Osteoporosis treatment in patients with renal failure: the gray zone...

Chronic kidney disease (CKD) patients develop significant changes in bone mineral density (BMD) and bone structure, which together with an increased risk for falls, put them at high risk for fracture. This can be due, in part, to renal osteodystrophy, since bone loss and reduced bone quality may be present in both low- (osteomalacia and adynamic bone disease) and high-turnover bone disease (osteitis fibrosa and mixed uremic osteodystrophy). In addition, some patients may have underlying traditional risk factors for bone loss, such as early menopause or smoking. The heterogeneity of bone loss in patients with CKD complicates its management, requiring frequently a combination of interventions. Performing a bone biopsy is the gold-standard to characterize potential etiologies though not frequently available in most centers. 


 One of the major challenges of treatment of osteoporosis in patients with eGFR below 30 mL/minute is the limited available data. Bisphosphonates are usually not advocated in this population since most agents have renal clearance and patients were frequently excluded from clinical trials. Post-hoc analyses of studies in postmenopausal women with grades 4 and 5 CKD and a definite diagnosis of osteoporosis revealed efficacy and short-term safety of bisphosphonates, denosumab, and raloxifene in addition to calcium and vitamin D supplementation. Bisphosphonates demonstrated increase in BMD, and reduction in vertebral fracture incidence regardless of degree of renal dysfunction. To date, anti-osteoporotic agents have not been recommended in CKD stage 5D due to lack of data on security and on its beneficial impact against fracture. Though some small studies have reported an amelioration of BMD with these drugs in hemodialysis patients. 

Monitoring: 

Patients with severe renal impairment are at higher risk for hypercalcemia due to calcium and vitamin D supplements, or for hypocalcemia if taking denosumab therapy. Therefore, serum calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D should be monitored at least every four months. Furthermore, renal function should be routinely measured in patients taking bisphosphonates. Markers of bone turnover, including but not limited to C terminal telopeptide (CTX), N terminal telopeptide (NTX), and pyridinolines (PYR) are metabolized and/or excreted renally, and will accumulate in renal dysfunction. Therefore, they should not be used to monitor response to therapy in patients with eGFR below 30 mL/minute. Despite neither predicting fracture risk nor the type of renal osteodysthrophy, bone densitometry of the hip and spine may be performed to monitor for changes in BMD. In complex patients, a bone biopsy should be considered prior to initiating osteoporosis treatment. 

Recommendations: 

• For patients with low BMD (T-score below 2.5) associated with fragility fracture and grades 4 or 5 CKD, pharmacologic therapy might be considered after excluding all other CKD-related low BMD diagnoses. 

• Adjusted dose of oral bisphophonates are typically recommended based on clinical experience and existing data. 

• Intravenous (IV) bisphosphonates should be used as a last resort only in patients who cannot tolerate previous therapies and are at high risk for multiple fractures. 

• Nephrotoxicity is a significant potential problem with IV bisphosphonates (Zoledronic acid). It is dependent on both dose and infusion rates. 

 • The patterns of nephrotoxicity from IV bisphosphonates include acute tubular necrosis and collapsing focal segmental glomerulosclerosis. 

 • Strict adherence to guidelines for monitoring renal function prior to each dose and temporarily withholding therapy in the setting of renal insufficiency, may help prevent nephrotoxicity from these agents. Denosumab can be an interesting alternative since it is not renally excreted. Further studies are required in patients with CKD. 

• Medications that increase bone formation, such as teriparatide and anti-sclerostin monoclonal antibodies (romosozumab and blosozumab) seem to be promising alternatives for treating osteoporosis in CKD patients with low-turnover bone disease.

Sandra El Hajj, PharmD

Steven Gabardi, PharmD, BCPS, FCCP

Fellype Barreto, MD, PhD

Leonardo Riella, MD, PhD

Additional References: 

1.        Miller PD,Roux C, Boonen S, et al. Safety and efficacy of risedronate in patients withage-related reduced renal function as estimated by the Cockcroft and Gaultmethod: a pooled analysis of nine clinical trials. J Bone Miner Res 2005;20:2105

2.         Jamal SA,Bauer DC, Ensrud KE, et al. Alendronate treatment in women with normal toseverely impaired renal function: an analysis of the fracture interventiontrial. J Bone Miner Res 2007; 22:503

3.   Ishani A,Blackwell T, Jamal SA, et al. The effect of raloxifene treatment inpostmenopausal women with CKD. J Am Soc Nephrol 2008; 19:1430.

