Week 14 – IDNT

“Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes”

aka the Irbesartan Diabetic Nephropathy Trial (IDNT)

N Engl J Med. 2001 Sep 20;345(12):851-60. [free full text]

Diabetes mellitus is the most common cause of ESRD in the US. In 1993, a landmark study in NEJM demonstrated that captopril (vs. placebo) slowed the deterioration in renal function in patients with T1DM. However, prior to this 2002 study, no study had addressed definitively whether a similar improvement in renal outcomes could be achieved with RAAS blockade in patients with T2DM. Irbesartan (Avapro) is an angiotensin II receptor blocker that was first approved in 1997 for the treatment of hypertension. Its marketer, Bristol-Meyers Squibb, sponsored this trial in hopes of broadening the market for its relatively new drug.

This trial randomized patients with T2DM, hypertension, and nephropathy (per proteinuria and elevated Cr) to treatment with either irbesartan, amlodipine, or placebo. The drug in each arm was titrated to achieve a target SBP ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed. The primary outcome was a composite of the doubling of serum Cr, onset of ESRD, or all-cause mortality. Secondary outcomes included individual components of the primary outcome and a composite cardiovascular outcome.

1715 patients were randomized. The mean blood pressure after the baseline visit was 140/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons of MAP between irbesartan or amlodipine and placebo). Regarding the primary composite renal endpoint, the unadjusted relative risk was 0.80 (95% CI 0.66-0.97, p = 0.02) for irbesartan vs. placebo, 1.04 (95% CI 0.86-1.25, p = 0.69) for amlodipine vs. placebo, and 0.77 (0.63-0.93, p = 0.006) for irbesartan vs. amlodipine. The groups also differed with respect to individual components of the primary outcome. The unadjusted relative risk of creatinine doubling was 33% lower among irbesartan patients than among placebo patients (p = 0.003) and was 37% lower than among amlodipine patients (p < 0.001). The relative risks of ESRD and all-cause mortality did not differ significantly among the groups. There were no significant group differences with respect to the composite cardiovascular outcome. Importantly, a sensitivity analysis was performed which demonstrated that the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

In summary, irbesartan treatment in T2DM resulted in superior renal outcomes when compared to both placebo and amlodipine. This beneficial effect was independent of blood pressure lowering. This was a well-designed, double-blind, randomized, controlled trial. However, it was industry-sponsored, and in retrospect, its choice of study drug seems quaint. The direct conclusion of this trial is that irbesartan is renoprotective in T2DM. In the discussion of IDNT, the authors hypothesize that “the mechanism of renoprotection by agents that block the action of angiotensin II may be complex, involving hemodynamic factors that lower the intraglomerular pressure, the beneficial effects of diminished proteinuria, and decreased collagen formation that may be related to decreased stimulation of transforming growth factor beta by angiotensin II.” In September 2002, on the basis of this trial, the FDA broadened the official indication of irbesartan to include the treatment of type 2 diabetic nephropathy. This trial was published concurrently in NEJM with the RENAAL trial [https://www.wikijournalclub.org/wiki/RENAAL]. RENAAL was a similar trial of losartan vs. placebo in T2DM and demonstrated a similar reduction in the doubling of serum creatinine as well as a 28% reduction in progression to ESRD. In conjunction with the original 1993 ACEi in T1DM study, these two 2002 ARB in T2DM studies led to the overall notion of a renoprotective class effect of ACEis/ARBs in diabetes. Enalapril and lisinopril’s patents expired in 2000 and 2002, respectively. Shortly afterward, generic, once-daily ACE inhibitors entered the US market. Ultimately, such drugs ended up commandeering much of the diabetic-nephropathy-in-T2DM market share for which irbesartan’s owners had hoped.

Further Reading/References:
1. “The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.” NEJM 1993.
2. CSG Captopril Trial @ Wiki Journal Club
3. IDNT @ Wiki Journal Club
4. IDNT @ 2 Minute Medicine
5. US Food and Drug Administration, New Drug Application #020757
6. RENAAL @ Wiki Journal Club
7. RENAAL @ 2 Minute Medicine

Summary by Duncan F. Moore, MD

Image Credit: Skirtick, CC BY-SA 4.0, via Wikimedia Commons

Week 6 – Bicarbonate and Progression of CKD

“Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status”

J Am Soc Nephrol. 2009 Sep;20(9):2075-84. [free full text]

Metabolic acidosis is a common complication of advanced CKD. Some animal models of CKD have suggested that worsening metabolic acidosis is associated with worsening proteinuria, tubulointerstitial fibrosis, and acceleration of decline of renal function. Short-term human studies have demonstrated that bicarbonate administration reduces protein catabolism and that metabolic acidosis is an independent risk factor for acceleration of decline of renal function. However, until this 2009 study by de Brito-Ashurst et al., there were no long-term studies demonstrating the beneficial effects of oral bicarbonate administration on CKD progression and nutritional status.

The study enrolled CKD patients with CrCl 15-30ml/min and plasma bicarbonate 16-20 mEq/L and randomized them to treatment with either sodium bicarbonate 600mg PO TID (with protocolized uptitration to achieve plasma HCO3  ≥ 23 mEq/L) for 2 years, or to routine care. The primary outcomes were: 1) the decline in CrCl at 2 years, 2) “rapid progression of renal failure” (defined as decline of CrCl > 3 ml/min per year), and 3) development of ESRD requiring dialysis. Secondary outcomes included 1) change in dietary protein intake, 2) change in normalized protein nitrogen appearance (nPNA), 3) change in serum albumin, and 4) change in mid-arm muscle circumference.

