1D; -5.64 vs -3.07 (P=.004) and -10.88 vs -9.94 (P=.70) for T2D; and -6.50 vs +0.91 (P<.001) and -13.28 vs -2.29 (P=.001) for DM with an additional CKD etiology. Glycemic control worsened in those who had T2D, whereas trends in total cholesterol levels improved in those who had T1D. CONCLUSION: After first DRC attendance, the absolute rate of estimated glomerular filtration rate decline remained similar for those who had T1D, but it slowed for those who had T2D or DM with additional CKD etiology. Thus, benefits of combined diabetology and nephrology consultation may vary for different diabetic subpopulations.

What should the characteristics and attributes of an accredited nephrology training programme be? Looking for high standards.

The Renal Section of the European Union of Medical Specialists is working towards harmonization and optimization of nephrology training across Europe and its Mediterranean borders. In addition to the need for harmonization of the heterogeneous time dedicated to training, it is necessary to ensure that the learning environment is of a sufficiently high standard to develop skilled specialists. Thus, there is a need to review the core educational infrastructure and resources that should be provided to trainees in order to be considered centres of excellence for nephrology training. This review addresses most of the characteristics and attributes that constitute a high-calibre training centre of excellence, considering that a training centre might not represent a single institution, but a network of institutions that provide a coordinated and complete curriculum to the trainee. The training institution should provide, apart from the classical current nephrological facilities (clinical nephrology, haemodialysis, peritoneal dialysis and transplantation), a number of other complementary facilities, including immunology, nephropathology-with a dedicated and expert renal pathologist-all the specialities of general medicine and general surgery and, in particular, vascular surgery, radiology and interventional radiology specialist services (renal biopsy, renal ultrasound and permanent vascular access) and intensive care unit. In addition to clinical training, a training centre of excellence should offer research facilities to allow trainees the opportunity to be involved in epidemiological, clinical, translational or basic scientific research. The training centres should ideally hold a certification of training accreditation. If the European and its Mediterranean border countries wish to guarantee a high standard of training in nephrology, their national health services need to recognize their responsibility towards the importance of doctor training, providing enough time for educational activities and investing in the resources required for high-standard specialist training.

Blood pressure measurement in peritoneal dialysis: which method is best?

BACKGROUND: The optimal approach to monitoring blood pressure (BP) in the peritoneal dialysis (PD) population is unclear. Ambulatory BP monitoring reliably predicts prognosis, but can be inconvenient. The accuracy of home BP monitoring in this population is unproven. The automated BpTRU device (BpTRU Medical Devices, Coquitlam, BC, Canada), which provides an average of up to 6 successive in-office BP measurements, has not been studied in this patient group. METHODS: We studied 17 patients (average age: 54 ± 12 years; 12 men, 5 women; 94% on automated PD) attending a single center. All patients underwent office, home, BpTRU, and ambulatory BP measurement. The reference standard for analysis was daytime ambulatory BP. Correlation between the referent method and each comparator method was determined (Pearson correlation coefficient), and Bland-Altman scatter plots depicting the differences in the BP measurements were constructed. RESULTS: Mean office BP (126.4 ± 16.9/78.8 ± 11.6 mmHg) and BpTRU BP (123.8 ± 13.7/80.7 ± 11.1 mmHg) closely approximated mean daytime ambulatory BP (129.3 ± 14.8/78.2 ± 7.9 mmHg). Mean home BP (143.8 ± 15.0/89.9 ± 28.1 mmHg) significantly overestimated mean daytime systolic BP by 14.2 mmHg (95% confidence interval: 4.3 mmHg to 24.1 mmHg; p = 0.008). Bland-Altman plots demonstrated poorest agreement between home BP and daytime ambulatory BP. No patient had "white-coat hypertension," and only 1 patient had false-resistant hypertension. Most patients showed abnormal nocturnal dipping patterns (non-dipping: n = 11; reverse-dipping: n = 5; normal dipping: n = 1). CONCLUSIONS: We report a novel finding that BP measurement using the BpTRU device is more accurate than home BP measurement in a PD population. Potential explanations for this observation include poor home BP measurement technique, use of poorly validated home BP measurement devices, or a reduced prevalence of white-coat effect among PD patients. Our study also confirms that, in the PD population, BP measurements vary considerably with patient location, time of day, and measurement technique.

