Acommon finding in hemodialysis patients

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1 AJH 1998;11: Bilateral Nephrectomy: The Best, but Often Overlooked, Treatment for Refractory Hypertension in Hemodialysis Patients Jan Zazgornik, Georg Biesenbach, Otmar Janko, Christoph Gross, Rudolf Mair, Peter Brücke, Alicja Debska-Slizien, and Boleslaw Rutkowski Bilateral nephrectomy for treatment of refractory hypertension in chronic hemodialyzed patients has been infrequently carried out. We analyzed the benefits of this operation on blood pressure, clinical state, drug treatment, and quality of life. In 10 hemodialyzed patients with refractory hypertension, systolic (SBP) and diastolic (DBP) blood pressure were measured 1 month before nephrectomy bilateral and 3, 6, 9, and 12 months after. In addition, the use of antihypertensive drugs before and after surgery was evaluated. Four patients had SBP and DBP values characteristic of malignant hypertension. In all 10 patients hypertension responded neither to reduction of plasma volume by ultrafiltration nor to multiple antihypertensive drug therapy. Hypertensive crises were associated with cerebral hemorrhage in two patients, severe encephalopathy with persistent Acommon finding in hemodialysis patients with chronic renal failure is hypertension, caused by sodium and water retention, 1 activation of the renin-angiotensin-aldosterone system, 2 and by increased activity of the sympathetic nervous system. 3 Received May 15, Accepted June 15, From the II. Medical Department (JZ, GB, OJ) and I. Department of Surgery (CG, RM, PB), General Hospital Linz, Linz, Austria, and the Department of Nephrology (AD-S, BR), University Gdansk, Gdansk, Poland. Address correspondence and reprint requests to Prof. Jan Zazgornik, MD, II Medical Department, General Hospital Linz, Krankenhausstraße 9, 4020 Linz, Austria. neural dysfunction in one patient, and encephalopathy and diplopia in another. Three months after bilateral nephrectomy blood pressure decreased significantly (P <.005) and was normal in nine patients. In one noncompliant patient with intradialytic body weight increases of nearly 10%, blood pressure was still elevated. Malignant or drug-resistant hypertension with hypertensive crises is an indication for bilateral nephrectomy. The clinical state and quality of life improved in all patients in the present study and antihypertensive treatment is no longer necessary. Am J Hypertens 1998;11: American Journal of Hypertension, Ltd. KEY WORDS: Hemodialysis patients, refractory hypertension, multiple antihypertensive drugs, bilateral nephrectomy. Increased ultrafiltration rates on hemodialysis with resultant reduction of plasma volume and body weight normalize elevated blood pressures in approximately 80% of hypertensive patients. In about 15% to 20%, however, hypertension persists or even increases despite reduction of plasma volume and therapy with multiple antihypertensive drugs. Therefore, in patients with refractory hypertension and poor response to antihypertensive drugs, bilateral nephrectomy is indicated. We present case reports of 10 patients on chronic hemodialysis who had refractory hypertension that normalized after bilateral nephrectomy or renal transplant removal by the American Journal of Hypertension, Ltd /98/$19.00 Published by Elsevier Science, Inc. PII S (98)00154-X

2 AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 BILATERAL NEPHRECTOMY IN HEMODIALYSIS PATIENTS 1365 PATIENTS Ten chronic hemodialysis patients with end stage renal disease and drug resistant hypertension were included in this study. The mean age was 39 (23 to 62) years, the mean time elapsed since bilateral nephrectomy or renal graft removal was 51 (9 to 264) months. The individual characteristics of the patients are presented below. Case 1 In a 39-year-old man (C.A.) hypertension had been present since the age of 17; proteinuria was found in In 1985 chronic glomerulonephritis was diagnosed by biopsy. In September 1987 chronic hemodialysis was initiated. Two renal grafts (1988 and 1990) were rejected, acute vascular rejection being diagnosed in both grafts by biopsy. Hypertension proved refractory both to antihypertensive drugs and to increased ultrafiltration rate on hemodialysis. In February 1991 bilateral nephrectomy was done. Over the next 12 months blood pressure (BP) returned to normal values and remained stable without antihypertensive drugs