134 patients were randomized, and baseline characteristics were similar among the two groups. Serum bicarbonate levels increased significantly in the treatment arm. (See Figure 2.) At two years, CrCl decline was 1.88 ml/min in the treatment group vs. 5.93 ml/min in the control group (p < 0.01). Rapid progression of renal failure was noted in 9% of intervention group vs. 45% of the control group (RR 0.15, 95% CI 0.06–0.40, p < 0.0001, NNT = 2.8), and ESRD developed in 6.5% of the intervention group vs. 33% of the control group (RR 0.13, 95% CI 0.04–0.40, p < 0.001; NNT = 3.8). Regarding nutritional status, dietary protein intake increased in the treatment group relative to the control group (p < 0.007). Normalized protein nitrogen appearance decreased in the treatment group and increased in the control group (p < 0.002). Serum albumin increased in the treatment group but was unchanged in the control group, and mean mid-arm muscle circumference increased by 1.5 cm in the intervention group vs. no change in the control group (p < 0.03).

In conclusion, oral bicarbonate supplementation in CKD patients with metabolic acidosis reduces the rate of CrCl decline and progression to ESRD and improves nutritional status. Primarily on the basis of this study, the KDIGO 2012 guidelines for the management of CKD recommend oral bicarbonate supplementation to maintain serum bicarbonate within the normal range (23-29 mEq/L). This is a remarkably cheap and effective intervention. Importantly, the rates of adverse events, particularly worsening hypertension and increasing edema, were unchanged among the two groups. Of note, sodium bicarbonate induces much less volume expansion than a comparable sodium load of sodium chloride.

In their discussion, the authors suggest that their results support the hypothesis of Nath et al. (1985) that “compensatory changes [in the setting of metabolic acidosis] such as increased ammonia production and the resultant complement cascade activation in remnant tubules in the declining renal mass [are] injurious to the tubulointerstitium.” The hypercatabolic state of advanced CKD appears to be mitigated by bicarbonate supplementation. The authors note that “an optimum nutritional status has positive implications on the clinical outcomes of dialysis patients, whereas [protein-energy wasting] is associated with increased morbidity and mortality.”

Limitations to this trial include its open-label, no-placebo design. Also, the applicable population is limited by study exclusion criteria of morbid obesity, overt CHF, and uncontrolled HTN.

Further Reading:
1. Nath et al. “Pathophysiology of chronic tubulo-interstitial disease in rats: Interactions of dietary acid load, ammonia, and complement component-C3” (1985)
2. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (see page 89)
3. UpToDate, “Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease”

Summary by Duncan F. Moore, MD

Week 48 – SYMPLICITY HTN-3

“A Controlled Trial of Renal Denervation for Resistant Hypertension”

N Engl J Med. 2014 Apr 10;370(15):1393-401 [free full text]

Approximately 10% of patients with hypertension have resistant hypertension (SBP > 140 despite adherence to three maximally tolerated doses of antihypertensives, including a diuretic). Evidence suggests that the sympathetic nervous system plays a large role in such cases, so catheter-based radiofrequency ablation of the renal arteries (renal denervation therapy) was developed as a potential treatment for resistant HTN. The 2010 SYMPLICITY HTN-2 trial was a small (n=106), non-blinded, randomized trial of renal denervation vs. continued care with oral antihypertensives that demonstrated a remarkable 30-mmHg greater decrease in SBP with renal denervation. Thus the 2014 SYMPLICITY HTN-3 trial was designed to evaluate the efficacy of renal denervation in a single-blinded trial with a sham-procedure control group.

The trial enrolled adults with resistant HTN with SBP ≥ 160 despite adherence to 3+ maximized antihypertensive drug classes, including a diuretic. (Pertinent exclusion criteria included secondary hypertension, renal artery stenosis > 50%, prior renal artery intervention.) Patients were randomized to either renal denervation with the Symplicity (Medtronic) radioablation catheter or to renal angiography only (sham procedure). The primary outcome was the mean change in office systolic BP from baseline at 6 months. (The examiner was blinded to intervention.) The secondary outcome was the change in mean 24-hour ambulatory SBP at 6 months. The primary safety endpoint was a composite of death, ESRD, embolic event with end-organ damage, renal artery or other vascular complication, hypertensive crisis within 30 days, or new renal artery stenosis of > 70%.

535 patients were randomized. On average, patients were receiving five antihypertensive medications. There was no significant difference in reduction of SBP between the two groups at 6 months. ∆SBP was -14.13 ± 23.93 mmHg in the denervation group vs. -11.74 ± 25.94 mmHg in the sham-procedure group for a between-group difference of -2.39 mmHg (95% CI -6.89 to 2.12, p = 0.26 with a superiority margin of 5 mmHg). The change in 24-hour ambulatory SBP at 6 months was -6.75 ± 15.11 mmHg in the denervation group vs. -4.79 ± 17.25 mmHg in the sham-procedure group for a between-group difference of -1.96 mmHg (95% CI -4.97 to 1.06, p = 0.98 with a superiority margin of 2 mmHg). There was no significant difference in the prevalence of the composite safety endpoint at 6 months with 4.0% of the denervation group and 5.8% of the sham-procedure group reaching the endpoint (percentage-point difference of -1.9, 95% CI -6.0 to 2.2).

