-
The Stages in Diabetic Renal DiseaseWith Emphasis on the Stageof Incipient Diabetic NephropathyC. E. MOGENSEN, C. K. CHRISTENSEN, AND E. VITTINGHUS
SUMMARYAlterations in renal function and structure are foundeven at the onset of diabetes mellitus. Studies per-formed over the last decade now allow definition of aseries of stages in the development of renal changesin diabetes. Such a classification may be useful bothin clinical work and in research activities.
Stage 1 is characterized by early hyperfunction andhypertrophy. These changes are found at diagnosis,before insulin treatment. Increased urinary albumin ex-cretion, aggravated during physical exercise, is also acharacteristic finding. Changes are at least partly re-versible by insulin treatment.
Stage 2 develops silently over many years and ischaracterized by morphologic lesions without signs ofclinical disease. However, kidney function tests andmorphometry on biopsy specimens reveal changes.The function is characterized by increased GFR. Dur-ing good diabetes control, abumin excretion is normal;however, physical exercise unmasks changes in albu-minuria not demonstrable in the resting situation. Dur-ing poor diabetes control albumin excretion goes upboth at rest and during exercise. A number of patientscontinue in stage 2 throughout their lives.
Stage 3, incipient diabetic nephropathy, is the fore-runner of overt diabetic nephropathy. Its main manifes-tation is abnormally elevated urinary albumin excre-tion, as measured by radioimmunoassay. A levelhigher than the values found in normal subjects butlower than in clinical disease is the main characteristicof this stage, which appeared to be between 15 and300 |xg/min in the baseline situation. A slow, gradualincrease over the years is a prominent feature in thisvery decisive phase of renal disease in diabetes whenblood pressure is rising. The increased rate in albuminexcretion is higher in patients with increased bloodpressure. GFR is still supranormal and antihyperten-sive treatment in this phase is under investigation, us-ing the physical exercise test.
From the Second University Clinic of Internal Medicine, Kommunehospitalet,8000 Aarhus C, Denmark.Address reprint requests to C. E. Mogensen at the above address.
Stage 4 is overt diabetic nephropathy, the classicentity characterized by persistent proteinuria (>0.5 g/24 h). When the associated high blood pressure is leftuntreated, renal function (GFR) declines, the mean fallrate being around 1 ml/min/mo. Long-term antihyper-tensive treatment reduces the fall rate by about 60%and thus postpones uremia considerably.
Stage 5 is end-stage renal failure with uremia due todiabetic nephropathy. As many as 25% of the popula-tion presently entering the end-stage renal failure pro-grams in the United States are diabetic. Diabetic ne-phropathy and diabetic vasculopathy constitute amajor medical problem in society today. DIABETES 32(Suppl. 2):64-78, 1983.
In comparison with other renal disorders, the natural his-tory of renal involvement in insulin-dependent diabetesfollows a very characteristic and probably unique pat-tern. For a long period of 10-20 yr or more, structuralcomponents in the kidney are enlarged with concomitanthyperfunction. Thereafter, in a large proportion of the pa-tients (around 30-50%), renal function starts to deteriorate,first evidenced by proteinuria.12 The initial phase of abnormalincrease in protein excretion is not detectable by ordinarylaboratory methods; it requires more sensitive methods, suchas radioimmunoassay34 or sophisticated immunochemicalmethods.
Thus, a series of stages in the development of renal changesin diabetes is recognizable:
(1) Early hypertrophy-hyperfunction. Changes are foundat diagnosis before insulin treatment is started. They maypersist for many years when diabetes control is poor.356
(2) Glomerular lesions without clinical disease. This silentstage develops over many years with structural lesions onbiopsy but without clinical or laboratory signs of renal dis-ease.78 About 30-50% of patients develop clinical nephrop-athy, and the remaining 50-70% do not. Further studies ofthis phase are necessary to identify factors of importancefor this progression into stages 3 and 4.
64 DIABETES, VOL 32, SUPPL 2, JUNE 1983
-
C. E. MOGENSEN, C. K. CHRISTENSEN. AND E VITTINGHUS
GFR
Onset of Clinical Insulindiabetes diagnosis treatment
+ 40%-
N(SD) --40%-
1 1 IStandard Proteinuria: fall in GFRcontrol ( +increased blood pressure)
INon-proteinuric patients
days weeks years 20 25 30 years
Albuminexcretion + 100% -
N(SD) -
FIGURE 1. Development of kidney functionchanges in juvenile diabetes mellitus: GFR andalbumin excretion.
Exercise
III
Proteinuria
Non-proteinuria
IV
days weeks years 20 25 30
(3) Incipient diabetic nephropathy. The primary manifes-tation of this stage is abnormally elevated baseline urinaryalbumin excretion as measured by radioimmunoassay. Basedon recent studies the range between 15 and 300 (j.g/min isused for diabetics in good metabolic control examined inthe laboratory in the sitting or recumbent position. Slowlyincreasing albumin excretion over several years is also afeature in this very decisive phase of renal disease in dia-betes.
(4) Overt diabetic nephropathy. This is the classic stagewith its major characteristic being a persistent proteinuria(>0.5 g/24 h) in the absence of findings of nondiabetic renaldisease.9 Renal function declines when associated high bloodpressure is left untreated; the mean fall rate in GFR is 1 ml/min/mo.10"12
(5) End-stage renal failure due to diabetic nephropathy.Uremia caused by diabetes mellitus, both insulin-dependentand non-insulin-dependent, is found in as many as 25% ofthe population presently entering end-stage renal failure pro-grams in the U.S. and constitutes a major medical problem;perhaps the most crucial problem in clinical nephrology.11314
Classifying patients into these five categories may be use-ful, both in clinical and in research activities. Identificationof the determinants for the transition from one stage to thenext is vital if related questions are to be clarified. Also, the
more general concept of the possible linking of the earlychanges, both the hemodynamic15 and metabolic/structuralentities,67 to the late clinical nephropathy is important for theunderstanding of diabetic renal disease,615 and possibly moreso for understanding the mechanism that governs the finalcommon pathway to decline in renal function and nephrondestruction in a variety of nephropathies.16 Figure 1 providesan outline of the changes described above. A different pat-tern may be relevant for type II diabetes.1314
STAGE 1. EARLY HYPERTROPHY-HYPERFUNCTIONSystematic studies over the last decade reveal that multiplerenal changes are already present at the clinical onset ofdiabetes mellitus. These changes are predominant with re-gard to structure, biochemistry, and function, justifying thedefinition of a new entity, and the early hypertrophy-hyper-function stage.36717 Renal size, in human diabetes and inthe experimental animal, is markedly increased early in thecourse and concomitantly increased function also is foundboth in human and experimental animal diabetes.1719 Stan-dard insulin treatment leads to reduction in both renal sizeand GFR over 3 mo, suggesting that the changes stem frommetabolic effects that are only slowly reversible.3 Partial nor-malization of the functional parameter is found earlier.5 It ispossible that in the early course of diabetes mellitus in-
TABLE 1Experimental setup in the exercise provocation test
Periods
Start Pre-exercise Exercisedrinking waterevery 20 min 1 2 1
-120 0 40
Postexercise
2 1 2
80
3
140 min
Measurements: Heart rate by counting pulse rate.Blood pressure by auscultatory technique.Urinary albumin excretion by RIA.Urinary B-2-microglobulin excretion by RIA.
