Liver Failure and Liver Disease
Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome
Article first published online: 2 JUN 2004
Copyright © 2004 American Association for the Study of Liver Diseases
Volume 40, Issue 1, pages 55–64, July 2004
How to Cite
Wong, F., Pantea, L. and Sniderman, K. (2004), Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology, 40: 55–64. doi: 10.1002/hep.20262
- Issue published online: 30 JUN 2004
- Article first published online: 2 JUN 2004
- Manuscript Accepted: 16 MAR 2004
- Manuscript Received: 13 OCT 2003
- Physicians Services Inc. of Ontario, Canada
Hepatorenal syndrome (HRS) is a functional renal disorder complicating decompensated cirrhosis. Treatments to date, except liver transplantation, have been able to improve but not normalize renal function. The aim of this study was to determine the efficacy of transjugular intrahepatic portosystemic stent shunt (TIPS) as a treatment for type 1 HRS in ascitic cirrhotic patients, following improvement in systemic hemodynamics with a combination of midodrine, octreotide, and albumin (medical treatment). Fourteen ascitic cirrhotic patients with type 1 HRS received medical therapy until their serum creatinine reached below 135 μmol/L for at least 3 days, followed by a TIPS if there were no contraindications. Patients were assessed before and after medical treatment, as well as at 1 week and 1, 3, 6, and 12 months post-TIPS with measurements of renal function, sodium handling, systemic hemodynamics, central blood volume, and hormonal markers. Medical therapy for 14 ± 3 days improved renal function (serum creatinine: 233 ± 29 μmol/L vs. 112 ± 8 μmol/L, P = .001) and renal sodium excretion (5 ± 2 mmol/d vs. 9 ± 2 mmol/d, P = .002) in 10 of the 14 patients. TIPS insertion in five of the responders further improved renal function and sodium excretion, so that by 12 months post-TIPS, glomerular filtration rate (96 ± 20 mL/min, P < .01 vs. pre-TIPS) and urinary sodium excretion (119 ± 15 mmol/d, P < .01 vs. pre-TIPS) were normal, associated with normalization of plasma renin and aldosterone levels and elimination of ascites. In conclusion, TIPS is an effective treatment for type 1 HRS in suitable patients with cirrhosis and ascites, following the improvement of renal function with combination therapy of midodrine, octreotide, and albumin. (HEPATOLOGY 2004;40:55–64.)
Hepatorenal syndrome (HRS) is a syndrome of functional renal failure occurring in patients with advanced liver failure in the absence of clinical, laboratory, or histological evidence of other known causes of renal failure.1 The development of HRS in patients with cirrhosis and ascites is associated with a significant worsening of their prognosis with a median survival time of 1.7 weeks.2
However, HRS has always been considered to be potentially reversible.3 Recent advances in the understanding of the pathophysiology and the management of cirrhotic patients with refractory ascites and HRS3 have proved that HRS can be reversed. These include various pharmacotherapies aimed at reversing the abnormal hemodynamics observed in patients with HRS.4 Various vasoconstrictors, such as terlipressin and norepinephrine, have been shown to improve renal function in approximately two thirds of patients with HRS.5, 6 Unfortunately, the use of vasoconstrictors has been associated with ischemic side effects in up to 5% of patients.5, 6 In another small study, the combination of midodrine, octreotide, and albumin resulted in a significant decrease in serum creatinine in three of five patients with HRS without any significant ischemic side effects,7 while the use of octreotide alone has not proved to be useful.8 Other treatment options include the use of a transjugular intrahepatic portosystemic stent shunt (TIPS), which led to a sustained reduction in serum creatinine and some improvement in renal sodium excretion in two thirds of patients.9, 10
Despite the encouraging results, all of the treatment options studied so far have been able to improve but not normalize renal function. It is postulated that by combining treatment options that correct different aspects of the pathophysiology of HRS, the beneficial effects may be enhanced. Midodrine is an alpha agonist that improves systemic blood pressure and hence improves renal perfusion pressure. Octreotide antagonizes the action of various splanchnic vasodilators and reduces the mismatch between the extent of arterial vasodilatation and the intravascular volume. Albumin increases circulatory volume. Their combined effects improve systemic hemodynamics and consequently improve renal circulation. TIPS returns a significant volume from the splanchnic to the systemic circulation. Therefore, TIPS insertion should further improve renal function following pharmacotherapy.
