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Circulation. 2001;104:508-510

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(Circulation. 2001;104:508.)
© 2001 American Heart Association, Inc.

Editorial

Who’s on First?

Does Hypertension in Type I Diabetics Result From Nephropathy or Metabolic Alterations?

Alan L. Hinderliter, MD; Marschall S. Runge, MD, PhD

From the Department of Medicine (M.S.R.) and the Division of Cardiology (A.L.H.), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC.

Correspondence to Alan L. Hinderliter, MD, Division of Cardiology, University of North Carolina, CB #7075, 338 Burnett-Womack, Chapel Hill, NC, 27599-7075 (E-mail hinderli{at}med.unc.edu) or to Marschall S. Runge, MD, PhD, Chair, Department of Medicine, University of North Carolina, CB #7005, Room 3033, Chapel Hill, NC 27599-7005 (E-mail mrunge@med.unc.edu).


Key Words: Editorials • hypertension • diabetes mellitus

It has long been assumed that end-organ damage by the metabolic abnormalities associated with type I diabetes mellitus occurs before clinically evident adverse outcomes. However, the study reported by Elliott et al1 in the present issue of Circulation suggests that it is time to reconsider this hypothesis.

See p 563

Patients with diabetes mellitus are at a high risk of cardiovascular events. Observational studies suggest that cardiovascular morbidity is {approx}2 times higher in diabetics than in the general population, and that cardiovascular disease accounts for {approx}70% of all deaths in people with diabetes mellitus.2,3 The risk of vascular events is further heightened by coexistent hypertension. As in the general population, there is a strong, graded relationship between hypertension and coronary heart disease and stroke in diabetic patients, independent of other traditional risk factors.4 In diabetics, as in nondiabetics, most studies focus on the treatment of hypertension as a surrogate end point for cardiac risk reduction.

Treatment of Hypertension in Patients With Diabetes Mellitus

Acknowledgment of the excessive risk of cardiovascular events in patients with diabetes and hypertension has led to numerous studies on the potential benefits of optimizing antihypertensive therapy in this population. The results of several recent clinical trials demonstrate that rigorous control of arterial pressure in patients with diabetes markedly reduces morbidity and mortality from cardiovascular disease. In the Hypertension Optimal Treatment (HOT) trial, hypertensive patients were randomized to 1 of 3 diastolic blood pressure targets: <=90 mm Hg, <=85 mm Hg, or <=80 mm Hg. Initial therapy was with felodipine, and an ACE inhibitor or ß-blocker was added if needed. In the subgroup of 1501 patients with diabetes, more intense blood pressure control led to a 51% reduction in cardiovascular events.5 The United Kingdom Prospective Diabetes Study (UKPDS) evaluated outcomes in hypertensive diabetic patients assigned to "intensive" therapy (treatment goal, <150/85 mm Hg) or "conventional" therapy (treatment goal, <180/105 mm Hg) using atenolol or captopril as the initial antihypertensive agent. Patients assigned to intensive blood pressure control had a 32% lower risk of death related to diabetes and a 44% lower risk of stroke. The degree of blood pressure lowering was more important than the choice of initial antihypertensive agent or the adequacy of glucose control in preventing cardiovascular end points.6 The results of these trials and other observational studies have led expert treatment panels to suggest treating even mildly elevated blood pressure in patients with diabetes, with a goal arterial pressure in the normal range (systolic blood pressure, <125 or 130 mm Hg; diastolic blood pressure, <80 or 85 mm Hg).

Most patients with hypertension and diabetes mellitus require multiple antihypertensive agents to normalize their arterial pressure, and numerous studies suggest that one of these agents should be an ACE inhibitor. The Captopril Prevention Project (CAPPP) was an unblinded trial in which patients with hypertension were randomized to receive either captopril, with the addition of a thiazide diuretic if necessary, or the clinician’s choice of a thiazide diuretic or ß-blocker. Although there was no advantage of one regimen over the others in the general population, cardiovascular end points were reduced by captopril in the diabetic cohort.7 The results of the microalbuminuria, cardiovascular, and renal outcomes (MICRO-HOPE) substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial provide further support for the treatment of diabetic patients with ACE inhibitors. In this trial, 3577 patients with diabetes and a history of either a prior cardiovascular event or at least one other cardiovascular risk factor were randomized to treatment with ramipril or placebo. Ramipril lowered the risk of myocardial infarction, stroke, or cardiovascular death by 25%, an effect that was independent of the relatively small reductions in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) blood pressures.8