DIABETES, VOL. 32, SUPPL. 2, JUNE 1983 65
-
STAGES IN DIABETIC RENAL DISEASE
100
60
= 20
(o-O) before insulin(-) after 6-15 daysof insulin treatmentin 6 diabetic patients
S 0 . 3
0.1
UrinaryB-2-microglobulin
1/2.Pre
i 2. M i 2.Exercise Post periods
Exercise loads; 450 and 600 kpm/min.
M - mean of 2.exercise and Lpost period.
FIGURE 2. Urinary albumin and p-2-microglobulin excretion at the on-set of diabetes, before and after insulin treatment.
creased size of the kidney and associated phenomena arelinked to the development of at least some aspects of thelate diabetic glomerulosclerosis.
It has also been established that the important parameterused in the evaluation of renal function in diabetes mellitus,urinary albumin excretion, is elevated in uncontrolled dia-betes mellitus. These changes are even more pronouncedduring a renal provocative test, i.e., the exercise provocationtest.418
The usual procedure in this test is shown in Table 1. It isimportant that a long baseline period, 2 h with water drinkingevery 20 min, is used, because a very modest temporaryincrease in urinary albumin excretion may be seen whennormal subjects start to drink water. Larger loads of water,e.g., 1 l_ water during 5 min, lead to a more pronouncedincrease in urinary albumin excretion.20 After 1.5 h, excretionrate is stable and the experimental urine collection may start.Exercise loads are used that do not normally provoke in-crease in albumin excretion in nondiabetic subjects of similarage and sex to the diabetics examined in this study.
As depicted in Figure 2, pronounced increases in albuminexcretion occur during the exercise provocation test in un-treated diabetics that is an aggravation of already higherbaseline value.18 After 6-15 days of ordinary insulin treat-ment, a perfectly normal test is seen, e.g., normal baselinevalues and no increase in albumin excretion during exercise.Exercise-induced changes in blood pressure were normalin these patients. No significant difference was found eitherbefore or after treatment. However, a significant fall in ex-ercise-induced tachycardia was observed after treatment.18Beta-2-microglobulin excretion did not increase during theexercise test, indicating undisturbed tubular function. Theabnormal excretion can be attributed to increased glomer-ular permeability and not a decreased tubular reabsorptionof proteins. The exact mechanism behind the exercise-in-duced increase in albumin excretion remains to be clarified.An abnormally high intraglomerular pressure may operateto produce increased permeability to protein in the untreated
situation, further aggravated by exercise. This abnormalityis readily normalized by standard insulin treatment.
After some years of diabetes, abnormal albumin excretionemerges during exercise. In this situation, the abnormalitiesprobably involve an abnormal structure of the glomerularbasement membrane. The changes are even more markedin diabetics with increased baseline albuminuria (incipientdiabetic nephropathy). In this stage, the mechanism mustbe different from abnormalities emerging in the untreatedsituation at diagnosis of diabetes.
These data, along with earlier described changes of GFR,RPF, and renal size, suggest a combination of structural andfunctional changes early in diabetes. No data are availableon the intraglomerular pressure in human diabetes, but inthe experimental animal, an increased transglomerular pres-sure gradient has been demonstrated.15
STAGE 2. GLOMERULAR LESIONS WITHOUT CLINICALDISEASEFor many years after the start of insulin treatment, duringstandard control, the characteristic feature is that all stan-dard clinical parameters related to renal function are normal.However, using the classical renal function test outlined byHomer Smith, numerous studies have shown a very con-sistent elevation of glomerular filtration rate. This increase ison the order of 20-30%, whereas the increase in the un-treated situation is on the order of 30-40%.358 The elevatedrenal function is most likely linked to the imperfect metaboliccontrol obtained during our standard insulin regimens. GFRwas shown to be more increased than extracellular volumein type I diabetes, suggesting what has been termed "a realrenal hyperfunction."21 Changes in growth hormone andglucagon may also influence the final level of renal func-tion. 23~25 In studies primarily in type II diabetes, exchange-able body sodium was increased.26
Data on renal plasma flow are conflicting.2225 Using la-beled hippuran for measuring renal plasma flow, a slight
500200
5 0 -E 20E
5 -2 -
0.2
0.05
Urinary
- T y
albumin
r
xxx
r
XXX /
/
Urinary B-2-microglobulin
- D (11)= N (10)
. T
Pre 300 450 600 750 900periods
1200
Exercise loads in kpm/min.
FIGURE 3. Graded exercise in diabetic and normal man.
66 DIABETES, VOL. 32, SUPPL. 2, JUNE 1983
-
MOGENSEN, C. K. CHRISTENSEN. AND E. VITTINGHUS
(jg/min |jg/min
200
150
18 yearsDiabetes duration
100
50
18 yearsDiabetes duration
12 15 yearsDiabetes duration
FIGURE 4. Albumin excretion in the development of incipient diabetic nephropathy: example of courses in three patients.
increase has been observed in some studies but normal oreven depressed values have been found in others.3 Thisdiscrepancy may be explained by different degrees of met-abolic control during the clearance procedure. Renal ex-traction of para-amino hippurate (PAH) proved to be normalin diabetic patients,27 so there is no firm evidence to suggestthat enhanced GFR is simply a consequence of increasedflow to the kidney. Indeed, when calculating RPF per gramkidney weight, the value is depressed.5 Well-preserved renalfunction is found in all patients without proteinuria despitevery long diabetes duration 3 This means that the majority oflong-standing diabetics continues to have elevated renalfunction and a much better prognosis than those with pro-teinuria.12
The well-preserved kidney function found in many patientsis evidenced by the fact that normal albumin excretion per-sists, despite the fact that pronounced structural alterationsmay be found when renal biopsy specimens are examined.It is characteristic that a gradual increase in the thicknessof the glomerular basement membrane is found with increasein duration of diabetes followed by changes in the volumeof the glomerular mesangium.7
The apparent paradox, i.e., structural abnormalities as-sociated with normal function, was the impetus for our de-velopment of a provocation test. It is based on the conceptthat some kind of provocation could disclose changes notreadily demonstrable in the baseline situation when abnor-malities are still suspected. Exercise seems a reasonable
choice since extreme exercise is known to provoke protein-uria in normal man. Our exercise test employed an exer-cise load insufficient to cause albumin excretion in normal
18,28-30
The exact relationship between intensity of exercise andincrease in aibuminuria was recently established.18 This studyconfirmed that diabetic patients, after some years' durationof the disease, exhibit increases in albumin excretion at awork load of 600 kpm/min during a 20-min period. The in-crease in albumin excretion is much more pronounced atmoderately high work loads, as shown in Figure 3. Com-parable controls show significant increase only at a muchhigher work load, namely 1200 kpm/min for 20 min, althoughthere was a clear tendency for an increment in aibuminuriaat 900 kpm/min. The increase in albumin excretion is of glo-
TABLE 2Yearly increase in albumin excretion in incipient and overtdiabetic nephropathy
Incipient diabetic nephropathy(N = 7)
Overt diabetic nephropathy(N = 7)
(range -1.2-76)2328 ^ ^ 3206 (SD)
yr(range -99-9087)
In both cases, progression in nephropathy was blood-pressuredependent.
