Drugs 35 (Suppl. 5): 59-61 (1988)DO 12-6667/88/0500-0059/$1.50/0© ADIS Press LimitedAll rights reserved .

Effects of Antihypertensive Therapy on KidneyFunction in Diabetic Patients

Bengt ScherstenDepartment of Community Health Sciences, University of Lund, Dalby

Summary Diabetic nephropathy is one ofthe major longterm complications responsible for mor­tality in diabetes mellitus. Whilestrictmetabolic controlofdiabetes probably hasa positiveinfluence on kidney disease, most evidence supports the view that the process leading toend-stage renalfailure has becomeindependent ofthe metabolic disturbances ofdiabetes,and that haemodynamicfactors in established nephropathy havebecomethe predominantcauses ofprogression of renal damage. In particular, increased intraglomerular pressureis thought 10 playa crucial part in the development of diabetic nephropathy. Therefore,drugs that can reduce intraglomerular pressure are ofinterest in treatmentofhypertensionin diabeticpatients. The angiotensin-converting enzyme (ACE) inhibitors havebeenshownto reduce intraglomerular pressure in animal studies, and the use of these drugs 10 treatinsulin-dependent diabetics with hypertension has produced a reduction in the rate ofde­clineofglomerularfiltration rate. Although some fJ-blockers canalsohavebeneficial effectson renalfunction. they may produce unwantedmetabolic effects. Thus the ACE inhibitorsseem to be the most suitable antihypertensive drugs for diabetic patients.

1. Hypertension and Renal Function inDiabetes

Several theories have been proposed to explainthe association between hypertension and diabetesin terms of the influence of sympathetic pathwayson both blood pressure and blood glucose regula­tion (Drury 1983).

Hyperinsulinaemia could contribute to hyper­tension by stimulating the activity of the sympath­etic nervous system or by increasing sodium andwater reabsorption in the kidney. Before consid­ering renal function in diabetics, it is important tonote that at any given level of blood pressure, dia­betic patients have an increased risk of coronaryheart disease which is associated with both glucoseintolerance and hyperinsulinaemia, As some anti-

hypertensive drugs deleteriously affect glucose, in­sulin and lipid metabolism, it is crucial to selectthe best treatment of diabetic patients with raisedblood pressure.

In insulin-dependent diabetes, the incidence ofhypertension increases with the duration of the dis­ease and has a close association with nephropathy.Approximately 40 to 50% of all insulin-dependentpatients develop persistent albuminuria, a declinein glomerular filtration rate (GFR) and elevatedarterial blood pressure. Renal failure is the leadingcause of death (30%) in these patients (Andersenet al. 1985; Knowler 1974). Furthermore, hyper­tension accelerates nephropathy, which con­sequently raises blood pressure (Parving et al.1985a).

Elevated GFR, which occurs in 25 to 40% of

Effects on Kidney Function in Diabetics

insulin-dependent diabetic patients (Mogensen etal. 1981), probably has a role in the initiation andevolution of diabetic nephropathy. Strict glycaemiccontrol has been shown to normalise the glomer­ular filtration rate, although the kidneys may re­main enlarged (Wiseman et al. 1986). Increasedlevels of glucagon and growth hormone usually ac­company diabetic hyperglycaemia, and each ofthese hormones is capable of inducing a rise in glo­merular filtration rate (Parving et al. 1980). How­ever, chronic renal disease has as its principalpathophysiologicalderangement the permanent lossof nephron units. In the early stages overall kidneyrenal function is maintained by structural hyper­trophy, and by compensatory elevation of thesingle-nephron GRF caused by the glomerular cap­illary plasma flow rate. This glomerular hyperper­fusion and hypertension may injure the remainingglomeruli and so may be responsible for the pro­gression of renal failure, albuminuria and glomer­ular sclerosis that follows reduction in nephronnumber (Anderson & Brenner 1986; Brenner 1985).Consequently, restriction of dietary protein, whichlimits glomerular capillary pressuresand flows, mayslow the development of glomerular injury in thehyperfiltrating kidney in diabetes.

