| Abstract|| |
Although not all renal disease that diabetic patients develop is due to diabetic glomerulosclerosis, the great majority of patients progressing to advanced renal failure suffer from diffuse or nodular (Kimmelstiel Wilson's) diabetic glomerulosclerosis. This condition has become the single most frequent cause of end-stage renal failure in the Western world. Recent studies indicate that an interplay between genetic predisposition and other factors such as hyperglycemia, blood pressure, age, gender, smoking and ethnicity, predispose to nephropathy both in type 1 and type 2 diabetes mellitus. It has also become clear that trace albuminuria ("microalbuminuria") provides a unique opportunity to recognize incipient renal involvement early on, particularly in type 1 and less specifically in type 2 diabetes. Increasing evidence indicates that early intervention delays progression of nephropathy. Factors which promote progression of nephropathy include hypertension, proteinuria, smoking, poor glycemic control and, less certainly, high dietary protein intake and hyperlipidemia. The most important strategies to combat the medical catastrophe of increasing numbers of diabetic patients with end-stage renal failure include (i) prevention of diabetes (mainly type 2), (ii) glycemic control to prevent onset of renal involvement and (iii) meticulous antihypertensive treatment to avoid progression of nephropathy. Survival of diabetic patients on dialysis and after transplantation is inferior to that of non-diabetic patients, mainly because of high rate of cardiovascular death. There is consensus that in the absence of major vascular disease the best treatment is renal transplantation in the type 2 diabetic patient and combined kidney and pancreas transplantation in the type 1 diabetic patient.
Keywords: Diabetic glomerulopathy, Proteinuria, Microalbuminuria, Hypertension, Glomerulosclerosis.
|How to cite this article:|
Schmidt S, Ismail A, Ritz E. Diabetic Glomerulopathy: Pathogenesis and Management. Saudi J Kidney Dis Transpl 2000;11:405-13
| Introduction|| |
Knowledge of the occurrence of diabetes mellitus has a long tradition in Arabian medical writing. Abu Ali Husayn Ibn Abdullah Sina (980-1037 AD), Avicenna in Western literature, mentioned in his Al Quanun Fit Tibb (Principles of Medicine) a syndrome of polydipsia, polyuria and malasm which he called aldulab, i.e. water wheel. Obviously, he distinguished already between harmless polyuria and diabetes.  Even at that time, diabetes mellitus was apparently quite prevalent in Eastern Mediterranean countries. A Jewish physician, writing under the Arabian name of Abu Amran Musa Ibn Maimon wrote that when he had lived in Spain he never saw a disease which was common in Cairo, i.e. polyuria, polydipsia and wasting, obviously diabetes mellitus.
In Western countries, the prevalence of diabetes mellitus is rising, both the autoimmune insulinopenic type 1 diabetes  and particularly, type 2 diabetes, presumably as a result of the life style of physical inactivity and calorie excess.  Type 2 diabetes is an important public health problem in Arabian countries as well. , Although several authors reported on prevalence rates of no more than approximately 5% (comparable to Western Europe), a recent study from the Western province of Saudi Arabia  identified diabetes mellitus in no less than 30% of the adult subjects. 
As recently outlined in detail,  end-stage renal disease (ESRD) in diabetes has become a medical catastrophe of world-wide dimensions. [Table - 1] documents that the incidence of ESRD in patients with diabetes has increased dramatically in the past decades, the increase starting first in the USA and Eastern Asia, but lately also in European countries. Renal disease in patients with diabetes, as a co-morbid condition, has become the most frequent cause of ESRD in most Western countries, as also in Japan.  As shown in [Table - 2], renal disease other than Kimmelstiel Wilson's glomerulosclerosis is frequently found in diabetic patients with ESRD. This is particularly true for ischemic nephropathy, which has been documented in 20% of patients with type 2 diabetes by clinical  and histological studies.  It is important that, in contrast to previous opinion, the risk to develop proteinuria or renal failure is similar for patients with type 1 and type 2 diabetes. 
There is a great need to prevent ESRD in diabetic patients because survival on renal replacement therapy is markedly less in diabetic compared to non-diabetic patients; survival being particularly poor in elderly type 2 diabetics [Table - 3]. Actuarial 5-year survival is extremely low in those countries where one finds high cardiovascular mortality in the general population. In such countries, survival of the diabetic patient on dialysis is comparable to that of a patient with metastasizing gastrointestinal carcinoma. 
Renal lesions and clinical presentation
The kidney of a diabetic patient is characterized by thickening of the basement membrane, but basement membrane thickness does not correlate to the risk to develop renal failure. Mauer et al.  showed that mesangial expansion is the morphological lesion, which is most closely related to the evolution of the glomerular filtration rate. The very first morphological lesion is the reduction of the number of podocytes.  With advancing nephropathy, either classical nodular lesions, first described by Kimmelstiel Wilson,  or more diffuse lesions are seen.
Definite renal lesions are seen in all type 1 diabetic patients who have elevated albumin excretion rates, i.e. in the microalbuminuric range or higher. In contrast, the renal morphology is less uniform in microalbuminuric type 2 diabetic patients. Fioretto et al  noted that only one third of microalbuminuric type 2 diabetic patients had Kimmelstiel Wilson's lesions, one third had non-specific lesions and one third had normal kidney by light microscopy.