In patients with resistant hypertension, renal denervation therapy provided no reduction in SBP at 6-month follow-up relative to a sham procedure.

This trial was an astounding failure for Medtronic and its Symplicity renal denervation radioablation catheter. The magnitude of the difference in results between the non-blinded, no-sham-procedure SYMPLICITY HTN-2 trial and this patient-blinded, sham-procedure-controlled trial is likely a product of 1) a marked placebo effect of procedural intervention, 2) Hawthorne effect in the non-blinded trial, and 3) regression toward the mean (patients were enrolled based on unusually high BP readings that over the course of the trial declined to reflect a lower true baseline).

Currently, there is no role for renal denervation therapy in the treatment of HTN (resistant or otherwise). However, despite the results of SYMPLICITY HTN-3, other companies and research groups are assessing the role of different radioablation catheters in patients with low-risk essential HTN and with resistant HTN. (For example, see https://www.ncbi.nlm.nih.gov/pubmed/29224639.)

Further Reading/References:
1. NephJC, SYMPLICITY HTN-3
2. UpToDate, “Treatment of resistant hypertension,” heading “Renal nerve denervation”

Summary by Duncan F. Moore, MD

Week 30 – Bicarbonate and Progression of CKD

“Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status”

J Am Soc Nephrol. 2009 Sep;20(9):2075-84. [free full text]

Metabolic acidosis is a common complication of advanced CKD. Some animal models of CKD have suggested that worsening metabolic acidosis is associated with worsening proteinuria, tubulointerstitial fibrosis, and acceleration of decline of renal function. Short-term human studies have demonstrated that bicarbonate administration reduces protein catabolism and that metabolic acidosis is an independent risk factor for acceleration of decline of renal function. However, until this 2009 study by de Brito-Ashurst et al., there were no long-term studies demonstrating the beneficial effects of oral bicarbonate administration on CKD progression and nutritional status.

The study enrolled CKD patients with CrCl 15-30ml/min and plasma bicarbonate 16-20 mEq/L and randomized them to treatment with either sodium bicarbonate 600mg PO TID (with protocolized uptitration to achieve plasma HCO3  ≥ 23 mEq/L) for 2 years, or to routine care. The primary outcomes were: 1) the decline in CrCl at 2 years, 2) “rapid progression of renal failure” (defined as decline of CrCl > 3 ml/min per year), and 3) development of ESRD requiring dialysis. Secondary outcomes included 1) change in dietary protein intake, 2) change in normalized protein nitrogen appearance (nPNA), 3) change in serum albumin, and 4) change in mid-arm muscle circumference.

134 patients were randomized, and baseline characteristics were similar among the two groups. Serum bicarbonate levels increased significantly in the treatment arm. (See Figure 2.) At two years, CrCl decline was 1.88 ml/min in the treatment group vs. 5.93 ml/min in the control group (p < 0.01). Rapid progression of renal failure was noted in 9% of intervention group vs. 45% of the control group (RR 0.15, 95% CI 0.06–0.40, p < 0.0001, NNT = 2.8), and ESRD developed in 6.5% of the intervention group vs. 33% of the control group (RR 0.13, 95% CI 0.04–0.40, p < 0.001; NNT = 3.8). Regarding nutritional status, dietary protein intake increased in the treatment group relative to the control group (p < 0.007). Normalized protein nitrogen appearance decreased in the treatment group and increased in the control group (p < 0.002). Serum albumin increased in the treatment group but was unchanged in the control group, and mean mid-arm muscle circumference increased by 1.5 cm in the intervention group vs. no change in the control group (p < 0.03).

In conclusion, oral bicarbonate supplementation in CKD patients with metabolic acidosis reduces the rate of CrCl decline and progression to ESRD and improves nutritional status. Primarily on the basis of this study, the KDIGO 2012 guidelines for the management of CKD recommend oral bicarbonate supplementation to maintain serum bicarbonate within the normal range (23-29 mEq/L). This is a remarkably cheap and effective intervention. Importantly, the rates of adverse events, particularly worsening hypertension and increasing edema, were unchanged among the two groups. Of note, sodium bicarbonate induces much less volume expansion than a comparable sodium load of sodium chloride.

In their discussion, the authors suggest that their results support the hypothesis of Nath et al. (1985) that “compensatory changes [in the setting of metabolic acidosis] such as increased ammonia production and the resultant complement cascade activation in remnant tubules in the declining renal mass [are] injurious to the tubulointerstitium.” The hypercatabolic state of advanced CKD appears to be mitigated by bicarbonate supplementation. The authors note that “an optimum nutritional status has positive implications on the clinical outcomes of dialysis patients, whereas [protein-energy wasting] is associated with increased morbidity and mortality.”

Limitations to this trial include its open-label, no-placebo design. Also, the applicable population is limited by study exclusion criteria of morbid obesity, overt CHF, and uncontrolled HTN.

