Rethinking Bone Disease in Kidney Disease


ABSTRACT

Renal osteodystrophy (ROD) is the bone component of chronic kidney disease mineral and bone disorder (CKD‐MBD). ROD affects bone quality and strength through the numerous hormonal and metabolic disturbances that occur in patients with kidney disease. Collectively these disorders in bone quality increase fracture risk in CKD patients compared with the general population. Fractures are a serious complication of kidney disease and are associated with higher morbidity and mortality compared with the general population. Furthermore, at a population level, fractures are at historically high levels in patients with end‐stage kidney disease (ESKD), whereas in contrast the general population has experienced a steady decline in fracture incidence rates. Based on these findings, it is clear that a paradigm shift is needed in our approach to diagnosing and managing ROD. In clinical practice, our ability to diagnose ROD and initiate antifracture treatments is impeded by the lack of accurate noninvasive methods that identify ROD type. The past decade has seen advances in the noninvasive measurement of bone quality and strength that have been studied in kidney disease patients. Below we review the current literature pertaining to the epidemiology, pathology, diagnosis, and management of ROD. We aim to highlight the pressing need for a greater awareness of this condition and the need for the implementation of strategies that prevent fractures in kidney disease patients. Research is needed for more accurate noninvasive assessment of ROD type, clinical studies of existing osteoporosis therapies in patients across the spectrum of kidney disease, and the development of CKD‐specific treatments. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Introduction

Renal bone disease or renal osteodystrophy (ROD) is a complex disorder of bone in patients with chronic kidney disease (CKD).13 Progressive kidney disease results in metabolic and hormonal disturbances that impair bone quality and is characterized by abnormal remodeling (low, normal or high turnover) with or without abnormalities in mineralization. Altered bone and mineral metabolism in kidney disease is part of a broader systemic disorder defined by the Kidney Disease Improving Global Outcomes (KIDGO) as CKD‐mineral and bone disorder (CKD‐MBD).4 CKD‐MBD is manifested by either one or a combination of: 1) abnormalities of calcium, phosphate, parathyroid hormone (PTH), or vitamin D metabolism; 2) abnormalities of bone turnover, mineralization, volume or strength, and linear growth; and 3) vascular or soft tissue calcification. Manifestations of CKD‐MBD begin early in CKD, with near‐normal kidney function, and the severity of CKD‐MBD and its clinical outcomes of increased fracture risk increase in parallel with declining renal function.57

In practical terms, our ability to confidently diagnose ROD type in CKD and to initiate strategies that could prevent fractures remains limited by the lack of accurate and noninvasive diagnostic tools. The measurement of calcium, phosphate, vitamin D, and PTH identify metabolic abnormalities associated with CKD‐MBD, but these remain poor markers of ROD and have insufficient discrimination of ROD turnover type and mineralization.8, 9 Bone turnover markers (BTMs), routinely used in non‐CKD patients to monitor fracture risk and osteoporosis therapy, lack validation in CKD and end‐stage chronic kidney disease (ESKD) and are consequently used infrequently. Transiliac crest bone biopsy remains the gold standard tool to assess bone quality in metabolic bone diseases; however, bone biopsy is invasive, expensive, painful, requires time‐consuming measurements, and is available at only a few centers worldwide.

Over the past decade, advancements in the field of metabolic bone diseases have the potential to alter the paradigm of how we approach renal bone disease. In 2017, KDIGO updated its guidelines to recommend risk classification of patients with kidney disease for fracture by measurement of areal bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA).10 Noninvasive measurement of cortical and trabecular microarchitecture is now possible with both high‐resolution imaging techniques and novel algorithms that reinterpret grayscale variation in DXA images. The diagnostic utility of BTMs in kidney disease is also being refined and fracture risk assessment tools based on clinical risk factors alone have been developed. Below we review the state of the field pertaining to the epidemiology, pathology, diagnosis, and management of renal bone disease in patients with CKD 3‐5D. Furthermore, we provide our personal interpretation of the current issues and advocate for a greater clinical awareness of this condition and the pressing need to develop and test strategies to prevent fractures in these patients.

Pathophysiology of Renal Osteodystrophy

ROD is the bone component of CKD‐MBD and is defined as alterations in bone morphology associated with progressive CKD that can be quantified by bone histomorphometry.(4) It is important to note that although CKD is defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2, changes of CKD‐MBD are present even with mild renal impairment (eGFR 60–90 mL/min/1.73m2).1113 The historically complex nomenclature pertaining to ROD was simplified by the KDIGO working group and aligned with the standard nomenclature recommended by the American Society for Bone and Mineral Research.4, 14 Classification of ROD type was based on the turnover (high, normal, or low), mineralization (normal or abnormal), and volume (high, normal, or low) of bone (TMV classification system, Table 1). The aim of the revised classification was to encompass the most significant bone abnormalities in kidney disease that would inform management decisions.

Table 1. Bone Turnover, Mineralization, and Volume (TMV) Classification System for Renal Osteodystrophya
Turnover Mineralization Volume
Low Low
Normal
Normal Normal
Abnormal
High High
  • Reprinted with permission from aMoe et al.4

Historically, bone abnormalities in patients with kidney disease were attributed to alterations in PTH and 1,25 dihydroxyvitamin D [1,25(OH)2D]. The characterization of circulating and bone‐derived hormones and the changes that occur with progressive kidney disease have fundamentally altered our understanding of the changes of CKD‐MBD and the pathogenesis of ROD. A detailed discussion of these changes is beyond the scope of this review. However, progressive CKD is generally associated with increased levels of PTH, fibroblast growth factor 23 (FGF‐23), osteoprotegerin, sclerostin, and Dickkopf‐related protein 1 (DKK1) and reductions in α‐Klotho, serum 25‐hydroxyvitamin D [25(OH)D], and [1,25(OH)2D].12, 13, 1522 The expression of bone turnover such as bone‐specific alkaline phosphatase (BSAP), procollagen type 1 N‐terminal (P1NP), C‐terminal telopeptide of type 1 collagen (CTX), and tartrate‐resistant acid phosphatase (TRAP‐5b) is more variable and dependent not only on the degree of renal impairment but also bone turnover.23 Together, these changes impact bone formation, resorption, and mineralization through their effects on osteoblast and osteocyte function.

Expression of skeletal proteins such as FGF‐23, dentin matrix protein 1, and matrix extracellular phosphoglycoprotein is also altered in CKD. In a study by Periera and colleagues,24 FGF‐23 and DMP1 expression was increased across all stages of CKD (compared with healthy controls), whereas there was no difference in MEPE expression. FGF‐23 and DMP1 were inversely related to osteoid accumulation, whereas MEPE was inversely related to bone volume, suggesting a role for FGF‐23 and DMP1 in bone mineralization and MEPE in the regulation of bone volume. The Wnt/β‐catenin pathway is essential for normal osteoblast differentiation and function and therefore normal bone formation. Sclerostin and Dickkopf‐1 (DKK1) are two circulating inhibitors of this pathway; these inhibit lipoprotein receptor‐related protein 5/6 activation of Wnt signaling and impair normal osteoblast differentiation.21, 2527 Sclerostin is primarily expressed in skeletal tissue, and its expression is maintained during aging; in contrast, expression of DKK1 is more general and decreases in bone with age.2830 Inhibition of sclerostin and DKK1 leads to increased bone formation in humans and animal models.3135 Furthermore, animal studies suggest that DKK1 overexpression negatively impacts bone healing, suggesting a role for DKK1 inhibition during the fracture repair process.36, 37 Sclerostin and DKK1 levels are elevated in CKD, with sclerostin levels increased early in CKD, and generally preceding the rise of FGF‐23 and β‐catenin.27, 38 In a study of ESKD patients, sclerostin levels were inversely associated with reduced bone formation and bone loss over a 1‐year period.39, 40 These studies highlight the complex endocrine and paracrine bone‐renal signaling pathways and suggest that the pathogenesis of ROD is driven by changes within osteocytes that occur early in CKD.

In 2001, the National Institutes of Health defined osteoporosis as a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture.41 Bone strength is a combined measure that reflects both bone density and quality. Bone density can be determined by DXA; however, bone quality is more broadly defined and pertains to bone material properties, such as bone remodeling, microdamage, microarchitecture, and collagen and mineral characteristics.42 Disorders of bone quality accumulate with age and directly affect the mechanical properties of bone and therefore fracture risk. In health, damaged areas of bone are constantly targeted for ongoing remodeling and repair. In CKD, some or all aspects of bone quality may be impaired (Table 2).4348 This includes defective mineralization (osteomalacia), abnormal remodeling (low‐ or high‐turnover bone disease), increased microarchitectural impairment (cortical porosity), and accumulation of microdamage and advanced glycation end products (AGE) cross‐linking.43, 44

Table 2. Bone Changes Associated With Hormonal and Metabolic Changes of End‐Stage Kidney Disease
Decreased bone density
Alterations in bone microarchitecture
• Cortical porosity
• Cortical thinning and trabecularization
• Trabecular thinning and dropout
• Disruption in balance and orientation of newly formed and mature bone
Decreased bone quality
• Mineralization (osteomalacia)
• Abnormal remodeling (loss of normal repair processes)
о Adynamic bone disease
о Low turnover
о High turnover
• Microdamage accumulation
о Reduced resistance to impact
• Advanced glycation end products cross‐linking
о Loss of elasticity and tissue embrittlement

Kidney disease patients have both traditional and CKD‐specific risk factors for bone disease and fractures (Table 3). For example, older age, low body weight, postmenopausal status, a history of previous fractures, increased risk of falls, and the use of immunosuppressive medications that promote bone loss are all common in CKD cohorts.4952 Metabolic disturbances that occur due to CKD, including decreased levels of nutritional and activated vitamin D, disordered calcium and phosphorous metabolism, premature hypogonadism, hyperparathyroidism, and metabolic acidosis all contribute to abnormalities in bone strength.4, 5356 Patients with kidney disease are also more likely to have reduced physical activity, postural hypotension, and decreased muscle mass, which increase susceptibility to falls and fractures.57, 58 The age‐specific risk of fracture associated with CKD is higher in younger age groups, but the absolute risk of fracture increases with age, suggesting an interaction between CKD‐specific and traditional risk factors for fracture in older CKD and ESKD patients.7, 59, 60

Table 3. General and CKD‐Specific Risk Factors for Bone Loss and Fractures
General risk factors CKD‐specific
Patient‐related (non‐modifiable) • Hyperparathyrodism
• Age • Low nutritional and activated vitamin D
• Sex • Disordered mineral metabolism
• Ethnicity • Chronic inflammation
• Past history of fracture • Metabolic acidosis
• Premature hypogonadism
General (modifiable) • Medications
• Low physical activity о Steroids
• Smoking о Phosphate binders (eg, aluminium)
• Alcohol о CNI
• Medications (eg, streoids) • Dietary restriction
• Diabetes • Dialysis‐related amyloidosis
• Sarcopenia
• Chronic inflammatory disorders • Higher prevalence of general risk factors for osteoporosis
  • CKD = chronic kidney disease; CNI = calcineurin inhibitor.

