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Diabetic nephropathy-a review Vidya N Acharya, Kala P ChawlaDepartment of Medicine, Seth G. S.Medical -College and K.E.M. Hospital, Parel, Bombay-400 012, India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 364042
Diabetic Nephropathy is a term used ti designate a syndrome, clinically manifested by varying combinations of protein uria, oedema, hypertension, azotaemi; and urinary tract infection. [78] It is a nephropathy of mixed aetiology to in elude degenerative and infectious processes which involve the renal parenchyma and contribute significantly to th( total disease. The description of intercapillary glomerulosclerosis by Kimmelstiel and Wilson [38] in 1936 represented a historical landmark in the recognition and an understanding of the extent and character of chronic renal disease associated with diabetes. By this time it was 12 years since Banting and Best [8] had discovered Insulin enabling, diabetic patients to live for a longer time As years rolled by it was recognised that particularly in younger population, small vessel disease was the most common leading cause of death as opposed to large vessel disease in the middle aged and older population. [14],[40]
Intensive studies with light and electron microscopy [69] has revealed that diabetic nephropathy is a small vessel disease [5],[6],[7],[13],[16],[20],[41],[49],[50],[59],[60],[68],[69],[79] (micro-angiopathy) with complex clinic-pathological picture of diffuse and nodula glomerulosclerosis (DGS), often associated with chronic pyelonephritis, arterio and arteriolo-sclerosis. [6],[51],[78] Before the description of intercapillary glomerulosclerosis, a process of glycogen nephrosis in the proximal tubule was first described by Armanni [4] and later by Ebstein [26] in 1882. Ritchie and Waugh [61] (1957) described this "glycogen nephrosis" as "Armanni and Ebstein diabetic nephropathy Kimmelstiel and Wilson [38] described the typical nodular lesion of glomerulosclerosis in autopsy studies in diabetic patients dying of advanced renal disease and called the clinical picture a. K.W. Syndrome. With the technique of renal biopsy [33],[36],[80] being made applicable to the study of diabetes during life particularly after Insulin era, more extensive study of early renal lesions it diabetics was made possible. Watkin, et al [76] have described results of a follow up renal biopsy studies in 1972. Thirtyone diabetic subjects on whom renal biopsies had been performed approximately 11 years previously were reviewed in order to determine the natural history of diabetic renal disease over a long period. At the time of biopsy it was shown that neither renal function nor proteinuria was closely related to histological changes. Although all the subjects with heavy proteinuria had advanced renal change, some patients with severe biopsy lesions had no proteinuria. When proteinuria was less in amount, the prognosis was variable, regardless of the histological change, and renal function sometimes remained unaltered for many years. All patients with heavy proteinuria and renal changes died during follow up. In 1559 autopsy cases studied by Bell, [9] it was noted that below the age of 20 years, no glomerulosclerosis was seen. He further noted that when the duration of diabetes was less than 10 years, the incidence of DGS was 3%, when the duration was between 10-20 years, 50% showed DGS and when the duration was more than 20 years, almost 100% manifested DGS. Combined biopsy and autopsy data has revealed that in DGS, three varieties of lesions [6],[21],[29],[58],[69],[76] viz. diffuse, nodular and exudative, are noted in the glomeruli, besides changes in the blood vessels and the interstitium. Mathur [52] et al (1964) in a study of 32 diabetic subjects with renal biopsy showed that 31 (96.9%) had definite renal lesions. In their study it was noted that 71.9% of them had diffuse lesions, 12.4% had combined diffuse and exudative lesions and 6.2% had diffuse and nodular lesions. They also noted localised capillary dilatation of the glomerular tuft, forming aneurysms in 3 cases. This aneurysm formation [2],[3],[27],[32] is supposed to result secondary to obstruction of the blood flow resulting from the nodule. Gupta and Chakravarty [33] in a study of 60 renal biopsies in 1964, noted changes of diabetic nephropathy in 30 (50%) of the cases. Very recently in 1975, Takazukura et al [71] from Japan have published their observations on the glomerular changes in diabetes by serial renal biopsy studies. They have concluded that diffuse, nodular and exudative lesions noted in the past are progressions of the same basic lesion seen in the glomeruli of diabetic kidneys. Gellman et a1 [29] classified the lesions into 4 grades. In grade I the lesion is local within each glomerulus and focal within each kidney. In grade II the mesangial thickening is diffuse within the glomerulus and generalised throughout the kidney. In grade III the capillary lumina are narrowed and only locally obliterated. An early nodular lesion appears in the peripheral portion of the glomerular loop. In grade IV the luminar narrowing appears generally. The whole glomerulus becomes ischaemic and appears hyalinised. The glomerulus contains a large nodular lesion. Study of biochemical [65],[66],[67] aspect has revealed that in diabetes, abnormal quantities of glycoproteins are formed from glucose in the absence of adequate Insulin to metabolise it. Mesangial cells are now recognised to play a major role in their production with involvement of the basement membrane of the glomeruli. [19] Due to the increased RNA production, both the renal size and renal function increase. [35],[44] The glycoprotein abnormality in