Changing dynamics of adynamic bone disease

by Divya Bajpai, MD (@divyaa24)

Disorders of mineral and bone metabolism (MBD) commence early in the course of chronic kidney disease (CKD). Kidney Disease Improving Global Outcomes (KDIGO) recommends the term CKD-MBD to describe this systemic disorder and restricts the use of the term renal osteodystrophy to define the bone histologic lesions. CKD-MBD is defined as an abnormality of one or more of the following:

A. Calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism.

B. Bone turnover, mineralization, volume linear growth, or strength.

C. Vascular or another soft-tissue calcification.

Bone turnover is an ongoing process of bone resorption which is replaced by the formation of new bone. Adynamic bone disease is characterized by a decrease in the number of bone cells (both osteoblasts and osteoclasts) associated with decreased accumulation of osteoid (osteoid volume <12% -15%), and no (or minimal) bone marrow fibrosis. It must be differentiated from another common low bone turnover disease - osteomalacia in which bone mineralization exceeds the defect in collagen synthesis by osteoblasts, resulting in increased osteoid formation.

Pathogenesis of low bone turnover in CKD

The major factor underlying adynamic bone disease (ABD) is either suppression of PTH release or resistance of PTH action on bones. The incidence of ABD has increased exponentially making it the most common form of renal osteodystrophy in dialysis patientsat present. This can be attributed to exogenous calcium loading via dialysate or via calcium-based phosphate binders but is primarily due to the evolution of effective measures to suppress PTH, like active vitamin D analogs and calcimimetics. Other possible risk factors like increased age and diabetes may also contribute to the rising incidence of ABD. Calcimimetics activate the calcium-sensing receptor (CaSR) on the parathyroid glands to suppress PTH release. In patients with chronic kidney disease, even higher than normal PTH levels are inadequate to maintain bone turnover. This is ascribed to the resistance to bone stimulatory effects of PTH due to the uremic milieu. Several mechanisms have been postulated to explain this PTH hyporesponsiveness – PTH receptor downregulation in the bone, decreased levels of bone morphogenetic proteins, increased levels of osteoprotegerin, uremic toxins, accumulation of N-terminal truncated PTH molecular species, and inhibition by inflammatory cytokines (figure 1). Due to this PTH resistance, serum PTH is not an optimal marker of bone turnover.

Clinical features and diagnosis

The majority of patients with ABD are asymptomatic; however, some may develop bone pain that results from the impaired ability to heal micro-fractures. Axial skeletal pain is a hallmark of aluminium-related ABD. These patients are at higher risk of fractures with PTH levels <195 pg/dL predicting fracture risk in a retrospective analysis. Additionally, there is a risk of developing hypercalcemia due to reduced buffering of calcium load by bones. Finally, ABD predisposes patients to vascular calcification which may add to the cardiovascular risk associated with CKD.

Documenting reduced bone formation rate (>1SD below the mean) on double-labeled bone biopsy from the anterior iliac crest remains the gold standard for the diagnosis of ABD. However, bone biopsies are invasive and their interpretation is difficult, hence they are rarely performed. Thus, surrogate markers of bone turnover like serum PTH, bone-specific alkaline phosphatase (BSAP), and serum C-telopeptide crosslink can be used. In patients on dialysis, a persistently low serum PTH (<100 pg/mL) is highly suggestive of ABD, especially in the presence of hypercalcemia. In patients not on dialysis, the progressive decreasing trend of PTH levels to less than the upper limit of normal (65 pg/ml) may reflect ABD. In the setting of unexplained hypercalcemia or bone pains and intermediate PTH levels, serum BSAP levels can be measured. Elevated BSAP levels (≥20 ng/mL) can rule out the diagnosis of ABD.

Can ABD occur in earlier stages of CKD?

ABD is common in patients on dialysis but its prevalence in earlier stages of CKD is less known. On reviewing bone histology studies from 1983 to 2006 the KDIGO Work Group found that the prevalence of ABD increased over the years and was present in up to 18% of patients with CKD stages 3 to 5.