Bone biopsy studies in CKD patients have provided important insights into the patterns of ROD observed in patients across the spectrum of CKD. In patients with CKD stages 3 to 5 (non‐dialysis), some data suggest that up to three‐quarters of patients have histologic evidence of renal osteodystrophy.1, 6166 Depending on the cohort studied, there is considerable variation in the prevalence of ROD types, and findings include a predominance of high or adynamic bone disease and even normal bone. In ESKD, recent large bone biopsy studies have characterized tissue‐level impairments in bone quality that reflect current CKD‐MBD management strategies. In a seminal study, Malluche and colleagues used the TMV classification system to evaluate 630 bone biopsies from adult hemodialysis patients from Europe and the United States.9 For turnover, 58%, 25%, and 18% of patients had low, high, and normal turnover, respectively. There were clear racial differences in turnover: low bone turnover predominated in whites (62%) and normal or high turnover predominated in blacks (68%). For mineralization, defects were uncommon (3% of patients). For volume, low, normal, or high cancellous bone volume was equally distributed among whites, but high volume predominated in blacks. Furthermore, blacks had normal cortical thickness with higher porosity, but whites had an equal distribution of low or normal thickness with high or normal porosity. Trabecular microarchitecture was also examined, with trabecular thickness being low in 37% of patients, normal in 40% of patients, and high in 13% of patients. Trabecular separation was normal in most (78%) of patients. Interestingly, both black and white patients with high bone turnover had increased porosity, and more than 80% of patients with low cancellous bone volume had thin trabeculae. These findings were supported in a recent study, where bone histomorphometric assessment of turnover (bone formation rate/bone surface [BFR/BS]) was performed in 492 dialysis patients.8 Low turnover was the dominant lesion being present in 59% (n = 289), whereas high turnover was present in 17% (n = 83). In a smaller study of 35 hemodialysis patients, those with low bone turnover had more microstructural abnormalities (lower cancellous bone volume and trabecular thickness) than those with high or normal turnover.67 Conversely, those with high turnover had reduced mineral content and reduced stiffness.

These data suggest that early CKD is characterized by high bone turnover. In ESKD, low‐turnover disease is the dominant lesion; however, high‐turnover lesions are present in a significant proportion of patients, whereas mineralization defects are comparably low in both groups. Importantly, the studies above highlight that ROD is more than bone turnover but a global disorder of bone quality and strength. It has been proposed that ROD and fractures related to kidney disease be considered as a subtype of osteoporosis (analogous to steroid‐induced osteoporosis), as bone quality and strength are impaired to a greater extent than age‐related osteoporosis.68 Although intentionally provocative, this definition highlights the need for a more practical and easily translatable definition of ROD. This should not only incorporate bone biopsy findings but surrogate parameters of bone strength (such as BTMs, DXA) that are easily accessible in daily clinical practice, facilitate diagnosis and inclusion in therapeutic trials, and inform treatment decisions.

Fracture Epidemiology in CKD and ESKD

The incidence and prevalence of fractures increases with CKD stage and has been reported to be 2‐ to 17‐fold higher in CKD patients compared with the general population.7, 59, 6972 Recent studies have provided important insights into secular trends of fracture epidemiology in ESKD, highlighting differences in fracture rates between general population and ESKD cohorts and in fracture incidence rates at the central and peripheral skeleton.

Longitudinal studies using USRDS and US Medicare data have compared the incidence of hip fractures in ESKD and non‐ESKD cohorts.73, 74 In general, hip fracture rates in ESKD increased steadily from the early 1990s until the mid 2000s (an increase of 43%), with a nonsignificant reduction in incidence after 2004 (Fig. 1).73 More recent data from the US Nationwide Inpatient Sample examined age‐ and sex‐standardized hip fracture rates in ESKD and found a 12.6% decrease between 2003 and 2011.75 However, in 2010, hip fracture rates in ESKD remained 27% higher compared with 1996, and individuals aged 66 years or older with ESKD had a markedly higher incidence of hip fractures compared with those without ESKD (31.9 versus 8.0 per 1000 patient‐years). Furthermore, although these data suggest that hip fracture rates are decreasing, peripheral (arm and leg) fractures have more than doubled over the corresponding period.60 It is important to put these data in perspective, and the small decrease in hip fractures reported must be interpreted in the context of a persistently high overall fracture rate in ESKD patients compared with the general population. All studies report that current fracture rates are significantly higher in ESKD compared with general population cohorts, and fractures remain more prevalent today than they were in 1996.

image
Adjusted hospitalized fracture rates per 1000 person‐years in Medicare point‐prevalent hemodialysis and non‐ESKD patients aged 66 years or older. Reprinted with permission from Arneson et al.73

The morbidity, mortality, and health care costs associated with fractures are higher for patients with kidney disease compared with the general population.68 Patients with CKD and ESKD experience longer hospitalization after a fracture, with reported mortality rates between 16% and 60%.74, 76, 77 Many patients do not return to their premorbid level of function after a hip fracture, with as many as 80% discharged to a long‐term‐care facility after a fracture.5 It was estimated that in 2010 hip fracture‐associated expenses in patients with CKD and ESKD were in excess of $600 million USD,(5) and in the general US population, the costs of fractures and associated morbidity are projected to increase to more than $25 billion USD by 2025.78

Noninvasive Assessment of Bone Quality and Fracture Risk in CKD

Bone biopsy is the gold standard for assessing bone quality in kidney disease and informs treatment options based on bone formation rates and mineralization characteristics. However, its utility as an everyday clinical tool is limited by lack of availability and long duration of time required to process and analyze bone tissue. Therefore, there is great interest in the use of noninvasive approaches to assess bone quality in kidney‐related bone disease so that fracture risk classification and the selection of antifracture treatments can be implemented broadly in the renal clinic. Imaging modalities such as DXA, Trabecular bone score (TBS), conventional Quantitative computed tomography (QCT), High‐resolution peripheral QCT (HR‐pQCT) and micro magnetic resonance imaging (MRI) assess bone density and/or structural aspects of bone quality, whereas PTH and BTMs assess aspects of bone quality that cannot be assessed by imaging, such as bone formation rates and mineralization. We will discuss the role of each of these in CKD.

Bone Density and the Fracture Risk Assessment Tool

DXA is the clinical standard to determine BMD and measure fracture risk in the general population and is integral to the World Health Organization definition of osteoporosis (T‐score ≤–2.5).79 Historically the role of DXA to assess bone health and fracture risk in CKD3‐5D was controversial, as small cross‐sectional studies did not demonstrate that DXA discriminated prevalent fractures, and BMD measurements did not predict type of ROD. However, several recent longitudinal studies in patients across the spectrum of CKD and ESKD have demonstrated that low BMD at the hip and forearm do predict incident fractures.8083 These studies reported that the WHO T‐scores perform similarly in patients with and without CKD, with regard to fracture prediction, and resulted in the revised KDIGO recommendation to include BMD measurement in patients with CKD 3‐5D to assess fracture risk.

In the general population, estimates of fracture prediction are improved by the addition of clinical risk factors to BMD measurements. The Fracture Risk Assessment (FRAX) was developed to provide 10‐year absolute risk of major osteoporotic or hip fracture by combining 10 clinical risk factors, with or without femoral neck BMD, into a fracture risk algorithm.51 The clinical relevance of FRAX in CKD remains unclear. In a study from the Canadian Multicentre Osteoporosis Study, 320 individuals with an eGFR <60 mL/min, and 1787 with an eGFR ≥60 mL/min were followed for a mean of 4.8 years.81 This study showed that FRAX did not differ in its ability to predict major osteoporotic fractures, despite differences in underlying renal function. It is important to note that the incidence of fractures in the CKD patients was low and most patients did not have evidence of CKD‐MBD. In a cross‐sectional study of 353 patients with CKD (mean eGFR of 28 mL/min), approximately 30% had prevalent fractures; FRAX with femoral neck BMD discriminated those with and without fractures but was not superior to femoral neck BMD alone.84 All three study groups (FRAX alone, FRAX with BMD, BMD alone) were better discriminants of fracture than age alone. In a study of 485 Japanese hemodialysis patients, FRAX did not predict increased fracture risk over a 3.3‐year median follow‐up.80 It is important to note the relatively short follow‐up of this study, along with concerns about the accuracy of the fracture risk assessment data. In a recent study of 718 hemodialysis patients who were followed for a period of 2 years, the area under the curve (AUC) for FRAX was 0.76 (95% confidence interval [CI] 0.69–0.82) for major fractures and 0.70 (95% CI 0.69–0.84) for hip fractures, and FRAX discriminated fractures better than individual elements in the FRAX algorithm, although this did not include BMD.85 These studies suggest that more research is needed to determine the usefulness of FRAX in CKD and ESKD. More specifically, some of the clinical factors included in current FRAX algorithms may not be relevant in these patients and CKD‐specific fracture assessment tools need to be developed. These should incorporate predictors of fracture specific to kidney disease, for example, bone alkaline phosphatase (BSAP) or PTH.86