DIABETES, VOL. 32, SUPPL. 2, JUNE 1983 67
-
STAGES IN DIABETIC RENAL DISEASE
Studies over 5.8 years
ug/minyear
50
R = 0.792p = 3.4%n -7
85 95 105 mm HgDiastolic pressure
FIGURE 5. Yearly increase in albumin excretion plotted against dia-stolic pressure in seven patients with incipient diabetic nephropathy.
merular origin both in normal and diabetic subjects. Thisconclusion is drawn from the observation that beta-2-mi-croglobulin excretion was not affected by exercise, exceptfrom a small increase in diabetic patients at 1200 kpm/min.
In percent of the maximal increase in heart rate, the ele-vation in albumin excretion in the diabetics was significantat 55% (-600 kpm/min) and the increase in albumin excre-tion was more pronounced at higher work loads (Figure 3).The albumin excretion in the controls showed a significantincrease only at 88% (-1200 kpm/min) of their maximal in-crease in heart rate, but there was a tendency to elevationalready at 65%. The diabetics showed a significant differ-ence to the normals in albumin excretion when they wereworking at 55-82% of the maximal heart rate. Then the besttest area seems to be from 55% to 65% of the maximal heartrate, where none of the controls showed elevated albuminexcretion.
Systolic blood pressure tended to increase markedly indiabetic patients although no significant difference could beestablished and there was no correlation between increasesin albuminuria and blood pressure increase, either in normalsor diabetics.1830 However, it is difficult to completely rule outthat an abnormal exercise-induced blood pressure increasecontributes to albuminuria in diabetic patients in this earlyphase of renal involvement. Exercise-induced increases inblood pressure and heart rate in diabetic patients are readilydepressed by acute administration of the cardioselectivebeta-blocking agent metropolol in doses of 5-10 mg i.v.30
The recent studies by Koivisto et al.31 and by Viberti et al.32documented normalization of exercise-induced albuminuriaafter treatment by continuous subcutaneous administrationof insulin using portable pumps. This normalization of ex-ercise-induced albuminuria probably reflects functionalchanges rather than a regression of structural lesions. This
new manner of treatment is promising for the ameliorationof renal complications, as well as other microvascular le-sions. It is indeed possible that vigorous control of metab-olism must be instituted early in the course, before organdamage both in the kidney and the retina is established.
A number of patients with still-normal baseline albuminuriaare expected to develop increased protein excretion andlater to develop overt nephropathy.
We are currently examining the possibility that the exerciseprovocation test may serve as an identifier of patients proneto nephropathy development. Preliminary data show that a
ug/min
150
100
50
O
GFR154
GFR142
GFR126
\
18 yearsDiabetes duration
300
250
200
150
100
50
0
GFR137
I
1
GF13
/
R
GFR135
yearsDiabetes duration
FIGURE 6. Albumin excretion before and during antihypertensivetreatment using cardioselective beta-blocking agents.
68 DIABETES, VOL 32, SUPPL. 2, JUNE 1983
-
C. E. MOGENSEN, C. K. CHRISTENSEN, AND E. VITTINGHUS
600
500
400
300
200
100
- 2 450 600kpm 1
Baseline EXERCISE Post exercise
FIGURE 7. Urinary albumin excretion during exercise in young malediabetics with incipient diabetic nephropathy.
rather long observation period is necessary. A group of pa-tients was reexamined 5 yr after the original exercise testwithout any definitive data on the predictive value of theexercise test. The predominant finding was that very fewpatients developed nephropathy in this period of time.
STAGE 3. INCIPIENT DIABETIC NEPHROPATHYThere can be no doubt that proteinuria is an important prog-nostic indicator in the course of diabetes mellitus. It is notvery harmful in itself, but it signals an increase in blood
pressure and future decline in renal function. This is a well-established fact, confirmed in numerous studies.
What is not clear, however, is the role of the incipient risein albuminuria or microalbuminuria found in diabetic patientsafter a duration of diabetes of about 10-15 yr. We call thisphase incipient diabetic nephropathy to distinguish it fromthe overt diabetic nephropathy. Little data are available onthis phase of renal disorder in diabetes despite the fact thatthis period is of particular interest from a clinical point ofview, since it is the stage where effective intervention standsa better chance. We are dealing with patients predicted todevelop pronounced renal damage, i.e., the interphase be-tween well-preserved even supranormal kidney function, andthe phase where deterioration in renal function is manifestand where effective intervention becomes difficult.
We propose to define incipient diabetic nephropathy asbaseline urinary albumin excretion between 15 and 300 |xg/min; this is above the normal range but below the valuesgenerally found in overt diabetic nephropathy. Importantly,GFR is well preserved, even supranormal in these patients.It may prove useful to use a more narrow range, thus ex-cluding patients with low excretion, who in long-term studieswould appear to show a nonprogressive pattern. Reducingthe upper limit may also prove useful, e.g., omitting patientswith more pronounced alterations in whom the deleteriouscourse with regard to renal damage may be more difficultto modify.
We have recently studied seven male patients mean age28 yr at entry of the study, with a 14 yr mean duration ofdiabetes. These patients have until now been observed in amean period of 6 yr. The above-mentioned definition wasused (15-300 fjug/min) as a well-defined baseline value.