Therefore, the aim of this study was to determine the efficacy of TIPS as a treatment for type 1 HRS in ascitic cirrhotic patients, in the setting of improved systemic hemodynamics using the combination therapy of midodrine, octreotide, and albumin.
Patients and Methods
From July 2000 to April 2003, 14 consecutive patients with biopsy-proven cirrhosis and ascites complicated by type 1 HRS as defined by the International Ascites Club1 were enrolled. The renal impairment was precipitated by excessive diuretic use in six patients (five responders and one nonresponder; see below for definitions of responders and nonresponders), large-volume paracentesis in three patients (all responders), spontaneous bacterial peritonitis in three patients (one responder and two nonresponders), and chest infection (responder) and massive upper gastrointestinal bleed (nonresponder) in each of the remaining two patients. All patients had been infection-free for at least 10 days prior to enrollment. Infection was excluded by two negative blood cultures, a normal chest X ray, a negative midstream urine culture, and an ascitic fluid cell count of less than 250 neutrophils/μL. The patient with massive gastrointestinal bleed had been adequately resuscitated and was hemodynamically stable for 7 days before entering the study. All diuretics had been withdrawn for 2 weeks and all patients received volume replacement of 50 g of albumin/d for 5 days without improvement in renal function. Likewise the patients whose HRS was precipitated by large-volume paracentesis had received albumin infusions of 6 to 8 g/L of ascitic fluid removed during the paracentesis, but renal function continued to deteriorate after the paracentesis. None of the patients received any nephrotoxic drugs, including radiographic dye. Organic renal disease was excluded by the absence of urinary sediment (no casts, no red blood cells, no white cells, no bacteria, no protein, and no crystals), 24-hour urinary protein excretion of less than 500 mg/d, and normal-sized kidneys on ultrasound. In addition, all patients had normal cardiac and pulmonary function as assessed by chest X ray, electrocardiograph, two-dimensional echocardiograph, pulmonary function tests, as well as a patent portal vein as assessed by Doppler ultrasound, which was required for TIPS insertion. Patients with hepatic encephalopathy above grade 2 (four patients) or the presence of a hepatoma (one patient) were excluded because the presence of these conditions would preclude the insertion of TIPS. The patient demographics are shown in Table 1.
|Age (y)||55.9 ± 2.3||52.7 ± 5.0|
|Hemoglobin (N: 120–170 g/L)||94 ± 4||97 ± 4|
|Platelet (N: 150–400 × 106)||102 ± 19||78 ± 22|
|International normalized ratio (N: 0.9–1.1)||1.72 ± 0.13||2.04 ± 0.25|
|Child-Turcotte-Pugh score||9.50 ± 0.56||10.75 ± 0.95|
|Aspartate aminotransferase (N: <35 IU/L)||38 ± 6||66 ± 11|
|Alanine aminotransferase (N: <40 IU/L)||19 ± 4||18 ± 5|
|Alkaline phosphatase (N: <110 IU/L)||104 ± 20||80 ± 40|
|Bilirubin (N: <22 μmol/L)||45 ± 8||71 ± 16|
|Albumin (N: 38–50 g/L)||32 ± 3||33 ± 5|
|Serum Na (N: 135–145 mmol/L)||131 ± 1||134 ± 2|
|Serum creatinine (N: 57–110 μmol/L)||233 ± 29||345 ± 83|
|BUN (N: 3.0–8.9 mmol/L)||21.1 ± 3.1||20.2 ± 3.8|
|Urinary volume (mL/d)||504 ± 50||438 ± 31|
|Urinary Na (mmol/d)||5 ± 2||2 ± 1|
|Etiology of cirrhosis|
|Alcohol + hepatitis C||2||1|
All patients signed an informed consent for the study, which was approved by the Research Ethics Board of the University Health Network, Toronto General Hospital.