The heavy burden of cardiovascular disease in patients with diabetes is compounded by the development of nephropathy. In diabetic patients with end-stage renal disease, cardiovascular morbidity is 3 to 5 times higher than in nondiabetic patients, and the risk of cardiovascular events is {approx}40 times that in the general population.9,10 It is estimated that one-third of diabetic patients die of coronary heart disease or stroke by the age of 55 years and that the risk is increased 10-fold with end-stage nephropathy.11

The Role of Renal/Pancreas Transplantation for End-Stage Renal Disease in Type I Diabetics

Although renal transplantation may improve survival and quality of life in many patients with diabetes and end-stage nephropathy, hypertension persists in the majority of patients after transplantation, and cardiovascular disease is the principal cause of late mortality. In this sense, although beneficial, renal transplantation fails to alter the long-term cardiovascular morbidity and mortality associated with type I diabetes. The study reported by Elliott et al1 offers hope that better long-term outcomes can be achieved with combined pancreas-kidney transplantation in patients with type I diabetes and renal insufficiency.

More than 900 pancreas transplantations are performed annually in the United States, and the vast majority of these are done in conjunction with kidney transplantation in patients with type I diabetes and renal insufficiency. Although hospital readmission rates for simultaneous pancreas-kidney recipients are greater than those for kidney recipients, 1-year pancreas and kidney graft survival rates approach 90% at some centers. Successful pancreas-kidney transplantation leads to more physiological glucose metabolism (with resultant independence from exogenous insulin therapy), normal blood glucose concentrations, and normal or near-normal glycosylated hemoglobin values.

In the series of patients described by Elliott et al,1 111 patients with type I diabetes mellitus underwent successful pancreas transplantation (106 with simultaneous kidney transplants), and 28 underwent isolated kidney transplantation. Blood pressures and medication use were monitored at clinic visits before and after transplantation. Nearly all patients in both groups were hypertensive and were treated with medications preoperatively. Among those undergoing pancreas-kidney transplantation, mean blood pressure fell from 151/88 mm Hg to 126/70 mm Hg, despite a decrease in the average number of antihypertensive medications from 2.5 to 0.9 drugs per patient. In contrast, no significant changes in blood pressure or medication use were observed in patients with isolated kidney transplants. Postoperative serum creatinine levels were similar in the 2 groups, but levels of glycosylated hemoglobin and glucose were significantly lower in recipients of combined organ transplants.

Although the data presented by Elliott et al1 are compelling, several limitations of the study should be acknowledged. Because patients were not randomized to pancreas-kidney or isolated kidney transplantation, it is possible that the difference in blood pressure responses to therapy reflected differences in baseline patient characteristics. Recipients of isolated kidney grafts were older and may have had other features that made them less suitable candidates for combined organ transplantation. In addition, blood pressure data are based on determinations performed during the course of clinic visits, and there is no indication that the technique used to measure this labile physiological parameter was rigorously standardized. Preoperative blood pressure levels were based on a single clinic measurement.

These methodological issues notwithstanding, the findings of Elliott et al1 are consistent with several previous reports of improved blood pressure control in patients with type I diabetes who undergo combined pancreas-kidney transplantation.12–14 In view of the prevalence of hypertension after isolated kidney transplantation and the contribution of high blood pressure to graft failure and cardiovascular events, this represents a significant advantage of combined organ transplantation. The greatest potential benefit of pancreas-kidney transplantation, however, is in the prevention of coronary heart disease and stroke. Whether the improved blood pressure and glucose metabolism achieved with this strategy translate to a reduction in cardiovascular morbidity and mortality can only be determined by long-term observational studies.

Mechanisms of Hypertension in Patients With Type I Diabetes Mellitus

In addition to supporting the value of pancreas-kidney transplantation as a therapeutic alternative, the study by Elliott et al1 provides insights into the pathophysiological mechanisms of hypertension in patients with type I diabetes.