The main purpose of the study is to evaluate progressionof incipient phase of nephropathy, manifested by increasein albuminuria (or microalbuminuria, see below) and to relateoccurrence of abnormal albumin excretion to changes inglomerular filtration rate and renal plasma flow. It would beof interest to examine blood pressure changes in relation toincrease in albuminuria. Intervention with antihypertensivetreatment may prove more effective in this early phase than
FIGURE 8. Increase in albumin excretion rateduring exercise plotted against increase in sys-tolic blood pressure during exercise (600 kpm/min).
r 0.72
2p- 0 395%
Increase in systolic blood_ _ j _ pressure (600 kpm/min)
150
DIABETES, VOL. 32, SUPPL. 2, JUNE 1983 69
-
STAGES IN DIABETIC RENAL DISEASE
ug/min.
600
400
200
GFR
137
155
122/90 135
A
ug/min,
300
200
100
-2 -1 450 kpm 600 kpm 2 3Lpostex
Baseline EXERCISE Postexercise
115/85 126
- 2
Baseline
Lpostex
EXERCISE Postexercise
FIGURE 9. Albumin excretion before and after antihypertensive treat-ment. Data from exercise provocation test.
in overt diabetic nephropathy where decline in renal functioncan be reduced but not arrested.1011 Figure 4 shows ex-amples of the progression in three patients examined severaltimes over the years with respect to baseline albuminuria. Itis evident that a rather variable course is found (Table 2).
Blood pressure was monitored in the observation periodand a correlation between blood pressure level and increasein albuminuria was established as documented in Figure 5.Most likely the increase in albuminuria is caused by the highblood pressure level observed in some patients, although itcannot be excluded that albuminuria may produce increasein systemic blood pressure. Also, both changes may becorrelated with the general severity of the disease, althoughno relevant parameter was identified. During the observationperiod, there were no changes in the metabolic control asevaluated by fasting plasma glucose. Beta-2-microglobulin
excretion did not increase, indicating that tubular function isundisturbed and that the changes observed in albumin ex-cretion are due to progressive glomerular changes.
Renal function was well preserved in these patients. Thusglomerular filtration rate was still clearly elevated both atentry in the study and after an observation period of 6 yr[142 ml/min 10 (SD) -> 139 ml/min 18 (SD)]. In contrast,a significant fall in renal plasma flow was noted in this period.Initial renal plasma flow values compare well with the leveltypically found in diabetic patients without proteinuria (530-550 ml/min).322-26 There was a significant increase in diastolicblood pressure during the observation period [86 mm Hg 9 (SD) -> 92 12]. It is tempting to speculate that thechanges in RPF reflect microcirculatory changes in glomeruliand may be related to the incipient blood pressure rise ob-served.
Based on these observations, we are conducting a trial ofthe effect of antihypertensive treatment on renal functionusing cardioselective beta-blocking agents in incipient di-abetic nephropathy. Preliminary data are shown in Figure 6in patients followed for 6 and 1.5 yr during hypertensivetreatment. A dramatic decrease in albuminuria is observedafter the initiation of antihypertensive treatment. Interventionin this phase would seem logical since renal function is stillwell preserved but appears bound to decline. In the sub-sequent phase, overt diabetic nephropathy, GFR is alreadydeclining and its rate of fall can be ameliorated by antihy-pertensive treatment. However, more effective treatment re-sulting in total elimination of decline in renal function appearsfeasible, and further trials should establish whether antihy-pertensive treatment in this early phase will prove effectivebefore the downhill course of renal function, characteristicfor diabetic nephropathy, is established.Exercise-induced albuminuria. We have recently studied14 patients in the stage of incipient diabetic nephropathy bythe exercise provocation test, using procedures describedearlier33 (Table 1). These patients exhibit well-preserved kid-ney function. Systolic blood pressure is not above the normalrange, although the mean values are higher than those foundin normal subjects. However, diastolic pressure is slightlybut significantly increased in these patients, namely 92.5 mmHg 8.1 versus 79.5 12.4 (SD) in normals (2P < 0.01).Systolic pressures were 130.2 11.8 versus 120 14.1 innormals. There was no correlation between baseline albu-minuria and blood pressure. All subjects were males with amean age of 26.3 yr and a mean duration of diabetes of 16yr.
Baseline albumin excretion values were increased as acriterion for subject selection. At an exercise load of 450kpm/min for 20 min further increase in albumin excretion isobserved (Figure 7). Patients with normal baseline excretionvalues only respond with a rise in albumin to 600 kpm/20min and above. The increase in incipient nephropathy isfurther aggravated at 600 kpm/min and in the first postex-ercise period, and thereafter values return to the preexerciselevel. These studies demonstrate that even light exercisefurther amplifies the already abnormal baseline values. Thevariability of diabetic albuminuria commonly seen in clinicalpractice may be explained by changes in physical activityduring 24-h collection periods.
Blood pressure involvement was unmasked during the ex-
70 DIABETES, VOL. 32, SUPPL. 2, JUNE 1983
-
C. E. MOGENSEN. C. K. CHRISTENSEN. AND E. VITTINGHUS
-Albuminuria (7.2 ug/mm) +Albuminuria (418 ug/min)
FIGURE 10. Percentage change in creatinineclearance after 8 IU insulin i.v. in five patientswith and without slight albuminuria. Difference inpercentage fall between groups: 3.9% versus17.1% (2P = 0.05).
MSEM 100
+ 3 periods
ercise test. Systolic pressure increased to abnormally highlevels in the diabetics. A highly significant correlation be-tween exercise-induced albumin excretion and systolic pres-sure was also documented (Figure 8). No correlation wasfound between exercise-induced albumin excretion and theexercise-mediated increase in heart rate.
The exercise test may prove useful in monitoring the prog-ress of nephropathy in the incipient phase, and also duringtherapeutical trials such as antihypertensive treatment orduring supercontrol of blood glucose. Figure 9 shows theeffect of antihypertensive treatment for 15 mo and 8 yr onthe exercise-induced albuminuria in patients with incipientdiabetic nephropathy. Marked depression of both baselineand exercise-induced albuminuria is found and trials arebeing undertaken to further establish these findings. Theexact mechanism responsible for the abnormal albuminuriaduring exercise in incipient nephropathy remains to be clar-ified. Other mechanisms may operate in incipient nephrop-athy compared with newly diagnosed diabetes. Blood pres-sure may play an important role for the enhancement ofalbuminuria in incipient nephropathy, but microcirculatorychanges in glomeruli may also be involved and, importantly,these patients would exhibit marked morphologic changes,although biopsies were not performed. Changes in renalautoregulation in connection with arteriolar hyalinosis maybe an important contributory factor.34 Evidently structural le-sions in the glomerulus proper are very likely to be involvedas the mechanism. Tubular alterations do not appear to playa role in the exercise-induced albuminuria, since beta-2-microglobulin excretion is undisturbed in these patients dur-ing physical exercise.The concept of microalbuminuria. Recent work has es-tablished an important role for microalbuminuria in monitor-ing the development of renal changes in diabetic patients.Our studies show that patients with baseline values greaterthan 15 |ig/min but less than 300 have a clear tendency toprogression, agreeing with the report of Viberti and co-work-ers on long-term follow-up studies in patients with baselinealbuminuria between 30 and 140 |xg/min.35
More work is needed to screen the diabetic population atrisk, e.g., insulin-dependent patients with diabetes durationof 10 yr or more but no clinically detectible proteinuria. In
the phase of incipient diabetic nephropathy, a large pro-portion of the patients have microalbuminuria (defined asabnormally increased values, but below the clinically de-tectible level).