the glomerular basement membrane, as well as the increase in the renal growth have a common origin in an increase in the size of renal uridine triphosphate pool and/or its rate of formation. Considering the pathogenesis of diabetic nephropathy it is noted that early in its course, even when there is no evidence of clinical nephropathy, there is an increased insulin clearance and an increase in the GFR due to functional microangiopathy. [6],[21],[23],[24],[46],[53],[54],[56] This results in an altered function of mesangial and endothelial cells. This, in turn, leads to the local accummulation of hyaline-PAS positive material which is either due to over production or decreased catabolism of glycoprotein with increase in the carbohydrate content. Presently diffuse and exudative lesions that are noted in the glomeruli are considered to be one and the same process resulting from abnormal glycoprotein metabolism. [6],[21],[42] In recent years, immunological mechanisms, [6],[12],[18],[28],[55] have been proposed as the responsible factors in the pathogenesis of diabetic micro-angiopathy. In DGS the glomerular basement membrane and the nodule have shown binding of fluorescent insulin, fluorescent antihuman globulin and fluorescent insulin antibodies. On the basis of these observations, the maturity onset diabetes is considered as an autoimmune disease with insulin as the responsible antigen. Tubulo-interstitial disease noted in DGS may also have an autoimmune basis. Lot of further work is needed to confirm this hypothesis, as tubulo-interstitial auto-immunity is itself a concept of recent origin. Epidemiological Data: Better control of diabetes with Insulin, diet and antidiabetic agents has markedly increased the life expectancy of diabetic patients. [6] The average duration of life in patients with the onset of diabetes below the age of 10 years, between 10-19 yrs. and between 20 to 39 yrs. has been reported to be 29.8 years, 26.7 years, and 27.2 yrs. respectively as compared to 1.3 years, 2.7 years and 4.3 years in the pre-insulin era. This has brought the consequence of diabetic micro-angiopathy in various organs to the forefront. Review of Western literature reveals that diabetic nephropathy is the most frequent cause of morbidity and mortality in patients with diabetes which has its onset early in life (below 40 years). [6],[11],[29],[76] There is truly a paucity of observation on renal involvement in diabetes in our own country. There is no data available on the incidence of renal involvement in diabetes, inspite of the fact that quite a few diabetic clinics are functioning in many major cities. Vaishnava et al [72] in their study of diabetics in South India in an inpatient series found an incidence of renal lesions to be The duration of diabetes was less than 10 years in this group. Their observation was not representative of true incidence due to a very selective indoor population studied. Our own work from the Diabetic Clinic of the K.E.M. Hospital, Bombay comprising of a prospective data from a population of 372 outpatient diabetics indicated an incidence of renal involvement of 8.9% [1] Though the series was small yet it might represent what one would see in a mixed urban population. Bell [10] in a study of 399 diabetics for vascular complications noted the incidence of nephropathy to be 10%. In diabetes with vascular complications and with a disease of more than 15 years' duration, it was found to be 34%. Commenting on the clinico-pathological correlation, it is noted that diffuse, exudative and nodular glomerular lesions, are all seen in DGS. Diffuse lesions however, were more frequent than the nodular ones, though the latter were more pathognomonic. In the light of newer understanding of these being continuous processes, the rationale of this is easily discernible. Though proteinuria may be absent in the milder forms, it is a constant manifestation in severe type of nephropathy. [6],[21] Gellmen [29] has pointed out the fact that progressive worsening of clinical syndrome was better correlated with a diffuse lesion than that of the nodular form. Observations of hypertension associated with diabetic nephropathy has been made by several authors. It is noted that arteriosclerosis seems to have more significant relationship to hypertension than does either form of glomerulosclerosis. Bell [11] has commented that hyaline arteriosclerosis is caused by diabetes and that hypertension is an effect of the arteriolar disease. A further marked correlation has been found between nodular lesion and the renal arteriolar hyalinisation. [69] Asymptomatic bacteriuria, urinary tract infection and acute pyelonephritis are considered as a continuous process (continuum). Sathe et al, [62] in a study of 50 diabetic subjects from the diabetic clinic of the J.J. Group of Hospitals in 1960 noted an evidence of urinary tract infection in 32% of the subjects. This was before the introduction of the concept of "quantitative bacteriuria" and hence there could be .a large element of overdiagnosis in their work. Vaishnava [73] and his group have made some observations on this in 1974 but there appears to be a lot of confusion in the understanding of various. nomenclatures in their work. For the purpose of any definite observation, "significant baeteriuria" [37] has to be more than 1,00,000 organisms/ml. in 3 consecutive MSU samples or a growth of organism from a single urine sample obtained by suprapubic bladder puncture. This alone would have 97 to 100% accuracy. Elsewhere in the congress we have reported an incidence of bacteriuria of 7.3% in an outpatient diabetic population of 302 subjects studied in a randomised fashion . [48] In this study it was noted that bacterial flora in the diabetics revealed a significant preponderance of gram positive organisms as compared to the pre-ponderance of E. coli in control subjects. In Joslin Clinic [57] an incidence of 34/0 was noted in an inpatient population amongst 68 pateints consecutively admitted to The New England Deaconnes Flospital. This incidence was even higher (68%) in patients who had been confined to bed before admission. After extensive studies, Vejlsgaard [74] has concluded that diabetic vascular disease was a contributory factor in the development of urinary tract infection in diabetes. Studies at Joslin Clinic have conclusively proved that bacteriuria and microangiopathy represented a particular hazard to pregnant diabetic women. [6]