Assessment of Bone Microarchitecture—High‐Resolution Imaging

An important limitation of DXA is that it does not assess the 3‐dimensional structure of bone. Therefore, high‐resolution imaging methods such as QCT, HR‐pQCT, and micro‐MRI have been developed to provide 3‐dimensional imaging of bone density and microarchitectural aspects of bone quality, including cortical and trabecular volumetric BMD, geometry, microarchitecture, and strength. The TBS, although not a high‐resolution imaging modality, has also emerged as an important tool in the assessment of bone microarchitecture and will be discussed below. Micro‐MRI assessment of bone microarchitecture has been evaluated in general and kidney disease cohorts; however, studies of fracture discrimination are lacking, as such no further discussion has been included in this review.8793

Conventional QCT has a resolution of 300 μm3 and quantifies volumetric BMD and cortical and trabecular geometry. In CKD and ESKD, studies utilizing QCT have shown that cortical deficits predominate and these could discriminate and predict future fractures.9496 HR‐pQCT has a higher nominal resolution (60 to 82 μm3), which allows for quantification of trabecular number, thickness, and separation (Fig. 2). Finite element analysis (FEA) has been used in biomechanics to determine the mechanical behavior (and therefore strength) of bone.97 The advent of high‐resolution imaging has allowed FEA to be used in the assessment of bone strength, stiffness, and failure load, either in its entirety or in individual (cortical or trabecular) compartments.98, 99 Recent developments in HR‐pQCT processing methods have been developed to characterize cortical porosity and trabecular rod and plate structure, which have been strongly associated with bone strength.100102

image
HR‐pQCT provides detailed images of bone microarchitecture at the radius (left) and tibia (right). Scout view (A) reference line position (solid line) and the measurement site (dotted line). Images from healthy, postmenopausal white female (B). Images from female with CKD, no fractures (C). Images from female with CKD and prevalent fractures (D). Reprinted with permission from Nickolas et al.103

The ability of HR‐pQCT analysis of bone microarchitecture at the distal radius and tibia to assess fracture risk and bone quality has been evaluated in kidney disease. Specifically, HR‐pQCT was reported to discriminate and predict fractures, define abnormalities in bone quality that adversely affect bone strength, and identify microstructural abnormalities that account for reduced bone density as measured by DXA.103108 Measures from DXA and HR‐pQCT were associated with prevalent fractures in patients with CKD.103, 104 Patients with fractures had lower BMD by DXA and lower cortical and trabecular volumetric BMD and thinner cortices and trabeculae by HR‐pQCT. These abnormalities were more severe with longer duration and severity of CKD. A study of 211 men and women with CKD 3–5 assessed the ability of areal BMD by DXA and volumetric BMD by HR‐pQCT to discriminate fractures.105 Both tests discriminated fracture status and the addition of HR‐pQCT measures to BMD by DXA did not improve discrimination. In a study of 74 prevalent hemodialysis patients, those with fractures had reduced cortical and trabecular microarchitecture compared with those without fractures.106 Changes to bone microarchitecture and calculated bone strength were assessed in 33 ESKD patients and 33 age‐matched controls.107 Cortical and trabecular bone microarchitecture and calculated bone strength were altered in ESKD patients; these changes were more pronounced in females. HR‐pQCT has also been used to determine the microarchitectural mechanisms of bone loss in CKD. In a longitudinal study of 54 patients with CKD 2‐5D, the mean annualized loss of bone density by DXA at the radius was 2.9%.108 With HR‐pQCT, this was characterized by loss of cortical area, density, and thickness and a significant increase in cortical porosity.

The use of HR‐pQCT in the clinic is not currently practical because of cost and limited availability. Thus, methods to assess bone microarchitecture that can be implanted in the clinic have high potential to assist with the diagnosis and management of patients with metabolic bone diseases. TBS was developed to assess trabecular microarchitecture (ie, bone quality) by using software analysis that measures grayscale homogeneity from lumbar DXA images.109 In early studies, TBS has been shown to correlate with trabecular microarchitecture as measured by micro‐computed tomography, HR‐pQCT, and iliac crest bone biopsy.110112 TBS was also shown to predict fractures independently of clinical risk factors and areal BMD by DXA113115 and has been incorporated into international fracture risk guidelines and predictive algorithms such as FRAX.116 TBS has also been investigated in patients with kidney disease. In a recent study of 50 patients with CKD 3‐5D, TBS was associated with trabecular bone volume, width, and spacing, as well as cortical width as measured by bone biopsy.117 Luckman and colleagues112 reported that TBS measures correlated with both cortical and trabecular microarchitecture by HR‐pQCT in ESKD patients before kidney transplantation and that changes in TBS measurements reflected changes in trabecular microarchitecture and failure load but not cortical microarchitecture 12 months after transplantation. In a Canadian cohort of 1476 patients, those with an eGFR <60 mL/min and a TBS value below the median (<1.277) had a higher 5‐year fracture probability that was independent of BMD and clinical risk factors for fracture (hazard ratio [HR] = 1.62 per SD decrease in TBS).118 Further verification and qualification of TBS as a fracture prediction tool in patients with kidney disease is needed.

Bone Turnover Markers

In patients without CKD, BTMs can be used to assess fracture risk and monitor osteoporosis therapy. In patients with CKD and ESKD, they provide mild to moderate accuracy in the noninvasive assessment of bone turnover and mineralization. In some cases, BTMs can be used instead of bone biopsy to inform antifracture strategies, although the utility of BTMs to improve patient‐related outcomes such as fractures remains unproven. Markers of bone formation (osteoblast function) include BSAP, osteocalcin, and P1NP. Bone resorption markers (osteoclast function) include TRAP‐5b and CTX.

In kidney disease, PTH and BSAP are the most widely tested BTMs to assess bone turnover, and BSAP, vitamin D, calcium, and phosphorus are used to assess mineralization.810, 67, 119 Generally, extremes of PTH and BSAP identify bone turnover type based on bone biopsy finding in CKD and ESKD. In a study of 132 patients with CKD 3–5, plasma PTH measurements effectively distinguished patients with and without low bone turnover, AUC 0.96 for CKD stages 3 and 4, and 0.86 for CKD stage 5.119 In a study of 141 hemodialysis patients, an intact PTH < 420 pg/mL increased the positive predictive value (PPV) for low bone turnover from 74% to 90% in white patients, whereas an intact PTH < 340 pg/mL increased the PPV for low bone turnover from 48% to 90% in black patients.120 In 492 ESKD patients, the AUC for discriminating low versus non‐low bone turnover was 0.701 for PTH, 0.757 for BSAP, and 0.718 for PTH and BSAP in combination.8 In another study of patients with ESKD, PTH values within the middle range (150 to 300 pg/mL) less reliably identified underlying histology.121 In age‐related osteoporosis, BSAP reflects bone formation and correlates with bone histology and other BTMs.122124 In a study of 42 ESKD patients, BSAP and PTH were compared with bone biopsy.122 BSAP levels were higher in patients with high compared with low turnover (66.9 versus 10.8 ng/mL, p < 0.0005), were more strongly correlated with bone formation than PTH, and levels > 20 ng/mL reliably excluded adynamic bone disease. Total ALP has sometimes been used as a surrogate marker of BSAP, particularly in the absence of liver disease. However, ALP has high biological variation (>20%), and a high BSAP can still result in a normal ALP level.125, 126

PTH and BTMs may also have clinical utility in predicting bone loss and fractures. In a cross‐sectional study of 82 CKD patients, higher levels of PTH and BTMs were associated with lower cortical and trabecular density and increased cortical and trabecular thinning.104 In the same study, higher levels of PINP, osteocalcin, and TRAP discriminated fracture. In a prospective 2‐year study of 89 hemodialysis patients, baseline BSAP was strongly associated with loss of BMD cortical mass and volume.127 In prospective studies of patients with CKD before (n = 52) and after renal transplantation (n = 47), the microarchitectural and biochemical mechanisms of bone loss were examined by BTMs, DXA, and HR‐pQCT.108, 128 Higher levels of PTH, BSAP, osteocalcin, PINP, TRAP, and CTX predicted the loss of cortical area, density, and thickness, increase in cortical porosity, and decreased bone strength. The ability of PTH and BTMs to predict fractures was assessed in a prospective study of 485 ESKD patients. Incident fracture was associated with PTH levels either <150 pg/mL or >300 pg/mL compared with 150 to 300 pg/mL (p < 0.01).80 In the same study, BSAP was a very useful surrogate marker for any type of incident fracture risk (AUC = 0.766, p < 0.0001).

These data suggest that PTH and BTMs may have greater clinical utility in assessing bone quality and fracture risk in CKD and ESKD, in particular when used in conjunction with bone imaging methods. For example, fracture risk can be estimated by DXA. However, deciding on a treatment (vitamin D, calcimimetic, antiresorptive, anabolic) will also require consideration of bone turnover. PTH and BTMs can potentially be used to inform which pharmacologic agent is most appropriate. However, before BTMs can be widely used to manage renal bone disease, significant barriers need to be overcome. BSAP lacks a readily available automated assay, and there are concerns of cross‐reactivity with the liver iso‐enzyme,129 there are no validated reference ranges of BTMs in patients with CKD and ESKD, many BTMs are cleared by the kidney (monomeric P1NP, osteocalcin, and CTX) and BTMs have high intra‐ and interassay variability and biological variability.130

Treatment of ROD and Preventing Fractures in CKD

Management of kidney‐associated bone disease for fracture risk reduction is controversial. First, until the release of the 2017 KDIGO guidelines, fracture risk classification in CKD3‐5D was not recommended. Second, there are no antifracture treatments that have been developed specifically for patients with CKD‐MBD. However, since emerging data and anecdotal experience with existing antifracture agents suggest that they are safe, we expect that these agents will be more widely used in patients with CKD 3‐5D, especially as more patients undergo DXA screening. In this section, we will briefly review the antifracture treatments that are in current clinical use and their potential application to patients with kidney disease.

