Original Investigation
Pathogenesis and Treatment of Kidney Disease
Therapeutic Response to Vasoconstrictors in Hepatorenal Syndrome Parallels Increase in Mean Arterial Pressure: A Pooled Analysis of Clinical Trials

https://doi.org/10.1053/j.ajkd.2011.07.017Get rights and content

Background

Vasoconstrictor therapy has been advocated as treatment for hepatorenal syndrome (HRS). Our aim was to explore across all tested vasoconstrictors whether achievement of a substantial increase in arterial blood pressure is associated with recovery of kidney function in HRS.

Study Design

Pooled analysis of published studies identified by electronic database search.

Setting & Population

Data pooled across 501 participants in 21 studies.

Selection Criteria for Studies

Human studies evaluating the efficacy of a vasoconstrictor administered for 72 hours or longer in adults with HRS type 1 or 2.

Intervention

Vasoconstrictor therapy.

Outcomes & Measurements

Cohorts' mean arterial pressure (MAP), serum creatinine level, urinary output, and plasma renin activity (PRA) at baseline and subsequent times during treatment. Linear regression models were constructed to estimate mean daily changes in MAP, serum creatinine level, urinary output, and PRA for each study subgroup. Correlations were used to assess for association between variables.

Results

An increase in MAP is associated strongly with a decrease in serum creatinine level, but is not associated with an increase in urinary output. Associations were stronger when analyses were restricted to randomized clinical trials and were not limited to cohorts with either lower baseline MAP or lower baseline serum creatinine level. Most studies tested terlipressin as vasoconstrictor, whereas fewer studies tested ornipressin, midodrine, octreotide, or norepinephrine. Excluding cohorts of participants treated with terlipressin or ornipressin did not eliminate the association. Furthermore, a decrease in PRA correlated with improvement in kidney function.

Limitations

Studies were not originally designed to test our question. We lacked access to individual patient data.

Conclusions

An increase in MAP during vasoconstrictor therapy in patients with HRS is associated with improvement in kidney function across the spectrum of drugs tested to date. These results support consideration for a goal-directed approach to the treatment of HRS.

Section snippets

Review Strategy and Study Selection

The electronic databases of PubMed, The Cochrane Library, Web of Science, and LILACS were searched for publications between 1966 and January 2011 that evaluated the efficacy of vasoconstrictor therapy for the reversal of HRS type 1 or 2. We searched for articles with the key words “hepatorenal syndrome” and cross-referenced them with “treatment,” “vasoconstrictor therapy,” “reversal,” “liver cirrhosis,” “terlipressin,” “ornipressin,” “vasopressin,” “midodrine,” “octreotide,” “dopamine,”

Study Characteristics

Table 1 lists general characteristics of the included studies. The series included publications between 1998 and 2010. Only 1 study was conducted, partially, in the United States.7 Two were from India,32, 33 1 was from Mexico,44 2 were from Canada,34, 43 and the rest were from Europe. Ten studies were conducted under a dual-arm design, whereas 11 studies had a single treatment arm. Because 6 of the single-arm studies reported their results in 2 subgroups based on either responder status or

Discussion

Our analysis shows a strong correlation between the increase in MAP during vasoconstrictor therapy in patients with HRS and therapeutic response. Improvement in kidney function tightly correlates with the magnitude of increase in MAP. Although these findings seem intuitive, no previous study was designed to specifically explore this relationship. Of note, several studies individually reported a similar association between improvement in systemic hemodynamics and HRS reversal.8, 27, 29, 30, 31,

Acknowledgements

A preliminary version of this study appeared in abstract form at the 43rd Annual Meeting and Scientific Exposure of the American Society of Nephrology Kidney Week 2010, November 16-21, 2010, Denver, CO.

We thank Dr Michael E. Ullian for critical review of this manuscript.

Support: This project was supported by the South Carolina Clinical & Translational Research Institute, Medical University of South Carolina's Clinical and Translational Science Award, National Institutes of Health (NIH)/National

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    Originally published online September 29, 2011.

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