Hypertension is about twice as prevalent in patients with diabetes as in those without the disease. In patients with type II diabetes, elevated blood pressure usually occurs in association with obesity and insulin resistance. Endothelial dysfunction and pressor effects of hyperinsulinemia may contribute directly to raised arterial pressure, which often precedes the development of overt nephropathy. In type I diabetes, however, hypertension is generally considered a renal phenomenon.

The primacy of renal structural disease in the pathogenesis of hypertension in type I diabetes is supported by studies demonstrating a close relationship between microalbuminuria and blood pressure elevation.15–18 Microalbuminuria is associated with structural lesions of the kidney, including increased basement membrane thickness and arteriolar and glomerular accumulation of extracellular matrix. Blood pressure is higher in type I diabetic patients with microalbuminuria than in those without it, and blood pressure increases as urinary albumin excretion rises. In some studies, microalbuminuria precedes a rise in blood pressure, and hypertension is no more prevalent in diabetic patients without albuminuria than in the nondiabetic population.

The data of Elliott et al1 fly in the face of conventional wisdom begging one to propose a mechanism by which type I diabetes causes hypertension if not by damaging the kidneys. There are several possibilities. Altered sodium handling is a consistent finding in patients with type I diabetes, and increased intravascular volume may contribute to elevated blood pressure. This may be due, at least in part, to enhanced proximal tubular reabsorption of sodium resulting from increased glomerular filtration of glucose. Hyperinsulinemia due to exogenous insulin administration may also play a role, because insulin stimulates sodium reabsorption.

Generalized dysfunction of the vascular endothelium may also contribute to the elevated arterial pressure observed in patients with type I diabetes. Endothelium-derived nitric oxide is an important determinant of renal natriuresis and of peripheral vascular tone. Although the available data are conflicting, a number of studies have demonstrated impaired vascular responses to endothelium-dependent vasodilators or reactive hyperemia in diabetic patients, suggesting impaired production or enhanced degradation of nitric oxide or depressed smooth muscle responses to nitric oxide. The mechanisms underlying this abnormality in vascular function are not well established. Animal data suggest that advanced glycosylation products (glucose-derived moieties that accumulate in subendothelial collagen at an accelerated rate when plasma glucose is elevated) inactivate endothelium-derived nitric oxide.19 Studies in cultured endothelial cell monolayers indicate that hyperglycemia inhibits vascular smooth muscle relaxation by interfering with nitric oxide–induced production of cyclic GMP.20

In interpreting the results reported by Elliott et al,1 it is important to recognize that pancreas transplantation may have important physiological effects in addition to improved glucose metabolism. In the vast majority of patients receiving pancreas grafts (97 of the 111), pancreatic exocrine secretions were drained to the bladder. This technique can be associated with urinary losses of sodium and bicarbonate, leading to volume depletion and metabolic acidosis. Although significant blood pressure reductions were also observed in the small number of patients with enteric pancreas drainage, a contribution of volume loss to the improved hemodynamics after pancreas-kidney transplantation cannot be excluded.

Conclusions and Future Perspectives

Despite advances in our understanding of the physiology of hypertension in diabetes and important improvements in treatment strategies, coronary heart disease and stroke continue to limit the productivity and longevity of many Americans with these common disorders. As with all interesting research, the report by Elliott et al1 answers some important questions but raises many others:

  1. What are the long-term cardiovascular benefits of pancreas-kidney transplantation? The value of this procedure will be greatly enhanced if the observed improvements in metabolic profile and systemic hemodynamics result in a reduced risk of coronary heart disease and stroke. Appropriate patient selection requires an assessment of whether benefits are realized in patients with preexisting occlusive vascular disease or only in patients treated early in the disease process. The role of pancreas transplantation before the development of end-stage nephropathy and cardiovascular disease should also be considered.
  2. What are the pathophysiological mechanisms underlying the blood pressure lowering observed in patients undergoing pancreas-kidney transplantation? Future studies should evaluate how systemic hemodynamics, renal hemodynamics, neurohormonal mechanisms, and endothelial function are modified by improving the metabolic profile.