Management of CKD‐MBD

Management of the abnormalities associated with CKD‐MBD must occur before initiating specific antifracture therapy in patients with CKD 3‐5D. A detailed discussion of this is comprehensively articulated in the updated KIDGO guidelines and associated publications.10, 53, 131 In brief, supplementing with vitamin D (nutritional and/or active), lowering phosphate, initiating calcimimetics, and deciding on the need for parathyroidectomy are critically important to treating kidney‐bone disease and can have some antifracture benefits.132137 In our opinion, after optimized management of CKD‐MBD, one should consider additive treatment with an agent demonstrated to have antifracture efficacy in the general population (Fig. 3). The updated 2017 KDIGO CKD‐MBD Guidelines clearly endorse the use specific antifracture therapies in CKD 1–2 and to a lesser extent in CKD stage 3 in the absence of abnormalities of CKD‐MBD (recommendation 4.3.1 and 4.3.2).10 However, In patients with CKD 3–5 and evidence of CKD‐MBD, the use of osteoporosis therapies is not directly addressed (recommendation 4.3.3): “In patients with CKD G3a–G5D with biochemical abnormalities of CKD‐MBD and low BMD and/or fragility fractures, we suggest that treatment choices take into account the magnitude and reversibility of the biochemical abnormalities and the progression of CKD, with consideration of a bone biopsy (2D).” It is noteworthy that the KDIGO update no longer mandates that a bone biopsy should be obtained before starting osteoporosis treatment, in part because of the increasing experience with the use of osteoporosis medications in CKD patients.

image
Algorithm for fracture risk screening and initiation of antifracture strategies in patients with CKD. DXA = dual‐energy X‐ray absorptiometry; CKD‐MBD = chronic kidney disease‐mineral and bone disorder; PTH = parathyroid hormone; BSAP = bone‐specific alkaline phosphatase; LLN = lower limit of the normal reference range; ULN = upper limit of the normal reference range. Lifestyle factors include weight‐bearing exercise, cessation of smoking, adequate nutrition, moderate alcohol intake, and fall prevention strategies. Management of CKD‐MBD includes phosphate lowering, vitamin D supplementation (nutritional and active), calcimimetics, and parathyroidectomy. Anabolic agents include teriparatide and abaloparatide. Antiresorptive agents include bisphosphonate and denosumab.

Antiresorptive Agents

Bisphosphonates and denosumab are commonly used in the treatment of senile and glucocorticoid‐induced osteoporosis; these agents lower remodeling rates and may be helpful in preventing bone loss and fracture in normal and high‐turnover bone disease. These should be avoided in patients with adynamic bone disease, but to date there are no studies in CKD that definitively demonstrate that bisphosphonates cause adynamic bone disease. There are no primary safety and efficacy data on the use of antiresorptive therapies in patients with CKD‐MBD, but there are post hoc analyses of the registration trials in patients with mild to moderate CKD (without biochemical manifestations of CKD‐MBD). These agents can therefore be used in CKD patients who have similar characteristics to the inclusion criteria of the registration trials, but in CKD 3‐5D patients with evidence of CKD‐MBD, further evaluation of the underlying ROD type needs to be undertaken before the use of these agents for fracture prevention.

Bisphosphonates

Bisphosphonates are selectively taken by osteoclasts, where they inhibit farnesyl pyrophosphate synthase and the synthesis of isoprenoid compounds, which are essential for osteoclast activity, thereby reducing osteoclast‐mediated bone resorption. Oral bisphosphonates have poor bioavailability (<1%); around 50% of the drug is not taken up by osteoclasts and cleared by the kidney. The actual amount of bisphosphonate retained in bone depends on the remodeling space, the GFR, and bone turnover rate.52 Given the lack of clinical trial data, oral bisphosphonates are not recommended in patients with eGFR < 30 mL/min because of concerns about excessive accumulation in bone and long‐term suppression of bone remodeling.

However, data from recent fracture intervention trials suggest that these drugs can be safely used in patients with reduced eGFR. In a post hoc analysis of 9 randomized, double‐blind trials comparing risedronate to placebo, 8996 females were identified as having kidney impairment, with the majority having a creatinine clearance of 30 to 80 mL/min.138 Risedronate effectively preserved BMD and reduced the incidence of vertebral fractures, and overall and renal function‐related adverse effects were similar in both groups and independent of renal function. Bone biopsy data of 57 patients with renal impairment showed no evidence of adynamic bone disease or mineralization defects. In a secondary analysis of the Fracture Intervention Trial, 581 women (9.9%) had a GFR < 45 mL/min.139 Women with a reduced eGFR had a 5.6% increase in total hip BMD, and alendronate increased BMD regardless of eGFR. Treatment with alendronate reduced clinical and spine fractures to a similar degree in those with and without renal impairment. There were no differences in adverse outcomes by renal function. A recent systematic review by Wilson and colleagues140 compared bisphosphonate to placebo in six studies (n = 1013) of patients with CKD (four of these were in renal transplant recipients).139, 141145 Given the heterogeneity of the studies included, the use of bisphosphonates was associated with a nonsignificant reduction in fracture risk and moderate evidence that bisphosphonates may reduce loss of lumbar spine BMD but not femoral neck BMD. A recent post hoc analysis of three Japanese RCTs146148 compared risedronate to placebo in 852 patients with an eGFR from 30 to >90 mL/min (with 228 having an eGFR <60).149 Patients were analyzed according to eGFR level ≥90, 60 to <90, and ≥30 to <60 mL/min/1.73 m2, and lumbar BMD, BTMs (CTX, P1NP, and BSAP) were evaluated at 48 weeks. The increase in lumbar BMD (p < 0.001) and inhibition of BTMs (p < 0.001) with the use of risedronate did not differ in the eGFR subgroups. There are no data on the optimal duration of bisphosphonate therapy in CKD or ESKD. General population data suggest 3 to 5 years of therapy, with a lack of evidence on fracture reduction beyond 5 years and concerns about atypical femoral fractures.150152

Denosumab

Denosumab is a humanized monoclonal antibody against the Receptor activator of nuclear factor kappa‐Β ligand (RANKL), reducing bone turnover by inhibiting osteoclast proliferation and development. The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Trial recruited 7808 postmenopausal women and demonstrated that denosumab administered twice yearly for 36 months was associated with a reduction in the risk of vertebral (68%), nonvertebral (20%), and hip fractures (40%) compared with placebo.153 Denosumab is not cleared by the kidney, so unlike bisphosphonates, there is no risk of excess drug accumulation. Its effectiveness and safety in CKD (without evidence of CKD‐MBD) were assessed in a secondary analysis of patients from the FREEDOM trial, where treatment effect was compared across CKD categories (CKD 4 = 73, CKD 3 = 2817, CKD 2 = 4069).154 There was no difference in treatment efficacy and adverse effects by renal function, and denosumab increased BMD at the spine and hip and showed a 62% reduction in incident vertebral fractures.

The secondary analysis of the FREEDOM trial did not describe an association between hypocalcemia and decreased renal function. However, case reports and anecdotal experience suggest that this may occur in patients with CKD, hyperparathyroidism, and low vitamin D. In a case series of 8 patients with ESKD and 6 patients with CKD treated with denosumab, 8 patients developed severe hypocalcemia.155 In two studies of single‐dose denosumab in CKD and ESKD, hypocalcemia was the most common side effect; however, appropriate pretreatment with calcium and calcitriol was protective of clinically significant hypocalcemia.156, 157 These and other clinical data suggest that denosumab may have a role in patients with CKD 3‐5D, with appropriate calcium, vitamin D supplementation, and monitoring for hypocalcemia. Denosumab is metabolized in the reticuloendothelial system, and its clinical effect wanes after 6 months; frequency and duration of treatment in CKD 3‐5D remain unclear.

The increasing off‐label use of antiresorptive therapies in kidney disease patients reflects not only the decreasing concern regarding their short‐term safety but also the lack of specific antifracture treatments for patients with CKD‐MBD. No doubt further observational data will continue to guide and refine clinical practice, but ultimately prospective trials are needed to better define safety and antifracture efficacy of these drugs in patients with CKD‐MBD and an eGFR of <30 mL/min/1.73m2.

Osteoanabolic Agents

Osteoanabolic agents are forms of recombinant PTH, and their use in CKD remains controversial. In CKD, high‐baseline PTH levels promote cortical bone loss; therefore, these agents should not be used in patients with high‐turnover bone disease. However, they may increase bone turnover and bone density in patients with adynamic bone disease.

Teriparatide is a recombinant peptide of the first 34 amino acids of human PTH. In health, its antifracture efficacy is caused by an increase in osteoblast number, leading to increased bone formation and thickening of trabecular and cortical bone.158 Its efficacy in primary osteoporosis was demonstrated in two large clinical trials.159, 160 A post hoc analysis of Fracture Prevention Trial examined the safety and efficacy of teriparatide in 736 women with CKD (majority GFR 50 to 79 mL/min, and none <30 mL/min).161 Compared with placebo, teriparatide significantly increased lumbar spine and femoral neck BMD and had similar efficacy in preventing vertebral and nonvertebral fractures across all stages of CKD. The main adverse effects were hypercalcemia and hyperuricemia and these were more common with reduced eGFR. In a separate post hoc analysis from the same trial, improvements in BMD were correlated with improvements in trabecular microarchitecture.162 Teriparatide has also been used in patients with adynamic bone disease, where it improved BMD at the lumbar spine but not the femoral neck.163 A prospective, 48‐week study examined the effect of once‐weekly teriparatide in 22 hemodialysis patients with low BMD and hypoparathyroidism.164 Over the treatment period, there was an increase in lumbar spine but not femoral neck BMD. The observed increase in BSAP strongly correlated with improvements in BMD. There was no clinically significant hypercalcemia, and hypotension was the most common adverse event.

Abaloparatide is a newer parathyroid hormone‐related protein (PTHrP) analog, with stronger affinity for the transient state of the PTH1/PTH receptor and a more anabolic profile (compared with teriparatide) given less bone resorption and hypercalcemia.165, 166 In a study of 222 postmenopausal women, daily abaloparatide (20, 40, or 60 μg) was compared with teriparatide 20 μg or placebo.167 BMD was increased at the lumbar spine, femoral neck in a dose‐dependent manner, and to a greater extent than with teriparatide. Abaloparatide was compared with placebo and open‐label teriparatide in a study of 2461 postmenopausal women.168 New vertebral fractures occurred less frequently in the active treatment groups, and BMD increases were greater with abaloparatide than placebo. The incidence of hypercalcemia was lower with abaloparatide compared with teriparatide. In a secondary analysis of changes on bone histomorphometry, there was no evidence of abnormal mineralization, bone marrow abnormalities, or presence of excess osteoid.169 Patients treated with abaloparatide had lower eroded surface on histomorphometry versus placebo but similar increase in cortical porosity compared with teriparatide. This is supported by a smaller increase in CTX (a resorption marker) with abaloparatide compared with teriparatide. Based on the available data, abaloparatide has the ability to increase bone mass and formation, with less bone resorption and hypercalcemia. It has the potential to become an ideal agent for the treatment of patients with CKD and low to normal bone turnover; however, that data is currently lacking.