4.       Jamal SA, Ljunggren O, Stehman-Breen C, et al.Effects of denosumab on fracture and bone mineral density by level of kidneyfunction. J Bone Miner Res 2011;26(8):182

UMOD, Translational Nephrology! Contender for Top 10 of 2013

Genome-wide association studies (GWAS) are large population based collaborative studies seeking genetic patterns that would explain common complex phenotypes. These large studies have given us much insight into the genetic risk profile of patients with diseases such as chronic kidney disease and hypertension. Frequently the genetic markers described as risk genotypes are single nucleotide polymorphisms (SNPs) that lie in regions of the genome yet to be ascribed a functional role. Trudu et al in Nature Medicine this month describe a beautiful set of experiments that explain how risk variants for CKD and hypertension found by GWAS effect blood pressure regulation at the molecular level.

A number of GWAS have described risk SNPs in the promoter region of UMOD (1, 2, 3,4, 5, 6, 7). The UMOD gene codes for uromodulin or Tamm-Horsfall protein, which is secreted into the urine by cells of the thick ascending loop of Henle (TAL). Uromodulin has been shown to reduce UTIs and regulate NKCC2 and ROMK, the two main channels responsible for NaCl transport in the TAL. Furthermore, UMOD mutations cause dominantly inherited CKD (MCKD2). Susceptibility variants found in the UMOD gene are at high frequency in the general population and confer a 20% increased risk of CKD and 15% risk of hypertension.

This paper set out to uncover the biological mechanism that would explain the increased CKD and hypertension in patients with these risk genotypes. They looked specifically at the 2 lead variants located in the UMOD promotor region. Briefly, in human nephrectomy samples (removed due to RCC), those with the risk genotypes had higher uromodulin expression than those with non-risk genotypes. They confirmed this association of UMOD promotor risk variants and higher urinary uromodulin in large population-based cohort (SKIPOGH). In mouse-models, mice over-expressing UMOD had higher blood pressures and more LVH than controls and had more interstitial pathology (despite normal renal function) than controls. They then showed that mice over-expressing UMOD had more active NKCC2 (furosemide sensitive channels) than controls. They also showed that the higher BP in UMOD over-expressing mice could be dropped to baseline levels by furosemide (all mice had comparable levels of ENaC and NCC). More work was done to further elucidate the mechanism of NKCC2 phosphorylation by UMOD. Finally the authors bring their attention back to humans. They used a never-treated human hypertensive cohort (MI_HPT) and stratified them according to one of the risk variant genotypes (rs4293393). Patients homozygous for the risk genotype had statistically significant higher baseline diastolic BP. Some of these patients underwent furosemide testing. Patients with the homozygous risk allele had a higher natriuretic response and diastolic BP drop than others (both statistically significant). To summarize the authors conclusions; patients with risk alleles in the UMOD promotor had greater risk of hypertension and CKD. These patients made more uromodulin. Uromodulin increases NKCC2 activity and thus salt sensitive hypertension. Also, UMOD over-expression increases interstitial kidney damage and thus increases the risk of CKD. These risk genotypes for disease are at high frequency in all ethnicities tested. The authors suggest that selective pressure for disease related variants in UMOD is similar to the APOL1 story. The protective effect of uromodulin on UTIs and ability to raise blood pressure may have lead to its selective over-expression.

This paper demonstrates the mutual importance of large-scale studies such as GWAS and studies of rare monogenetic diseases such as Bartter and Gitelman syndromes. This paper is a worthy contender of a top ten listing this year with a truly translational set of studies combining modern basic science with clinical studies.

I also want to give a shout out for stories on new targets for ADPKD and the new AHA Cholesterol guidelines.

Cholesterol Management.

Cholesterol management, what to do?

New guidelines on managing cholesterol were published in Circulation this month by the ACC/AHA task force. As we spend much of our time in CKD clinic managing cardiovascular risk factors such as blood pressure, diabetes, lifestyle factors and cholesterol I think it is important we are up to date on the latest guidelines.

The task force based their recommendations based on randomized controlled trials based on fixed doses of statins in those at risk for atherosclerotic cardiovascular disease. The authors also emphasize the continuing importance of lifestyle modification for the reduction of ASCVD.

Those who benefit from statins are (Task Force Summary):

1. Individuals with clinical ASCVD

2. Individuals with primary elevations of LDL–C ≥190 mg/dL

3. Individuals 40 to 75 years of age with diabetes and LDL–C 70 to189 mg/dL without clinical ASCVD

4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher.

Risk calculator

The Caveats; no evidence for statin therapy in these groups:

Primary prevention in over 75s unless clinically evident ASCVD present

Those with NYHA HF class II – IV

Those on hemodialysis

Significant changes to note:

No specific LDL-C and non-HDL-C targets recommended once on statin therapy

The de-emphasis of surrogate markers such as CRP and calcium scores.