during the following 6 years. Case 2 In a 26-year-old woman (L.S.) the right kidney was removed because Wilms tumor was diagnosed in Malignant hypertension due to nephrosclerosis of the left kidney led to renal failure and in May 1989 renal transplantation was performed. In the following years chronic rejection developed. In February 1994 hemodialysis was started. The renal graft was removed in June Refractory hypertension persisted, the blood pressure was 220/140 mm Hg despite high ultrafiltration rates on hemodialysis and as many as five antihypertensive drugs. The body weight was 45 to 46 kg (height 167 cm). Nephrectomy of the patient s remaining kidney was performed in July One day after surgery a relaparatomy was necessary because of abdominal wall bleeding. The patient become normotensive without antihypertensive medication, and the nutritional state improved, the body weight increasing to 52 kg. Case 3 A 62-year-old man (T.A.) suffered from malignant hypertension (BP 250/130 mm Hg) due to nephrosclerosis and medullary sponge kidneys. Hemodialysis was started in December Hypertension was refractory to combined antihypertensive therapy, and hypertensive crises caused encephalopathy with severe psychological changes. After bilateral nephrectomy in October 1993, blood pressure normalized. In March 1995 a successful renal transplantation was performed. Renal function remains good, but diffuse cerebral dysfunction persists. Case 4 In a 46-year-old woman (H.H.) chronic glomerulonephritis was diagnosed in April 1973, after her first pregnancy. Malignant hypertension (BP 220/ 125 mm Hg) was present. Hemodialysis was initiated in May Bilateral nephrectomy was performed together with renal transplantation in September 1974, but following acute rejection the graft was removed. Blood pressure ranged between 100 and 140/60 and 90 mm Hg during the next 22 years. Parathyroidectomy was done because of carcinoma of the parathyroid gland (parathyroid hormone (PTH) 2500 pg/ ml). A transient increase of blood pressure was associated with erythropoietin therapy (increased dose of erythropoietin administration), after discontinuation of which blood pressure returned to normal values. Case 5 A 43-year-old man (R.R.) had chronic glomerulonephritis and drug-resistant hypertension. In December 1993 after a drinking bout he developed a stroke caused by cerebral hemorrhage, verified by computed tomography (CT) scan, leading to hemiparesis with sensory loss in the face and right arm. Hemodialysis was started in April Refractory hypertension persisted despite treatment with multiple antihypertensive drugs. In November 1994 bilateral nephrectomy was performed. One year after surgery the patient became normotensive with only light antihypertensive medication, which was discontinued 18 months after the operation. The clinical signs and symptoms of stroke disappeared. Successful renal transplantation was carried out in August Case 6 A 25-year-old man (A.F.) had suffered from vesicourethral reflux and nephropathy since childhood. In 1973 at the age of 3 years the left kidney and ureter were removed. Glomerulonephritis with nephrotic syndrome and renal hypertension developed. Hemodialysis was started in July In the following years three renal transplantations (1981, 1985, and 1993) were carried out. During this period the patient spent 6 months on hemodialysis, which was restarted in June Because of hypertension the patient s remaining (right) kidney was removed together with the last graft in November The patient became normo- or hypotensive without antihypertensive medication during the follow-up period of nearly 5 years. Case 7 A 46-year-old woman (S.S.) had focal segmental glomerulonephritis and markedly elevated blood pressure ( 230/130 mm Hg). In June 1995 hemodialysis was initiated. Despite multiple forms of antihypertensive therapy, she experienced a hypertensive crisis, encephalopathy, and diplopia. In February 1996 bilateral nephrectomy was done. The blood pressure returned to and remains normal, whereas diplopia persisted for 6 months before disappearing. A transient increase of blood pressure was associated