2. Antihypertensive Therapy in Diabetes

The Working Group on Hypertension in Dia­betes (1987) made the following statement in theirguidelines on pharmacological treatment of dia­betes mellitus with renal (parenchymal) hyperten­sion:

'The a-adrenergic inhibitor prazosin, ACE in­hibitors, and calcium channel blockers may haveadvantages over thiazide diuretics and {j-adrener­gic blockers as a first-line therapy in patients withboth diabetes mellitus and hypertension. Admin­istration of these drugs does not alter insulin se­cretion and has little or no effect on control of dia­betes mellitus. Further, they do not aggravate lipidabnormalities and rarely cause impotence. Use ofthese drugs has none of the potential adverse ef­fects found with blockade of 132 receptors'.

In a special communication , Kaplan et al. (1987)

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agreed with this, especially with the statement thatadministration of angiotensin-converting enzyme(ACE) inhibitors may 'become a valuable first-lineantihypertensive drug therapy in diabetic nephro­pathy'. In addition, they favoured the use of a­

blockers and calcium antagonists before the use ofdiuretics and {j-blockers.

There have been several reviews of the renal ef­fects of ACE inhibitors (Bauer 1984; Bauer &Gaddy 1985; Bauer & Reams 1987); these con­cluded that the interruption of the renin-angioten­sin-aldosterone axis has the potential to produce avariety offavourable renal responses, including re­duction of renal vascular resistance, enhancementof renal blood flow, enhancement of GFR, acutenatriuresis, sustained diuresis, and a decrease inurinary protein excretion. In both insulin-depend­ent and non-insulin-dependent diabetics, plasma­renin activity and angiotensin II may be inappro­priately high for body sodium content and plasmavolume (Connell 1987); furthermore , the pressorsensitivity to angiotensin II and noradrenaline maybe increased in these subjects (Drury et al. 1984).ACE inhibitors should therefore be suitable drugswith which to treat hypertension in diabeticpatients.

In studies of nephrectomised rats made diabeticby streptozocin treatment, the ACE inhibitor en­alapril lowered both the systolic blood pressure(SBP) and the elevated GFR to normal levels andalso prevented the progression of proteinuria.However, treatment with the calcium antagonistverapamil produced equivalent falls in SBP but didnot alter intrarenal haemodynamics, nor did it in­fluence the progressive increase in proteinuria inthe diabetic rat (Jackson et al. 1986). This differ­ence between ACE inhibitors and calcium antag­onists probably reflects differences in their effecton intrarenal haemodynamics . Angiotensin II pref­erentially constricts the efferent glomerular arter­iole and so maintains glomerular pressure, filtra­tion pressure and GFR. ACE inhibition thereforeleads to a fall in these parameters (Anderson et al.1985). In contrast , calcium is important for bothefferent and afferent smooth muscle tone and

Effects of Kidney Function in Diabetics

therefore calcium antagonism would theoreticallylead to little change in glomerular haemodynamics.

Hommel et al. (1986) found that GFR is notdependent on angiotensin II in mild hypertensiveinsulin-dependent diabetics with early nephro­pathy, and enhanced renal plasma flow has beendemonstrated during ACE inhibition in essentialhypertension, despite the reduction in blood pres­sure (Simon et al. 1983). Additionally, in a 2-yearprospective study of patients with diabetic nephro­pathy and hypertension, captopril decreased the rateof deterioration of GFR from 10.3 to 2.4 ml/min/year (Bjorck et al. 1986).

Long term antihypertensive treatment with me­toprolol (100 to 400 mg/day), hydralazine (50 to200 mg/day) and/or frusemide (80 to 500 rng/day)in insulin-dependent diabetic patients withnephropathy similarly caused a slowing of the rateof decline of GFR to 4.4 ml/rnin/year, comparedwith 10.1 ml/rnin/year in an untreated group(Parving et al. 1985b). However, even though fl­blockade may bean effective and safe way of low­ering blood pressure, it could be dangerous in dia­betic patients with nephropathy because of simul­taneous autonomous neuropathy, which, togetherwith fl-blockade , may mask clinical signs ofhypoglycaemia.

3. Conclusions

There is increasing evidence that treatment ofhypertension in diabetic patients is beneficial, sinceit prevents progression of diabetic complications,especially nephropathy. The most promising agentsin the treatment of diabetic nephropathy withhypertension seem to be ACE inhibitors.

References

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Anderson S, Meyer TW, Rennke HG, Brenner BM. Control ofglomerular hypertension limits glomerular injury in rats with

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Author's address : Prof. Hengl Schersten, Department of Com­munity Health Sciences, Lund University Health Sciences Centre,VArdcentralen, S-240 10 Dalby (Sweden).