Cautious use and clinical judgment in those over 75 years without clinical ASCVD

What about renal patients?

The Task Force Authors looked at the TNT trial and the subgroup analysis from Shepard et al. The guidelines do not explicitly recommend the use of statins in CKD patients but they do highlight the beneficial findings of high dose (80mg) atorvastatin.

Shepard et al did a subgroup analysis of the TNT trial looking at secondary prevention of major cardiovascular events in patients with an MDRD eGFR less than 60. In the original TNT study patients were age 35 to 75 and patients on long-term immunosuppression or with nephrotic syndrome were excluded. At baseline patients already had an LDL-C of less than 130mg/dl. Shepard showed that 80mg of atorvastatin reduced the RR of a major CV by 32% compared with 10mg of atorvastatin.

My impression is that we should use statins in our CKD patients but remain cautious with respect to drug interactions and side effects.

Cholesterol RCTs in renal patients (a refresher on the evidence ).

4D - Die Deutsche Diabetes Dialyse Studie.

N Engl J Med, 353 (2005), pp. 238–248

This German trial looked at 18 to 80 year olds with type 2 DM on hemodialysis for less than 2 years. Patients with LDL-C outside the 80 to 190 range were excluded as were failed kidney transplant patients. After a 4 week lipid-med free wash out patients were assigned to atorvastatin 20mg or placebo. The primary outcome was a composite of cardiovascular death. About 1200 patients were enrolled for a mean of nearly 4 years. In this trial statin did reduce LDL-C levels but there was no significant difference in the primary or secondary outcomes.

AURORA.

N Engl J Med. 2009 Apr 2;360(14):1395-407

Were the 4D study focused on the high risk diabetic population on HD this trial investigated the efficacy of statin therapy in the general dialysis population. Patients were 50 to 80 years and on regular hemodialysis or filtration for 3 months. Expected transplantation within the next year or statin therapy within the last 6 months excluded patients. Randomization was to rosuvastatin 10mg or placebo and the primary endpoint was cardiovascular death or non-fatal stroke or MI. Again, statin therapy reduced cholesterol levels significantly but there was no difference in primary or secondary outcomes. Further more, there was no correlation between primary outcome and baseline LDL-C or 3 month LDL-C.

SHARP.

Lancet. 2011 Jun 25;377(9784):2181-92.

This trial attempted to look at the effects of simvastatin 20mg + ezetimibe 10mg versus placebo on major atherosclerotic events in patients with CKD with no previous MI or revascularization3. About 3000 of the 9000 patients were on dialysis. The authors concluded that combination therapy produced a relative risk reduction of 17% for major ASCVD outcomes. This trial came in for a lot of criticism mainly because the authors appeared to extrapolate their results by assuming all patients actually took their assigned meds. 2700 patients were enrolled for a mean trial length of over 3 years.

ALERT (Assessment of LEscol in Renal Transplantation)

Lancet, 361 (2003), pp. 2024–2031

This study assessed the use of statin therapy on transplant patients. Enrolled patients were between 30 and 75 and had a kidney or KP transplant for more than 6 months with stable renal function. All patients were on ciclosporin and had total cholesterol levels between 4 and 8 mmol/l. Patients were excluded if they had rejection in the last 3 months or were already on statin therapy. 2100 patients were enrolled and followed for a mean of 5 years. Randomization was to fluvastatin 40mg or placebo. The primary end point was cardiac death, non-fatal MI or coronary revascularization. Fluvastatin lowered LDL-C by 32% but there was no significant difference in the primary endpoints. Interestingly in this study only about 13% in each group had diabetic nephropathy and about 5% had ‘hypertensive nephrosclerosis’ as a cause of their primary renal failure. This study was conducted in Canada and Europe.

Aristolochic Acid Nephropathy

Aristolochic acids (AA) are found in products derived from the aristolochia genus of plants which are used extensively in herbal medicines, particularly in Asia. Nephrotoxicity resulting from AA exposure was originally described in a case series of women taking diet supplements in Belgium but has subsequently been identified in the US, Europe and Asia. Consumption of products containing AA remains endemic in some areas with an estimated exposure in up to 40% of the Taiwanese population. The disease known as Balkan endemic nephropathy – described the population living around tributaries of the Danube river- is now thought to result from contamination of wheat flour with seeds of plants containing AA.

Patients with AA nephropathy typically present with renal insufficiency and anemia. Urinalysis reveals a few red cells and mild proteinuria. The rate of decline of renal function varies but may depend on the cumulative dose of AA. Renal histology is characterized by extensive interstitial fibrosis with tubular atrophy and low numbers of inflammatory cells. There is a very high incidence of urothelial atypia and carcinoma. Exposure to AA can be confirmed by the presence of AA-DNA in biopsy tissue. 