Sclerostin is a protein encoded by the SOST gene and secreted by osteocytes. Loss‐of‐function SOST mutations result in a high bone mass phenotype through increased bone formation, and sclerostin has predominantly anti‐anabolic effects on bone through inhibition of the Wnt‐signaling pathway. Inhibition of sclerostin is therefore of great interest in patients with CKD 3‐5D, particularly those with low bone mass and low bone turnover where antiresorptive therapies are contraindicated. In trials of postmenopausal women with osteoporosis, romosozumab increased BMD to a greater extent than existing anabolic agents and decreased vertebral and nonvertebral fractures.170172 In another study, comparing romosozumab to teriparatide, there was a greater increase in cortical BMD (compared with trabecular BMD) in the romosozumab arm compared with a reduction in cortical BMD in the teriparatide group.173 Increased cardiovascular events were reported in one (but no other) romosozumab study.171 As such, it remains unclear whether romosozumab increases cardiac risk, but given the large CVD burden in patients with kidney disease, further study of romosozumab in CKD and ESKD should be suspended until these issues are clarified in future studies. Inhibition of DKK1 is another target for potential novel anabolic agents, although the clinical development of these drugs lags behind that of sclerostin inhibitors. In animal models, inhibition of DKK1 by monoclonal antibodies (DKK1‐ab) generally increased bone formation and mass. In a mouse model, changes of CKD‐MBD including ROD were ameliorated after the administration of DKK1‐ab (in combination with phosphate binder therapy).174 In patients with multiple myeloma, administration of DKK1‐ab reduced bone resorption and reduced bone formation.34 Finally, the dual inhibition of sclerostin and DKK‐1 leads to synergistic bone formation in rodents and non‐human primates.175 These studies have important implications for patients with kidney disease, and clinical studies of DKK1‐ab are needed in CKD and ESKD cohorts.

Take‐Home Messages and Rethinking Bone Disease in CKD

In CKD patients, fracture rates are more than 10‐fold higher compared with age‐ and sex‐matched individuals without CKD. Although fracture incidence in the general population has fallen over the last two decades, it has increased in patients with ESKD. In the clinic, treatment of CKD‐MBD is focused on the correction of abnormalities associated with parathyroid hormone and phosphate, a strategy that has not mitigated the effects of CKD on fracture risk. Despite advances that have improved our ability to assess fracture risk in the clinic, we continue to lack noninvasive tools that predict turnover and diagnose ROD type, which would inform fracture prevention strategies. Furthermore, despite an ever‐increasing choice of antifracture treatments in the general population, we lack data on their safety and efficacy in CKD 3‐5D. Therefore, it is time to rethink bone disease in patients with kidney disease.

Kidney‐related bone disease is complex and multifaceted, as such any gains are likely to be incremental rather than revolutionary. A starting point could be implementation of the successful fracture screening, prevention, and treatment programs used in the general population to CKD 3‐5D. The 2017 KDIGO guidelines justify the use of DXA, a readily available and inexpensive fracture risk screening tool. Lifestyle measures such as smoking cessation, weight‐bearing exercise, alcohol moderation, and improved nutrition all have proven antifracture efficacy in the general population and could be argued as being even more important in CKD. Vitamin D deficiency is common in CKD and should be routinely supplemented given its skeletal benefits and low risk of adverse consequences. The role of calcium supplementation is less well defined in CKD and ESKD and cannot be recommended in these patients.

Our ability to initiate specific, mostly antiresorptive osteoporosis treatments in CKD 3‐5D remains limited by our inability to effectively assess bone turnover and a historical fear of propagating low turnover and atypical femoral fractures. In the clinic setting, the interpretation and treatment of the current markers of CKD‐MBD should not occur in isolation but in view of the broader endocrine and skeletal disturbances. Although imperfect, PTH and BSAP improve our ability to discriminate bone turnover and some of the microstructural derangements. These should be used with DXA and be further studied with novel algorithms such as TBS that can inform on bone microarchitecture, with only minimal modifications to existing imaging infrastructure. Finally, fracture prediction algorithms such as FRAX should be broadly utilized to increase awareness of fractures; however, these need further validation and refinement to improve their accuracy in patients with kidney disease. Many, if not all, of these measures are feasible and could be readily implemented in most developed countries.

Ongoing work in improving diagnosis of ROD type is needed. Bone biopsy will remain the gold standard; however, given the required expertise, its role will always be confined to specialized tertiary institutions. High‐resolution imaging techniques provide a glimpse of the future, where imaging could obviate the need for a physical biopsy. However, today, even the most advanced high‐resolution imaging techniques remain inadequate at evaluating bone turnover and mineralization, both of which remain essential to informing treatment decisions. We have no doubt that high‐resolution imaging will continue to evolve and there are countless examples in medicine where technology has diminished the need for invasive diagnostic tests but seldom have these been superseded. Therefore, we believe that bone biopsy will remain an important diagnostic and research tool, such as in validating studies of high‐resolution imaging techniques. As such, its availability should be fostered and rationally coordinated across regions and health care networks.

CKD patients are historically disadvantaged by their exclusion from large general population clinical trials, and this is clearly the case in osteoporosis. Much of the current data come from secondary analyses of large osteoporosis trials, where patients were excluded if they had evidence of CKD‐MBD. The safety and efficacy of existing and novel agents in CKD 3‐5D remain unclear, and studies of these drugs are urgently needed in these cohorts. Future studies also need to target patients at various stages in the evolution of renal bone disease; for example, prevention of bone loss in CKD, reduction of fractures in ESKD, as well as any effects on the systemic aspects of CKD‐MBD. For this to occur, stronger advocacy from kidney societies and a paradigm shift from drug companies around the world are required. As physicians, we need to recognize the burden of fractures and bone disease in our patients and work tirelessly to promote better awareness and utilization of available diagnostic and therapeutic resources, such as greater off‐label use of osteoporosis medications in CKD 3‐5D. To this end, collaborations with our endocrinology colleagues should be fostered in both the research and clinical settings. In the words of Lao‐Tzu, “A journey of a thousand miles begins with a single step.” No doubt the road ahead is long, harboring many challenges and false starts; however, to accept the status quo is simply not an option.

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Do Neprilysin Inhibitors Have a Role in Patients With CKD?


Neprilysin inhibitors offer a new target for therapeutics. Neprilysin is an enzyme that degrades endogenous natriuretic peptides.[1] These peptides are secreted during times of fluid overload natriuretic peptidesthe heart (specifically the atrium) is stretched. The peptides signal the kidneys to increase elimination of salt to help reduce the excess volume, but neprilysin curtails that response by degrading natriuretic peptides. Unfortunately, the body can overcome the effect of neprilysin inhibitors by increasing production of angiotensin II. Thus, a combination of inhibitors (ie, neprilysin inhibitor plus angiotensin II-receptor blocker) could potentiate the effect of these peptides and facilitate a greater amount/duration of natriuresis that can restore the patient to euvolemia.

Indeed, in the PARADIGM-HF trial, a combination of sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II-receptor blocker) resulted in improved cardiovascular outcomes.[2] In a subgroup analysis, the combination pill seemed to retard the progression of kidney function decline and generated the hypothesis that dual therapy could preserve kidney function better than monotherapy with an angiotensin II-receptor blocker alone. These findings formed the basis for the UK HARP-III trial.[3]

 

In the UK HARP-III trial, 414 patients with kidney disease were randomly assigned to receive sacubitril/valsartan versus irbesartan alone.[3] The patients had relatively mild-moderate kidney disease (estimated glomerular filtration rate [eGFR] of 45-60 mL/min/1.73 m2 and a urine albumin:creatinine ratio [UACR] of 177 mg/g or greater, or an eGFR 20-44 mL/min/1.73 m2, irrespective of UACR) and were followed for 12 months. The primary outcome was the measured kidney function at the end of the study period.

Unfortunately, the positive results seen with cardiovascular outcomes in PARADIGM-HF were not seen observed in the UK HARP-III trial. The mean eGFR was 35.5 mL/min/1.73 m2 and fell to 29.8 and 29.9 ml/min/1.73 m2 in the dual-therapy and monotherapy arms, respectively (P = .86). In the prespecified subgroup analyses, there were no differences in the eGFR at study’s end in either group when filtered for age, sex, magnitude of proteinuria, or etiology of chronic kidney disease. In fact, at no time point during the 12-month study period was the eGFR higher in the neprilysin arm than in the ARB arm.

What Are Your Thoughts on Neprilysin Inhibitors for CKD?

Despite the current negative findings, I wonder whether neprilysin inhibition can still have a role in patients with proteinuric kidney disease. While the majority of patients enrolled were assumed to have diabetic kidney disease, the mean proteinuria was 310 mg/g.

I also wonder whether a longer duration of treatment is required to see a difference in eGFR. I don’t think we should shut the door on neprilysin inhibitors just yet as they relate to renal protection.

What do you think? Is the UK HARP-III trial a definitive trial on this subject? What type of patients would you like to see enrolled in a future trial that studies neprilysin inhibitors? Tell us in the comments section below.

Age related BP targets for chronic kidney disease patients work better


A cautious approach to lowering blood pressure (BP) in elderly patients with chronic kidney disease (CKD) is recommended, said US-based researchers. Treatment of hypertension in younger patients with CKD can follow current clinical guidelines, they added.

“Hypertension affects almost all patients with CKD, and is one of the few conditions that is treatable with a wide array of medications,” said lead author Professor Casaba P. Kovesdy, from the Division of Nephrology, Memphis Veterans Affairs Medical Center, Memphis, Tennessee, US.

