Clinical Presentation from the Mario Negri Institute, Bergamo

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Nephrol Dial Transplant (90) 5:623-627 90 European Dialysis and Transplant Association-European Renal Association Nephrology Dialysis Transplantation Clinical Presentation from the Mario Negri

1 Nephrol Dial Transplant (90) 5: European Dialysis and Transplant Association-European Renal Association Nephrology Dialysis Transplantation Clinical Presentation from the Mario Negri Institute, Bergamo The Role of Hypertension in Diabetic Nephropathy E. Ritz and Ch. Hasslacher Department of Internal Medicine, University of Heidelberg, Germany Abstract. Hypertension in diabetes mellitus has recently come under intense investigation. In type I diabetes its relation to nephropathy appears to be causal. It has been clearly demonstrated that control of retards progression of diabetic nephropathy and presumably also the occurrence of cardiovascular accidents. The relation between type II diabetes and is more complex. Hypertension may be present even in the absence of clinically overt nephropathy. This may be related to the recently postulated aetiological roles of insulin resistance and hyperinsulinaemia in blood pressure elevation. Recognition and treatment of even minor blood pressure elevation in diabetes is a challenge to the diabetologist and nephrologist alike. Key words: Hypertension; Diabetes mellitus; Diabetic nephropathy; Proteinuria; Renal failure; Diabetes type I and type II Case A male patient, KG, born in 36, was presented to the nephrology out-patient clinic in April 82. Insulindependent diabetes had been recognised in 49, proteinuria was first documented in 77, and he had been known to be hypertensive since 79. He presented with marked elevation of blood pressure (225/110 mmhg) normal serum creatinine (1.2mg/dl), and nephrotic range Correspondence and offprint requests to: Professor Dr E. Ritz, Department of Internal Medicine, Bergheimer Str. 58, D-6900 Heidelberg, FRG. proteinuria (4.59g/24h). He was prescribed captopril 50 mg/day. In addition, he had received chlorthalidone loomg/day, and atenolol 100 mg/day was continued. Compliance was suboptimal, and in January 83 he presented with average BP of 180/100 mmhg, serum creatinine had increased to 1.7mg/dl, but proteinuria was reduced to 1.1 g/24 h. Subsequently compliance was markedly improved. Because of ageusia, he was changed to enalapril 10 mg/day and chlorthalidone was changed for frusemide 125 mg/day. The rest of the course was uneventful. In March 88 he was normotensive throughout, i.e. during all self-measurements. He presented in the out-patient clinic with BP of 140/90 mmhg, unchanged serum creatinine (1.8mg/dl), and further reduction of proteinuria (0.8 g/24 h). This case is a good illustration of the usual course of diabetic nephropathy in the past, with mostly poor control of, and the change brought about by more recently available possibilities of therapeutic intervention. It sets the stage for a brief discussion, based primarily on our local experience, of the role of in the genesis and evolution of nephropathy. For a long time has been the Cinderella of diabetology. This complication of diabetes was well known, but little studied and even less treated. It is only in the past few years that the impact of arterial on the prognosis of the diabetic patient and its relation to diabetic nephropathy have been assessed in detail. This has led to a true renaissance of research on in diabetes. Although increased prevalence of in diabetic patients was noted decades ago [1], the relation of blood pressure elevation to the prevalence and progression of diabetic nephropathy has been appreciated only in