All ascitic cirrhotic patients with renal dysfunction were admitted as inpatients into the metabolic bed in the hepatology ward for assessment and diagnosis of type 1 HRS. Once admitted, all patients were prescribed a 22-mmol sodium, 1-L/d fluid diet as described in all our previous studies11–13 that was maintained throughout the duration of the study. Once the inclusion and exclusion criteria and the diagnosis for type 1 HRS were met, the patients underwent measurements of glomerular filtration rate and renal plasma flow with inulin and para-aminohippurate clearances, respectively.14 Central blood volume measurements—including cardiac chamber volume measurements—were also performed using radionuclide angiography.15 These were subsequently used to calculate the stroke volume and then the cardiac output. Blood samples for supine renin, aldosterone, and norepinephrine levels were taken to assess the fullness of the effective arterial blood volume. All patients then received medical therapy consisting of a combination of 2.5 mg/d oral midodrine, 25 μg/h intravenous octreotide after a bolus injection of 25 μg, and 50 g/d intravenous albumin. Midodrine was temporarily withheld if the patient's systolic blood pressure was above 120 mm Hg. Patients were monitored before and during medical therapy every 6 hours for heart rate and blood pressure and were monitored daily for complete blood count, international normalized ratio, serum electrolytes and creatinine, weight, urinary volume, and urinary electrolytes. Liver function tests were measured twice weekly. Once the serum creatinine dropped below 135 μmol/L for 3 consecutive days, patients underwent repeat inulin and para-aminohippurate clearances and all neurohormonal measurements. Based on the literature, the combined therapy should result in a significant reduction in serum creatinine in 7 to 10 days.7 Therefore, patients who showed either a rise or no reduction in their serum creatinine levels after 7 days of medical therapy were discontinued from the treatment and followed until death or liver transplantation.
In the patients who showed a reduction in their serum creatinine (once the serum creatinine remained stable at less than 135 μg/L for 3 days) and who otherwise did not have any contraindication for TIPS insertion, TIPS placement was performed. The contraindications for TIPS insertion included an international normalized ratio greater than 2, a serum bilirubin above 85 μmol/L (5 mg/dL), a Child-Turcotte-Pugh score of 12 or more, or thrombosed portal vein and active infection within the previous 2 weeks.16 Five patients did not receive a TIPS because either their international normalized ratio was greater than 2 (two patients), their serum bilirubin was above 85 μmol/L (two patients), or their Child-Turcotte-Pugh score was 12 or more (one patient). The technique of TIPS placement is described in Wong et al.11 One or 2 Wallstents were placed in the intrahepatic tract and dilated to lower the portosystemic gradient to 8 mm Hg or less, the portal pressure threshold for elimination of ascites at our institution,17 although slightly higher thresholds (mean of 8.3 mm Hg and 8.7 mm Hg) have been used in other studies.18, 19
After completion of TIPS insertion, the intravascular volume was maintained with 50 g of albumin to reach a central venous pressure of 10 mm Hg or more for 3 days post-TIPS. All patients were commenced on 30 mL lactulose three times a day immediately post-TIPS, and none of the patients was ever placed on diuretics in the post-TIPS period as per our usual protocol. A Doppler ultrasound was performed on the first post-TIPS day and thereafter at 3 monthly intervals to ensure patency of the TIPS as indicated by a shunt flow velocity of 100 cm/min or more. Any suggestion of TIPS dysfunction on Doppler ultrasound required a hepatic venogram; occlusion or stenosis of the TIPS was dealt with as per protocol at our institution to achieve a portal systemic gradient of 8 mm Hg or less. Doppler ultrasound was always repeated after each manipulation of the TIPS to ensure adequate shunt patency.
Patients were discharged after TIPS insertion when medically fit and re-evaluated at week 1, month 1, and thereafter at 3 monthly intervals until 1 year, death, or liver transplantation. Routine biochemistry, liver function tests, complete blood count, international normalized ratio, 24-hour urinary volume and sodium excretion, supine hormone levels, and weight were measured at week 1. Inulin and para-aminohippurate clearances and central blood volume measurements were also performed in addition to the above at 1 month and during each visit at 3, 6, and 12 months.
Detailed descriptions of inulin and para-aminohippurate clearances as well as central blood volume measurement are available in Wong et al.11 Renal blood flow, renal vascular resistance, mean arterial pressure, cardiac output and systemic vascular resistance were calculated from standard formulae.11
Analytical Techniques and Assays.