3 1366 ZAZGORNIK ET AL AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 with an intradialytic weight gain of 10% of the dry weight. Case 8 A 25-year-old woman (K.R.) had suffered from refluxnephropathy with contracted right kidney since childhood, the right kidney and ureter being removed at the age of eleven. Hemodialysis was started in May Malignant hypertension developed due to focal segmental glomerulosclerosis of the left kidney, which was removed in January Blood pressure normalized 3 months after surgery. In the following years three renal transplantations were performed, the first, in June 1985, being removed the following month after acute rejection. In the second renal transplantation, performed in July 1986, chronic rejection developed. The patient became pregnant, and owing to graft failure hemodialysis was restarted 14 weeks into gestation. Hypertension was drug resistant, blood pressure was very high ( 210/125 mm Hg) and associated with severe headache. In June 1991 delivery by section and renal transplantectomy were done simultaneously. Both mother and child were well. On June 1992 the patient developed a hypertensive crisis (BP 220/130 mm Hg) with stupor and alteration of consciouness. After a CT scan, a subdural hematoma was diagnosed. After osteoplastic trepanation (Neurosurgery Department of the Wagner-Jauregg Hospital Linz) a chronic subdural hematoma with membrane in the frontotemporoparietal region and acute bleeding in the right hemisphere were found. A third renal transplantation was carried out in August 1992 and removed (chronic rejection) in January Blood pressure was normal. Case 9 A 23-year-old man (L.F.) had chronic glomerulonephritis and renal hypertension since childhood. In September 1984 hemodialysis treatment was started. In October 1986 a successful renal transplantation was performed, but the graft later failed because of membranous glomerulopathy. Hemodialysis was restarted in January 1996, and severe hypertension was treated with three to four antihypertensive drugs. In April 1996 bilateral nephrectomy and transplant nephrectomy were carried out. Blood pressure normalized 2 months after surgery. Case 10 A 52-year-old man (K.B.) had focal segmental glomerulonephritis and hypertension since Hemodialysis was started in December Two years later a renal transplantation was performed but graft function deteriorated because of recurrence of focal segmental glomerulonephritis and drug-resistant hypertension. Hemodialysis was restarted. In June 1993 bilateral nephrectomy and in October 1993 transplantectomy were performed. Two months after surgery the patient was hypotensive, in the following months blood pressure normalized. A successful second renal transplantation was carried out in July METHODS We compared systolic (SBP) and diastolic (DBP) blood pressure 1 month before (weekly measurements; 4 to 5 per month) and 3, 6, 9, and 12 months after bilateral nephrectomy. SBP and DBP were expressed as mean SEM, and the mean blood pressure (MBP) SBP DBP/2 was calculated. The effect of ultrafiltration and volume depletion in the 10 hypertensive patients was calculated by difference in dry body weight at the start of hemodialysis treatment and bilateral nephrectomy. For statistical analysis Student s t test for paired samples was applied. RESULTS These 10 patients on chronic hemodialysis had drug resistant hypertension. In four patients the mean systolic blood pressure was 200 mg Hg; in four patients the mean diastolic blood pressure was 120 mm Hg. Thus four patients had malignant hypertension (Table 1). Hypertensive crises were associated with stroke due to cerebral haemorrhage in two patients (R.R. and K.R.). In addition, severe cerebral dysfunction were found in one (T.G.) and persistent diplopia in another patient (S.S.). In nine patients bilateral nephrectomy or transplantectomy were without complications, in one patient (L.S.) a relaparotomy was necessary because of abdominal haematoma. The volume reduction calculated from the changes in dry body weight between the start of hemodialysis and bilateral nephrectomy are seen in Table 2. In six of these patients dry body weight decreased ( 0.5 to 21.6 kg), in four patients (three had been hemodialyzed since childhood, one adult patient with very low initial body weight) dry body weight increased ( 3.0 to 35.0 kg). In one patient (A.F.) three renal transplantation were carried out, the increase of body weight was associated with prednisone therapy. Blood Pressure After Bilateral Nephrectomy Both mean systolic and diastolic blood pressure values decreased significantly one month after surgery compared with the values before bilateral nephrectomy ( v , P.005 and v 87 14, P.005) (Table 1). The individual mean blood pressures of these patients are shown in Figure 1. In one patient (S.S.) blood pressure again increased because of hypervolemia because of poor compliance and body weight increase of nearly 10% in intradialytic intervals. In the remaining nine SBP and DBP were normal 12 months after surgery. Antihypertensive Drugs Before and After Bilateral Nephrectomy Types of antihypertensive drugs used were: calcium entry blockers (cases 1 3, 5 10),