2 624 E. Ritz and Ch. Hasslacher recent years [2,3]- Our own retrospective observations [4] in the diabetes out-patient clinics of Heidelberg and Leiden elucidate the relative roles of metabolic control and in diabetic nephropathy. Although today more sophisticated tools have become available to assess metabolic control, e.g. glycosyted haemoglobin, and to detect incipient nephropathy, e.g. microalbuminuria, such methodology was not available when the data were collected. Nevertheless, the observations are of interest, not least because it will be impossible to replicate them in the future, now that arterial no longer goes virtually untreated. Prevalence of Diabetic Nephropathy in Type I Diabetes Mellitus As documented by the experience of the Joslin Clinic [5] and many others, and as illustrated by our own observations (Fig. 1), persistent proteinuria (as an index of advanced clinical neprhopathy) is infrequently seen before the 1 Oth year of duration of diabetes; its incidence increases thereafter with one (or two) peaks of incidence around the 20th year of diabetes (or 15th and 23rd respectively) with a subsequent decline. The cumulative prevalence of persistent proteinuria after 25 years duration of diabetes increases to 46% of patients at risk, in good agreement with the experience of others [5]. The appearance of persistent proteinuria of diabetic patients has been recognised as an ominous sign with respect to life expectancy. Even before the advances of renal replacement therapy, this was not due only to death from ureamia; in the study of Borch- Johnsen [6], cardiovascular mortality in diabetic patients who failed to develop proteinuria was only twice that of the corresponding general population, but it was increased 30-fold in diabetic patients with albuminuria. Albuminuria may thus be a marker for more widespread vascular dysfunction, e.g. disturbed endothelial barrier function, as recently suggested by some investigators. There is no doubt, however, that excess cardiovascular mortality in the diabetic with nephropathy is due in large part to its association with arterial. Clinical Correlates in Proteinuric Patients s. 3 C Q> S 5 01 u c4> O U ! V, Years after diagnosis of diabetes Fig. 1. Incidence and prevalence of persistent proteinuria in Type I diabetic patients. proteinuria were studied [4] in 82 patients with type I diabetes seen in our diabetes out-patient clinic between 65 and 83. All patients were seen at least six times per year; 52 developed proteinuria and 25 renal failure. As shown in Table 1, median time to onset of persistent proteinuria was shorter when metabolic control, as assessed by median annual postprandial glucose concentrations, was poor. In contrast, the relatively crude procedure of classifying patients according to blood pressure status showed no noticeable difference with respect to the time of onset of persistent proteinuria. Although poor metabolic control is obviously one major determinant of diabetic nephropathy, an enormous overlap (Fig. 2) of median annual postprandial glucose concentrations during the years prior to the-onset of persistent proteinuria existed between patients with subsequent nephropathy and without. This shows that important factors other than metabolic control also determine the onset of diabetic nephropathy. Genetic predisposition has been recognised as an important factor for the development of diabetic nephropathy [7], and this may potentially be related to genes coding for type IV collagen [8] or determinants of [9]. However, diabetologists have also long been convinced that metabolic control is another important determinant of diabetic nephropathy. The relative contributions of metabolic control and blood pressure elevation for the appearance of persistent Evolution of Proteinuria: Relation to Blood Pressure Although previous investigators could demonstrate that blood pressure increases within the range of normotension when microalbuminuria appears in type I diabetes [ 10], it is in proteinuric type I diabetes that the impact of on the evolution of nephropathy (and proliferative retinopathy; [11]) is most obvious. Table 2 shows that

3 Hypertension in Diabetes Table 1. Time interval between diagnosis of diabetes and onset of proteinuria in relation to blood pressure status and metabolic control Annual median blood glucose (mg/dl) Persistent < 200 Intermittent > 200 Persistent > 200 Annual median blood pressure (mmhg) Persistent < 160/95 Intermittent > 160/95 Persistent > 160/ o 250 <L> 8 u. 200 T3 8 c I 150 Time interval (years) With nephropathy Without nephropathy Fig. 2. Dispersion of median postprandial glucose in diabetic patients (Type I) with and without subsequent nephropathy. proteinuric type I diabetic patients who go into renal failure are more frequently hypertensive and have more elevated median systolic and diastolic blood pressures than patients who do not develop elevated serum creatinine over a comparable duration of follow-up. Onset of renal failure was also more rapid in hypertensive patients, as illustrated in Fig. 3. In this context it is noteworthy that at this stage of advanced diabetic nephropathy, metabolic control no longer had a recognisable influence on the risk of developing renal failure, i.e. postprandial glucose was similar in patients with and without ultimate renal failure. Nevertheless, renal failure developed more rapidly in patients 625 with poorly controlled diabetes; the correlation between median postprandial glucose values and the time interval between onset of persisting proteinuria and of renal failure was modest (r=0.53) but statistically significant (P=0.01). Since metabolic control is not closely related to further progression in patients with advanced nephropathy, some discussions in the past on whether [12] or not [13] metabolic control influences progression of established diabetic nephropathy may be explained by problems of biostatistics. Because initial hyperperfusion occurs in parallel both in the renal and retinal microcirculations [14] it is interesting that the onset of the prognostically more adverse type of retinopathy, i.e. proliferative retinopathy, occurred sooner in the more hypertensive patients [15,16]. An adverse effect of on the progression of renal failure was still demonstrable in patients with advanced renal failure. Progression, as evaluated by 1/ creatinine (mg/dl) versus time of observation (months) was significantly more rapid in patients with persistent (r= 0.185) than with intermittent (/ = 0.078). We classified as 'intermittent ' those patients who presented in the outpatient clinic sometimes with normal and sometimes with elevated blood pressures, and we classified as persistent those patients who were always hypertensive despite antihypertenisve treatment. Hypertension in Type II Diabetes Mellitus In type I diabetes there is some (still controversial) evidence of a role for genetic predisposition to primary in the genesis of nephropathy [9]. About 40% of patients are hypertensive in the years immediately preceding persistent proteinuria. This proportion is greater than the percentage of hypertensives in the general population [18], presumably since blood pressure begins to increase before overt proteinuria has set in [10]. In contrast, a very large proportion of newly diagnosed type II diabetic patients without persisting proteinuria are hypertensive, vastly more than expected in the general population when matched for age, sex and body mass index. This is in agreement with old observations of Pell and D'Alonzo [] who documented in a longitudinal study that blood pressure elevation precedes the onset of overt diabetes. More recent studies of Ferranini et al [20], confirming previous observations [21], demonstrate the presence of impaired glucose tolerance, fasting hyperinsulinaemia, and insulin resistance in non-obese individuals with primary. This finding raises the intriguing possibility that insulin resistance and hyperinsulinaemia may be related to blood pressure elevation [22]. Proposed mechanisms include augmented tubular Na reabsorption under the influence of insulin [23],