Kovesdy and team examined systolic BP (SBP) and diastolic BP (DBP) with all-cause mortality, together with the incidence of chronic heart disease (CHD), ischaemic stroke, and end stage renal disease (ESRD) in 339,887 patients with CKD. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.08660815]

During the 4.8 year median follow-up 100,763 patients died (95 percent confidence interval [CI], 62.6- 63.4). Mortality rates were high in older SBP patients. SBP ≥ 140mmHg and <120 mmHg was associated with higher mortality rates across all age groups. Lowest mortality was seen in SBP 120-139 mmHg for patients <80 years, and SBP 120-159 mmHg for patients ≥80 years.

Compared to SBP of 130-139 mmHg, SBP ≥170mmHg in patients aged <50, 50-59, 60-69, 70-79, and ≥80 years were adjusted hazard ratio [aHR], 1.95, 95 percent CI, 1.34-2.84; aHR, 2.01, 95 percent CI, 1.75-2.30; aHR, 1.68, 95 percent CI, 1.49-1.89; aHR, 1.39, 95 percent CI, 1.25-1.54; and aHR, 1.30, 95 percent CI, 1.17-1.44, respectively.

Lower DBP was associated with high mortality. DBP of 70-79 mmHg in patients <50 years and 80-89 mmHg in patients ≥50 years had the lowest mortality.

CHD was experienced in 9,450 patients during the study period (95 percent CI, 9.6-10.0). Higher SBP was associated with higher CHD rates in patients <80 years. However, lowest CHD rates were associated with SBP<110 mmHg in patients <70 years and SBP<140 mmHg in patients ≥70 years. DBP on the other hand had no association with CHD.

Ischaemic stroke was experienced by 14,557 patients (95 percent CI, 10.2-10.6). While higher SPB was associated with higher stroke rates across all age groups, DBP showed no association. Lowest stroke risk was seen in patients with SBP <100mmHg.

ESRD rates were found to be lower in older individuals compared to younger patients. ESRD was seen in 5,161 patients (95 percent CI, 3.2-3.3). DBP was found to have no association with ESRD, but high SBP was associated with high ESRD incidence. Patients <80 years with SBP ≥170mmHg had high ESRD risk, but SBP <170mmHg in this age group had no associated risk.

“Our results reinforce the significant association of elevated SBP with all the studied outcomes but suggest weak association in the elderly, especially in patients aged ≥80years,” said Kovesdy. “The best outcomes were seen with SBP of 120-130 mmHg in patients <80 years and of 120-159 mmHg in those ≥80years.”

In a separate editorial, Assistant Professor Jessica W. Weiss from the Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, US said that the study by Kovesdy and team added to the collective understanding of the relationship between BP and a wide range of various clinical outcomes in older adults with CKD, a group rarely studied. This, she said, may be useful in guiding the design of future studies in this area. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.03100316]

“These results may also add a note of caution to newfound enthusiasm for lower BP targets after the release of the SPRINT* via the suggestion that harm may persist at upper and lower extremes of BP among populations more comorbid and complex than those evaluated in the setting of a clinical trial,” said Weiss.

 

Managing hypertension may prevent chronic kidney disease


Health education combined with general practitioner (GP) training in managing blood pressure delayed decline of kidney function and lowered the risk of death from kidney failure in individuals with hypertension, according to an extended analysis of the COBRA* study.

“Our findings indicate that public health interventions using effective lifestyle modification approaches and training of providers in a primary care setting can yield long-term benefits for preserving kidney function,” said lead author Dr. Tazeen Jafar, a professor of Health Services and Systems Research at the Duke-NUS Graduate Medical School in Singapore, Singapore.

The study included 1,271 hypertensive individuals aged ≥40 years from low-income communities in Pakistan. The participants were randomly assigned to a control group, which received standard care, or an intervention group, which received health education emphasising healthy lifestyle and adherence to antihypertensive medication, and/or care from GP trained in hypertension management for 2 years. [Clin J Am Soc Nephrol 2016;doi:10.2215/CJN.05300515]

The participants were evaluated for changes in kidney function from baseline to 7 years after the start of intervention.

Kidney function, measured as the estimated glomerular filtration rate (eGFR), of the intervention group did not changed significantly (-0.3 ml/min per 1.73m2, 95 percent confidence interval [CI], -3.5 to 2.9 ml/min per 1.73m2) after 7 years, compared with the control group, which saw a -3.6 ml/min per 1.73m2 decline in eGFR (95 percent CI, -5.7 to -2.0 ml/min per 1.73m2) (p=0.01).

Participants receiving intervention were half as likely as participants on standard care to experience a >20 percent decline in kidney function (adjusted risk ratio [adjRR], 0.53, 95 percent CI, 0.29-0.96; p=0.04).

Also, the risk of death from kidney failure or >20 percent kidney function decline was significantly lower in the intervention group compared with control group (adjRR, 0.47, 95 percent CI, 0.25-0.89).

“Blood pressure control is a cornerstone of management to both prevent the onset and delay the progression of CKD,” said Drs. Min Jun and Brenda Hemmelgarn from the Department of Medicine at the University of Calgary in Alberta, Canada in a separate editorial. [Clin J Am Soc Nephrol 2016;11:932–934]

“Current clinical guidelines widely advocate blood pressure reduction strategies, including both pharmacologic and lifestyle interventions.”

Previous studies showed that improvement in diet and exercise had beneficial effects on cardiometabolic parameters and preserving kidney function. [Cochrane Database Syst Rev 2011;(10): CD003236, Nephrology (Carlton) 2015;20:61–67]

These simple interventions could be implemented in low- and middle-income countries to help prevent chronic kidney diseases (CKD), suggested Jafar.

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Low-protein Diet in Chronic Kidney Disease


Abstract

Intention-to-treat and per-protocol analyses provide complementary information about the usefulness of therapies. While intention-to-treat analyses of trials that tested low-protein diets remain debated, per-protocol analyses of the same trials show that low protein intake actually reduces the risk of kidney failure. Per-protocol analyses are notoriously open to bias but intention-to-treat analyses are less immaculate than commonly realized because they critically depend on adherence to the treatment being tested and therefore may not be directly relevant for informing clinical decisions when different degrees of adherence to therapy occur. Over the last 20 years new statistical techniques censoring patients at the time when they become uncompliant and that adjust for confounding attributable to incomplete adherence, i.e. for prognostic factors that predict adherence to treatment, have been developed. These techniques can be usefully applied to reanalyse the Modification Diet in Renal Disease (MDRD) and other trials. Intensive surveillance of patients on a low-protein diet is fundamental for early detection of malnutrition. However, the resources demanded by such surveillance are likely superior to the actual dietitians workforce dedicated to follow-up of the chronic kidney disease (CKD) population. Surveillance efforts may perhaps be preferentially devoted to preselected patients, i.e. patients that maintain good compliance and an adequate metabolic and nutritional status, while patients who are resistant to educational efforts and show persisting uncompliance may be reallocated to a diet with a higher protein content, which poses a lower risk of malnutrition and other adverse health outcomes.

Inflammatory biomarkers foreshadow CKD, study finds


The central idea of the film Minority Report—that a “precrime” police unit can predict and prevent crimes—still mostly inhabits the realm of science fiction. Luckily, in medicine, researchers studying “predisease” can make headway on prevention by analyzing the laboratory test results from samples collected years earlier, when patients showed no clinical symptoms, that might have been able to predict disorders such as chronic kidney disease (CKD) in those patients.

One of the latest such studies was possible thanks to the trove of data from the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study, which allowed investigation of biomarkers in two follow-up windows: up to three years (short term) and up to 10 years (long term). Through a prospective evaluation of markers of inflammation and endothelial dysfunction, a study team from the Medical University of South Carolina, the VA Medical Center of Charleston, SC, and Bristol-Myers Squibb found that these markers are associated with progression to kidney dysfunction in type 1 diabetes during both short- and long-term follow-up.

The study, “Association between inflammatory markers and progression to kidney dysfunction: examining different assessment windows in patients with type 1 diabetes” (Baker NL, et al. Diabetes Care. 2018;41[1]:128–135), confirmed that the biomarkers sE-selectin and sTNFR-1 and -2 are associated with the long-term development of macroalbuminuria. Higher levels indicated the possible development of macroalbuminuria in participants—all patients with type 1 diabetes—who had been free of clinically detectable kidney disease at baseline. Similarly, the biomarkers sTNFR-1/2, sE-selectin, PAI-1, and fibrinogen were found to be associated with progression to chronic kidney disease stage three or worse.

Baker

With this prospective evaluation of DCCT and EDIC test results, the researchers hoped to expand on observations from previous studies, says study coauthor Nathaniel L. Baker, MS, a statistician with MUSC. The study team had conducted two of those earlier studies. “We looked at some of these biomarkers of inflammatory, thrombosis, and endothelial dysfunction in a cross-sectional study of patients who progressed to kidney dysfunction in DCCT and early in EDIC,” Baker says. In 2008, “We found that sE-selectin was strongly associated with concurrent abnormal albuminuria” (Lopes-Virella MF, et al. Diabetes Care. 2008;31[10]:2006–2012). In 2013, “We found that higher levels of sE-selectin and sTNF receptors 1 and 2 are strongly associated with long-term progression to macroalbuminuria” (Lopes-Virella MF, et al. Diabetes Care. 2013;36[8]:2317–2323).

While the pathological mechanisms of development and progression of kidney disease in patients with diabetes are not well understood, other studies such as the EURODIAB Prospective Complications Study had also provided strong evidence for the clinical significance of biomarkers of inflammation and endothelial dysfunction in predicting complications of diabetes, such as albuminuria, retinopathy, and cardiovascular disease, the coauthors of the new study note.

For this biomarkers study, “We looked at several samples that were collected during DCCT and EDIC,” Baker says. “We wanted to explore the cross-sectional association to see if they could be measured earlier in the disease progression.” As the study notes, most of the biomarkers that have been shown to correlate with renal function deterioration in patients with diabetes seem to have long-term predictive value. But only a limited number can predict the onset of chronic disease closer to the development of macroalbuminuria and CKD. “We wanted to see how close we could get.” For clinical trials of relatively short duration, the study found the most useful biomarkers for inclusion would be sTNFR-1 and sTNFR-2.