There may well exist a stage where effective interventionis possible both with antihypertensive treatment, but possiblyalso with supercontrol of blood glucose by continuous sub-cutaneous insulin infusion.
^g/min
7O0Or
yearsDiabetes duration
FIGURE 11. Albumin excretion in the development of incipient andovert diabetic nephropathy.
DIABETES, VOL. 32, SUPPL 2, JUNE 1983 71
-
STAGES IN DIABETIC RENAL DISEASE
10 20 50 40 50 60 70 loo noMonths
so o IOO n o 120
GFRml /min
100-
75-
50-
25-
eatment
10 20 30 50Months
Start ol treatment
I Start of treatment
FIGURE 12. GFR before and during antihypertensive treatment in five diabetic patients with overt diabetic nephropathy.
Possible manifestations of loss of autoregulation in thekidney in early diabetic nephropathy. Recent studies havedocumented that administration of large doses of intrave-nous insulin provokes increased albumin excretion in pa-tients with normal baseline albumin excretion.36 However,patients with enhanced baseline values show a paradoxicdecline in albuminuria.37 Marked reduction in creatinine ex-cretion, probably reflecting a fall in GFR, was found afteradministration of insulin to patients with early nephropathy(Figure 10). It is possible that this is a manifestation of im-paired renovascular autoregulation in this phase of the dis-ease. Such a loss of autoregulation may also be responsiblefor generation of high systemic pressures, e.g., during ex-ercise to the glomerular capillary bed. Blood pressure ele-vation may be of importance as an aggravator of nephrop-athy responsible for the rapid progression seen several yearsafter a slowly progressive increase in microalbuminuria. Thecourse of an individual patient is depicted in Figure 11.
STAGE 4. OVERT DIABETIC NEPHROPATHYPatients with persistent and pronounced proteinuria all evi-dence decrease in glomerular filtration rate. In our studies,the fall rate of GFR has been correlated with diastolic bloodpressure at the end of the control period. The mean decreasewas found to be of the order of 1 ml/min/mo.1011 A similardecline in renal function has been observed by otherinvestigators1238 and also during pregnancy in patients withdiabetic nephropathy.39
Antihypertensive trials, conducted for a number of years,have shown that effective treatment reduces the rate of de-cline of GFR.101140 In Figure 12 is shown the decline rates ofGFR in individual patients before and during antihyperten-sive treatment. Progression of nephropathy, measured byincrease in albuminuria, expressed as albumin clearance aspercent of GFR, was markedly ameliorated by antihyperten-sive treatment (Figure 13). As summarized in Figure 14, pro-gression of nephropathy as rate of decline of GFR is reduced
72 DIABETES, VOL. 32, SUPPL. 2, JUNE 1983
-
C. E. MOGENSEN, C. K. CHRISTENSEN, AND E. VITTINGHUS
per centof GFR
SO 00 ro 80 90 100 HO 120
0 10 X 30 40 -1
Albumin clearanceper centof GFR
per centol GFR
1.0-
0.1-
Start of treatment
Oo o
Start ol treatment
Start ol treatment
10 20 30 40 50Months
Albumin clearanceas % of GRF1.0 T Start of treatment
FIGURE 13. Albumin clearance as percent of GFR before and during antihypertensive treatment. Patients with overt diabetic nephropathy.
by 60% during antihypertensive treatment. Progression inalbuminuria was completely halted during long-term treat-ment, and blood pressure level was significantly reducedfrom 162 14 (SD)/103 9 to 144 11 /95 8 (2P < 0.02).
It is important to note that filtration rate still declines sig-nificantly during antihypertensive treatment,40 and indeed insome patients effective blood pressure control was difficultto achieve, not close to the goal of 140/90 or lower (Figure15). To examine the effect of intervention at an earlier stagewould therefore be the next logical step in a series of sub-sequent investigation.
Benefit from antihypertensive treatment in diabetic ne-phropathy was further supported by the finding of Parvingand co-workers. Their studies agree with our findings.12
The mechanism of proteinuria in the late phase of diabetic
nephropathy was studied using very high-molecular-weightdextran and long renal clearance collection period. Diabeticpatients with heavy proteinuria exhibit an abnormal enhance-ment in very high-molecular-weight dextran clearance (Fig-ure 16). The changes detectible with the dextran clearancetechnique are very small; at highest a few-fold increase inthe very high-molecular-weight dextrans, compared with a1000-fold increase or more in albumin excretion. These dataagree with the recent studies of Myers and co-workers.4142The higher-molecular-weight dextran and longer clearanceperiods used in our study appear to increase the test's sen-sitivity; abnormalities may be detectible in less advanceddiabetic nephropathy. In early diabetic nephropathy, dextranclearance is normal when expressed as percent of GFR.34142It is likely that the late changes found in the advanced di-
DIABETES, VOL. 32, SUPPL. 2, JUNE 1983 73
-
STAGES IN DIABETIC RENAL DISEASE
Fall rate of GFR
2.0-
1.0
1.24'
Beforetreatment
2p = 0.042
Duringtreatment
60
40
20
25.8
Beforetreatment
Duringtreatment
2p = 0.009
FIGURE 14. Fall rate of GFR and increase in albuminuria before andduring antihypertensive treatment in overt diabetic nephropathy.
abetic nephropathy are quite nonspecific and comparableto changes found in advanced nephropathy due to otherrenal disorders.Progression from one stage to a more advanced stage.Early changes in renal function in diabetes may set the stagefor late diabetic nephropathy, as evidenced by hemody-
namic studies.1543 Hemodynamic changes appear to be im-portant modulating factors rather than being directly re-sponsible for the development of late diabetic nephropathy.8
Changes in early diabetes producing late diabetic ne-phropathy may involve the following mechanisms operatingalone or in combination: (1) increased basement membranematerial, found early as an increase in the filtration surfacearea, could be regarded as a forerunner of later increase inbasement membrane thickness, eventually producing clin-ical glomerulosclerosis; (2) hemodynamic changes, pre-dominantly an increase in filtration pressure, may produceglomerular structural disruption. Supporting evidence is ob-tained in the rat model;15 (3) abnormal extravasation of plasmaprotein, probably in connection with increased pressure, mayalso be of pathogenic importance.812
One should stress that all the changes are strongly de-pendent upon the metabolic control, supporting the view thatevery effort should be undertaken to optimize diabetes con-trol.