Further Reading:
1. Nath et al. “Pathophysiology of chronic tubulo-interstitial disease in rats: Interactions of dietary acid load, ammonia, and complement component-C3” (1985)
2. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (see page 89)
3. UpToDate, “Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease”

Week 27 – Mortality in Patients on Dialysis and Transplant Recipients

“Comparison of Mortality in All Patients on Dialysis, Patients on Dialysis Awaiting Transplantation, and Recipients of a First Cadaveric Transplant”

N Engl J Med. 1999 Dec 2;341(23):1725-30. [free full text]

Renal transplant is the treatment of choice in patients with ESRD. Since the advent of renal transplant, it has been known that transplant improves both quality of life and survival relative to dialysis. However, these findings were derived from retrospective data and reflected inherent selection bias (patients who received transplants were healthier, younger, and of higher socioeconomic status than patients who remained on dialysis). While some smaller studies (i.e. single center or statewide database) published in the early to mid 1990s attempted to account for this selection bias by comparing outcomes among patients who received a transplant versus patients who were listed for transplant but had not yet received one, this 1999 study by Wolfe et al. was a notable step forward in that it used the large, nationwide US Renal Data System dataset and a robust multivariate hazards model to control for baseline covariates. To this day, Wolfe et al. remains a defining testament to the sustained, life-prolonging benefit of renal transplantation itself.

Using the comprehensive US Renal Data System database, the authors evaluated patients who began treatment for ESRD between 1991 and 1996. Notable exclusion criteria were age ≥ 70 and transplant prior to initiating dialysis. Of the 228,552 patients evaluated, 46,164 were placed on the transplant waitlist, and 23,275 received a transplant by the end of the study period (12/31/1997). The primary outcome was survival reported in unadjusted death rates per 100 patient-years, standardized mortality ratios (adjusted for age, race, sex, and diabetes as the cause of ESRD), and adjusted relative risk of death in transplant patients relative to waitlisted patients. Subgroup analyses were performed.

Results:
Regarding baseline characteristics, listed or transplanted patients were younger, more likely to be white or Asian, and less likely to have diabetes as the cause of their ESRD (see Table 1). Unadjusted death rates per 100 patient-years at risk: dialysis 16.1, waitlist 6.3, and transplant recipients 3.8 (no p value given, see Table 2). The standardized mortality ratio (adjusted for age, race, sex, and diabetes as the cause of ESRD) was 49% lower (RR 0.51, 95% CI 0.49–0.53, p<0.001) among patients on the waitlist and 69% lower among transplant recipients (p value not reported). The lower standardized mortality ratio of waitlisted patients relative to dialysis patients was sustained in all subgroup analyses (see Figure 1). The relative risk of death (adjusted for age, sex, race, cause of ESRD, year placed on waitlist, and time from first treatment of ESRD to placement on waitlist) is visually depicted in Figure 2. Importantly, relative to waitlisted patients, transplant recipients had a 2.8x higher risk of death during the first two weeks post-transplant. Thereafter, risk declined until the likelihood of survival equalized at 106 days post-transplant. Long term (3-4 years of follow-up in this study), mortality risk was 68% lower among transplanted patients than among waitlisted patients (RR 0.32, 95% CI 0.30–0.35, p< 0.001). The magnitude of this survival benefit varied by subgroup but was strong and statistically significant in all subgroups (ranging from 3 to 17 additional projected years of life, see Table 3).

Implication/Discussion:
Retrospective analysis of this nationwide ESRD database has clearly demonstrated the marked mortality benefit of renal transplantation over waitlisted status. This finding is present to varying degrees in all subgroups and leads to a projected additional 3 to 17 years of lifespan post-transplant. (There is an expected, mild increase in mortality risk immediately following transplantation. This increase reflects operative risk and immediate complications but is present for only 2 weeks post-transplantation.) As expected and as previously described in other datasets, this study also demonstrated that substantially healthier ESRD patients are selected for transplantation listing in the US in comparison to patients who remain on dialysis not on the waitlist.

Relative strengths of this study include its comprehensive national dataset and intention-to-treat analysis. Its multivariate analyses robustly controlled for factors, such as time on the waitlist, that may have influenced mortality. However, this study is limited in that its retrospective comparison of listed to transplanted does not entirely eliminate selection bias. (For example, listed patients may have developed illnesses that ultimately prevented transplant and lead to death.) Additionally, the mortality benefits demonstrated in this study from the first half of the 1990s may not reflect those of current practice, given that prevention and treatment of ASCVD (a primary driver of mortality in ESRD) has improved markedly in the ensuing decades and may favor one group disproportionately.

As suggested by the authors at UpToDate, improved survival post-transplant may be due to the following factors: increased clearance of uremic toxins, reduction in inflammation and/or oxidative stress, reduced microvascular disease in diabetes mellitus, and improvement of LVH.

As a final note: in this modern era, it is surprising to see both a retrospective cohort study published in NEJM as well as the lack of preregistration of its analysis protocol prior to the study being conducted. Preregistration, even of interventional trials, did not become routine until the years following the announcement of the International Committee of Medical Journal Editors (ICMJE) trial registration policy in 2004 (Zarin et al.). Although, even today, retrospective cohort studies are not routinely preregistered, high profile journals increasingly require it because it helps differentiate between confirmatory versus exploratory research and reduce the appearance of post-hoc data dredging (i.e. p-hacking). Please see the Center for Open Science – Preregistration for further information. Here is another helpful discussion in PowerPoint form by Deborah A. Zarin, MD, Director of ClinicalTrials.gov.