The DCCT, a large longitudinal study that ran from 1983 to 1993, collected data from two study cohorts with type 1 diabetes, a total of 1,441 patients ages 13–39. The first cohort had no retinopathy on the basis of fundus photography, diabetes for one to five years, and no microalbuminuria (

At their baseline visits, the DCCT participants underwent a physical examination, medical history, and routine laboratory analysis including serum creatinine, lipid profile, and HbA1c. Then they were assigned randomly to either intensive or conventional insulin therapy. The DCCT was halted in 1993, ahead of schedule, because of the consistent beneficial impact of intensive therapy on diabetes complications. But most of the DCCT participants went on to be enrolled in the EDIC observational follow-up study.

The new biomarkers study looked at markers of inflammation, endothelial dysfunction, and fibrinolysis from samples taken at four study time points: DCCT baseline, DCCT closeout, EDIC years four through six, and EDIC years eight through 11. “The samples from DCCT baseline and closeout were collected by the centers at the time of the DCCT trial and we received a frozen aliquot when we requested it from the NIDDK [National Institute of Diabetes and Digestive and Kidney Diseases],” Baker explains. “The first time the sample was unfrozen it was aliquoted, and from there on each new test was performed on aliquots from the original samples. The blood glucose samples were received frozen from the centers where they were collected and the same process was followed. The first time they were used they were aliquoted.”

The aim was to see if those test results would be associated with development of kidney dysfunction within follow-up windows of up to three years and up to 10 years. The kidney dysfunction of interest included incident macroalbuminuria and CKD stage three or worse. Using levels of eGFR to define progression to CKD, and albumin excretion rate values to define progression to macroalbuminuria, the researchers analyzed 4,378 paired biomarker and disease outcome measurements taken in 1,396 participants.

Of those participants, 94, or 6.7 percent, progressed to CKD stage three or worse during DCCT or during the first 18 years of EDIC follow-up (21–28 years of follow-up time since enrollment in the DCCT study). The median progression time from the DCCT baseline was 19.3 years. Progression to CKD stage three or worse occurred, on average, within 5.3 years after the last available biomarker measurement. Within the 10-year window, increased levels of some inflammation markers (cytokines) and endothelial dysfunction were associated with higher risk of progression to CKD.

A higher percentage of the DCCT participants (161, or 11.5 percent) progressed to macroalbuminuria during that trial or during the first 18 years of the EDIC follow-up. Forty-four of those progressed within a three-year window and 143 progressed to macroalbuminuria within a 10-year window since the last available measurement. The biomarkers sTNFR-1/2, sE-selectin, and PAI-1 were associated with progression to macroalbuminuria during the 10-year follow-up window, but more weakly associated within the three-year window.

Within the population studied, levels of C-reactive protein, fibrinogen, sTNFR-1, and active PAI-1 increased over time, exhibiting a sustained trend with age, while levels of sE-selectin decreased over time. By contrast, for the participants who developed impaired eGFR and macroalbuminuria compared with those who maintained normal kidney function, the overall levels of all the biomarkers increased, except IL-6, which did not show an appreciable difference, and VCAM-1, which was lower in participants who developed nephropathy.

Two main goals drove the study, says coauthor Maria F. Lopes-Virella, MD, PhD, an endocrinologist and clinical pathologist at MUSC. “One was to find biomarkers that would identify patients at high risk of developing CKD and MA [macroalbuminuria]. And that, of course, could be applied clinically.” The other goal was to help in recruiting the best patients for clinical trials of promising drugs. “We cannot do trials that extend 15 years,” she says. “We have a shorter period of time to test proposed treatments, so we need to be aware of biomarkers that can help us recruit patients who will develop a disease during the follow-up period and therefore allow us to determine whether or not a drug works.”

The study concluded that biomarkers associated with diabetes complications in a close temporal relationship with CKD or macroalbuminuria “could be useful in clinical trials for the recruitment of patients more likely to have [a kidney] event during the trial, thus increasing the number of events and, therefore, enhancing the power of the study and validity of the conclusions.”

Dr. Lopes-Virella

Says Dr. Lopes-Virella: “Our idea was to see if some biomarkers could help us choose patients who start with more of a chance of having the event. Then, if you are looking at a drug and the effects of a drug, you can see more easily if some do not develop the disease when they are treated.” The study team also wants to help other trials expose fewer patients to the drugs being studied, Baker says. “You can do that if you can choose patients for your study pool who are more likely to acquire the disease.”

The researchers chose to study short-term and long-term time frames because they have different purposes, Dr. Lopes-Virella says. “The short term was mostly to help in recruitment of patients if you are doing clinical studies. Those patients are in more immediate need of treatment because they are not doing well. But the long term, in my opinion, is more important because they are the ones who tell you which patients need help and need to be treated more intensively to prevent the development of complications.”

With most clinical trials funded by the National Institutes of Health, Baker notes, “you don’t get 10 or 20 years of follow-up data. You get three. So being able to use biomarkers to identify at-risk patients is very important.”

But he is interested not only in how the biomarker works to help but also in how the biomarker represents one of the mechanisms of the disease. “I personally don’t like biomarkers that I don’t think are somehow related to the pathophysiology of disease,” he says. As the study notes, identifying biomarkers associated with long-term disease progression helps illuminate the underlying mechanism of disease development.

“There are a lot of publications and a lot of data to suggest that the pathogenesis of diabetes complications has a strong link to the complement system, and also indicators of signaling operations in membrane structures that lead to different signal pathways. All of that seems to be very much involved in the complications of diabetes. So we were looking partly at what we know was involved in the complications and trying to figure out the biomarkers,” Baker says.

Baker and Dr. Lopes-Virella note that this study does not provide added clinical utility for disease prediction beyond the traditional risk factors, and that further classification analysis, including prediction models, should be conducted.

“In a sense, many of the clinical implications depend a lot on which pathway is implicated in the disease process,” Dr. Lopes-Virella says. Clinicians do not want, when trying to prevent one problem, to create another, she points out. For example, with inflammation, “you need to be very careful with your conclusions because inflammation is a necessary process in the body.” Since inflammation is part of a protective immune response, “if you attack inflammation, you may have unwanted side effects.” Sometimes researchers can find very specific pathways that do not have general effects. “Targeting these pathways, I think, may have clinical implications and help with the discovery of drugs to treat the disease.”

“I think as we work toward a more discriminative model, a panel-type model” for predicting kidney dysfunction, “we’ll get closer to clinical utility,” Baker says. “But with individual biomarkers, we are still kind of exploring the relationship not just to CKD but to the heart as well. Once we get a panel together, we will have a lot more clinical utility from our findings.”

That milestone is still a step or two away. “We are talking about building a full panel and possibly developing a risk score that will help assess patients with additional biomarkers. But we haven’t yet concluded which ones,” Baker says. “In this study, we were looking at sE-selectin and sTNFR-1/2 because they seem to have a tremendous impact in the kidney.”

The biomarkers study had a well-defined population that was followed for a significant time, but limitations of the study do temper the results, the authors note. The number of events in the cohort studied was relatively small in the three-year follow-up window, detracting from its statistical significance. There were variations in testing, including participant albumin excretion rate values that were measured annually during DCCT but only every other year during EDIC, making it difficult to measure persistent macroalbuminuria in the presence of treatment with ACE/ARB medications.

The NIH and pharmaceutical companies are paying attention to different biomarkers and how they could help in treating and preventing complications in diabetes and other diseases, Dr. Lopes-Virella says. “They want to use, as much as possible, plasma/serum/urine biomarkers and avoid invasive procedures to identify patients at high risk. That way you can more easily identify patients who are at high risk and really need treatment. You cannot treat everyone, but it helps if you considerably reduce the number of patients who will progress if left untreated.”

A population of only type 1 diabetes patients was the subject of the study. But could the study’s findings be helpful in predicting type 2 diabetes? Maybe, says Baker. “Diabetes is a very interesting disease. With type 2, I don’t think we really know when the disease starts. It’s a continuum from metabolic syndrome to prediabetes to diabetes. So I think these biomarkers are definitely something that could be helpful.” But, he says, since the population of patients in this study all had diabetes and various stages of kidney disease, the biomarkers were not predicting progression to diabetes.

Dr. Lopes-Virella believes the biomarkers shown to be correlated with renal function deterioration in patients with diabetes could potentially help with prediction of prediabetes. “These biomarkers will probably help identify patients at risk. Could they help more than the traditional markers we already know? I don’t know. But there are studies looking at this question.”

Anticoagulants increase stroke risk in people over 65 with kidney disease


https://speciality.medicaldialogues.in/anticoagulants-increase-stroke-risk-in-people-over-65-with-kidney-disease/

Clotting risk factors in chronic kidney disease


https://speciality.medicaldialogues.in/clotting-risk-factors-in-chronic-kidney-disease/

PPIs Tied to Increased Risk for Chronic Kidney Disease


Regular use of proton pump inhibitors appears to be linked to chronic kidney disease, but additional studies are needed to determine whether the drugs actually cause kidney damage, and, if so, how, researchers said.
In a prospective, community-based study involving more than 10,000 adults followed for a median of 14 years, baseline use of a proton pump inhibitor (PPI) was independently associated with a 20% to 50% higher risk for incident chronic kidney disease (CKD).

