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  * Professor ** Reader Department of Medicine (Nephrology)*** Associate Professor Department of BiochemistryPt. BD Sharma PGIMS, Rohtak-124 001(Haryana). REVIEW ARTICLE Recent Advances in the Management of Diabetic Nephropathy Nitya Nand*, HK Aggarwal**, M Sharma***  Introduction Diabetic nephropathy is an importantmicrovascular complication of long standing non-insulin dependent diabetes mellitus (NIDDM) aswell as insulin dependent diabetes mellitus (IDDM)associated with considerable morbidity andmortality. Prevalence of diabetes mellitus is on therise and it is estimated that there are 30 milliondiabetics in India, of which 6.6 million areexpected to develop diabetic nephropathy (DN) 1 .Further, type 2 diabetes mellitus is 5 times morecommon and microalbuminuria is higher inIndians than Europeans 2 . Overt diabeticnephropathy is preceded by a stage of microalbuminuria which cannot be diagnosed bythe routine dip-stick method.Majority of the epidemiological studies of diabeticnephropathy are available in insulin-dependentpatients due to the earlier manifestation (< 40yr.) of diabetes in these patients leading to longer follow-up period. In IDDM, the prevalence of nephropathy peaks at 21% after 20 to 25 yearsof clinically detected diabetes and then declinesto 10%. However, in NIDDM, prevalence of proteinuria increases steadily with duration of diabetes, i.e., 20 to 35% in patients who havehad diabetes for more than 20 to 25 years 3 .The natural history of diabetic nephropathy isevident by the phase of glomerular hyperfiltration during which importantabnormalities of renal function and structure(nephromegaly) take place. The next stage isthe appearance of microalbuminuria, theexcretion of albumin in the range of 30-300mg/d, which appears to be due to decreasedconcentration of anionic heparin sulfate-proteoglycan in the glomerular basementmembrane. If adequate therapeutic measuresare not taken at the initial stage, there developsthe stage of clinical nephropathy after a variableperiod, signalled by the appearance of persistent proteinuria (albumin excretion rateof > 300 mg/day). At this stage there is a steadydecline in renal function with glomerular filtration rate (GFR) falling, on an average, byabout 1 ml/min/month. A plot of the reciprocalof serum creatinine level against time usuallyyields a straight line and allows prediction of the rate of deterioration. The average timebetween onset of persistent proteinuria and end-stage renal failure has been calculated as 7years to 15 years. Recently, association of ‘Ischaemic Nephropathy’ has also beenreported alongwith DN. The hallmark of thiscondition is ischaemia, which is caused byreduction in calibre of renal artery and can alsoresult from multiple thrombi, dissection of aorta,or cholesterol embolism. In an autopsy study,bilateral disease was seen in 43% patients withdiabetes mellitus and 30% of non-diabeticpatients 4 . The risk of ischaemic nephropathy inthe setting of DN is further increased if the ageof patient is more than 70 years associated withcigarette smoking and hypertension of recentonset 5 .The earliest morphologic abnormalities indiabetic nephropathy are thickening of theglomerular basement membrane (GBM) andexpansion of the mesangium due to theaccumulation of extracellular martrix. Thevarious stages of diabetic nephropathy areshown in Table I.  Table I : Various stages of diabetic nephropathy. Stage I Stage II Stage III Stage IV Stage VStage and Variable duration After 2 years of After 10-20 years Several years later chronology from diagnosis diabetes, then of diabetes(imperfect glycaemic progressioncontrol)Features Renal hypertrophy Silent stage Incipient Overt nephropathy Uraemiaand hyperfunction nephropathyMain Large kidneys, Normal urinary Microalbuminuria Macroalbuminuria Progressionglomerular albumin excretion (undetectable on (often nephrotic) to ESRDhyperfiltration dipstic)Glomerular Glomerular Thickening of Same, with Diffuse or nodular Glomerular pathology hypertrophy, glomerular increasing glomerulosclerosis obsolescencenormal basement basement severitymembrane membrane,and measangium measangialexpansion.Glomerular 160 160 130 70-10 10-0filtrationrate ml/minUrinary < 30 mg/day 30-60 mg/day 60-200 mg/day, Several g/day Several g/dayalbumin increasingexcretionBlood pressure Normal Normal Rising High High Various genetic, metabolic, and heamodynamicfactors that appear to be important in thepathogenesis of DN are hyperglycaemia,hypertension, microalbuminuria, ethnicity, gender,family history, duration of