Further Reading/References:
1. UpToDate, “Patient Survival After Renal Transplantation”
2. Zarin et al. “Update on Trial Registration 11 Years after the ICMJE Policy Was Established.” NEJM 2017

Summary by Duncan F. Moore, MD

Image Credit: Anna Frodesiak, CC0 1.0, via Wikimedia Commons

Week 5 – IDNT

“Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes”

aka the Irbesartan Diabetic Nephropathy Trial (IDNT)

N Engl J Med. 2001 Sep 20;345(12):851-60. [free full text]

Diabetes mellitus is the most common cause of ESRD in the US. In 1993, a landmark study in NEJM demonstrated that captopril (vs. placebo) slowed the deterioration in renal function in patients with T1DM. However, prior to this 2002 study, no study had addressed definitively whether a similar improvement in renal outcomes could be achieved with RAAS blockade in patients with T2DM. Irbesartan (Avapro) is an angiotensin II receptor blocker that was first approved in 1997 for the treatment of hypertension. Its marketer, Bristol-Meyers Squibb, sponsored this trial in hopes of broadening the market for its relatively new drug.

This trial randomized patients with T2DM, hypertension, and nephropathy (per proteinuria and elevated Cr) to treatment with either irbesartan, amlodipine, or placebo. The drug in each arm was titrated to achieve a target SBP ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed. The primary outcome was a composite of the doubling of serum Cr, onset of ESRD, or all-cause mortality. Secondary outcomes included individual components of the primary outcome and a composite cardiovascular outcome.

1715 patients were randomized. The mean blood pressure after the baseline visit was 140/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons of MAP between irbesartan or amlodipine and placebo). Regarding the primary composite renal endpoint, the unadjusted relative risk was 0.80 (95% CI 0.66-0.97, p = 0.02) for irbesartan vs. placebo, 1.04 (95% CI 0.86-1.25, p = 0.69) for amlodipine vs. placebo, and 0.77 (0.63-0.93, p = 0.006) for irbesartan vs. amlodipine. The groups also differed with respect to individual components of the primary outcome. The unadjusted relative risk of creatinine doubling was 33% lower among irbesartan patients than among placebo patients (p = 0.003) and was 37% lower than among amlodipine patients (p < 0.001). The relative risks of ESRD and all-cause mortality did not differ significantly among the groups. There were no significant group differences with respect to the composite cardiovascular outcome. Importantly, a sensitivity analysis was performed which demonstrated that the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

In summary, irbesartan treatment in T2DM resulted in superior renal outcomes when compared to both placebo and amlodipine. This beneficial effect was independent of blood pressure lowering. This was a well-designed, double-blind, randomized, controlled trial. However, it was industry-sponsored, and in retrospect, its choice of study drug seems quaint. The direct conclusion of this trial is that irbesartan is renoprotective in T2DM. In the discussion of IDNT, the authors hypothesize that “the mechanism of renoprotection by agents that block the action of angiotensin II may be complex, involving hemodynamic factors that lower the intraglomerular pressure, the beneficial effects of diminished proteinuria, and decreased collagen formation that may be related to decreased stimulation of transforming growth factor beta by angiotensin II.” In September 2002, on the basis of this trial, the FDA broadened the official indication of irbesartan to include the treatment of type 2 diabetic nephropathy. This trial was published concurrently in NEJM with the RENAAL trial. RENAAL was a similar trial of losartan vs. placebo in T2DM and demonstrated a similar reduction in the doubling of serum creatinine as well as a 28% reduction in progression to ESRD. In conjunction with the original 1993 ACEi in T1DM study, these two 2002 ARB in T2DM studies led to the overall notion of a renoprotective class effect of ACEis/ARBs in diabetes. Enalapril and lisinopril’s patents expired in 2000 and 2002, respectively. Shortly afterward, generic, once-daily ACE inhibitors entered the US market. Ultimately, such drugs ended up commandeering much of the diabetic-nephropathy-in-T2DM market share for which irbesartan’s owners had hoped.

Further Reading/References:
1. “The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.” NEJM 1993.
2. CSG Captopril Trial @ Wiki Journal Club
3. IDNT @ Wiki Journal Club
4. IDNT @ 2 Minute Medicine
5. US Food and Drug Administration, New Drug Application #020757
6. RENAAL @ Wiki Journal Club
7. RENAAL @ 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 3 – CHOIR

“Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease”

by the Investigators in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)

N Engl J Med. 2006 Nov 16;355(20):2085-98. [free full text]

Anemia is a prevalent condition in CKD and ESRD. The anemia is largely attributable to the loss of erythropoietin production due to the destruction of kidney parenchyma. Thus erythropoiesis-stimulating agents (ESAs) were introduced to improve this condition. Retrospective data and small interventional trials suggested that treatment to higher hemoglobin goals (such as > 12 g/dL) was associated with improved cardiovascular outcomes. However, in 1998, a prospective trial in ESRD patients on HD with a hematocrit treatment target of 42% versus 30% demonstrated a trend toward increased rates of non-fatal MI and death in the higher-target group. In an effort to clarify the hemoglobin goal in CKD patients, the 2006 CHOIR trial was designed. It was hypothesized that treatment of anemia in CKD to a target of 13.5 g/dL would lead to fewer cardiac events and reduced mortality when compared to a target of 11.3 g/dL.

The trial enrolled adults with CKD (eGFR 15-50ml/min) and Hgb < 11.0 g/dL and notably excluded patients with active cancer. The patients were randomized to erythropoietin support regimens targeting a hemoglobin of either 13.5 g/dL or 11.3 g/dL. The primary outcome was a composite of death, MI, hospitalization for CHF, or stroke. Secondary outcomes included individual components of the primary outcome, need for renal replacement therapy, all-cause hospitalization, and various quality-of-life scores.

