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VA NEPHRON-D Trial: Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy


The VA NEPHRON-D trial tackled an important question about the combination therapy of ACEi and ARBs. We know from the RENAAL trial that losartan has significant benefits in diabetic nephropathy. The authors of the VA NEPHRON-D tiral aimed to assess if the addition of an ACE inhibitor to ARB therapy prevent eGFR reduction, ESRD, or death in patients with T2DM, CKD stage 2-3, and elevated urine albumin: creatinine. The trial included a reasonable number of 1448 patients who were randomized to losartan + placebo group and combination group of losartan and lisinopril. The trial was ended earlier due to inconclusive results. The authors of VA NEPHRON-D trial concluded that combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. Source: NEJM

CREDENCE Trial: Canagliflozin and renal outcomes in type II diabetes and nephropathy

CREDENCE Trial Visual Abstract

In CREDENCE trial, the authors objective was to assess the effect of canagliflozin on renal outcomes in patients with type 2 DM and CKD. 4,401 patients with CKD and DM2 were enrolled to be treated with either 100 mg canagliflozin daily or matched placebo. The primary outcome of ESRD, worsening CKD or CV death was significantly lower in patients on canagliflozin (P=0.0001). The authors concluded that canagliflozin can significantly protect kidney in patients with diabetes. Take a look and share the visual abstract for quick learning.

Source: NEJM

PIVOTAL Trial (2019): Intravenous Iron in Patients Undergoing Maintenance Hemodialysis

PIVOTAL Trial Summary: Macdougall et al. randomized 2141 adults undergoing maintenance HD to receive either high-dose IV iron sucrose in a proactive fashion (400 mg monthly, unless ferritin >700 μg/l or transferrin saturation ≥40%), or low-dose IV iron, in a reactive fashion (0 to 400mg monthly, with a ferritin<200 μg/l or a transferrin saturation <20% being a trigger for iron administration). The primary objective was to assess if high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen given reactively to patients on maintenance hemodialysis. The primary outcome (composite of nonfatal MI, stroke, hospitalization for HF, or death) was significantly lower in patients receiving high-dose proactive iron therapy. The authors of the PIVOTAL trial concluded that Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered.

Source: NEJM

CARRESS-HF Trial (2012): Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

CARRESS HF Trial Summary: Bart et al. randomized 188 patients with decompensated acute heart failure and worsening renal function (Increase in serum creatinine ≥0.3 mg/dL) – [cardiorenal syndrome] to ultrafiltration (fluid removal of 200 mL/hr, n=94) or medical therapy (Protocol driven IV diuresis, n=94). The primary objective was to assess if ultrafiltration improves volume removal, renal function, and reduce HF complications when compared to medical therapy in acutely decompensated heart failure and cardiorenal syndrome. The results showed worsening of change in serum creatinine level and change in weight at day 4 in the ultrafiltration group (P=0.003). The authors of CARRESS HF trial concluded that in patients with acute decompensated HF and cardiorenal syndrome, ultrafiltration is associated with more adverse events, worsening renal function, and no change in weight when compared to medical therapy.

Source: NEJM

IDNT Trial (2001): Irbesartan in diabetic nephropathy

Source: NEJM

RENAL Trial (2009): Intensity of CRRT in Critically Ill Patients

RENAL trial visual abstract graphical summary
RENAL Trial Visual Abstract Summary

2009, Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients (RENAL), NEJM

The RENAL trial was one of the largest trials that addressed an important question of doing continuous renal replacement therapy (CRRT) in critically ill patients with renal impairment. Based on this trial, high intensity CRRT at flow rate of 40 ml/kg/hr was found to have no benefits when compared to conventional CRRT at 25 ml/kg/hr.

Prior to this trial, the ATN trial was done in 2008 and compared high intensity renal replacement therapy with conventional approach in similar critically ill population. Both trials showed no benefits in the high intensity approach. In ATN trial, the stable patients were randomized to intermittent hemodialysis (HD) and the CRRT was reserved for unstable patients only. In contrast, RENAL trial addressed the intensity of CRRT and didn’t involve HD.