Published in the recent issue of KI reports, the study by Husseini et al evaluates renal osteodystrophy and vascular calcification (VC) in 32 patients with CKD stages II to IV (mean eGFR = 44 ± 16 ml/min per 1.73 m2). Patients with systemic illnesses, which could potentially affect bone health, were excluded. Also, patients on treatment affecting bone metabolism (except calcium and parent vitamin D) like vitamin D analogs, bisphosphonates, calcimimetics, systemic anticoagulants, glucocorticoids, and other immunosuppressants were excluded. All patients underwent serum bone marker analysis, dual-energy X-ray absorptiometry (DXA) assessment, thoracic computed tomography for VC scoring, anterior iliac crest bone biopsy for mineralized bone histology, histomorphometry, and Fourier transform infrared spectroscopy (FTIR). Low bone turnover was found in 84% of patients. An inverse relationship was found between eGFR and bone turnover (in caucasian participants), which remained after adjustment for age and the presence of diabetes. The occurrence of low bone turnover in this cohort with moderately increased PTH levels despite the use of PTH lowering therapies indicates that secondary hyperparathyroidism is an adaptive mechanism to overcome the PTH hypo-responsiveness and maintain bone health in the early stages of CKD. With the use of FITR, they showed impaired mineral-to-matrix ratios in the early stages of CKD which correlate with reduced fracture resistance. Coronary artery calcification was found in 72% and 81% had aortic calcifications. They correlated negatively with bone formation rate and trabecular bone scores.

Visual abstract by @divyaa24

Despite being limited by the cross-sectional design and small sample size, this study employed a comprehensive evaluation of bone metabolism including an assessment of bone quality by FITR. The association of abnormal bone quality with VC in early CKD is intriguing and paves the path for future longitudinal studies. This study also underscores the need for control of risk factors and a high degree of suspicion for early diagnosis and management.

Social Inequities and Access to Kidney Replacement Therapies in Children

By Swasti Chaturvedi, MD (@SwastiThinks)

Social inequities play a significant role in the initiation and progression in chronic kidney disease (CKD) From disadvantage to end-stage renal disease; Progression of chronic kidney disease in rural Manitoba Indigenous communities.

Low socioeconomic status (SES) is associated with increased prevalence of low birth weight and prematurity which has been shown to be linked to a lower nephron mass Early-life course socioeconomic factors and chronic kidney disease There are significant pathophysiological links between low nephron endowment and subsequent kidney disease in adulthood Is low birth weight an antecedent of CKD in later life?. Furthermore, low SES has been associated with reduced glomerular filtration rate, higher albuminuria and higher risk of end stage kidney disease (ESKD) Socioeconomic disparities in chronic kidney disease.

Low SES also impacts access to kidney replacement therapy (KRT). Various studies among adult CKD patients have identified reduced access to KRT and transplant among lower SES or socially disadvantaged populations Indigenous people. Previous studies have recognized multiple barriers that contribute to longer waiting times and poorer transplant access among socially deprived populations such as Indigenous patients. Some of the factors include remoteness, poor access to tertiary dialysis and transplant center access, healthcare practitioner’s attitudes and limited health care literacy IMPAKT. These disparities are further amplified in countries where there is lack of or inadequate universal health coverage and patients need to pay for their treatment Burden, Access, and Disparities in Kidney Disease.

There are very few studies investigating the role of social deprivation in children undergoing KRT initiation in countries with a universal health system. A recent KI Reports Australian study found that Australian Aboriginal children and young adults have rising incidence of ESKD and had poorer access to kidney transplant Rising Incidence of End-Stage Kidney Disease. A study from the United Kingdom found that social deprivation was not associated with late referral, but was strongly associated with reduced access to pre-emptive kidney transplantation Associations between Deprivation.

This brings us to our current study, Social Deprivation Is Associated With Lower Access to Pre-emptive Kidney Transplantation and More Urgent-Start Dialysis in the Pediatric Population by Driollet et al, which examined the association between socioeconomic factors and the different indicators at kidney replacement therapy (KRT) initiation in the French pediatric End Stage Kidney Disease (ESKD) population.

This cross-sectional study included all patients with ESKD who started KRT before 20 years of age in metropolitan France between 2002 and 2015. Data were collected from the comprehensive French Renal Epidemiology and Information Network (REIN), a national KRT registry.

The authors investigated different scenarios at KRT initiation including:

1. KRT modality (dialysis vs. pre-emptive transplantation)

2. Timing of referral to a nephrologist and

3. Dialysis modality

Patients who initiated on KRT were further divided into:

1. Haemodialysis (HD) vs. peritoneal dialysis (PD)

2. Urgent vs. planned start of dialysis

3. Use of catheter vs. use of fistula for HD vascular access.

The authors used European Deprivation Index (EDI), a validated ecological index of deprivation as a proxy for social deprivation. The authors used the continuous version of the EDI and its quintiles to categorize each patient into each 5 groups of deprivation, from the least deprived (Q1) to the most deprived (Q5).