4 626 E. Ritz and Ch. Hasslacher Table 2. Blood pressure and metabolic control in type I diabetic patients with persistent proteinuria; comparison of patients with and without development of renal failure Group Number of patients with: No Intermittent Persistent Blood pressure (mmhg) Diabetic patients with increase of serum creatinine (n = 25) Diabetic patients without increase of serum creatinine (n = 23) 2 (8%) 12(52%) 13(52%) 9(39%) 10 (40%) 2 (9%) 160( ) 90(80-122) 142( ) 84(76-110) Table 3. Change of incidence of renal failure and of quality of blood pressure control in the past two decades Onset of persistent proteinuria I 80 '5 B 60 c v. 15 Ol 0> 5 I Prevalence of renal failure (at 5-year follow-up) 77% 53% 29% Without With Prevalence of and median blood pressure (mmhg) 77% (161/101) 59% (154/84) 54% (144/88) ^100 -i g.i soil* 61» 20 Median postprandial blood glucose (mg/dl) 2 ( ) 215 (98-250) 183 ( ) Type 1 diabetes Median BP (mmhg) 138/84 148/88 c % Type II diabetes 158/ Years after onset of proteinuria Type I diabetes Fig. 3. Time course of onset of renal failure in proteinuric Type I diabetics with and without. increased sympathetic activity [24] and others [25]. In type II diabetes the prevalence and severity of increased with advancing stages of diabetic nephropathy, but much less so than in type I diabetes (Fig. 4). It is of note that type II diabetic patients who subsequently developed persistent proteinuria or renal failure had o 20 Median BP (mmhg) 164/86 no proteinuria 166/89 persistent proteinuria 168/93 S. creat. >!.< mg/dl Fig. 4. Blood pressure as a function of nephropathy in Type I and Type II diabetes. Hypertension is defined as blood pressure (BP) greater than 140/90 mmhg taken on three occasions while sitting. more elevated blood pressures in the preproteinuric and proteinuric stages respectively than matched patients who failed to develop nephropalhy or renal failure [26].

Hypertension in Diabetes Changing Prognosis in Hypertensive Diabetic Patients The abysmally poor prognosis of proteinuric diabetic patients in the past is illustrated by the observation of Parving