These questions notwithstanding, the report by Elliott et al1 challenges the conventional wisdom that hypertension is a consequence of nephropathy in patients with type I diabetes. Their findings suggest the possibility that the metabolic abnormalities associated with diabetes—abnormalities that are ameliorated by pancreas transplantation—play a significant role in the maintenance of high blood pressure in these patients. Dramatic new therapies like pancreas-kidney transplantation may significantly improve the lives of many patients with type I diabetes and nephropathy. Careful observation and study of these patients will enhance our understanding of the pathophysiological basis of hypertension and diabetes and will stimulate the development of novel therapies that can be applied earlier in the disease process.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. Elliott MD, Kapoor A, Parker MA, et al. Improvement in hypertension in patients with diabetes mellitus after kidney/pancreas transplantation. Circulation. 2001; 104: 563–569.[Abstract/Free Full Text]
  2. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA. 1979; 241: 2035–2038.[Abstract]
  3. Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes. 1999; 48: 937–942.[Abstract]
  4. Turner RC, Millns H, Neil HAW, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998; 316: 823–828.[Abstract/Free Full Text]
  5. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial: the HOT Study Group. Lancet. 1998; 351: 1755–1762.[Medline] [Order article via Infotrieve]
  6. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317: 703–713.[Abstract/Free Full Text]
  7. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet. 1999; 353: 611–616.[Medline] [Order article via Infotrieve]
  8. Effects of ramipril on cardiovascular and microvascular outcomes in peoples with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000; 355: 253–259.[Medline] [Order article via Infotrieve]
  9. Brown JH, Hunt LP, Vites NP, et al. Comparative mortality from cardiovascular disease in patients with chronic renal failure. Nephrol Dial Transplant. 1994; 9: 1136–1142.[Abstract/Free Full Text]
  10. Ritz E, Strumpf C, Katz F, et al. Hypertension and cardiovascular risk factors in hemodialyzed diabetic patients. Hypertension. 1985; 7: II-118–II-124.
  11. Jensen T. Micro-albuminuria and large vessel disease in diabetes. J Hypertens. 1992; 10: S21–S24.
  12. Raja RM, Lerner L, Morris M. Hypertension with combined pancreas-kidney transplantation in patients with diabetic nephropathy. Transplantation. 1993; 55: 1187–1188.[Medline] [Order article via Infotrieve]
  13. La Rocca E, Gobbi C, Ciurlino D, et al. Improvement of glucose/insulin metabolism reduces hypertension in insulin-dependent diabetes mellitus recipients of kidney-pancreas transplantation. Transplantation. 1998; 65: 390–393.[Medline] [Order article via Infotrieve]
  14. Hricik DE, Chareandee C, Knauss TC, et al. Hypertension after pancreas-kidney transplantation: role of bladder versus enteric pancreatic drainage. Transplantation. 2000; 70: 494–496.[Medline] [Order article via Infotrieve]
  15. Christiansen JS. Glomerular hyperfiltration in diabetes mellitus. Diabet Med. 1985; 2: 235–239.[Medline] [Order article via Infotrieve]
  16. Mogensen CE, Osterby R, Hansen KW, et al. Blood pressure elevation versus abnormal albuminuria in the genesis and prediction of renal disease in diabetes. Diabetes Care. 1992; 15: 1192–1204.[Abstract]
  17. Mathiesen E, Ronn B, Jensen T, et al. Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria. Diabetes. 1990; 39: 245–249.[Abstract]
  18. Tarn AC, Drury PL. Blood pressure in children, adolescents and young adults with Type 1 (insulin-dependent) diabetes. Diabetologia. 1994; 29: 275–281.
  19. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation produces quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991; 21: 271–277.
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Related Article:

Improvement in Hypertension in Patients With Diabetes Mellitus After Kidney/Pancreas Transplantation
Michael D. Elliott, Ajoy Kapoor, Michele A. Parker, Dixon B. Kaufman, Robert O. Bonow, and Mihai Gheorghiade
Circulation 2001 104: 563-569. [Abstract] [Full Text]




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