The study was terminated early due to an interim analysis revealing a < 5% chance that there would be a demonstrated benefit for the high-hemoglobin group by the scheduled end of the study. Results from 715 high-hemoglobin and 717 low-hemoglobin patients were analyzed. The mean change in hemoglobin was +2.5 g/dL in the high-hemoglobin group versus +1.2g/dL in the low-hemoglobin group (p<0.001). The primary endpoint occurred in 125 of the high-hemoglobin patients (17.5%) versus 97 of the low-hemoglobin patients (13.5%) [HR 1.34, 95% CI 1.03-1.74, p=0.03; number needed to harm = 25]. There were no significant group differences among the four components of the primary endpoint when analyzed as individual secondary outcomes, nor was there a difference in rates of renal replacement therapy. Any-cause hospitalization rates were 51.6% in the high-hemoglobin group versus 46.6% in the low-hemoglobin group (p=0.03). Regarding quality-of-life scores, both groups demonstrated similar, statistically significant improvements from their respective baseline values.

In patients with anemia and CKD, treatment to a higher hemoglobin goal of 13.5g/dL was associated with an increased incidence of a composite endpoint of death, MI, hospitalization for CHF, or stroke relative to a treatment goal of 11.3g/dL. There were no differences between the two groups in hospitalization rates or progression to renal replacement therapy, and the improvement in quality of life was similar among the two treatment groups. Thus this study demonstrated no additional benefit and some harm with the higher treatment goal. The authors noted that “this study did not provide a mechanistic explanation for the poorer outcome with the use of a high target hemoglobin level.” Limitations of this trial included its non-blinded nature and relatively high patient withdrawal rates. Following this trial, the KDOQI clinical practice guidelines for the management of anemia in CKD were updated to recommend a Hgb target of 11.0-12.0 g/dL. However, this guideline was superseded by the 2012 KDIGO guidelines which, on the basis of further evidence, ultimately recommend initiating ESA therapy only in iron-replete CKD patients with Hgb < 10 g/dL with the goal of maintaining Hgb between 10 and 11.5 g/dL. Treatment should be individualized in patients with concurrent malignancy.

Further Reading/References:
1. Besarab et al. “The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin.” N Engl J Med. 1998 Aug 27;339(9):584-90.
2. Wiki Journal Club
3. 2 Minute Medicine
4. National Kidney Foundation Releases Anemia Guidelines Update (2007) []
5. Pfeffer et al. “A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.” N Engl J Med. 2009;361(21):2019.
6. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

Summary by Duncan F. Moore, MD

Week 47 – VA NEPHRON-D

“Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy”

by the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Investigators

N Engl J Med. 2013 Nov 14;369(20):1892-903. [free full text]

Inhibition of the renin-angiotensin-aldosterone system (RAAS) decreases the progression of proteinuric kidney disease, such as diabetic nephropathy. Prior studies have demonstrated that the greater the proteinuria is reduced by RAAS inhibition, the slower the further loss of GFR. Therefore, it had been hypothesized that combination RAAS inhibition with both an ACEi and an ARB in diabetic kidney disease would reduce the rate of renal decline and incidence of ESRD. The investigators of the VA NEPHRON-D trial hypothesized that “the benefit in slowing the progression of kidney disease would outweigh the risks of hyperkalemia and AKI associated with more intensive blockade of the RAAS.”

Population: US veterans with T2DM, eGFR 30.0-89.9 ml/min, and urinary albumin/Cr ratio ≥ 300

Notable exclusion criteria: nondiabetic kidney disease, K > 5.5, current treatment with sodium polystyrene sulfonate (Kayexalate)

Intervention: losartan 100mg PO daily and lisinopril 10mg, uptitrated q2 weeks to 20mg and then 40mg, respectively, as tolerated (meaning no hyperkalemia or Cr rise > 30%)

Comparison: losartan 100mg PO daily and placebo, uptitrated q2 weeks as tolerated

(Note: prior to randomization, there was a run-in period with uptitration to target dose of losartan to ensure hyperkalemia did not develop prior to initiating the study drug.)

Outcome:
Primary – time to first occurrence of composite endpoint of decline in eGFR (≥ 30 ml/min if baseline eGFR ≥60 ml/min, or relative decrease of ≥ 50% if baseline eGFR < 60 ml/min), ESRD, or death

Secondary, selected:

  • first occurrence of decline in eGFR or ESRD
  • ESRD
  • cardiovascular events (MI, stroke, or hospitalization for CHF)
  • all-cause mortality
  • hyperkalemia (> 6, or requiring ED visit/hospitalization/dialysis)
  • AKI


Results
:
724 patients were randomized to each treatment arm. Baseline characteristics were similar among the two groups. The trial was stopped early after the data and safety monitoring committee found increased rates of serious adverse events, hyperkalemia, and AKI in the combination-therapy group. Median follow-up at time of study closure was 2.2 years.

132 patients in the combination-therapy group (18.2%) and 152 patients in the monotherapy group (21.0%) met the primary composite endpoint of decline in eGFR, ESRD, or death (p = 0.30).

Decline in eGFR or progression to ESRD occurred in 77 (10.6%) of the combination-therapy group and 101 (14.0%) of the monotherapy group (p = 0.10). There were also no significant group differences in the individual rates of ESRD, all-cause mortality, or MI/stroke/CHF.

AKI events occurred 190 times in 130 patients in the combination-therapy group (12.2 events per 100 person-years). In comparison, there were only 105 AKI events in 80 patients in the monotherapy group (6.7 events per 100 person-years) [HR 1.7, 95% CI 1.3-2.2, p < 0.001]. Hyperkalemia occurred in 72 (9.9%) of the combination-therapy patients versus 32 (4.4%) of the monotherapy patients (p < 0.001).

