Evidence

Peer Reviewed Studies

Most evidence connecting midodrine to renal failure has emerged incidentally, often in cases where patients in the midodrine group experienced worsening renal function. Despite the absence of targeted studies, the evidence presented below clearly indicates that midodrine has the potential to cause kidney injury or failure under certain conditions. Furthermore, evidence suggests a profound association between midodrine use and an increased risk of mortality in dialysis patients.

Study 1: Demonstrates That Midodrine Can Rapidly Induce Severe Kidney Injury.

A randomized controlled trial, the gold standard for proving causation, provided compelling evidence that midodrine can cause severe kidney injury/failure. Patients who received midodrine in this study experienced a dramatic rise in creatinine levels, increasing from 0.99 to 3.02, a clear indicator of severe kidney injury . In contrast, the control group showed no such changes. Alarmingly, seven patients in the midodrine group died during the study, while no deaths occurred in the control group.

This study stands as one of the strongest pieces of evidence linking midodrine to kidney failure. The patients in the study were carefully matched across numerous factors, significantly reducing the likelihood that these findings were influenced by other variables.

Midodrine Kidney Failure - Evidence of Midodrine Induced Kidney Injury

Note: This image was created to summarize the study's results. Although it was not part of the original publication, the data presented in the figure is directly derived from the study's findings.
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Study 2: Demonstrates That Midodrine Is Associated With Increased Mortality Rates (Death☠ ) in Dialysis Patients.

This study is a retrospective analysis, which makes it more challenging to establish causation. However, its strength lies in the large dataset, including 1,406 patients on midodrine (at unspecified doses) and 2,037 controls. Notably, the study was affiliated with DaVita. The fact that a prominent dialysis company acknowledges these concerning findings adds weight to the evidence against midodrine's safety.

The study revealed that patients taking midodrine faced significantly higher risks of hospitalization, cardiovascular-related hospitalizations, and death. Critics may argue that the retrospective design makes it difficult to definitively attribute these outcomes to midodrine. Nonetheless, to the best of our knowledge, this is the largest study available assessing the safety of midodrine, and its findings raise serious concerns—especially given the drug’s accelerated FDA approval.

Conclusion: “Although residual confounding may have influenced the results, the associations observed here are not consistent with a potent beneficial effect of midodrine with respect to either clinical or hemodynamic outcomes.”

Midodrine Increases Mortality in Dialysis Patients

Source

Study 3: Highlights A Case of Renal Failure In A Patient On Midodrine

In this study, a patient who received midodrine developed liver and renal failure, ultimately resulting in death. No adverse renal outcomes or fatalities occurred in the control group. Although this patient was excluded from the primary analysis, a description of their clinical course is included in the discussion. It should be noted that the evidence derived from this case is limited due to the involvement of a single patient, and, as such, its contribution to the overall findings is comparatively minimal.

Excerpt:

“One patient in the midodrine group developed HRS type 1 after developing pneumonia as a potential precipitating factor besides large-volume paracentesis (defined by the diagnostic criteria for HRS of the International Ascites Club) (13) on day 2. We started treatment for HRS type 1 with the vasoconstrictor terlipressin and daily albumin infusions. Despite this treatment, the patient died after 3 weeks as a consequence of liver failure complicated by acute renal failure. Because the patient received the vasoconstrictor terlipressin, his data could not be analysed on day 6 and he was excluded from the statistical analysis.
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FDA Drug Label

The FDA label repeatedly highlights concerns about midodrine use in patients with kidney injury. These warnings primarily stem from the fact that the clinical trials used the initial approval of midodrine did not evaluate the long-term effects of midodrine dosing on kidney function.
Note: ProAmatine is the brand name of midodrine.