diabetes, smoking, andgenetic susceptibility. Hypertension (HT) is a criticalfactor in development and progression of DN. It isan ominous sign because once HT develops, thereis an accelerated decline in GFR and increase inalbuminuria. Therefore if treated aggressively it is akey factor in slowing the rate and extent of declinein renal functions because HT contributes tohyperfiltration and haemodynamic abnormalities 6 .Therefore current strategies designed to preventprogression of diabetic nephropathy include :  Glycaemic control   ACE inhibition (microalbuminuria)  Blood pressure control  Smoking cessation  Protein restriction  Cholesterol reduction (possibly) ManagementBlood pressure control It has become apparent that progressive fall inGFR in IDDM patients correlates closely with bothincreasing albuminuria and blood pressure (BP).Further, reduction in BP slows the rate of declineof GFR and checks the increasing albuminuria. Aprospective study of 6 years duration demonstratedthat effective BP treatment decreased albuminexcretion rate of 50% and the rate of decline of GFR from 0.9 ml/min/month to 0.29 ml/min/month 7 . Further, numerous studies have shown thatlowering of BP in normotensive diabetics has clear renal benefits. Although appropriate BP goal indiabetics is not clearly defined, a lower targetdiastolic pressure of 80 mm Hg is aimed at.However, better end point of antihypertensive (antiHT) treatment is not the BP level but the rate of albumin exeretion because this is the indicator thatpredicts the rate of decline in GFR 8 . Therefore,there is widespread consensus for using  Journal, Indian Academy of Clinical Medicine    Vol. 2, No. 1 and 2    January-June 200179  80Journal, Indian Academy of Clinical Medicine    Vol. 2, No. 1 and 2    January-June 2001 antihypertensive medication that has mostbeneficial effect on reducing microalbuminuriaand using them in normotensive microalbuminuriacases. The other factors which need to beconsidered in choosing the drug are the side effectprofile and its potential effect on cardiovascular mortality. The characteristics of an idealantihypertensive drug are given in table II.Table II : Characteristics of an idealantihypertensive drug.  Has hypotensive efficacy  Inhibits renal disease progression  Reduces cardiovascular mortality  Improves insulin resistance  No adverse effect on glucose metabolism  Neutral or beneficial effect on lipidmetabolism.  No significant adverse side effects (sexualdysfunction, orthostatic hypotension, inhibitionof counter regulatory hormones). Among the available choices of antihypertensiveswhich have reno-protective property, other factorslike neutral effect on lipid profile and improvementin insulin sensitivity; ACE-I (Angiotensin ConvertingEnzyme Inhibitors), Angiotensin II receptor antagonists, nondihydropyridine calcium channelblockers, adrenergic antagonists, andcardioselective B Blockers (Carvedilol) appear tooffer most advantages 9 . However, the only classof drug which has shown to benefit with regard toreduction in cardiovascular deaths are ACE-I andlow dose diuretics 10 . A number of studies have suggested that not onlya benefit of antihypertensive treatment but arelatively greater beneficial effect of ACE inhibitionon kidney is found over that achieved by BP controlalone. Enthusiasm has been generated in thenephrological community by the recent evidencethat ACE-I are superior to other antihypertensiveagents in attenuating progressive loss of renalfunction. The idea of a specific nephroprotectiveeffect of ACE inhibitors goes back to theobservation of Anderson 11 . There is improvementin glomerular membrane size, a selective propertyseems to be unique to ACE-I and is independentof systemic BP changes 12 . One importantconfounder (with obvious consequences, for themanagement of renal patient) is sodium intake.High sodium intake obliterates the beneficial effectof ACE inhibitors on development of glomerulosclerosis in animals 13  and on proteinuriain renal patients 14 . It emerges from this, that inorder to obtain maximal benefit from ACE-I,dietary sodium restriction, with or without diuretics,is indispensable. More recently it has becomeobvious that ACE-I, besides efferent arteriolar vasodilatation have many non-haemodynamiceffects which may well be relevant in inhibition of progression. These include inhibitory action onmesangial cell proliferation in vitro 15  andglomerular growth in vivo 16 , as well as the effectson the electrical change of the glomerular membrane 17 , and even actions on non-glomerular cells, particularly interstitial fibroblasts 18 . Theseprocesses are relevant in the genesis of glomerular and interstitial scarring and in the developmentof proteinuria.The non-dihydropyridine subclass of calciumchannel blockers including diltiazem andverapamil, which cause vasodilatation of afferentarterioles have been shown to decrease proteinexcretion; several reports in literature haverecommended continuation of these drugs with ACE inhibition at lower doses of each agent andhence achieved greater reduction in proteinuriaand better results in reducing decline in GFR 19 .However, use of ACE-I should be monitoredclinically, biochemically, and by using isotopestudies, especially if serum creatinine is more than2.5 mg %. The increments in serum creatininebeyond 70% of the baseline value should raisesuspicion and prompt treatment for predisposingfactors listed in table III. The risk of hyperkalaemiais usually not clinically important, if loop diureticsare administered concomitantly with ACE-I.Therefore, anti-HT treatment appears to beprotective and delays the progression of establishment of diabetic nephropathy. If started   Journal, Indian Academy of Clinical Medicine    Vol. 2, No. 1 and 2    January-June 200181 at the stage of microalbuminuria, it may evenprevent, or at least retard, the amount of clinicallyovert renal disease. Aggressive anti-HT therapyhas also been found to decrease albuminuria inthe stage of overt nephropathy.Table III : Side effects of ACE inhibitors in renalpatients. A.Decrease of GFR/oliguria  Renal artery stenosis –Bilateral –Single kidney (including renal graft)  Hyper-reninaemic status from accompanyingconditions. –Preceding diuretic treatment –Congestive heart failure –Liver cirrhosis  From specific primary renal diseases –Haemolytic uraemic syndrome/scleroderma crisis –Malignant hypertension –Autosomal dominant polycystic kidneydiseaseB.Hyperkalaemia  Hyporeninaemic hypoaldosteronism (elderlytype 2 diabetics)  Hyperchloraemic metabolic acidosis(tubulointerstitial disease)C.Aggravation of metabolic acidosis Aggravation of hyporegenerative anaemia(decreased EPO) Dietary treatment Restriction of protein intake has long beenadvocated in the treatment of CRF, and diabeticnephropathy is no exception. Meta-analysis of efficacy of protein restriction in both diabetic andnon diabetic renal disease has confirmed that suchrestriction slows the progression of renal diseasein general 20 . Zetter et al   demonstrated 3-4 folddecline in rate of fall of GFR on a protein restricteddiet (0.6 g/kg/day) 21 . Effect on albumin excretionespecially in microalbuminuric type 1 and 2diabetics have also been demonstrated.However, protein restriction should be avoided inhypercatabolic patients with advanced DN as itmay cause malnutrition. The mode of action of low protein diet (LPD) is complex and unlikely tobe mediated simply by haemodynamic changes. Although haemodynamic factors are important inthe pathogenesis of nephropathy and LPD reducesintraglomerular pressure and microalbuminexeretion but changes in other nutritionalcomponents such as phosphorus and lipids mayalso be contributing. Further, it is also clear thatan important interaction exists between glycaemiccontrol and haemodynamic response of kidneyto a protein load and strict glycaemic controlenhances the beneficial effect of LPD on renalfunctions 22,23 . Therefore this approach is safe andis probably an effective primary or secondarypreventive measure for DN. Protein restriction of 0.75-0.8 g/kg/day is widely recommended in type1 diabetes. Glycaemic control Poor glycaemic control leads to accumulation of advanced glycosylation end products in tissues,hence DN is four times more common in IDDMpatients with poor glycaemic control. The onset of microalbuminuria correlates closely with glycaemiccontrol, with a gradual rise in rate as theglycosylated haemoglobin level increases from6.1% to 8.1% and a sharp rise occurring above8.1% 24 . However, blood glucose control appearsto have limited impact on the progression of diabetic renal failure which suggests that there isa point of no return for kidney, beyond which thenephropathic process becomes self perpetuatingand independent of diabetic metabolicabnormalities which initiated it. Therefore goodglycaemic control is of prime importance in theearlier stages of renal disease (i.e., before theonset of overt proteinuria) and reduction inalbumin excretion rate and annual decline in GFRhave been obtained by strict control of the glucoselevels and it is the blood glucose concentrationrather than the method of its control which
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