Implication/Discussion:
Among patients with T2DM, CKD, and proteinuria, combination therapy with an ARB and ACEi did not reduce the progression of kidney disease or mortality relative to an ARB alone; in fact, combination therapy increased the risks of AKI and hyperkalemia.

This was a well-designed, double-blind, randomized, controlled trial with definitive results. Its results align with those of its contemporary studies ONTARGET (2008, combination ARB and ACEi vs. monotherapy) and ALTITUDE (2012, ARB or ACEi plus the direct renin inhibitor aliskiren vs. ARB or ACEi monotherapy), which demonstrated no benefit and increased adverse event rates with combination therapy.

Although dual RAAS blockade reduces proteinuria in diabetic nephropathy greater than monotherapy, it is not recommended currently due to a lack of benefit and increased adverse events.

Further Reading/References:
1. VA NEPHRON-D @ Wiki Journal Club
2. ONTARGET @ Wiki Journal Club
3. ALTITUDE @ PubMed

Summary by Duncan F. Moore, MD

Week 42 – IDNT

“Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes”

aka the Irbesartan Diabetic Nephropathy Trial (IDNT)

N Engl J Med. 2001 Sep 20;345(12):851-60. [free full text]

Diabetes mellitus is the most common cause of ESRD in the US. In 1993, a landmark study in NEJM demonstrated that captopril (vs. placebo) slowed the deterioration in renal function in patients with T1DM. However, prior to this 2002 study, no study had definitively addressed whether a similar improvement in renal outcomes could be achieved with RAAS blockade in patients with T2DM. Irbesartan (Avapro) is an angiotensin II receptor blocker that was first approved in 1997 for the treatment of hypertension. Its marketer, Bristol-Meyers Squibb, sponsored this trial in hopes of broadening the market for its relatively new drug.

Population: patients age 30-70 with T2DM, HTN, proteinuria (≥ 900mg/24hrs), and Cr 1.0-3.0 in women and 1.2-3.0 in men

Intervention: irbesartan, titrated from 75mg to 300mg per day

Comparison #1: amlodipine, titrated from 2.5mg to 10mg per day
Comparison #2: placebo

(All patients had a target SBP goal ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed.)

Outcomes:
Primary – time to doubling of serum Cr, onset of ESRD, or all-cause mortality

Secondary

  • individual components of the primary outcome
  • composite cardiovascular outcome – death from CV causes, nonfatal MI, hospitalization for CHF, CVA with permanent neurologic deficit, or lower limb amputation above ankle

Results:
1715 patients were randomized. Baseline characteristics were similar among the groups, except for a slightly lower proportion of women in the placebo group. The mean blood pressure after the baseline visit was 144/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons between irbesartan or amlodipine and placebo).

Regarding the primary composite renal endpoint, the unadjusted relative risk was 0.80 (95% CI 0.66-0.97, p = 0.02) for irbesartan vs. placebo, 1.04 (95% CI 0.86-1.25, p = 0.69) for amlodipine vs. placebo, and 0.77 (0.63-0.93, p = 0.006) for irbesartan vs. amlodipine.

The groups also differed with respect to individual components of the primary outcome. The unadjusted relative risk of creatinine doubling was 33% lower among irbesartan patients than among placebo patients (p = 0.003) and was 37% lower than among amlodipine patients (p < 0.001). The relative risks of ESRD and all-cause mortality did not differ significantly among the groups.

There were no significant group differences with respect to the secondary, cardiovascular outcome (see Table 3).

Sensitivity analyses were performed. Inclusion of baseline covariates in a Cox regression of the primary outcome did not alter the conclusions. Similarly, the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

Hyperkalemia occurred in 1.9% of the irbesartan patients, but only 0.5% of the amlodipine patients and 0.4% of the placebo patients (p = 0.01 for both pairwise comparisons with irbesartan).


Implication/Discussion
:
Irbesartan treatment in T2DM resulted in superior renal outcomes when compared to both placebo and amlodipine. This beneficial effect was independent of blood pressure lowering.

This was a well-designed, double-blind, randomized, controlled trial. However, it was industry-sponsored, and in retrospect, its choice of study drug seems quaint.

The direct conclusion of this trial is that irbesartan is renoprotective in T2DM. In the discussion of IDNT, the authors hypothesize that “the mechanism of renoprotection by agents that block the action of angiotensin II may be complex, involving hemodynamic factors that lower the intraglomerular pressure, the beneficial effects of diminished proteinuria, and decreased collagen formation that may be related to decreased stimulation of transforming growth factor beta by angiotensin II.”

In September 2002, on the basis of this trial, the FDA broadened the official indication of irbesartan to include the treatment of type 2 diabetic nephropathy.

This trial was published concurrently in NEJM with the RENAAL trial. RENAAL was a similar trial of losartan vs. placebo in T2DM, and demonstrated a similar reduction in the doubling of serum creatinine, as well as a 28% reduction in progression to ESRD.

In conjunction with the original 1993 ACEi in T1DM study, these two 2002 ARB in T2DM studies led to the overall notion of a renoprotective class effect of ACEis/ARBs in diabetes.

Enalapril and lisinopril’s patents expired in 2000 and 2002, respectively. Shortly afterward, generic, once-daily ACE inhibitors entered the US market. Ultimately, such drugs ended up commandeering much of the diabetic-nephropathy-in-T2DM market share for which irbesartan’s owners had hoped.