We are still faced with the fact that overt diabetic nephrop-athy (stage 4) develops in only a large minority of the patientsdespite the fact that early changes probably are found in allpatients, although to a variable extent. Other factors maydetermine the progression and transmission from one phaseto another. In this respect, the phase of incipient diabeticnephropathy is of particular interest.
Identification of the factor or factors responsible for tran-sition from the rather slow progression in albuminuria in theincipient phase to the more dramatic increase in overt ne-phropathy, depicted in Figure 17, is of great importance.Abnormal blood pressure, linked to glomerular microcircu-latory changes, may play a role. Advanced changes in thearteriolar system may modulate the course by systemic bloodpressure rises that would be transmitted to the glomerularcirculation, resulting in structural disruption in glomerulus.
Table 3 is a recapitulation of the development of renallesions in diabetes. It is evident that the phase of incipientdiabetic nephropathy is a very central entity and it wouldseem a fruitful working hypothesis that diabetic nephropathymay be held in this phase with well-preserved kidney function
FIGURE 15. Blood pressure levels and decline in kidney function dur-ing antihypertensive treatment in diabetic patients with overt nephrop-athy. Pressure level of -141/92 mm Hg corresponding to a fall rate of0.2 ml/min/mo.
74 DIABETES, VOL. 32, SUPPL. 2, JUNE 1983
-
MOGENSEN. C. K. CHRISTENSEN. AND E. VITTINGHUS
ml/min
Absolute values
0.5
of GFR 5
0.5
40,000 50,000 60,000 70,000
2p = 3.5%
t40,000 50,000 60,000 70,000
ml/min.
B
Per centof GFR 5
40 50 60 70
Absolute clearancevalues.
1
40 50 60 70Mol.-weight*10'
Clearance values expressedas per cent of GFR.
FIGURE 16. (A) Dextran clearance using Macrodex (R) in four proteinuric diabetics and four normals. Long-term dextran clearance period wasused (3 periods of 4 h each). GFR in the normals was in mean 116 ml/min 1 4 (SD), in the diabetics 95.2 35. Urinary albumin excretion was inthe diabetics in mean 2274 (range 523-5450). The normals had albumin excretion values of 8.0 (range 5.1-12.8). With respect to dextran clear-ance a significant increase in clearance of the 70,000-mol-wt dextrans as percent of GFR was established (2P - 3.5%), whereas there was notsignificant difference in lower-molecular-weight dextrans. The individual value for the 70,000-mol-wt was in the normals 0.36, 0.41, 0.28, and0.44% in contrast to 0.45, 0.47, 0.52, and 0.63% in the diabetics. The diabetic patients with the highest albumin excretion and lowest GFR alsoexhibited the most abnormal dextran clearance value of 63% at mol wt 70,000, and throughout the molecular weight ranges, they exhibited thehighest clearances. Dextran was separated according to molecular size as described earlier.3 (B) High-molecular-weight dextran clearance innormal subjects (hatched area) and six diabetic patients without proteinuria and with normal albumin excretion (dots).
DIABETES, VOL. 32, SUPPL. 2, JUNE 1983 75
-
TABL
E 3
Stag
es in
a
deve
lopm
ent
of re
nal c
hang
es an
d le
sions
in
di
abet
es m
ellitu
s (ty
pe I)
Stag
eCh
rono
logy
Mai
n st
ruct
ural
chan
ges
orle
sions
GFR
RPF
Func
tiona
l cha
nges
Dext
ran
clea
ranc
e(%
of
GF
R)
Albu
min
ex
cret
ion
Base
line
Exer
cise-
indu
ced
Reve
rsib
le by
Ar
rest
able
or
re
-
stric
t ins
ulin
ve
rsib
le by
an
ti-Bl
ood
treat
men
t hy
perte
nsive
pres
sure
(e.
g., CS
II) tre
atm
ent
Rem
arks
1 Ea
rly re
nal h
yper
-
Pres
ent
at di
agno
-
Incr
ease
d kid
ney
size.
In
crea
sed
by
Norm
al or
troph
y-hy
per-
func
tion (be
fore
insu
lin tre
atm
ent)
sis of
di
abet
es(m
ay co
ntin
uefo
r m
any
year
sw
hen co
ntro
lpo
or)
Incr
ease
d gl
omer
ular
size.
Ne
phro
n hy
per-
troph
y an
d hy
perp
la-
sia
2 Re
nal l
esio
ns, w
ith-
Dete
ctab
le af
ter
2 On
re
nal b
iops
y, in
-
out c
linic
al si
gns
yr of
di
abet
es,
prog
ress
ion
over
se
vera
l yr
cre
ase
d ba
sem
ent
mem
bran
e th
ickn
ess,
mes
angia
l exp
ansio
n
st
ages
3,
4
20-4
0%
20-3
0%
sligh
tly in
-
cre
ase
d
Incr
ease
d by
No
rmal
or
slig
htly
in-
cre
ase
d
Norm
al
Norm
al in
m
ost
patie
nts
Incr
ease
d (be
-
fore
in
sulin
treat
men
t)
Abno
rmal
af
ter
Norm
ala
few
ye
ars
Yes
Unkn
own
(stag
e I
chan
ges
re-
vers
ible
)
No hy
perte
nsio
npr
esen
t. M
icro-
circu
lato
rygl
omer
ular
alte
ratio
ns m
od-
ifiabl
e?
May
lin
k to
cl
inic
al ne
-
phro
path
y or
m
odu
-
late
ad
vers
ely
the
cour
se
Prog
ress
to
cl
inic
al ne
-
phro
path
y in
30
-
40%
of
pa
tient
s
Incip
ient
di
abet
icnep
hrop
athy
Afte
r 10
-15
yr (in
30-4
0% of
pa
-
tient
s)
Not v
ery
wel
l stu
died
Clin
ical o
vert
dia-
Af
ter
15-2
0 yr
(in
Di
ffuse
an
d nod
ular
betic
n
eph
ropa
-
thy
30-4
0% of
pa
-
tient
s)gl
omer
ulos
clero
sis:
Caps
ular
drop
s. Fi
-
bron
oid
caps
. Ar
terio
-
lar hy
alin
osis
Still
in-
cre
ase
d by
20-3
0%
With
out
treat
-
men
t: de
-
cline
~
1
ml/m
inm
o
Incip
ient
, slo
w
decli
ne
With
out
treat
-
men
t: de
-
clin
e
5
ml/m
inm
o
Norm
al
Abno
rmal
to
very
hi
ghm
ol.-w
eigh
t-de
xtra
ns(no
nspe
cific
for
diab
etes
)
15-3
00 jjig
/min.