Of the 1262 eligible patients, 31 were excluded because they had not reached ESKD before KRT (Figure 1). Among the remaining 1231 children, 116 were further excluded because of missing residential address data. A total of 1115 patients were thus included in the main statistical analysis.

Figure 1: Flow chart showing the screening and selection of children in the study from the French renal registry (REIN), 2002 to 2015.

Among the 1115 patients included, 59% were males and the median age at KRT initiation was 14.4 years. Most patients were from urban areas (79%) and the commonest cause of ESKD was glomerular or vascular disease (36.8%) (Table 1).

Not surprisingly, the majority of patients started KRT with dialysis (approximately 80%), and only 38.4% were registered preemptively on the transplant waiting list. Interestingly, in terms of patient distribution, quintile 1 to 4 (Q1-Q4) each had 12% to 20% of patients, whereas 39% patients belonged to the most deprived quintile (Q5), thus suggesting that the pediatric ESKD patients came from the most deprived backgrounds.

Patients in Q1 to Q3 of EDI were more likely to be placed preemptively on the waiting list (~48%) than those from quintiles Q4 and Q5 (~ 33%), and patients in Q1 were younger at registration than in Q5 (13.7 years vs. 15.1 years). Moreover, patients in Q1 started dialysis less frequently with HD than those in Q5 (46.0% vs. 65.0%) and more often received a preemptive kidney transplantation (25.8% vs. 15.5%) (Table 2)

Furthermore, the odds of initiating KRT with dialysis (vs. pre-emptive transplantation) increased with increasing EDI even after adjusting for potential confounders (Figure 2) and was almost twice as high for children from the most deprived than for the least deprived area (Q5 vs. Q1: aOR 1.88, 95% CI 1.15–3.07) (Table 3).

Among those who started dialysis, urgent initiation, use of a catheter (vs. arteriovenous fistula) and late referral were seen in more deprived children (Figure 2 andTable 3).

Figure 2: Association between social deprivation measured by the EDI (in continuous) and care indicators at kidney replacement therapy initiation in young patients in Metropolitan France. Adjusted for age at KRT initiation (spline), context of rural environment (rural/urban), and primary kidney disease (4 categories).

The current study does have significant strengths and limitations. A strength of the study was the use of the comprehensive nationwide REIN registry, use of a validated SES index and consideration of multiple important outcomes. A limitation of the study was that the authors could not take into account patient comorbidities, due to missing data. However, the authors have previously shown that adjusting for comorbidities did not affect the results in a prior study investigating the association between EDI and kidney graft failure.

To conclude, this study suggests that lower socioeconomic status is associated with poorer outcomes due to limited access to providers and pre-emptive transplantation. This inequity may lead to the loss of vital productive years in this population of French children.

This study and previous studies highlight the urgent need for policy level changes in reducing the risk of urgent-start dialysis and optimizing access to kidney transplantation in socially deprived children.

The visual abstract by @galindozip summarizes the study.

Read more about how social inequities impact kidney health around the world, and what can be done about them, in the recently concluded NephMadness Social Inequities blog #NephMadness 2022: Inequities Region – AJKD Blog

Sodium Glucose Co-Transporter 2 Inhibitors and Kidney Disease: The Past, Present, and Future

By: Sai Santhoshini Achi, MD MBA (@SaiAchi01)

For decades, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were the main agents available to slow the progression of diabetic kidney disease (DKD). More recently, sodium glucose co-transporter 2 inhibitors (SGLT-2i) emerged as central players in CKD progression reduction, essentially stealing the limelight from our tried and true renin-angiotensin-aldosterone system inhibitor (RAASi) mainstays.

The first SGLT2i study with primary renal endpoints, the CREDENCE trial, showed that canagliflozin slows the progression of CKD to ESKD and cardiovascular or renal death in patients with type 2 diabetes with albuminuria. In DAPA-CKD, summarized beautifully in this NephJC article, investigators demonstrated that dapagliflozin reduced progression of CKD regardless of diabetes mellitus status. Along with numerous other cardiovascular SGLT2i trials, CREDENCE and DAPA-CKD were foundational in placing SGLT2i center stage in the management of CKD and establishing it as a mainstay in goal directed therapy.

In the same year as DAPA-CKD, results of the FIDELIO-DKD trial were released, which looked at the effect of finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) in chronic kidney disease and type 2 diabetes. The association of mineralocorticoid receptor overactivation with renal and cardiovascular disease has been well-described. Non-steroidal MRAs are thought to have greater antifibrotic and anti-inflammatory effects with fewer gonadal effects compared to their steroidal MRA counterparts. Steroidal MRAs like spironolactone and eplerenone have been effective in reducing albuminuria in patients with chronic kidney disease and type 2 diabetes clinically, but have fallen short in demonstrating statistical benefit in reducing the risk of kidney disease progression. Results of the FIDELIO-DKD trial demonstrated that finerenone resulted in lower risk of CKD progression and cardiovascular events compared to placebo in patients with CKD and type 2 diabetes. The FIGARO-DKD trial studied the effects of finererone in patient populations that were understudied or excluded in the FIEDLIO-DKD trial. FIGARO-DKD showed a reduction of cardiovascular events in patients with CKD, and a slowing of the progression to ESKD, even in patients with more mild kidney disease.

Which brings us to our current study, The Kidney Protective Effects of the Sodium–Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists by Provenzano et al, which examined the benefits of SGLT-2 inhibitors in combination with MRAs. Specifically, investigators sought to determine if there are additive benefits in CKD similar to the combination therapy recommended for patients with heart failure with reduced ejection fraction.

The study was a subgroup analysis of the DAPA-CKD trial evaluating the efficacy of dapagliflozin in those patients who were treated with MRAs compared with patients who only received SGLT-2 inhibitors. It was a time-to-event analysis assessing the effects of dapagliflozin compared with placebo. Eligible members were adults with or without DM, eGFR between 25 to 75 ml/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) 200 to 5000 mg/g. All patients were on an ACEi or ARB for at least 4 weeks prior to study initiation and could be on MRAs as well. Participants were followed for 2 weeks after study initiation, at 2 and 4 months, and then at 4 month intervals afterwards. Of the 4304 participants, 229 were treated with MRAs at baseline, 109 were in the dapagliflozin group and 120 were in the placebo group. Table 1 below highlights the baseline characteristics of the participants.

Interestingly, those patients included for evaluation were more frequently males and more likely to have histories of heart failure, DM, higher BMI, and higher UACR. Those receiving MRAs were also more likely to be receiving other cardiovascular therapies. The benefits of dapagliflozin in patients with CKD with and without type 2 DM were still seen whether or not the patients were on MRAs.

Regardless of MRA use, those patients in the dapagliflozin group had a slower decline eGFR versus placebo. The study concluded that the use of SGLT-2 inhibitors and MRAs in combination appears beneficial and warrants further study.

The nephro-protective effects of SGLT-2 inhibitors and MRAs may be explained through a few mechanistic pathways. Both affect hemodynamics and decrease the intraglomerular pressure thereby allowing for the long term stabilization of the kidney function. The improvement of systemic blood pressure is also beneficial in decreasing cardiovascular and kidney disease. In addition, SGLT-2 inhibitors have been shown to improve tubular oxygen and reduce tubular hypoxic stress. Finally, MRAs deactivate the mineralocorticoid receptors in the fibroblasts, thereby leading to a reduction in renal fibrosis and glomerulosclerosis.

Other interesting data suggest promise in studying the combination effects of MRAs and SGLT-2 inhibitors. First, MRAs have been shown to cause hyperkalemia and SGLT-2 inhibitors provide the opposite effect. In the DAPA-CKD trial, regardless of MRA use, fewer patients experienced hyperkalemia thereby giving a rationale for the efficacy of combination of SGLT-2 inhibitors and MRA therapies in those patients with CKD and heart failure. While MRAs block the effects of aldosterone in the kidney, leading to hyperkalemia, SGLT-2 inhibitors increase tubule sodium delivery to the distal nephron, leading to potassium excretion.

The current study does have significant limitations. Given the small number of patients on combination MRA and SGLT-2 inhibitors, and the fact that some were on MRAs prior to study initiation, makes interpretation of the combined effect of these medications difficult.

That being said, the study showed no harm from the combined effect of MRAs and SGLT-2 inhibitors. There has already been a preclinical rat study of the cardio-renal disease pattern which showed that a combination of finererone and empagliflozin have a synergistic effect on lowering albuminuria and improved survival in comparison to single agent therapy.

This study highlighted that in patients receiving MRAs and SGLT-2 inhibitors, the combination therapy was safe and efficacious in reducing unfavorable kidney outcomes. Further prospective studies, in patients with varying severity of cardiovascular and kidney disease, will help determine which patients are most likely to benefit from combination therapy.

The visual abstract below wonderfully summarizes the study.

Visual abstract by Sophia Ambruso (@Sophia_Kidney)