Further Reading/References
:
1. “The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.” NEJM 1993.
2. CSG Captopril Trial @ Wiki Journal Club
3. IDNT @ Wiki Journal Club
4. IDNT @ 2 Minute Medicine
5. US Food and Drug Administration, New Drug Application #020757
6. RENAAL @ Wiki Journal Club
7. RENAAL @ 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 33 – CHOIR

“Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease”

by the Investigators in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)

N Engl J Med. 2006 Nov 16;355(20):2085-98. [free full text]

Anemia is a highly prevalent condition in CKD and ESRD. The anemia is largely attributable to the loss of erythropoietin production due to the destruction of kidney parenchyma. Thus erythropoiesis-stimulating agents (ESAs) were introduced to improve this condition. Retrospective data and small interventional trials suggested that treatment to higher hemoglobin goals (such as > 12g/dL) was associated with improved cardiovascular outcomes. However, a prospective trial in ESRD patients on HD with a hemocrit treatment target of 42% vs. 30% demonstrated a trend toward increased rates of non-fatal MI and death in the higher-target group. In an effort to clarify the hemoglobin goal in CKD patients, the 2006 CHOIR trial was designed. It was hypothesized that treatment of anemia in CKD to a target of 13.5g/dL would lead to fewer cardiac events and reduced mortality when compared to a target of 11.3g/dL.

Population: adults with CKD (eGFR 15-50ml/min) and Hgb < 11.0 g/dL

Notable exclusion criteria: active cancer, prior therapy with epo.

Patients who developed a requirement for dialysis were terminated from the study.

Intervention: target hemoglobin 13.5 g/dL with a regimen of epo support

Comparison: target hemoglobin 11.3 g/dL with a regimen of epo support

Outcome:

Primary – composite of death, MI, hospitalization for CHF, or stroke

Secondary:

  • each of the four components of the composite primary endpoint
  • need for renal replacement therapy
  • hospitalization for any cause
  • quality of life as measured by the Linear Analogue Self-Assessment (LASA), Kidney Disease Questionnaire (KDQ), and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36)

 

Results:
This study was terminated early due to an interim analysis revealing a < 5% chance that there would be a demonstrated benefit for the high-hemoglobin group by the scheduled end of the study.

Results from 715 high-hemoglobin and 717 low-hemoglobin patients were analyzed.

Baseline characteristics were similar among the two groups aside from for higher rates of HTN (p=0.03) and CABG (p=0.05) in the high-hemoglobin group. Rates of iron supplementation during the study were similar among the two groups (~50%).

The mean change in hemoglobin was +2.5 g/dL in the high-hemoglobin group versus +1.2g/dL in the low-hemoglobin group (p<0.001).

The primary endpoint occurred in 125 of the high-hemoglobin patients (17.5%) versus 97 of the low-hemoglobin patients (13.5%) [HR 1.34, 95% CI 1.03-1.74, p=0.03; number needed to harm = 25].

There were no significant group differences among the four components of the primary endpoint when analyzed as individual secondary outcomes. Rates of renal replacement therapy (thus requiring termination from the study protocol) were 21.7% in the high-hemoglobin group versus 18.7% in the low-hemoglobin group (p=0.15). Any-cause hospitalization rates were 51.6% in the high-hemoglobin group versus 46.6% in the low-hemoglobin group (p=0.03).

Quality-of-life scores were assessed by the LASA, KDQ, and SF-36. Both groups demonstrated similar, statistically significant improvements from their respective baseline values, with the exception of a higher improvement in the emotional subset of SF-36 within the low-hemoglobin group.

The mean weekly dose of epoetin alfa required to maintain the target hemoglobin was 11,215 units/week in the high-hemoglobin group versus 6.276 units/week in the low-hemoglobin group.


Implication/Discussion
:
In patients with anemia and CKD, treatment to a higher hemoglobin goal of 13.5g/dL was associated with an increased incidence of a composite endpoint of death, MI, hospitalization for CHF, or stroke relative to a treatment goal of 11.3g/dL. The higher treatment goal also led to higher utilization of epoetin alfa. There were no differences between the two groups in hospitalization rates or progression to renal replacement therapy, and the improvement in quality of life was similar among the two treatment groups.

Thus this study demonstrated no additional benefit and some harm with the higher treatment goal.

The authors note that “this study did not provide a mechanistic explanation for the poorer outcome with the use of a high target hemoglobin level.”

Limitations of this trial included its non-blinded nature and relatively high patient withdrawal rates.

Following this trial, the KDOQI guidelines for the management of anemia in CKD were changed to state that “in dialysis and nondialysis patients with CKD receiving ESA therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dL.”

Expert opinion at UpToDate recommends administration of ESAs in iron-replete CKD and ESRD patients with Hgb < 10 g/dL with the goal of maintaining Hgb between 10 and 11.5 g/dL. Treatment should be individualized in patients with concurrent malignancy.


Further Reading/References
:
1. Wiki Journal Club
2. 2 Minute Medicine
3. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 Update of Hemoglobin Target
4. Pfeffer et al. “A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.” N Engl J Med. 2009;361(21):2019.
5. UpToDate, “Treatment of anemia in nondialysis chronic kidney disease”
6. UpToDate, “Treatment of anemia in hemodialysis patients”

Summary by Duncan F. Moore, MD