Incr
ease
by
nc
^g/
min
yr
Prog
ress
ive cli
ni-
cal p
rote
inur
ia
Abno
rmal
, a
g-gr
avat
ion of
base
line
ab-
nor
mal
ities
Not
stud
ied
Incip
ient
in
-
cre
ase
, a
g-gr
avat
eddu
ring
ex-
ercis
e
Abno
rmal
(~ 16
0/10
5)
Unkn
own,
to
be in
vest
i-ga
ted
Neith
er re
-
vers
ible
no
r
arre
stab
le
Prob
ably,
st
udie
sar
e in
pr
ogre
ss
Prog
ress
ion re
-
duce
d, ea
rlytre
atm
ent
advis
-
able
(ai
ming
at
140/
85-9
0 m
m
Hg)
Grea
t effo
rt sh
ould
t
take
n to
ar
rest
ne
phro
path
y at
th
isst
age
Clos
e bl
ood
pres
sui
cont
rol i
n al
l dia
-
betic
s (al
ong
with
oph
thal
mos
copy
)
End-
stag
e re
nal
failu
reFi
nal o
utco
me,
afte
r 25
-30
yrG
lomer
ular
closu
relow
Ofte
n so
me
de-
Not
stud
ied
dine
du
e to
ne
-
phro
n cl
osur
e
High
- 25
% of
e
nd-
stag
ere
nal f
ailu
re pa
tient
sin
US
A ar
e di
abet
ics
-
MOGENSEN, C. K. CHRISTENSEN, AND E. VITTINGHUS
pg/min
Ovnrt nephropathy 2500 pg/minyear
(wide range)
Incipient nephropathy
~ 25jjg/mm (wide range)
Antihypertensivetreatment?
12 15 18 21 years.DD
FIGURE 17. Outline of albumin excretion in the development of incipi-ent and overt diabetic nephropathy.
by antihypertensive treatment or other measures includingoptimizing diabetes control.
Great advances in the treatment of end-stage renal failurein diabetic patients have been achieved over the last dec-ade, and diabetic patients now account for approximately25% of the population in the U. S. now entering these pro-grams in the stage of uremia. Future emphasis should beon preventative measures. One logical course is careful met-abolic control throughout the lifespan of diabetic patients.The portable subcutaneous insulin infusion devices presenta technologic and conceptual breakthrough, and with moreeffective application these devices may greatly improve theoverall metabolic control.44 46 An additional promising ave-nue that may be comparable in importance is effective bloodpressure control. Both metabolism and hemodynamics, evi-denced by blood pressure rise, should be controlled as ef-fectively as possible.
REFERENCES1 McCrary, R. F., Pitts, T. 0., and Puschett, J. B.: Diabetic nephropathy.
Natural course, survivorship, and therapy. Am. J. Nephrol. 1981; 1:206-18.2 Deckert, T., and Poulsen, J E.: Diabetic nephropathy. Fault of destiny?
Diabetologia 1981; 21:178-83.3 Mogensen, C. E.: Pathophysiology of diabetic complications. Abnor-
mal physiological processes in kidney. In Handbook of Diabetes, Vol. 4: Bio-chemical Pathology. Brownlee, M., Ed. New York, London, Garland STPMPress, 1981:23-85.
4 Viberti, G. C, Mackintosh, D., Bilous, R. W., Pickup, J. C, and Keen,
H.: Proteinuria in diabetes mellitus. Role of spontaneous and experimentalvariation of glycemia. Kidney Int. 1982; 21:714-20.
5 Christiansen, J. S., Gammelgaard, J., Tronier, B., Svendsen, P. Aa.,
and Parving, H.-H: Kidney function and size in diabetics before and duringintitial insulin treatment. Kidney Int. 1982; 21:683-88.
6 Cortes, P., Dumler, F., Venkatachalam, K. K., and Levin, N. W.: The
effect of diabetes on renal metabolism. In press. Mineral Electrolyte Metab.1983.
7 0sterby, R.: Diabetic glomerulopathy: structural characteristics of the
early and advanced stages of diabetes mellitus. Diabetes (this issue).8 Mogensen, C. E.: Introduction. Diabetes mellitus and the kidney. Kid-
ney Int. 1982; 21:673-75.9Carstens, S. A., Hebert, L. A., Garancis, J. C, Piering, W. F., and
Lemann, J.: Rapidly progressive glomerulonephritis superimposed on dia-betic glomerulosclerosis. Recognition and treatment. JAMA 1982; 247:1453-57.
10 Mogensen, C. E.: Antihypertensive treatment inhibiting the progres-
sion of diabetic nephropathy. Acta Endocrinol. (Copenh.) 1980; 94 (Suppl.238):103-11.
11 Mogensen, C. E.: Preazotemic diabetic nephropathy. Inhibited by
antihypertensive treatment. In Diabetic Renal/Retinal Syndrome. Friedman, E.A., and L'Esperance, F. A., Eds. New York, Grune and Stratton, 1980:183-98.
12 Parving, H.-H., Andersen, A. R., Smidt, U. M., and Svendsen, P. Aa.:
Early and aggressive antihypertensive treatment reduces the rate of declinein kidney function in diabetic nephropathy. In press. Lancet 1983.
13 Friedman, E. A.: Nephrology Forum. Diabetic nephropathy. Strate-
gies in prevention and management. Kidney Int. 1982; 21:780-91.14
Friedman, E. A., and L'Esperance, F. A.: Second Diabetic Renal/Retinal Syndrome. New York, Grune and Stratton, 1982.
15 Hostetter, T. H., Rennke, H. G., and Brenner, B. M.: The case for
intrarenal hypertension in the initiation and progression of diabetic and otherglomerulopathies. Am. J. Med. 1982; 72:375-80.
16 Hostetter, T. H., Rennke, H. G., and Brenner, B. M.: Compensatory
renal hemodynamic injury. A final common pathway of residual nephron de-struction. Am. J. Kidney Dis. 1982; 1:310-14.
17 Mogensen, C. E., Steffes, M. W., Deckert, T., and Christiansen, J. S.:
Functional and morphological renal manifestations in diabetes mellitus. Dia-betologia 1981; 21:89-93.
18 Vittinghus, E., and Mogensen, C. E.: Graded exercise and protein
excretion in diabetic man and the effect of insulin treatment. Kidney Int. 1982;21:725-29.
19 Brown, D. M., Andres, G. A., Hostetter, T. H, Mauer, S. M., Price,
R., and Venkatachalam, M. A.: Kidney complications. Diabetes 1982; 31 (Suppl1)71-81.