Standard analytical methods were used to measure serum and urinary electrolytes and liver function tests. Blood samples for renin, aldosterone, and norepinephrine determinations were collected on ice. Plasma active renin was measured by using the RENIN III Generation Pasteur immunoradiometric procedure. Plasma aldosterone was assayed using a radioimmunoassay technique with a commercial kit (Coat-A-Count Aldosterone Kit, Diagnostic Products Corporation, Los Angeles, CA). Plasma norepinephrine concentrations were determined using high performance liquid chromatography as described by Eriksson and Persson20 and Weicker et al.21 with modifications. Inulin concentrations in plasma and urine were measured using a modified technique of Walser et al.22; para-aminohippurate concentrations were measured using a spectrophotometric method of Brun.23
The various parameters of systemic and renal hemodynamics, renal function, and hormonal profile were assessed over time. Differences between the various time intervals for each parameter were compared using repeated measures of ANOVA with Bonferroni correction. Results between responders and nonresponders were compared using unpaired Student's t test. Differences were considered significant if the null hypothesis could be rejected at the .05 probability level.
All 14 patients received the combined treatment of oral midodrine, intravenous octreotide, and albumin daily. Midodrine was withheld temporarily in two patients on day 5 and day 7 for 4 days and 2 days, respectively, because their systolic blood pressure was above 120 mm Hg (124 mm Hg and 127 mm Hg, respectively). The total length of treatment was 14 ± 3 days (range: 5–47 days). Ten patients responded at a mean of 16 ± 4 days with a graduate reduction of their serum creatinine (Fig. 1), while the remaining four patients did not show any change in their serum creatinine despite receiving treatment for a mean of 10 ± 2 days (range: 8–14 days). Five of the responders fulfilled the criteria for TIPS insertion and therefore received a TIPS following normalization of their serum creatinine. This brought their portosystemic gradient from 16.6 ± 0.6 mm Hg to 7.8 ± 1.8 mm Hg. One of the post-TIPS patients subsequently received a living related liver transplant at 13 months, while the other four post-TIPS patients have remained alive at 17 ± 5 months (range: 6–30 months) without a liver transplant and with minimal ascites. Two of the remaining responders had their medical treatment discontinued at 2 and 4 weeks when their serum creatinine levels were normal and a donor liver became available. All three transplanted patients had a prolonged postoperative course with lengthy stays in the intensive care unit that was complicated by infections. All three posttransplant patients have remained alive at 27, 7, and 6 months, with one patient remaining hospitalized for the entire 7 months of his postoperative course. The remaining three responders died from septicemia (3 months), liver failure (3 months), and arrhythmia (1 month). The four nonresponders died from multiorgan failure at 2 weeks to 2 months from enrolment. Overall, there were 7 survivors from the initial cohort (50%), with the longest survivor being alive at 30 months after enrollment without liver transplantation and without ascites (see Fig. 1).
The daily serum creatinine levels during the medical treatment phase for both the responders and the nonresponders are shown in Fig. 2. In the responders, the serum creatinine levels decreased significantly from 233 ± 29 μmol/L at baseline to 177 ± 33 μmol/L on day 6 (P = .04). This continued to decrease to 112 ± 8 μmol/L on the last day of treatment (P = .001 vs. baseline). This fall in serum creatinine was associated with significantly improved renal hemodynamics (P < .05) and renal sodium and water handling (P < .05), although the final readings were still abnormal (Table 2). In contrast, all the nonresponders had a continued rise in their serum creatinine levels (see Fig. 2). The renal hemodynamics and sodium handling were worse than those of the responders, and these remained unchanged at the end of the medical treatment period (see Table 2).
|Responders (n = 10)||Nonresponders (n = 4)|
|Pre-Rx||End of Rx||Pre-Rx||End of Rx|
|GFR (N: 90–120 mL/min)||12.8 ± 2.2||25.9 ± 4.0**||4.8 ± 1.6||4.8 ± 1.2|
|Serum creatinine (N: <99 μmol/L)||233 ± 29||113 ± 8**||345 ± 119||476 ± 139##|
|Urea (N: 4.0–8.2 mmol/L)||21.1 ± 3.1||11.5 ± 1.1**||20.2 ± 3.8||30.2 ± 5.5##|
|RPF (N: 460–550 mL/min)||157 ± 27||225 ± 31**||127 ± 37||99 ± 36#|
|RVR (N: 10–16 × 103 dyn.s.cm−6)||65,588 ± 16,687||42,258 ± 8,603*||122,810 ± 36,070||133,214 ± 28,039#|
|Urinary volume (mL/d)||504 ± 50||889 ± 128**||438 ± 31||367 ± 38##|
|Urinary Na (mmol/d)||5 ± 2||9 ± 2**||2 ± 1||2 ± 1#|
|FENa (%)||0.63 ± 0.26||1.04 ± 0.65||0.29 ± 0.09||0.17 ± 0.11#|
In the five patients who received a TIPS, renal function continued to improve. Glomerular filtration rate, as measured by inulin clearance, steadily increased and approached near normal levels by 12 months post-TIPS. Similarly, renal plasma flow increased and renal vascular resistance decreased (Fig. 3), which was associated with significantly increased natriuresis, even in the absence of diuretics (Fig. 4). Negative sodium balance while on a 22-mmol sodium/d diet was achieved by 1 month post-TIPS. However, complete elimination of ascites did not occur until at least 6 months post-TIPS insertion.