Updated programme for harmonization of training in nephrology in the European Union.

In 1996, the first European Union of Medical Specialists (UEMS) minimum standards programme in nephrology was published. Since then, medical practice in an expanded European Union (EU) has evolved significantly. These changes have prompted the UEMS Nephrology Section to update and review the programme on harmonization of nephrology training in the EU. Although directives of the EU indicate that a specialist from one EU member state must be recognized in all EU member states, the current practical implications of these directives are limited due to the important existing differences in the EU member states' training programmes. Although not exhaustive, the present document aims to profile a minimum common framework of nephrology training in the EU for both trainers and higher-specialty trainees. The nephrology programme addresses several topics, among them enrolment requirements, duration and organization of the training and a detailed description of the knowledge, competences, practical skills and attitudes necessary to become a specialist in nephrology. Whilst the development of a standard, pan-EU nephrology training programme is not realistic, the UEMS Nephrology section believes that this does not diminish the need for improving harmonization of training in the EU.

Sudden cardiac death in dialysis: do current guidelines for implantable cardioverter defibrillator therapy apply to patients with end-stage kidney disease?

Arrhythmic mechanisms account for one in four deaths in end-stage kidney disease. Large-scale randomized controlled trials have demonstrated a mortality benefit from implantable cardioverter defibrillator therapy in carefully selected patient groups at high risk for sudden cardiac death. Unfortunately, patients with end-stage kidney disease were systematically excluded from these trials. Consequently, the applicability of American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines on implantable cardioverter defibrillator therapy to dialysis patients remains uncertain. Observational data suggest that secondary preventative implantable cardioverter defibrillator therapy following resuscitated cardiac arrest prolongs the lives of dialysis patients. This intervention may also offer a survival advantage as a primary preventative strategy in end-stage kidney disease. However, competing risk from co-morbidity can negate any perceived benefit. Device-related complications also negatively impact outcome. The recommendation that primary preventative device implantation be reserved for patients with severely impaired left ventricular function may be excessively restrictive in this high-risk population. Trials of implantable cardioverter defibrillator therapy that include dialysis patients are required to validate existing device eligibility criteria in this unique population. Novel indications for this intervention in dialysis patients should also be identified.

In-office assessment of blood pressure in chronic kidney disease: usual measurement versus automated BpTRU measurement.

OBJECTIVES: The automated BpTRU device has been shown to improve the accuracy of in-office blood pressure assessment in hypertensive populations. We aimed to determine whether this was also true for patients with chronic kidney disease. MATERIALS AND METHODS: We recorded the blood pressure of 80 hypertensive outpatients with chronic kidney disease by usual automated measurement and BpTRU automated measurement. We established whether there were any statistically significant differences in the absolute blood pressure values measured by either method and whether these differences had any impact on the assessment of blood pressure control. RESULTS: Systolic and diastolic blood pressures were significantly lower by BpTRU measurement than by usual measurement, by 10.1±12.2 mmHg (95% confidence interval: 7.4-12.8 mmHg, P<0.001) and 2.8±10.6 mmHg (95% confidence interval: 0.4-5.1 mmHg, P=0.02), respectively. Significantly, more patients achieved their blood pressure target of 130/80 mmHg or less by BpTRU measurement than by usual measurement (72.5 vs. 48.8% for systolic blood pressure, P<0.001; 68.8 vs. 61.3% for diastolic blood pressure, P=0.02). Systolic blood pressures remained significantly lower by BpTRU measurement than by usual measurement in all predefined study subgroups (estimated glomerular filtration rate <30 vs ≥30 ml/min/1.73m; transplant vs. nontransplant). We detected more hypotension by BpTRU measurement than by usual measurement. CONCLUSION: Our study suggests that the BpTRU device can negate white coat effect in patients with chronic kidney disease. The use of this device in routine clinical practice could improve the overall accuracy of in-office blood pressure assessment in this high-risk population, minimizing the potential for undertreatment and overtreatment of hypertension.

Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a frequent complication in patients with diabetes mellitus. To find improved intervention strategies in this disease, it is necessary to investigate the molecular mechanisms involved. To obtain more insight into processes that lead to DN, messenger RNA expression profiles of diabetic glomeruli and glomeruli from healthy individuals were compared. METHODS: Two morphologically normal kidneys and 2 kidneys from patients with DN were used for the study. Glomerular RNA was hybridized in duplicate on Human Genome U95Av2 Arrays (Affymetrix, Santa Clara, CA). Several transcripts were tested further in independent patient groups and at the protein level by immunohistochemistry. RESULTS: Ninety-six genes were upregulated in diabetic glomeruli, whereas 519 genes were downregulated. The list of overexpressed genes in DN includes aquaporin 1, calpain 3, hyaluronoglucosidase, and platelet/endothelial cell adhesion molecule. The list of downregulated genes includes bone morphogenetic protein 2, vascular endothelial growth factor (VEGF), fibroblast growth factor 1, insulin-like growth factor binding protein 2, and nephrin. A decrease in VEGF and nephrin could be validated at the protein level and also at the RNA level in renal biopsy specimens from 5 additional patients with diabetes. CONCLUSION: Results of oligonucleotide microarray analyses on control and diabetic glomeruli are presented and discussed in their relation to vascular damage, mesangial matrix expansion, proliferation, and proteinuria. Our findings suggest that progression of DN might result from diminished tissue repair capability.

DNA oligonucleotide microarray technology identifies fisp-12 among other potential fibrogenic genes following murine unilateral ureteral obstruction (UUO): modulation during epithelial-mesenchymal transition.

BACKGROUND: Tubulointerstitial inflammation and fibrosis are pathologic hallmarks of end-stage renal disease (ESRD). Here we have used DNA microarray technology to monitor the transcriptomic responses to murine unilateral ureteral obstruction (UUO) with a view to identifying molecular modulators of tubulointerstitial fibrosis. METHODS: Using Affymetrix Mu74Av2 microarrays, gene expression 4 and 10 days postobstruction was investigated relative to control contralateral kidneys. Candidate profibrogenic genes were further investigated in epithelial cells undergoing epithelial to mesenchymal transition (EMT) in vitro. RESULTS: mRNA levels for 1091 gene/EST sequences, of a total of 12,488 displayed on the microarray, were altered twofold or greater by days 4 and 10 postobstruction compared to contralateral control kidneys. Genes were categorised into functional groups, including modulators of cytoskeletal and extracellular matrix metabolism, cell growth, signalling, and transcription/translational events. Among the potentially profibrogenic genes, whose mRNA levels were increased after UUO, were fibroblast-inducible secreted protein (fisp-12), the murine homologue of connective tissue growth factor (CTGF), collagen XVIIIalpha1, secreted protein acidic and rich in cysteine (SPARC), and src-suppressed C-kinase substrate (SSeCKS). A sustained increase in fisp-12 mRNA level was observed during EMT induced by transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF). CONCLUSION: Altered gene expression in murine UUO has been demonstrated. Increased expression of fisp-12, SPARC, and SSeCKS has been shown in response to TGF-beta1 treatment and during EMT, suggesting that these genes may offer potential therapeutic targets against tubulointerstitial fibrosis.

Gremlin: an example of the re-emergence of developmental programmes in diabetic nephropathy.

The past two decades have yielded major advances in our understanding of the pathogenetic mechanisms that cause diabetic nephropathy. Of particular interest is the emerging paradigm of the recapitulation of developmental programmes within the diabetic kidney. Recently we have used the complementary techniques of suppression subtractive hybridization and Affymetrix GeneChips to assess changes in gene expression in human mesangial cells subjected to high ambient glucose concentrations and cyclic mechanical strain in vitro, the latter being models of hyperglycaemia and glomerular hypertension, respectively. In this review, we will focus on the potential role of one such differentially expressed gene, namely gremlin, in the pathogenesis of diabetic nephropathy. In the context of developmental nephrology, gremlin warrants special mention. Gremlin is a 184 amino acid protein and a member of the cysteine knot superfamily. The protein is highly conserved during evolution and is present in soluble and cell-associated forms. It belongs to a novel family of bone morphogenetic protein (BMP) antagonists that includes the head-inducing factor Cerberus and the tumour suppressor DAN. These proteins play important roles in limb development and neural crest cell differentiation. Evidence will be presented that mesangial cell gremlin expression is up-regulated by high ambient glucose, cyclic mechanical strain and transforming growth factor-beta (TGF-beta) and that gremlin may be an important modulator of mesangial cell proliferation and epithelial-mesenchymal transdifferentiation in a diabetic milieu.