20 Viberti, G. C , Mogensen, C. E., Keen, H., Jacobsen, F. K., Jarrett,
R. J., and Christensen, C. K.: Urinary excretion of albumin in normal man.The effect of water loading. Scand. J. Clin. Lab. Invest. 1982; 42:147-51.
21 Brochner-Mortensen, J., and Ditzel, J.: Glomerular filtration rate and
extracellular fluid volume in insulin-dependent patients with diabetes mellitus.Kidney Int. 1982; 21:696-98.
22 Mogensen, C. E.: Renal plasma flow in juvenile diabetes. Acta En-
docrinol. (Copenh.) 1981; 94 (Suppl. 242):33-35.23
Parving, H.-H., Christiansen, J. S., Noer, I., Tronier, B., and Mogen-sen, C. E.: The effect of glucagon infusion on kidney function in short-terminsulin-dependent juvenile diabetics. Diabetologia 1980; 19:350-54.
24 Christiansen, J. S., Gammelgaard, J., Frandsen, M., Orskov, H., and
Parving, H.-H.: Kidney function and size in type I (insulin-dependent) diabeticpatients before and during growth hormone adminstration for one week. Dia-betologia 1982; 22:333-37.
25 Christiansen, J. S., Gammelgaard, J., Orskov, H., Andersen, A. R.,
Telmer, S., and Parving, H.-H.: Kidney function and size in normal subjectsbefore and during growth hormone administration for one week. Eur. J. Clin.Invest. 1981; 11:487-90.
26Weidman, P.: Recent pathogenic aspects in essential hypertensionand hypertension associated with diabetes mellitus. Klin. Wochenschr. 1980;58:1071-89.
27 Nyberg, G., Granerus, G., and Aurell, M.: Renal extraction ratios for
51Cr-EDTA, PAH, and glucose in early insulin-dependent diabetic patients.Kidney Int. 1982; 21:706-708.
28 Mogensen, C. E., Soiling, K., and Vittinghus, E.: Studies on mech-
anisms of proteinuria using amino acid-induced inhibition of tubular reab-sorption in normal and diabetic man. Contr. Nephrol. 1981; 26:50-65.
29 Mogensen, C. E., Christensen, C. K., Christensen, N. J., Gundersen,
H. J. G., Jacobsen, F. K., Pedersen, E. B., and Vittinghus, E.: Renal proteinhandling in normal, hypertensive, and diabetic man. Contr. Nephrol. 1981;24:139-52.
30 Mogensen, C. E., Christensen, C. K., and Vitt inghus, E.: Changes in
renal funct ion and b lood pressure control in diabetes mellitus. With specialreference to exerc ise- induced changes in albumin excretion and blood pres-sure. In Second Diabetic Renal/Retinal Syndrome. Friedman, E. A., and L'Es-perance, F. A., Eds. New York, Grune and Stratton, 1982:41-64.
31 Koivisto, V. A., Huttunen, N. P., and Vierikko, P.: Continuous subcu-
taneous insulin infusion corrects exerc ise- induced albuminuria in juvenile d i -abetes. Br. Med. J . 1981; 282 :778-79 .
32 Vibert i , G., Pickup, J . C , Bilous, R. W., Keen, H., and Macintosh, D.:
Correct ion of exerc ise- induced microalbuminur ia in insul in-dependent dia-
DIABETES, VOL. 32, SUPPL. 2, JUNE 1983 77
-
STAGES IN DIABETIC RENAL DISEASE
betics after three weeks of subcutaneous insulin infusion. Diabetes 1981;30:818-23.
33 Vittinghus, E., and Mogensen, C. E.: Albumin excretion and renal
hemodynamic response to physical exercise in normal and diabetic man.Scand. J. Clin. Lab. Invest. 1981; 41:627-32.
34 McMillan, D. E.: The functional and degenerative pathology of the
diabetic kidney. In Microcirculation. New York, Academic Press, 1981:229-45.
35 Viberti, G. C, Mackintosh, D., and Keen, H.: Determinants of the
penetration of proteins through the glomerular barrier in insulin-dependentdiabetes mellitus. Diabetes (this issue).
36 Mogensen, C. E., Christensen, N. J., and Gundersen, H. J. G.: The
acute effect of insulin in heart rate, plasma noradrenaline, and urinary albuminexcretion. The role of changes in blood glucose. Diabetologia 1980; 18:453-57.
37 Christensen, N. J., Gundersen, H. J. G., Mogensen, C. E., and Vit-
tinghus, E.: Intravenous insulin decreases urinary albumin excretion in long-term diabetics with nephropathy. Diabetologia 1980; 18:285-88.
38 Viberti, G. C, Bilous, R. W, Macintosh, D., Bending, J. J , and Keen,
H.: Long-term correction of hyperglycaemia and progression of renal failurein insulin-dependent diabetes. Br. Med. J. 1983; 286:598-602.
39 Kitzmiller, J. L, Brown, E. R., Phillippe, M., Stark, A. R., Acker, D.,
Kaldany, A., Singh, S., and Hare, J. W.: Diabetic nephropathy and perinataloutcome. Am. J. Obstet. Gynecol. 1981; 141 741-51.
40 Mogensen , C. E.: Long- term ant ihypertensive treatment inhibit ing the
progression of diabetic nephropathy Br Med. J. 1982; 285:685-88.41
Myers, B. D., Winetz, J. A., Chui, R, and Michaels, A. S.: Mechanismsof proteinuria in diabetic nephropathy. A study of glomerular barrier functionKidney Int. 1982; 21:633-41
42 Winetz , J . A., Go lbe tz , H. V , Spencer , R. J . , Lee, J . A., and Myers ,
B. D.: Glomerular function in advanced human diabetic nephropathy. KidneyInt. 1982; 21:750-56.
43 Hostetter, T. H., Troy, J. L. and Brenner, B. M.: Glomerular hemo-
dynamics in experimental diabetes mellitus Kidney Int. 1981; 19:410-15.44
Keen, H., Pickup, J. C, Viberti, G. C, Bilous, R., and Williams, G.:Aspects of continuous subcutaneous insulin infusion (CSII) in diabetes Di-abetes Care 1981; 4:54-57
45 Lauritsen, T., Rrost-Larsen, K , Svendsen, P. Aa., Larsen, H.-W., Deck-
ert, T., Christiansen, J. S., Parving, H.-H., Binder, C, Nerup, J., Deckert, M.,Larsen, A., Lorup, B., Bojsen, J., and Beck Jensen, L.: Effect of six monthsof strict metabolic control on eye and kidney function in insulin-dependentdiabetics with background retinopathy Lancet 1982; 1:121-24.
46 Keen, H., and Viberti, G. C Genesis and evolution of diabetic ne-
phropathy. J. Clin. Pathol. 1981; 34:1261-66.
78 DIABETES, VOL. 32, SUPPL. 2, JUNE 1983