Therapy consists of routine management of CKD alongside regular screening for urothelial malignancy. A trial of steroids can be considered in selected patients. The risk of urothelial malignancy is so high that some consider patients for bilateral nephrouretecomy once RRT as been established.

Despite being banned in many countries, products containing AA remain available. The true incidence of CKD and urothelial malignancy resulting from AA exposure remains unknown. It is possible that a lack of awareness means that a significant proportion of AA resulted morbidity remains undiagnosed.  For a comprehensive review of the subject see here.

Image from Wikipedia.

Posted by Jonathan Dick

Statins and Chronic Kidney Disease

There is an excellent review of the use of statins is CKD in KI from last month. The authors point out that the association between LDL cholesterol and CVD is not as strong in patients with CKD, particularly in stages IV and V. In fact, the clearer association between hypertriglyceridemia, low HDL and CVD in patients with advanced CKD suggests that statins may not be the best treatment in this setting. The results of clinical trials are conflicting. However, the authors of the current study came up with some suggested guidelines for the management of hyperlipidemia in CKD reproduced below:

1. LDL cholesterol-lowering strategies include either statins or ezetemibe, or both, and target the reduction of LDL to <70 mg/dl as recommended for patients with CVD or an equivalent disorder in the general population
2. Start LDL cholesterol-lowering treatment in stages 1-4 CKD patients with preexisting CV events or those with multiple risk factors and at high risk for coronary heart disease and LDL cholesterol > 70 mg/dl
3. Continue LDL cholesterol-lowering strategies in patients developing CKD stage 1 or more or those starting dialysis who were previously on such treatment
4. Do not use LDL cholesterol-lowering strategies in CKD patients with inflammation/malnutrition, nor start such treatment in dialysis patients who are treatment-naive until additional literature data in favor of a different therapeutic approach become available

What do you think? Do these recommendations make sense?

Thromboembolic Prophylaxis in Patients with AFib and CKD: Caught between the Devil and the Deep Blue Sea

I often get curb-sided by cardiologists and internists for my opinion on using warfarin or other anticoagulants for thromboembolic risk prophylaxis in CKD +/- Afib patients. A similar conundrum of using anticoagulation for stroke prophylaxis in dialysis patients was discussed about three years ago on this blog by Conall. Like many other issues in patients with CKD, things are not always black-and-white, and a lot could depend on patient and physician preference.  This often makes the “right answer” a confusing exercise, since CKD patients are also at a higher bleeding risk. Most randomized trials addressing this issue have excluded patients with a GFR below 30. Furthermore, newer direct thrombin inhibitors (dabigatran), or Factor Xa inhibitors (apixaban, rivaroxaban) are available, which might be better than warfarin, at least in the early-CKD patient (although the lack of a reversing antidote is a potential pitfall). Finally, warfarin has a well-established link with vascular calcification (a mortality risk) in dialysis patients. As nephrologists, it is imperative that we are knowledgeable about the best-available data that can help us make an evidence-based recommendation, and so I put together a concise decision-table with links to primary literature sources.

In addition to the “traditional” risk factors for stroke in patients with AFib (as exemplified by the acronym CHADS), it is known that CKD itself is an independent risk factor for stroke. Thus CKD patients, both with, and without AFib, are at an increased risk of stroke. This has been demonstrated in CKD as well as dialysis patients, and the risk worsens with decline in GFR. 

Thus, with the above background in mind, the two main variables that determine what, if any, anticoagulation is to be used in this setting, are (1) the stage of CKD, and (2) the CHADS2 score:

CHADS2 Score	CKD STAGE
	Stage 3, eGFR 30-59	Stage 4, eGFR 15-29	Stage 5, eGFR less than 15, or dialysis
0	Either ASA or AC (weak recommendation)	ASA vs. AC (warfarin) vs. no antithrombotic treatment given bleeding risk??	ASA vs. AC (warfarin) vs. no antithrombotic treatment given bleeding risk??
>1	AC (Direct thrombin inhibitors (dabigatran), and Factor Xa inhibitors (rivaroxaban, apixaban) potentially superior to warfarin	AC (warfarin preferred since no data on direct thrombin or factor Xa inhibitors)	AC (warfarin preferred since no data on direct thrombin or factor Xa inhibitors)

 

ASA = Aspirin

AC = Anticoagulation

?? = Expert opinion only, no strong evidence available - weight risks vs. benefits

Remember that no antithrombotic therapy is warranted if bleeding is a concern

Posted by Veeraish Chuahan

(Apologies for any formatting issues)