Gremlins: is this what renal fibrogenesis has come to?

Gremlin is a member of the differential screening-selected gene aberrative in the neuroblastoma (DAN) family of bone morphogenetic protein (BMP) antagonists. Gremlin influences diverse processes in growth, differentiation and development. Increased expression of gremlin has recently been demonstrated in several models of diabetic nephropathy. Gremlin arrests the cell cycle in mesangial cells and has also been shown to be upregulated in transdifferentiated renal proximal tubular cells. This review summarizes emerging evidence implicating gremlin in the pathophysiology of glomerulosclerosis and tubulointerstitial fibrosis. Gremlin is a potential novel therapeutic target in progressive renal diseases.

15-Epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester, a synthetic analogue of 15-epi-lipoxin A(4), is protective in experimental ischemic acute renal failure.

Lipoxins are endogenous lipoxygenase-derived eicosanoids, generated during inflammatory, hypersensitivity, and vascular events, that display vasodilatory, antiinflammatory, and pro-resolution activity. Here, we evaluated the efficacy of 15-epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester (15-epi-16-(FPhO)-LXA(4)-Me), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A(4) in ischemic acute renal failure (ARF) in NIH Swiss mice. ARF was induced by 30-min crossclamping of renal pedicles and was associated with elevated serum creatinine, morphologic injury, polymorphonuclear leukocyte (PMN) recruitment, and increased mRNA levels for adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]), chemokines (growth regulated oncogene-1 [GRO1]), and cytokines (interleukin-1beta [IL-1beta] and IL-6) after 24-h reperfusion. A single bolus of 15-epi-16-(FPhO)-LXA(4)-Me afforded striking functional (mean +/- SEM creatinine in mg/dl: sham-operated, 0.77 +/- 0.04; ARF + vehicle, 2.49 +/- 0.19; ARF + 15-epi-16-(FPhO)-LXA(4)-Me, 0.75 +/- 0.12; P < 0.001) and morphologic protection and reduced PMN infiltration. Treatment with 15-epi-16-(FPhO)-LXA(4)-Me was also associated with lower IL-1beta, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Compatible with these results, LXA(4) blunted chemoattractant-stimulated PMN migration across HK-2 renal epithelial cell monolayers in vitro, but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA(4)-Me-treated animals also displayed increased renal mRNA levels for suppressors of cytokine signaling-1 (SOCS-1) and SOCS-2, but not CIS-1, endogenous inhibitors of cytokine-elicited Jak/Stat-signaling pathways. These results indicate that 15-epi-16-(FPhO)-LXA(4)-Me is protective in renal ischemia reperfusion injury in vivo, at least partially by modulating cytokine and chemokine expression and PMN recruitment, and provides a rationale for further exploration of the efficacy of LXA(4) structural analogues in ischemic ARF and other renal diseases.

Gene responses to hyperglycaemia.

The rising tide of diabetic nephropathy (DN) is arguably the most challenging clinical problem confronting nephrologists at the beginning of the new century. Central to the development of novel diagnostic and therapeutic strategies will be the elucidation of the molecular events that drive this complex disease. In this review, we briefly discuss the major growth factors and cytokines identified as mediators of tissue injury in DN in the "pre-gene subtraction" era. We then highlight the remarkable array of new molecular players already identified with the introduction of gene subtraction techniques, such as differential-display PCR, suppression-subtractive hybridization, and nucleotide micro-arrays, and discuss the likely impact of these technologies going forward. Finally, we summarize the current knowledge on the cell signalling events triggered by high glucose levels that influence gene expression in DN and that represent additional therapeutic targets in this setting.