IDEAL: Early versus Late Dialysis in Patients with ESRD


2010, Does early initiation of dialysis in CKD improves survival, NEJM

SALT-ED: Balanced crystalloids versus saline in non-critically ill adults

2018, Lactated Ringer’s or Plasma-Lyte vs normal saline in non-critically ill patients, NEJM

CHOIR: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease

2006, CHOIR trial: anemia correction in patients with CKD, NEJM

SPYRAL HTN-ON MED Trial: Renal Denervation in Uncontrolled Hypertension

The SPYRAL HTN-ON MED trial was a large multicenter global scale trial that compared the effect of renal denervation + antihypertensive medications with antihypertensive medications alone. The results were significantly in favor of renal denervation in patients who had uncontrolled hypertension noticed in the clinic settings. Check out the visual abstract and following text for the trial summary.

SPYRAL HTN-ON MED trial Summary

The role of the sympathetic nervous system in the pathogenesis of hypertension (HTN) is well known. Activation of afferent sympathetic fibers results in renin release, retention of sodium, and reduction in renal blood flow that lead to the increase in blood pressure (BP) values. Hypertension usually requires life-long medication regimen; however, many studies have highlighted the averseness of many patients to maintain the stable regimen.


Recently, surgical renal denervation (RDN) has emerged as an efficient way of diminishing the renal sympathetic stimulation, decreasing the release of renin, while maintaining the normal glomerular filtration rate and renal blood flow.


SPYRAL HTN-ON MED trial is a randomized, single-blind, sham-controlled proof-of-concept trial carried out by Kandazi DE, et al. to assess the safety and efficacy of renal denervation on BP in patients with uncontrolled HTN who were on antihypertensive medication. The RDN of the main renal artery and accessory branches was performed with a Spyral multi-electrode radiofrequency ablation device. The primary results of the first 80 patients in the SPYRAL HTN-ON MED trial were published in 2018, which demonstrated a significant decrease in office and 24-hour ambulatory BP from baseline to 6 months in RDN group compared to sham-control, with a mean drug adherence of 60%.


The previous SPYRAL HTN-OFF MED trial of the SPYRAL series by Townsend RR, et al. was published in 2017. This trial used the similar ablation device as in HTN-ON MED trial but was conducted in the absence of antihypertensive medications. This trial also demonstrated a significant reduction in 24-hour ambulatory BP from baseline at 3 months follow-up.


Furthermore, the reduction in systolic BP of approximately 5.5 to 9 mmHg in these SPYRAL trials corresponds to the effect of one antihypertensive drug. It is also important to note that the short-term safety profile of this new intervention is favorable with no major adverse effects recorded. These results have shown a promising future of RDN in the treatment of HTN, especially in patients with medication noncompliance or those with adverse effects of medication.


However, before RDN becomes a mainstream management option for the treatment of HTN, further research needs to show the improvements in cardiovascular morbidity and mortality with the use of RDN. Additionally, further research is also needed to establish a long-term safety beyond the initial 6 months post-procedure.


Summarized by / Author: Muhammad Uzair Lodhi, MD (1)

Summary Reviewer: Mustafa Rahim, MD, FACP, FASPC (1)


Authors Affiliation:

1. Department of Medicine, West Virginia University Robert C. Byrd Health Sciences Center, WV




ACT Trial: Acetylcysteine in patients undergoing Angiography

ACT trial on angiography visual abstract

ACT trial was the initial large sized randomized controlled trial that was initiated to test the role of acetylcysteine in protecting kidneys from contrast. More than 2000 patients were enrolled in this placebo-controlled trial. The results failed to establish any renal protective role of acetylcysteine in patients undergoing coronary or peripheral angiography.


Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function

Visual Abstract: Metformin use based on kidney function. Over ~1 million patients are not on guideline-directed therapy of metformin due to abnormal kidney function. Thee present study studies the relationship of metformin with lactic acidosis over a wide range of eGFR in patients. Patients were followed up for years and were assesed for decline in kidney function via eGFR calculation and risk of development of lactic acidosis due to metformin use. The results were consistent with previously stated guidelines as to which metformin is safe to use in eGFR > 30 over all ranges while risk of lactic acidosis doubles once eGFR drops below 30  mL/min/1.73 m2

Source: JAMA Intern Med

SMART Trial: Balanced Crystalloids versus Saline in Critically Ill Adults

Source: NEJM

AKIKI Trial: Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

Source: NEJM

PRESERVE Trial: Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine

Study Question: Does the use of sodium bicarbonate or acetylcysteine affect outcomes after angiography

Trial Summarized by: Hajra Munawar, MD; Hasan Shafiq, MD

Contribution to literature

This trial revealed that the patients with impaired kidney function who were undergoing angiography showed no benefit of periprocedural IV isotonic sodium bicarbonate over IV isotonic sodium chloride or of oral acetylcysteine over placebo with respect to major adverse kidney events, death, or acute kidney injury.

Description of the trail

The goal of this trial was to compare renal complications in patients who were scheduled for angiography to receive IV 1.26% sodium bicarbonate or IV 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo, and assess the overall difference among the composite of death, need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine levels at 90 days.

Study Design

It was a double-blinded, placebo and comparator-drug controlled, randomized trial sponsored by U.S Department of Veterans Affairs Cooperative Studies Program and George Institute for Global Health from February 2013 through March 2017, patients were enrolled at 53 medical centers in the United states (35 veterans Affairs sites),Australia(13 sites),Malaysia(3 sites) and New Zealand(2 sites).

Patients were randomly assigned to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and oral acetylcysteine capsule or matched placebo capsules. The administration of trial IV fluids was based on protocol-specified ranges: 1 to 3 ml/kg/hr during a period of 1 to 12 hours for a total of 3 to 12 ml/kg/hr before angiography, 1 to 1.5 ml/kg/hr during angiography, 1 to 3ml/kg/hr during the period of 2 to 12 hrs for total volume of 6 to 12 ml/kg after angiography.

From each patient, a blood sample collected before the initiation of trial intravenous fluids and at 3 to 5 days and 90 t0 104 days after angiography. Urine samples are collected for local measurement of albumin and creatinine at the time of angiography and for PH measurement 2 to 4 hours after angiography.

  • Total number of patients: 5177(4441 at Veterans Affairs sites and 736 at George Institute sites) underwent randomization after randomization 184 patients were withdrawn, which resulted in 4993 patients for primary analysis.
  • Duration of follow up: from February through March 2017
  • Mean patient age: 69 year
  • Percentage male: 93.6%
  • Percentage diabetics:80.9%
  • Median serum Cr:1.5mg/dl
  • Median eGFR:50.2 ml per min per 1.73m2
  • Median volume of contrast material administered was 85ml.
  • Median volume of trial IV fluid administered was 344ml before,114ml during,570ml after angiography.
  • After angiography mean urine PH was 6.7 +/- 0.8 in the sodium bicarbonate group and 6 +/_ 0.8 in sodium chloride group (p=<.001)

Statistical Analysis:

Modified intention to treat analysis was used that included all the patients who had undergone randomization and who had received the assigned trial interventions, regardless of whether they had undergone angiography. The comparison was done using the t-test for normally distributed continuous variables, the Wilcoxon rank-sum test for variables without a normal distribution and the chi-square test for categorical variables. To test the interaction between sodium bicarbonate and acetylcysteine, a multivariable logistic regression model was used.