4 AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 BILATERAL NEPHRECTOMY IN HEMODIALYSIS PATIENTS 1367 TABLE 1. SBP AND DBP BEFORE AND 3, 6, 9, AND 12 MONTHS AFTER BILATERAL NEPHRECTOMY After Bilateral Nephrectomy Patient Before 3 Months 6 Months 9 Months 12 Months SBP DBP SBP DBP SBP DBP SBP DBP SBP DBP 1. C.A L.S T.A H.H R.R A.F S.S K.R L.F K.B Mean SEM Data are given as mean SEM (mm Hg). -blockers (cases 1 to 10), -blockers (cases 1 3,5,7,9,10), angiotensin-converting enzyme (ACE) inhibitors (cases 2,3,5,7,8), centrally acting vasodilators (cases 1,3 8), and others (cases 2,4,7,10) (Table 3). Three or more (up to six) antihypertensive drugs failed to decrease adequately the high blood pressure in these patients. One year after bilateral nephrectomy only one patient (R.R.) still received mild antihypertensive therapy, which was discontinued 18 months after surgery; the remaining nine were without antihypertensive medication. DISCUSSION Hypertension is frequently observed in patients on hemodialysis. It is a leading cause of left ventricular hypertrophy and a predictor of patient survival. 4,5 In our data from 22 dialysis centers in Austria on 1087 patients on renal replacement therapy we found hypertension in 653 (60%) patients. In 425 (39%) patients hypertension was mild to moderate, whereas in the remaining 228 (21%) patients hypertension was severe. Moreover, many of these latter patients with severely hypertension were hypertensive despite antihypertensive drugs. 6 The prevalence of hypertension in patients on renal replacement therapy (RRT) in Austria is high, but comparable with data in other reports. 7,8 In contrast to this figure, Raine et al 9 reported that only 32 percent of both men and women had a predialysis systolic blood pressure 160 mm Hg. The impressive results of the Tassin center (10 12) showed that a longer dialysis time is the best and simplest method to normalize hypertension in hemodialyzed patients. The dialysis regimen in this center TABLE 2. AGE AND BODY WEIGHT AT THE START OF HD AND AT BILATERAL NEPHRECTOMY AS WELL AS BODY WEIGHT DIFFERENCES AND THE DIALYSIS PERIODS (YEARS/MONTHS) UNTIL BILATERAL NEPHRECTOMY OF THE 10 PATIENTS WITH REFRACTORY HYPERTENSION Patient Start of Hemodialysis (HD) Age (years) Body Weight (kg) Body Weight (kg) Bilateral Nephrectomy Weight-Difference (kg) After Start of HD (years) C.A L.S T.A H.H months R.R months A.F S.S K.R L.F K.B

5 1368 ZAZGORNIK ET AL AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 FIGURE 1. Mean blood pressures over time for the patients in this study. Time after surgery is given. is 24 h/week. They believe that this long, slow dialysis technique normalizes elevated blood pressure in hypertensive hemodialyzed patients. In Austria the dialysis time ranged between 9 and 15 h/week in different dialysis centers. The short dialysis time is the leading cause of poorer compliance in dialysis patients resulting in higher water and salt intake. As a consequence extracellular volume expansion exacerbate hypertension. The most important therapeutic procedure for the treatment of refractory hypertension in dialysis Patient patients is ultrafiltration during hemodialysis sessions resulting in volume depletion and lowering of the elevated blood pressure. 10,13 Extensive ultrafiltration also influences the renin-angiotensin-aldosterone system, which plays an important role in hypertensive patients with end-stage renal failure. 2,14,15 In patients on chronic hemodialysis plasma renin activity ranged from subnormal to excessively elevated values and correlated significantly with plasma aldosterone concentrations. 2,15 In hemodialyzed patients with normal TABLE 3. ANTIHYPERTENSIVE DRUGS ADMINISTERED BEFORE BILATERAL NEPHRECTOMY Calcium Entry Blocker -Blocker ACE Inhibitor -Blocker Centrally Acting Vasodilatator Others 1. C.A. 2. L.S. 3. T.A. 4. H.H. 5. R.R. 6. A.F. 7. S.S. 8. K.R. 9. L.F. 10. K.B. ACE, angiotensin converting enzyme.