Two of the five responders who did not receive a TIPS underwent liver transplantation within 1 month after enrollment, and their serum creatinine remained normal (88 mol/L, 54 μmol/L) at the time of liver transplantation despite discontinuation of medical therapy. The serum creatinine of the remaining three nonresponders were 113 μmol/L, 94 μmol/L, and 67 μmol/L 1 month after enrollment.
Systemic Hemodynamics and Central Blood Volume.
Both the responders and the nonresponders had normal mean arterial pressure and heart rates at baseline (Table 3). Medical treatment increased the mean arterial pressure in both groups (81 ± 5 mm Hg to 87 ± 3 mm Hg in the responders, P > .05; 79 ± 4 mm Hg to 84 ± 5 mm Hg in the nonresponders, P = .02), but the increase was only significant in the nonresponders. There was also a slight and insignificant fall in heart rate with medical treatment in both groups. Radionuclide angiography was not repeated in the immediate post–medical treatment period, because it was unethical to expose the patients to radioactivity within such a short space of time. Therefore, no cardiac output or systemic vascular resistance could be calculated for the post–medical treatment period.
|Nonresponders Baseline (n = 4)||Responders|
|Baseline (n = 10)||Post-TIPS|
|M1 (n = 5)||M3 (n = 5)||M6 (n = 5)||M12 (n = 4)|
|MAP (N: 70–105 mm Hg)||79 ± 4||81 ± 5||88 ± 4||89 ± 5||93 ± 4||101 ± 3|
|Heart rate (N: 60–100 beats/min)||91 ± 3||75 ± 5||75 ± 7||68 ± 7||64 ± 4||69 ± 5|
|Cardiac output (N: 4.2–6.6 L/min)||6.24 ± 1.20||6.27 ± 0.93||7.16 ± 0.79||9.71 ± 1.16**||8.75 ± 0.97**||7.53 ± 1.10*|
|SVR (N: 700–1,600 dyn.s.cm−5)||1,236 ± 141||1,320 ± 165||1,229 ± 142||787 ± 49**||888 ± 79**||1,076 ± 137|
|CBV (N: 2,214 ± 173 mL)||1,270 ± 375||1,071 ± 156||1,472 ± 230||1,676 ± 363**||1,698 ± 318**||1,081 ± 191|
|Left lung vascular volume (N: 185 ± 18 mL)||117 ± 25||112 ± 19||120 ± 25||133 ± 25||163 ± 45*||114 ± 12|
|Right lung vascular volume (N: 220 ± 20 mL)||129 ± 21||134 ± 20||174 ± 29||175 ± 37||222 ± 42*||136 ± 22|
|CCvV (N: 1,522 ± 106 mL)||1,024 ± 298||826 ± 122||1,178 ± 293||1,368 ± 308**||1,313 ± 267*||841 ± 125|
In those patients who received a TIPS, there was evidence of worsening of the hyperdynamic circulation with further increase in the cardiac output and further reduction in the systemic vascular resistance, which was associated with increased mean arterial pressure until 6 months post-TIPS. There was a significant increase in the central blood volume during the same period (see Table 3). Thereafter, the systemic hemodynamics improved toward normal, which was associated with simultaneous reduction of the central blood volume (see Table 3).