Excerpt:

“ProAmatine® use has not been studied in patients with renal impairment. Because desglymidodrine is eliminated via the kidneys, and higher blood levels would be expected in such patients, ProAmatine® should be used with caution in patients with renal impairment, with a starting dose of 2.5 mg (see DOSAGE AND ADMINISTRATION). Renal function should be assessed prior to initial use of ProAmatine®.
“After initiation of treatment, ProAmatine® should be continued only for patients who report significant symptomatic improvement.”
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Basic Science

Midodrine is a textbook example of a drug that can cause kidney failure. By constricting the veins supplying the kidneys, it reduces blood flow and compromises kidney function. Under certain conditions, midodrine can be highly damaging to the kidneys—a fact that has been well-documented in the medical literature since the 1960s. For reference, this diagram depicts how alpha agonists, such as midodrine, contribute to renal failure.

On the other hand, there is some evidence suggesting that midodrine may improve kidney function in specific situations. Although the data is conflicting, nephrologists often cite these studies to justify prescribing midodrine to patients with renal failure. One of the primary indications for its use in this context is a condition known as hepatorenal syndrome.

Most doctors have limited knowledge about midodrine and its potential effects on the kidneys. The mechanisms by which midodrine may harm or benefit renal function remain largely theoretical, leading most physicians to defer decision-making to nephrologists.

This image shows how alpha agonists (i.e. midodrine) can cause kidney failure by constricting blood vessels leading to the kidney.

Original FDA Approval Documents

Note: Midodrine was approved under accelerated approval in 1996. This means that preclinical trial requirements were not as comprehensize or rigorous. In 2010, the FDA proposed withdrawing midodrine from the market after the manufacturer failed to complete the required post market studies. After public push back, the FDA backtracked. In 2019 the FDA published a statement stating:

“FDA has determined under § 314.161 that PROAMATINE (midodrine hydrochloride) tablets, 2.5 mg, 5 mg, and 10 mg, were not withdrawn from sale for reasons of safety or effectiveness.”
“The clinical benefit of PROAMATINE (midodrine hydrochloride) tablets, 2.5 mg, 5 mg, and 10 mg, remains subject to verification”

These documents reveal the process by which midodrine received FDA approval under the accelerated approval pathway (Subpart H). While several issues are highlighted in the document, one particularly troubling concern stands out: the mechanism of renal excretion for midodrine was not thoroughly understood or explained. This gap in knowledge raises serious questions about the drug’s safety, particularly for patients with compromised kidney function, and underscores the potential risks of approving medications without a full understanding of their impact on critical organ systems.

Excerpts From Original Approval Document:

Deficiencies in Orginal Approval Documents

Another alarming finding in this document is that midodrine can remain in the system much longer than anticipated, leading to a "second kick." This delayed absorption significantly increases the risk of overdose, especially in patients with renal failure, who have a reduced capacity to excrete the drugs metabolites effectively. The data below, derived from a single oral dose of midodrine, suggest a two-phase absorption process: an initial peak following stomach absorption, and a secondary phase triggered by bacterial activation of the drug as it enters the colon. (See Image Below)

Note: The image on the left has been enhanced with added colors and labels to emphasize the concerning findings.

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SORO-ESRD - Rapid Renal Decline

Midodrine can cause severe kidney injury much more rapidly than kidney injury due to other causes. Chronic kidney disease is generally characterized by a gradual decline in kidney function over years. In contrast, midodrine can trigger a sudden and dramatic deterioration in renal function, a phenomenon referred to as Syndrome of Rapid-Onset End-Stage Renal Disease (SORO-ESRD). The image below illustrates this stark difference, with SORO-ESRD progressing in days rather than years.

Top Image: Classic ESRD, progression over 6 years
Bottom Image: SORO-ESRD, rapid progression over 4 days

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Case Reports

Report 1: Published in 2024, this presentation details a case of kidney failure in a 66-year-old male, attributed to midodrine use, which resolved following the discontinuation of the drug.

Source (Report 1)

Report 2: Published in 2006, this case report highlights an 82-year-old female who developed severe proteinuria (protein in the urine)—an indicator of kidney injury—linked to the use of midodrine. Although protein levels in her urine decreased slightly after discontinuing the drug, they remained substantially above the normal range.

Source (Report 2)