6 AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 BILATERAL NEPHRECTOMY IN HEMODIALYSIS PATIENTS 1369 blood pressure or controllable hypertension plasma renin levels are usually normal or only slightly elevated. However, patients with uncontrollable hypertension, in whom blood pressure could not be lowered by sodium restriction and ultrafiltration have significant higher plasma renin and aldosterone levels. After bilateral nephrectomy plasma renin was undetectable or very low as was the aldosterone concentration. 2 Angiotensin II is known to be a direct mediator of aldosterone release. Angiotensin II triggers generalized vasoconstriction, resulting in a rapid and sustained increase in blood pressure. Furthermore, angiotensin II increases sympathetic activity, and is involved in thirst stimulation and in the release of vasopressin. Bilateral nephrectomy therefore not only reduces the levels of renin, aldosterone, and angiotensin II, causing a decrease of blood pressure, but also decreases sympathetic activity. This may explain the continuous decline of blood pressure after a 3-month period in most of the patients. Hypertension is the major factor determining the clinical course of the progression of ocular, cerebrovascular, and cardiovascular complications. 5,16,17 In the 10 patients with refractory hypertension blood pressure could not be lowered either by ultrafiltration during dialysis sessions (despite decreasing dry body weight; Table 2), or by antihypertensive drugs. All 10 patients showed hypertensive retinopathy as well as left ventricular hypertrophy, which was diagnosed by electrocardiogram (ECG) or echocardiography. In addition, there was a stroke in the history of a 41-yearold man and a 25-year-old woman. Severe encephalopathy with persistent neural dysfunction was found in one patient and encephalopathy with diplopia in another. In all 10 patients the mean values of both systolic and diastolic blood pressure were very high before bilateral nephrectomy (Table 1). In the month following successful surgery blood pressure decreased continuously to the normal range. However, in rare cases with poor compliance and an intradialytic weight gain of 5% of dry weight, blood pressure may again increase because of hypervolemiea, but it normalize after ultrafiltration during hemodialysis. Charra et al 10 from Tassin reported that their seven anephric patients have a significant lower mean predialysis blood pressure than the 30 nonanephric patients (SBP mm Hg v mm Hg and mm Hg v mm Hg, P.001). Our own experience and previous reports 1,3,17 indicate that bilateral nephrectomy is the best procedure for the treatment of drug-resistant hypertension in hemodialysis patients. According to the 1991 report on management of renal failure in Europe, bilateral nephrectomy has not often been undertaken as a treatment for intractable hypertension, its prevalence varying between 0% and 7% in most countries. 9 At the end of the 1970s and during the 1980s, bilateral nephrectomy was frequently performed as an adjuvant operation to the transplant procedure. According to our previous study on risk factors of cardiovascular disease in 100 renal transplant patients, bilateral nephrectomy was performed in 82 patients either before or simultaneously with transplantation. 18 In our hemodialyzed patients with refractory hypertension all classes of antihypertensive drugs were used. In a previous report 6 on 1087 patients on RRT in Austria, calcium anagonists were the antihypertensive drugs most frequently administered (71%), followed by ACE inhibitors (57%), -blockers (31%), and -blockers (28%). However, controlled studies to identify the best drugs in hypertensive patients on RRT are lacking. The conclusion may be drawn that bilateral nephrectomy is indicated in hemodialysis patients with severe, refractory hypertension. This operation normalized both systolic and diastolic blood pressure and improved ocular, neurological and cardiovascular complications caused by hypertension. Furthermore the use of antihypertensive drugs can be radically reduced or even discontinued completely. As each patient with refractory hypertension needed three or more antihypertensive drugs, a significant cost savings is an additional benefit. Finally, quality of life can be improved in all patients. Bilateral nephrectomy is a safe and curative method for the treatment of refractory hypertension in patients on hemodialysis. Renal anemia can be reliably corrected by erythropoietin administration. REFERENCES 1. 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7 1370 ZAZGORNIK ET AL AJH NOVEMBER 1998 VOL. 11, NO. 11, PART 1 9. Raine AEG, Margreiter R, Brunner FP, et al: Report on management of renal failure in Europe, XXII, Nephrol Dial Transplant; 1992;(suppl 2): Charra B, Calemard E, Cuche M, Laurent G: Control of hypertension and prolonged survival on maintenance hemodialysis. Nephron 1983;33: Charra B, Calemard E, Ruffet M, et al: Survival as an index of adequacy of dialysis. Kidney Int 1992;41: Laurent G: How to keep the dialysis patients normotensive? What is the secret of Tassin? Nephrol Dial Transplant 1997;12: Ok E, Akcicek F, Dorhout Mees EJ, et al: Malignant hypertension in a haemodialysis patient treated by ultrafiltration. Nephrol Dial Transplant 1995;10(2): Kuska J, Kokot F, Libera T, Sledzinski Z: The influence of upright position and sodium restriction in the diet on plasma renin activity (PRA) and aldosteronemia in patients with chronic nephritis. Materia Medica Polona 1977;9: Kuska Jadwiga, Kokot F, Panusz J: Regulation and significance of renin-angiotensin-aldosterone axis in the patients with chronic nephritis. Materia Medica Polona 1978;10: Degoulet P, Legrain M, Reach J, et al: Mortality risk factors in patients treated by chronic hemodialysis. Nephron 1982;31: Vertes V, Cangiano JL, Berman LB, Gould A: Hypertension in end-stage renal disease. N Engl J Med 1969; 280: Zazgornik J, Regal H, Druml W, et al: Lipid metabolism disturbances and other risk factors of cardiovascular disease in renal transplant patients. Dialysis Transplant 1982;11: