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Kidney International (2016) 89, 257–258; http://dx.doi.org/10.1016/j.kint.2015.12.027
Ramipril versus placebo in kidney transplant patients with proteinuria: a multicenter, double-blind, randomized controlled trial Knoll et al. (Lancet Diabetes Endocrinol. 2015; http://dx.doi.org/10.1016/ S2213-8587(15)00368-X)
In the renal transplant population, evidence supporting the use of angiotensin-converting enzyme inhibitors in proteinuric states is lacking. Knoll et al. performed a large multicenter, double-blind, randomized, placebo-controlled trial conducted at 14 academic centers in Canada and New Zealand comparing ramipril with placebo in kidney transplant recipients with proteinuria. The study inclusion criteria were adult renal transplant recipients at least 3 months posttransplant with an estimated glomerular filtration rate of 20 ml/min per 1.73 m2 or greater and proteinuria greater than 0.2 g per day. Treatment (ramipril 5 mg twice daily or placebo) was randomly assigned (1:1) by centrally generated randomization. The primary end point was a composite measure consisting of a doubling of serum creatinine, endstage renal disease, or death. From 2008 until 2012, a total of 213 patients were randomized, 109 allocated to placebo and 104 allocated to ramipril. The primary end point occurred in 19 patients (17%) in the placebo group and 14 patients (14%) in the ramipril group (hazard ratio 0.76, 95% confidence interval [CI] 0.38–1.51). In the trial extension phase of an extra 4 years, conducted to ensure adequate participation, the time to primary outcome did not differ (Figure). However, the proportion of patients with blood pressure less than 130/80 was higher in the ramipril group than in the placebo group. There was also no significant difference in patients reaching the secondary end point of measured glomerular filtration rate over time. Thus, ramipril
Cumulative event percentage (%)
100
Placebo Ramipril
Log-rank test: P = 0.89
80
60
40
20
0 0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
30 28
19 18
13 11
4 5
2 1
Months from randomization Number at risk Placebo Ramipril
109 103
105 103 102 99
100 98
98 93
90 87
82 76
74 69
54 49
36 34
Time to the primary outcome of doubling of serum creatinine, end-stage renal disease, or death during the extension phase of the study. Reprinted from Knoll et al., The Lancet Diabetes & Endocrinology, ª 2015, with permission from Elsevier. Kidney International (2016) 89, 257–258
ª 2016 International Society of Nephrology
did not significantly prevent the occurrence of clinically important events in proteinuric transplant recipients. In this very important investigator-initiated study, Knoll et al. show that data from the general renal population cannot be extrapolated directly to transplant recipients. While ramipril is a safe and effective treatment for hypertension in proteinuria renal transplant recipients, it does not lead to benefit in hard renal end points. —P. Toby Coates
Anaphylaxis with intravenous iron products Wang et al. (JAMA. 2015;314:2062–2068)
Oral iron replacement is the primary treatment strategy for iron deficiency anemia in the general population. However, it is inadequate for many patients, in particular those with chronic kidney disease, because of impaired intestinal absorption, gastrointestinal intolerance, and nonadherence. Intravenous iron is a helpful alternative, used most easily in those with a preexisting vascular access. As of June 2013, there were five i.v. iron products marketed in the United States. While their efficacy has long been established, the most important safety concerns relate to the risks of systemic iron overload and of serious and fatal anaphylaxis. The latter may occur at both first and subsequent exposures. Wang et al. have compared the relative risk of anaphylaxis among the following US marketed i.v. iron brands: high– and low–molecular weight iron dextran (considered together), gluconate, sucrose, and ferumoxytol. The analysis was based on a retrospective new-user cohort study of 688,183 i.v. iron recipients enrolled in the US fee-for-service Medicare program from January 2003 to December 2013 including patients with chronic kidney disease. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. Anaphylaxis was identified using a prespecified and validated algorithm. A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent i.v. iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI 57.8–78.7 per 100,000) and 24 per 100,000 persons for all non-dextran i.v. iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI 20.0–29.5 per 100,000), with an adjusted odds ratio of 2.6 (95% CI 2.0–3.3). At first exposure, when compared with iron sucrose, the adjusted odds ratio of anaphylaxis for iron dextran was 3.6; for iron gluconate, 2.0; and for ferumoxytol, 2.2. In conclusion, among patients in the US Medicare nondialysis population with first exposure to i.v. iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose. —Tilman B. Drüeke 257
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Urine excretion strategy for stem cell–generated embryonic kidneys Yokote et al. (Proc Natl Acad Sci U S A. 2015;112:12980–12985)
Regeneration of the functional whole kidney from stem cells is a dream of many nephrologists and patients. However, one of the crucial obstacles is construction of a urinary excretion pathway for the stem cell–generated embryonic kidney. Yokote et al. transplanted metanephroi from cloned pig fetuses into young female pigs. The metanephroi grew and produced urine, but hydronephrosis eventually was observed because of the lack of an excretion pathway. The construction of urine excretion pathways utilizing artificial tubing has been unsuccessful because peristalsis of the excretion pathways is essential. The direct connection of a recipient ureter with the ureter of a transplant-grown metanephros (uretero-ureterostomy) to create a urine excretion channel for a neo-kidney is also difficult for various reasons including a technical problem. Thus, the investigators decided to perform proof-ofconcept studies to transplant rat metanephroi or metanephroi with bladders (developed from cloacas) into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Connection of the host animal’s ureter to the cloacal-developed bladder, a technique they called the stepwise peristaltic ureter system, avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter. Finally, the authors demonstrated a viable preclinical application of the stepwise peristaltic ureter system in cloned pigs. The system also inhibited hydronephrosis in the pig study. This is an important study that showed resolution of 2 important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney. Thanks to devotion by researchers in nephrology and developmental biology,1 the possible use of stem cells in regenerative medicine is moving from dream to reality. —Masaomi Nangaku 1
Kidney Int. 2014;86:23–27.
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Renal artery stent outcomes: effect of baseline blood pressure, stenosis severity, and translesion pressure gradient Murphy et al. (J Am Coll Cardiol. 2015;66:2487–2494)
Multiple uncontrolled trials of renal artery angioplasty and stent placement reported beneficial effects of intervention compared to standard medical therapy, whereas several randomized controlled trials of renal artery stenting did not demonstrate a benefit for patients. However, these trials were criticized for patient selection bias, excluding patients for whom clinicians thought intervention was clinically warranted, and use of interventional techniques that potentially increased the risk of cholesterol emboli. The Cardiovascular Outcomes in Renal Atherosclerotic Lesions trial (CORAL) recruited 947 patients randomized to renal artery angioplasty and stenting with optimal medical management or optimal medical therapy alone. The overall outcome showed no benefit from interventional therapy. Subsequent post hoc analysis noted no advantage for those patients with cardiac failure. The investigators now report the outcomes of patients with severe renal artery stenosis, assessed by radiologic imaging or direct pressure measurements, and also of those with severe systolic hypertension. These groups of patients had been typically thought to benefit from interventional therapy. However, the results of the CORAL study did not show any difference in the primary end point of event-free survival after 2 years, defined as a composite of heart attack, stroke, hospitalization for congestive heart failure, progressive renal insufficiency or end-stage renal disease, and cardiovascular or renal-related death. Although there could be physician bias in patient recruitment, this post hoc analysis of the largest clinical trial argues in favor of optimal medical management for patients with atheromatous renovascular disease, even for groups historically thought to benefit from intervention. —Andrew Davenport
Kidney International (2016) 89, 257–258