In a study of 1559 diabetic patients at autopsy, Bell [10] accounted for 5.3% of deaths as due to renal disease. Lundbaek [47] reported renal disease as a cause in 35% of patients with diabetes mellitus, diagnosed before the age of 40 years and 12% diagnosed after 40 years of age. Warren et al [75] list 12% of 1036 deaths in diabetic patients at New England Deaconnes Hospital as due to renal failure. Over a 8 years' study, Joslin Clinic [6] reported 6800 deaths in diabetic patients. Renal involvement due to diabetes accounted for 6% of deaths in total population and almost 2/3rd diabetic deaths were due to diabetic nephropathy. Once diabetic renal lesion of grade III or so has set in, there is no effective treatment to slow down or change the course of diabetic renal failure. Until means are at hand to prevent diabetic renal disease, it is pertinent on both the medical profession and the public to increase efforts to correct renal failure when it develops. Rehabilitation of patients of end stage diabetic nephropathy with renal failure would involve regular dialysis treatment followed by renal transplantation. The diabetic patients have severe generalised vascular, retinal, metabolic and neurological disease, which precludes reason-able patient rehabilitation and survival. [15],[25],[30],[43],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77] Experience of workers at the Minneopolis Medical Research Foundation [63] has indicated that if any satisfactory results are to be obtained in diabetic patients, the dialysis has to be initiated when their average residual renal function and urine output are higher than they are in non-diabetic patients. Diabetic patients do not tolerate severe renal insufficiency in the same manner as non diabetic patients, probably because of multisystem disease. [63] Effective rehabilitation is difficult to achieve in dialysed diabetic patients. Very few patients have been able to continue with their previous employment on dialysis. Coming to the problem of renal transplantation, the Minnesota group [39] has had patients with juvenile onset insulin dependent diabetes, who have received transplants in 63 instances. Their figures indicate that these patients do worse than non-diabetic transplant patients. However, these patients do even worse on dialysis as compared to cadaver donor transplantation. Post-operative urological complications are much more in this group as compared to non-diabetic patients. Late deaths caused by cardiovascular complications and infections have dramatically worsened the prognosis of survival for diabetics with cadaver donor transplantation. Certain groups of workers [31] have attempted heroic surgery of combined pancreatic and renal transplant with a view to offer simultaneous cure to both diabetes and renal failure. The results of these have not been encouraging so far. Thus for pure survival, live related donor kidney transplantation is the treatment of choice, whereas dialysis is the least successful choice of treatment. [39] Certain groups of workers from U.S.A. [31] and Japan [17] have collected their cummulative experience with 15 patients treated with long term peritoneal dialysis. From their experience it is felt that he patients above the age of 40 years, where haemodialysis and renal transplantation are associated with poor prognosis and in those with cardiovascular disease, peritoneal dialysis may offer successful prolongation of life. This is particularly likely to succeed with stress on avoidance of chances of infection, with the use of Tenckhoff Silastic Catheter, a closed dialysate delivery system and rigid adherance to sterile technique. Thus a well motivated patient may achieve satisfactory rehabilitation while peritoneal dialysis is performed during sleep three to five nights per week. Study of diabetic patients with successful transplants have shown marked improvement in their physical well being, activity level, level of happiness, self image, degree of anxiety, level of sexual performance and in their marital and other relationship. [64] Successful pregnancy has been reported recently in a juvenile diabetic female after renal transplantation. [70] This is certainly a small but cheer ful front in a gloomy outlook of patients with end stage diabetic nephropathy. We, in our country have however, to step away from the romance of rehabilitation by dialysis and renal transplantation. which arouses our curiosity and accelerates our sense of suspense to more basic problem of preventive management. It is worth spending maximum possible resources and finance on early detection of renal lesion, definitive and prolonged management of urinary tract infection, and education of each diabetic patient and family regarding frequent and long term follow up to prevent these highly disabling consequences of long term diabetes. This alone would be a retional solution to the staggering cost of rehabilitation of patients of end stage renal disease.
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