The pretreatment hormonal levels were markedly elevated in all study patients, with the levels in the nonresponders being higher than in the responders (Table 4), but the differences between the responders and the nonresponders were not statistically significant. In the responders, medical treatment significantly reduced the plasma renin (201 ± 78 ng/L baseline vs. 39 ± 2ng/L posttreatment, P = .05) and aldosterone levels (2574 ± 375 pmol/L baseline vs. 930 ± 341 pmol/L posttreatment, P = .001). The norepinephrine levels, however, did not decrease following medical therapy even in the responders (3.93 ± 0.54 nmol/L baseline vs. 4.03 ± 0.90 nmol/L posttreatment, P > .05). The nonresponders, as expected, did not show any changes in their hormonal levels with medical therapy. Therefore, their end-of-treatment hormonal levels were higher compared with the responders, and significantly so with respect to plasma renin (39 ± 2 ng/L in the responders vs. 380 ± 194 ng/L in the nonresponders, P = .02) and aldosterone levels (930 ± 341 pmol/L in the responders vs. 4025 ± 1036 pmol/L in the nonresponders, P = .01).
|Responders (n = 10)||Nonresponders (n = 4)|
|Pre-Rx||End of Rx||Pre-Rx||End of Rx|
|Renin (N: 6.4–23.8 ng/L)||201 ± 78||39 ± 12*||418 ± 228||380 ± 194#|
|Aldosterone (N: 27–444 pmol/L)||2574 ± 375||930 ± 341**||3912 ± 853||4125 ± 1036##|
|Norepinephrine (N: 0.8–2.4 nmol/L)||3.93 ± 0.54||4.03 ± 0.90||7.20 ± 2.40||9.00 ± 2.69|
In those patients who received a TIPS, there was a significant reduction of plasma renin (P < .01) and aldosterone (P < .01) levels at 1 month, and thereafter the levels plateaued for the remainder of the study period (Fig. 5). The norepinephrine levels, however, did not change significantly until 12 months after TIPS placement (see Fig. 5).
This study confirms that type 1 HRS is a functional renal disorder that is potentially completely reversible. Our results are similar to those of Angeli et al.,7 who reported that the combination of octreotide, midodrine, and intravenous albumin could improve but not normalize renal function in patients with type 1 HRS. The new finding is that the insertion of TIPS in the appropriate patients following their response to medical therapy can completely return their renal function to normal with the gradual elimination of ascites.
The impetus for this study came from the fact that terlipressin, a vasoconstrictor widely used in the management of cirrhotic patients with type 1 HRS in Europe,5 is not available in North America. Although the results of Angeli et al.7 are encouraging and seem to make physiological sense, the combination of midodrine, octreotide, and intravenous albumin was only given to five patients. Our study in a larger cohort of type 1 HRS patients with a similar protocol shows that the combination is effective in improving renal function in approximately two thirds of such patients. The rationale for using combination treatment was to combine the α-adrenergic agonist effect of midodrine and vasodilatation-inhibitory effect of octreotide to reduce the vascular capacitance and to use albumin to refill the intravascular volume. The results compared favorably with those following the use of terlipressin, which decreased serum creatinine from 272 ± 114 μmol/L to 138 ± 59 μmol/L in 64% of type 1 HRS patients.5 Thus the combination of midodrine, octreotide, and albumin could potentially be used as an alternative for the treatment of type 1 HRS in North America.