Inclusion criteria

  • Patients who were scheduled to undergo coronary or noncoronary angiography
  • Patients who had an eGFR of 55 -44.9ml per min per 1.73 m2
  • Patients with diabetes mellitus and e GFR 45 -59.9 ml per minute per 1.73 m2

Exclusion criteria

Patients who were undergoing emergency angiography
Patients with unstable baseline levels of blood creatinine( increase or decrease of >25% within 3 days before angiography)

Primary outcomes

  • The primary composite endpoint occurred in 110 patients in the sodium bicarbonate group as compared with 116 patients in the sodium chloride groups(odds ratio: 0.93; 95% CI, 0.72 to 1.22 ;P =0.62) and in 114 patients in the acetylcysteine group as compared with 112 in the placebo group (odds ratio:1.02; 95% CI ,0.78 – 1.33 ;P = 0.88).There were no significant differences in the primary composite end point in the comparison of treatment combination groups.
  • There was also no significant difference in the need for dialysis, or a persistent increase of at least 50% from baseline in serum creatinine level at 90 to 140 days after angiography in the comparison of sodium bicarbonate with sodium chloride or in the combinations of acetylcysteine with placebo.
  • There was a significantly higher risk of the primary composite endpoint in sodium bicarbonate as compared to sodium chloride in patients who have undergone noncoronary angiography.(odds ratio,3.19;95%CI ,1.03 to 9.94)

Secondary Outcomes

  • Contrast associated acute kidney injury occurred in 239 patients in the sodium bicarbonate group as compared with 206 in the sodium chloride group (odds ratio ,1.16;CI,0.96-1.41 ;P=0.13)and in 228 patients in the acetylcysteine group as compared with 217 in the placebo group (odds ratio ,1.06;95%CI, 0.87 -1.28; P =0.58)
  • There were no significant differences in the incidence of, death within 90 days; dialysis of any kind within 90 days; confirmed persistent kidney impairment at 90 to 104 days; hospitalization with ACS, heart failure or stroke within 90 days; and hospitalization for any cause within 90 days.


In patients with chronic kidney disease who underwent angiography, no benefit of IV sodium bicarbonate over IV sodium chloride or of oral acetylcysteine was seen compared to placebo. Unlike most previous trials in which primary endpoint was a small increase in the blood creatinine level occurring within days after the IV contrast, the primary endpoint in this trial was a composite of serious adverse outcomes such as mortality, need for dialysis and worsening of renal function.

Steven D. Weisbord, M.DMartin Gallagher, M.D., Ph.D., Hani Jneid, M.D., Santiago Garcia, M.D., Alan Cass, M.D., Ph.D., Soe-Soe Thwin, Ph.D., Todd A. Conner, Pharm.D., Glenn M. Chertow, M.D., M.P.H., Deepak L. Bhatt, M.D., M.P.H., Kendrick Shunk, M.D., Ph.D., Chirag R. Parikh, M.D., Ph.D., Edward O. McFalls, M.D., PhD., et al., for the PRESERVE Trial Group*

Source: NEJM

DOSE Trial: Diuretic Strategies in Patients with Acute Decompensated Heart Failure

Source: NEJM

RENAAL Trial: Losartan in Patients with Type 2 Diabetes and Nephropathy

RENAAL Trial Visual Abstract

Source: NEJM

RENAAL Trial Key Points
1. Losartan was found to have significant reno-protective role in patients with type II diabetes and nephropathy.
2. Losartan did not affect mortality in this patient population.
3. Proteinuria significant improved in patients taking losartan compared to placebo.
4. The IDNT trial tested irbesartan and reported similar renoprotective role in diabetic nephropathy.

Guideline Recommendations based on RENAAL Trial:

The JNC8 guidelines recommend: In patients who are diabetic with high levels of albuminuria, the medication regimen should include an ACE inhibitor or an ARB alone or in combination with medication from another drug class for treatment of HTN.

The KDIGO guidelines recommend use of an ACE or an ARB and a BP goal <130/80 mmHg in all patients with CKD and albuminuria irrespective of diabetes status.


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