In a replication cohort, PPI use was associated with an increased risk for CKD in all analyses, and twice-daily dosing was associated with a higher risk (adjusted HR 1.46; 95% CI 1.28-1.67) than once-daily dosing (adjusted HR 1.15; 95% CI 1.09-1.21), researcher Morgan Erika Grams, MD, of Johns Hopkins University, Baltimore, and colleagues wrote in the journal JAMA Internal Medicine, published online Jan. 11.
“The risk was specific to PPI medications because the use of H2 receptor antagonists, which are prescribed for the same indication as PPIs, was not independently associated with CKD,” the researchers wrote.
Proton pump inhibitors are among the most widely prescribed and overprescribed medications. Studies suggest that between 25% and 70% of prescriptions written for the drugs in the U.S. do not have appropriate medical indications, the researchers wrote.
They noted that since their introduction more than 2 decades ago, PPIs use has been linked to several uncommon adverse events in a series of observational studies, including pneumonia, C. difficile infection, acute interstitial nephritis, and acute kidney injury.
“When PPIs first came out they were thought of as a miracle drug with no associated side effects,” said Adam Jacob Schoenfeld, MD, of the University of California San Francisco, who wrote an editorial accompanying the latest research.
“Over the years evidence has emerged which shows pretty convincingly that their use is probably associated with a number of side effects, even though these side effects are rare,” he told MedPage Today. “There is no doubt that people with severe GERD benefit, but there is also no doubt that these drugs are overprescribed.”
In the newly published study, the researchers used data from the NIH-funded Atherosclerosis Risk in Communities (ARIC) study to examine the association between PPI use and incident CKD. The analysis included 10,482 study participants with estimated glomerular filtration rates of at least 60 mL/min/1.73 m2 who were followed from their baseline examinations between early 1996 and early 1999 to the end of 2011.
A replication cohort of 248,751 enrollees in the Geisinger Health System with similar estimated glomerular filtration rates were also included in the analysis.
PPI use was self-reported in the ARIC cohort and determined by outpatient PPI prescription in the Geisinger cohort. Incident CKD was defined using diagnostic codes at hospital discharge of death in the ARIC group and by sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 in the Geisinger cohort.
The mean age of the ARIC cohort was 63 and 43.9% were male. At baseline, PPI users in both cohorts were more likely to be Caucasian, obese and users of antihypertensive drugs, aspirin and statins.
Among the study findings:
In the ARIC cohort, PPI use was associated with incident CKD in unadjusted analysis (hazard ratio 1.45; 95% CI 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR 1.50; 95% CI 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR 1.35; 95% CI 1.17-1.55)
The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR 1.39; 95% CI 1.01-1.91) and with propensity score–matched non-users (HR 1.76; 95% CI 1.13-2.74)
In the Geisinger cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI 1.20-1.28), with twice daily dosing associated with a larger risk than once daily dosing
It has been suggested that the possible impact of PPIs on acute kidney injury is mediated through acute interstitial nephritis, and Schoenfeld suggested that repeated insults from acute injury could potentially lead to chronic kidney damage.
“Obviously more studies are needed to examine this,” he said. “These are relatively rare side effects.”
In their editorial, Schoenfeld and UCSF colleague Deborah Grady, MD, wrote that PPIs should be prescribed cautiously to patients at high risk for kidney disease, as well as other conditions that may be linked to the drugs, including hypomagnesemia, C. difficile infection, and osteoporotic fracture.
“In patients with symptomatic gastrointestinal reflux, ulcer disease and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms,” they wrote. “However, for less serious symptoms and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits.”

Anaemia in Chronic Kidney Disease.


In patients with chronic kidney disease, normochromic normocytic anaemia mainly develops from decreased renal synthesis of erythropoietin. The anaemia becomes more severe as the glomerular filtration rate (GFR) progressively decreases. No reticulocyte response occurs, red blood cell survival is decreased and there is an associated increased bleeding tendency due to uraemia-induced platelet dysfunction.

Iron deficiency is also common in patients with chronic kidney disease (CKD). The iron deficiency may be absolute, often due to poor dietary intake or sometimes occult bleeding, or functional, when there is an imbalance between the iron requirements of the erythroid marrow and the actual iron supply. Iron deficiency leads to a reduction in formation of red cell haemoglobin, causing hypochromic microcytic anaemia. Other causes for anaemia in chronic kidney disease include the presence of uraemic inhibitors (eg, parathyroid hormone, inflammatory cytokines), reduced half-life of circulating blood cells and deficiencies of folate or vitamin B12.

  • Studies of patients with CKD have shown that the prevalence of anaemia (defined as a haemoglobin level less than 12 g/dL in men and postmenopausal women and less than 11 g/dL in premenopausal women) is about 12%.[3]
  • The National Health and Nutrition Examination Survey (NHANES) III study showed that the prevalence of anaemia increases as eGFR falls. Data collected in 2007-2010 showed that anaemia was twice as prevalent in people with CKD (15.4%) as it was in the general population (7.6%). The prevalence increased with the stage of CKD, from 8.4% at stage 1 to 53.4% at stage 5.[1]
  • In patients with CKD, patients with diabetes are at a greater risk of developing anaemia earlier in the course of their disease (associated with inappropriately low levels of erythropoietin). Comparing patients with similar eGFR and erythropoietin levels, those with type 2 diabetes are generally more anaemic.[3]
  • It is often diagnosed by routine review blood tests.
  • Renal anaemia may lead to the onset or aggravation of lethargy, cold intolerance and loss of stamina.
  • Anaemia increases cardiac output, therefore contributing to the development of left ventricular hypertrophy and dilatation.

Causes of anaemia in patients with CKD, other than renal failure itself, include:

Investigate patients with CKD if their haemoglobin falls to 11 g/dL or less, or they get symptoms due to anaemia, such as tiredness or breathlessness.[3]

This will involve ruling out other causes of anaemia, assessment of kidney function, assessment of any cardiovascular and other complications of anaemia or CKD.

  • Kidney function, eGFR and electrolytes.
  • FBC, blood film, iron studies (ferritin, transferrin saturation, iron), B12 and folate. Where ferritin is <100 μg/L there is iron-deficiency anaemia. If ferritin is above this level, a functional iron deficiency (and hence a requirement for iron supplementation) is defined by the percentage of hypochromic red cells >6% (if test is available) or otherwise a transferrin saturation <20%.[3][4]
  • Other investigations will be determined by likely alternative diagnoses and cardiovascular effects of anaemia – eg, TFTs, renal ultrasound, echocardiography, investigations for gastrointestinal bleeding.
  • Any patient with CKD presenting with anaemia:
    • Should be referred to the local specialist renal department for full assessment and management. Clinical assessment should include an assessment of nutrition, general well-being and other possible causes for anaemia (eg, occult blood loss).
    • Blood pressure should also be checked and any other factor suggesting acute on chronic kidney disease – eg, infection.
    • The basic blood test investigations as outlined above should be sent (ensuring the results are available at the renal department).
  • Management of anaemia should be considered in people with anaemia of CKD when the haemoglobin level is less than or equal to 11 g/dL (or 10 g/dL if under 2 years of age).
  • In people with anaemia of CKD, treatment should aim to maintain stable haemoglobin levels between 10 and 12 g/dL for adults and children aged over 2 years and between 9.5 and 11.5 g/dL in children aged under 2 years.
  • Treatment with erythropoiesis-stimulating agents should be offered to patients with anaemia of CKD who are likely to benefit in terms of quality of life and physical function.[5] There are few studies comparing the efficacy of the various agents. One study reported that darbepoetin alfa weekly or every two weeks was more efficient in achieving target haemoglobin than those on weekly epoetin alfa, with fewer dose changes and minor vascular access complications.[6]
  • The time taken for erythropoetin treatment to be effective will depend on individual patient factors, such as degree of anaemia, degree of kidney disease and presence of other adverse factors – eg, iron deficiency.
  • Contra-indications for erythropoetin treatment include uncontrolled hypertension.[7]
  • Potential side-effects of erythropoetin include increase in blood pressure or aggravation of hypertension, headache, increase in platelet count, influenza-like symptoms (may be reduced if intravenous injection is given over five minutes), thromboembolic events, pure red cell aplasia, hyperkalaemia and skin reactions.
  • Increasing concerns over the risk of cardiovascular events have led to a reduction in the use of erythropoetins as a group in recent years.[8]
    There have been very rare reports of pure red cell aplasia in patients treated with epoetin alfa. The Commission on Human Medicines has advised that in patients developing epoetin alfa failure with a diagnosis of pure red cell aplasia, treatment with epoetin alfa must be discontinued and testing for erythropoietin antibodies considered. Patients who develop pure red cell aplasia should not be switched to another erythropoietin.[7]
  • Monitoring: in people with anaemia of CKD, haemoglobin should be monitored:
    • Every 2-4 weeks in the induction phase of erythropoiesis-stimulating agent therapy.
    • Every 1-3 months in the maintenance phase of erythropoiesis-stimulating agent therapy.
    • More actively after dose adjustment of the erythropoiesis-stimulating agent.
    • Epoetin alfa:
      • Epoetin (recombinant human erythropoietin) is used for the anaemia associated with erythropoietin deficiency in CKD. The clinical efficacy of epoetin alfa and epoetin beta is similar.
      • It is also used to increase the yield of autologous blood in normal individuals and to shorten the period of anaemia in patients receiving cytotoxic chemotherapy.
      • Epoetin beta is also used for the prevention of anaemia in preterm neonates of low birth weight.
    • Darbepoetin:
      • Is a hyperglycosylated derivative of epoetin which has a longer half-life and may be administered less frequently than epoetin.
    • Methoxy polyethylene glycol-epoetin beta:[9]
      • Is a continuous erythropoietin receptor activator. It is licensed for the treatment of anaemia associated with CKD in patients who are symptomatic. It has a longer duration of action than epoetin.
  • Other factors which contribute to the anaemia of CKD (eg, iron or folate deficiency) should be corrected before treatment and monitored during therapy.
  • Aluminium toxicity, concurrent infection or other inflammatory disease may impair the response to erythropoietin.[7]
  • People receiving erythropoiesis-stimulating agent maintenance therapy should be given iron supplements (often requires intravenous iron) to keep their:
    • Serum ferritin between 200 and 500 μg/L and either:
      • The transferrin saturation level above 20% (unless ferritin is >800 μg/L); or
      • Percentage hypochromic red cells less than 6% (unless ferritin is >800 μg/L).
  • In view of the concerns about the adverse effects of erythropoietins, other therapeutic options are being explored. These include hypoxia inducible factor-1 alpha (HIF-1α) stimulators. HIF-1α is known to be associated with oxygenation of the kidney tubule.[8]
  • Clinically relevant hyperparathyroidism should be treated in order to improve anaemia management in patients with anaemia of CKD.
  • Where possible, blood transfusions should be avoided in patients in whom kidney transplant is a treatment option.
  • Untreated anaemia of CKD is strongly associated with cardiovascular and renal complications, resulting in increased hospitalisations and mortality.Therefore, correcting anaemia is considered an important part of slowing or even stopping the progression of CKD.[10]
  • Treatment with recombinant human erythropoietin in pre-dialysis patients corrects anaemia, avoids the requirement for blood transfusions and also improves quality of life and exercise capacity.[11][12]

Restricting the progression of CKD – eg, smoking cessation, optimal control of diabetes.

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