The pathophysiology in the patients who responded to the combination of octreotide, midodrine, and albumin seems to follow what has been described in the classical “peripheral arterial vasodilatation hypothesis.”24 That is, renal dysfunction in cirrhosis is the result of severe renal vasoconstriction, secondary to systemic arterial vasodilatation with consequent arterial underfilling and activation of various vasoconstrictor systems. Therefore, by reducing the extent of arterial vasodilatation and improving the intravascular volume, plasma renin and aldosterone decreased and renal function improved with increased natriuresis. However, the combination of midodrine, octreotide, and albumin increased glomerular filtration rate, renal plasma flow, and renal sodium excretion to certain levels, and continued administration did not seem to result in further improvement in either renal hemodynamics nor sodium excretion. In the nonresponders, despite maneuvers to reduce the mismatch between the extent of arterial vasodilatation and the intravascular volume, the various hormonal markers of vascular filling remained elevated and the renal function continued to deteriorate despite treatment. It is possible that the nonresponders were “refractory” to the vasoconstrictive effects of midodrine and octreotide. Vascular nonresponsiveness is well described in cirrhosis,25–27 and this has been attributed to both an excess of vasodilators such as nitric oxide,28 or a peripheral vascular defect.27 Thus the extent of arterial vasodilatation in the nonresponders could have exceeded that in the responders, making the doses used relatively inadequate, although that was not obvious in the hemodynamic parameters that were measured. However, the nonresponders did appear to have more hemodynamic disturbance with relative greater arterial underfilling as indicated by higher plasma renin, aldosterone, and norepinephrine levels. This may also explain why octreotide alone has been reported to be ineffective in reversing HRS.8 Furthermore, the nonresponders tended to have more severe liver disease with higher Child-Turcotte-Pugh scores, which has been shown to correlate with the severity of the hemodynamic disturbance.29, 30
The fact that combined medical therapy did not affect the nonresponders, nor could it completely normalize renal function even in the responders, suggests that factors in addition to a reduction in effective arterial underfilling also contribute to the pathogenesis of renal dysfunction in cirrhosis. This is in keeping with reports on treatments for type 1 HRS in the literature. So far, none of the treatment modalities described can completely normalize renal function.5–7, 9, 10 The presence of excess “toxins” such as cytokines may well have prevented the renal function from returning to normal, especially in the nonresponders. Such toxins could affect mesangeal contraction, lowering glomerular capillary ultrafiltration coefficient with reduction of glomerular filtration.31 This is supported by the fact that removal of such “toxins” by molecular adsorbent recirculating system32 has been successful in improving HRS. Furthermore, the inhibition of synthesis of one of these toxins, TNF, with the use of pentoxyfylline, was able to prevent the development of HRS in patients with alcoholic hepatitis.33
Therefore, there may be a need to combine treatment options to correct different aspects of the pathophysiological processes that lead to the development of HRS. In our study, patients who fulfilled the criteria for TIPS insertion16 received a TIPS in an attempt to further improve renal function. The rationale for placing a TIPS in these patients was that it completely eliminates portal hypertension, a factor that has been shown to be critical in the pathogenesis of abnormal renal hemodynamics34 and sodium retention in cirrhosis.17 Furthermore, it returns a large blood volume from the splanchnic to the systemic circulation11 and thereby adds to the filling of the systemic circulation. The insertion of TIPS in five patients who responded to medical therapy resulted in significant increase in the central blood volume, with further gradual improvement of their renal function, which was associated with slow reductions in plasma renin and aldosterone but not norepinephrine levels. The persistently unexplained elevated norepinephrine levels may be the reason for the mildly reduced renal plasma flow in these patients at 12 months post-TIPS, although their glomerular filtration rate and renal sodium excretion had returned to normal by then. The response to TIPS in this group of patients with prior renal dysfunction was not dissimilar to those without prior renal dysfunction,13 once again underscoring the functional nature of the renal failure in cirrhosis.
The presence of type 1 HRS in cirrhosis with ascites has been regarded as a bad prognostic sign for survival with2 or without liver transplantation.35, 36 Our study shows that even with improvement of renal function with medical therapy with or without TIPS, there may not be significant improvement in the morbidity of these patients. Two of the responders still succumbed to the usual complications of end-stage cirrhosis such as septicemia and liver failure. In those patients who received a liver transplant with normal renal function, their prolonged postoperative course suggests that their prior renal dysfunction was only part of the advanced stage of their cirrhosis, which predisposed them to the multiple complications in the posttransplant period; however, recent literature in three type 1 HRS patients suggests that they may do equally well as non-HRS patients after liver transplantation.37 Despite this, the survival of the responders to medical therapy was certainly better compared with no treatment, and that of medical treatment plus TIPS seemed better than either medical therapy alone or TIPS alone9 as reported in the literature.
At present, it is clear that HRS is a treatable complication of cirrhosis. However, it is still unclear which combined approach will yield the best results. The results of this pilot study are encouraging and should provide the basis for larger randomized controlled trials to confirm the findings. In addition, other studies need to be done to identify predictors of nonresponsiveness so that patients who are unlikely to respond to medical therapy could be offered liver transplantation early.
In conclusion, the use of TIPS as a treatment for type 1 HRS in suitable patients with cirrhosis and ascites, following the improvement of renal function with the combination therapy of midodrine, octreotide, and albumin, could be effective in both reversing the renal impairment and in eliminating ascites. The challenge ahead is how to best use our understanding of the pathophysiology of HRS to select the most appropriate patients for this combined treatment option.