5 Hypertension in Diabetes Changing Prognosis in Hypertensive Diabetic Patients The abysmally poor prognosis of proteinuric diabetic patients in the past is illustrated by the observation of Parving and Hommel [27] that 10 years after onset of proteinuria only 20%-30% of patients were still alive. This is in agreement with our own observations [28]. In parallel the cumulative prevalence of renal failure decreased progressively from 66 to 83 (Table 3). At least prior to 82 metabolic control, which may influence the rate of progression [12], had not improved. Amelioration of renal prognosis, i.e. absence of renal failure 5 years after onset of proteinuria, was paralleled by lower median blood pressures. The latter must be attributed largely to the availability of modern antihypertensive agents with fewer side-effects, permitting more effective antihypertensive treatment [16]. Nevertheless, in one past [28] and one ongoing (unpublished) study on diabetic patients admitted for maintenance haemodialysis, blood pressure control in diabetic versus matched non-diabetic patients continues to be significantly poorer. In parallel with improved renal prognosis, patient survival has also progressively improved in the above patient cohort [29], confirming the observations of Parving and Hommel [27]. Although both observations [27,29] are not the result of a controlled trial on antihypertensive intervention, and although overall management of diabetic patients has also changed, ourfindingsare encouraging. They are consistent with an important effect of on renal survival and overall survival in nephropathic diabetic patients. There is every hope that with wider use of more efficacious antihypertensive agents, i.e. ACE inhibitors and calcium antagonists [16,17], this prognosis can be further improved in the future. Acknowledgements. The generous contribution of Hospal S.p.A., Bologna, enabled the Clinical Presentation to take place in Bergamo on 24 October 89. References 1. Hitzenberger K. Ober den Blutdruck bei Diabetes mellitus. Wien Arch Inn Med 21; 2: Mogensen CE. Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. BrMedJ 82; 285: Parving HH, Smidt UM, Andersen AR, Svendsen PA. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 83; I: Hasslacher CH, Stech W, Wahl P, Ritz E. Blood pressure and metabolic control as risk factors for nephropathy in type I diabetics. Diabetologia 85; 28: Krolewski AS, Canessa M, Warram JH et al. Predisposition to and susceptibility to renal disease in insulin-dependent diabetes mellitus. N EnglJ Med 88; 318: Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in type I (insulin-dependent) diabetes mellitus. Diabetologia 85; 28: Seaquist ER, Goetz FC, Rich S. Barbosa J. Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility todiabetic nephropathy. N EnglJ Med 89: 320: Krolewski A, Tryggvason K, Warram J, Laffel L, Housman D. Diabetic nephropathy and polymorphism in the gene coding for the alpha 1 chain of collagen IV. Kidney Int 90; 37: 510a 9. Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti G. Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. N EnglJ Med 88; 318: Feldt-Rasmussen B, Borch-Johnsen K, Mathiesen ER. Hypertension in diabetes as related to nephropathy. Early blood pressure changes. Hypertension 85; 7 [Suppl II): II Hasslacher C, Ritz E, Terpstra J, GallaschG, Kunowski G, Rail C. Natural history of nephropathy in type I diabetes. Relationship to metabolic control and blood pressure. Hypertension 85; 7 [Suppl II]: II74-H Nyberg J, Blohme G, Norden G. Impact of metabolic control on progression of clinical diabetic nephropathy. Diabetologia 87; 30: Viberti GC, Bilous RW, Mackintosh D, Bending JJ, Keen H. Longterm correction of hyperglycaemia and progression of renal failure in insulin-dependent diabetes. Br MedJ 83; 286: L'Esperance Jr RA, Friedman EA. Natural history of diabetic retinopathy, in: Diabetic Renal-Retinal Syndrome. Grune and Stratton 80: Hasslacher C, Rambausek M, Ritz E. Genesis and management of in diabetic nephropathy, in Keen H, Legrain M, ed. Prevention and Treatment of Diabetic Nephropathy. MTP Press, 83: Hasslacher C, Ritz E, Tschope W, Gallasch G, Mann JFE. Hypertension in diabetes mellitus. Kidney Int 88; 34 [Suppl 25]: S133-S Ritz E, Hasslacher C, Mann J, Guo JZ. Hypertension and vascular disease as complications of diabetes. In Laragh JH, Bremer BM eds. Hypertension-Pathophysiology, Diagnosis and Management. Raven Press, New York, 90: Stieber J, Doring A, Keil U. Haufigkcit, Bekanntheits- und Behandlungsgrad der Hypertonie in einer GroBstadtbevolkerung. Mchn med Wschr 82; 124: Pell S, D'Alonzo CA. Some aspects of in diabetes mellitus. JAMA 67; 202: Ferrannini E, Buzzigoli G, Bonadonna R et al. Insulin resistance in essential. N EnglJ Med 87; 317: Dieterle P, Fehm H, Stroder W, Henner J, Bottermann P, Schwarz K. Asymptomatischer Diabetes mellitus bei normalgewichtigen Hypertonikern. Dtsch Med Wochenschr 67; 92: Modan M, Halkin H, Almong S et al. Hyperinsulinemia. A link between, obesity and glucose intolerance. J Clin Invest 85:75: Baum M. Insulin stimulates volume absorption in the rabbit proximal convoluted tubule. J Clin Invest 87; 79: Rowe JW, Young JB, Minaker KL, Stevens AL, Pallotta J, Landsberg C. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes 81; 30: Ferranini E, Defronzo RA. The association of, diabetes and obesity: a review. J Nephrol 89; I: Hasslacher CH, Wolfram M, Stech G, Wahl R, Ritz E. Diabetische Nephropathie bei Typ II Diabetes. Dtsch Med Wochenschr 87; 112: Parving HH, Hommel E. Prognosis in diabetic nephropathy. Br MedJ 89; 299: Ritz E, Strumpf C, Katz, Wing AJ, Quellhorst E. Hypertension and cardiovascular risk factors in hemodialyzed diabetic patients. Hypertension 85; 7 (Suppl II): Hasslacher C, Borgholtz G, Ritz E, Wahl P. Impact of on prognosis in IDDM. Diabete Metab 89; 15: Hasslacher C. Ritz E. Hypertonie und Diabetes. Internist 90; 31: Received for publication Accepted in revised form

Natural History of Nephropathy in Type I Diabetes. Relationship to Metabolic Control and Blood Pressure

Natural History of Nephropathy in Type I Diabetes Relationship to Metabolic Control and Blood Pressure CHRISTOPH HASSLACHER, EBERHARD RITZ, JANKE TERPSTRA, GEBHARD GALLASCH, GABRIELE KUNOWSKI, AND CORNELIA