Evolution of diabetic nephropathy
There are few renal diseases which follow such a predictable evolution as is found in diabetic nephropathy. A modified scheme after Mogensen is shown in [Table - 4]. At least in type 1 diabetic patients (this is less well documented in type 2 diabetes), an initial stage of glomerular hyperfiltration is followed by a stage of clinical latency. The first clinical sign of renal involvement is the appearance of microalbuminuria, i.e. albumin excretion rates that cannot be discovered by routine measurements of proteinuria, but are detectable by specific assays sensitive enough to detect very low albumin concentrations. In parallel with albumin excretion, blood pressure rises usually within the range of normotensive values.
When macroalbuminuria, (i.e. excretion rate > 300 mg/day) is present, patients usually develop clinically manifest hypertension and, in the course of few years, progress into ESRD.
The stage of microalbuminuria provides a unique window of opportunity, since by appropriate interventions, particularly administration of angiotensin converting enzyme (ACE) inhibitors,  further progression can be delayed or even halted at a stage when glomerular filtration rate has not yet decreased. Although appropriate long-term studies are currently not available, it appears that such early intervention is much more efficacious than intervention in later stages of diabetic nephropathy.
Pathogenesis of diabetic nephropathy
The onset of diabetic nephropathy is determined both by genetic and by nongenetic factors. One important argument for strong genetic determination is the observation of familial clustering of nephropathy both in type 1  and type 2  diabetes. It has been found that cardio-vascular events and hypertension in first degree relatives were the single most powerful predictors of early microalbuminuria in patients with recent onset type 2 diabetes. There is apparently a strong interaction between the genetic risk, i.e. a family history of cardiovascular events in first-degree relatives, and glycemic control  [Table - 5]. Today, taking the family history, and in the future presumably monitoring of genes determining the renal risk, is of importance to target preventive measures to those individuals with the greatest renal risk.
Several genes have been implicated as determinants of the risk of nephropathy, but so far no genetic test has been sufficiently sensitive and specific to gain acceptance by clinicians. A polymorphism in the ACE gene apparently explains a small proportion of the variance according to a prospective study in type 1 diabetic patients (Personal Communication). Another predictor is an elevated sodium-lithium counter trans-port, which is a phenotypically stable abnormality in patients with diabetic nephropathy and is found even in skin fibroblast cultures. 
Hyperglycemia has been documented as an extremely important risk factor for the onset of microalbuminuria both in type 1  and type 2 diabetes. , There is no risk threshold, i.e. the renal risk increases progressively with higher HbA1c values.
In the patient with type 1 diabetes, the presence of hypertension usually indicates the presence of renal disease. In contrast, in type 2 diabetes, very frequently hypertension precedes the onset of type 2 diabetes by years or decades. In these patients, hypertension is one facet of the so called metabolic syndrome, which is a condition predisposing to, and occurring before the onset of, type 2 diabetes. Studies in Pima Indians showed that hypertension prior to the onset of diabetes (pre-diabetic hypertension) was a strong predictor of the risk to develop proteinuria once diabetes mellitus had set in.  Whether treatment of hypertension prior to the onset of diabetes or proteinuria attenuates the risk to develop diabetic nephropathy has not been clarified.
Another strong determinant of the risk of nephropathy is smoking.  According to Sawicki,  cessation of smoking markedly reduces the renal risk. Accordingly, diabetic patients should be encouraged to stop smoking.
Management of the patient with diabetic nephropathy
It is said that even today diabetic nephropathy or even diabetes per se, is frequently diagnosed only in late stages of the disease. In a recent study on 173 diabetic patients (16 with type 1, 157 type 2 diabetes) admitted to German renal units, we found that the patients were referred to the nephrologist with an average creatinine clearance of 29 ml/min, at a known duration of diabetes (in the type 2 diabetic patients) of 0-44 years and with a median systolic blood pressure of 170 mmHg (120-260) and diastolic blood pressure of 90 mmHg (60180).  Thirty-two of the 173 patients received no antihypertensive medication. Median LDL cholesterol was 176 mg/dl (67-307), but only 15% had received lipid-lowering treatment. This observation illustrates that non-specialists neglect nephropathy as a complication of diabetes. It is a strong argument for early diagnosis and treatment.
The key finding to recognize incipient renal involvement is monitoring the rate of urinary albumin excretion (UAE). The upper limit of normal for UAE is 30 mg/24 h (20 µg/min). Microalbuminuria is defined as an albumin excretion rate between 20 and 200 µg/min (or 30-300 mg/24 h). The potential presence of confounding factors which may limit the specificity of albuminuria has to be excluded, i.e. uncontrolled hypertension, urinary tract infection, heart failure or acute conditions such as uncontrolled hyperglycemia, fever or excessive physical exercise. Because of the considerable dayto-day variability (variation coefficient 30%) at least two out of three determinations must be positive on separate occasions. A single demonstration of elevated UAE is not diagnostic.
[Table - 6] summarizes the measures which should be taken to prevent progression of overt nephropathy. These comprise: (i) adequate glycemic control, (ii) lowering of blood pressure with the specific aim to reduce proteinuria, since proteinuria strongly correlates to progression of renal failure and since proteinuria has been recently shown to be a "nephrotoxin"  , (iii) cessation of smoking and (iv) possibly (although the value of this is less well documented) restriction of dietary protein intake.
Of particular importance is the selection of an adequately low target blood pressure. In type 2 diabetic patients, the UKPDS study  showed that "tight control of blood pressure" compared to "less tight blood control" had a dramatic effect on outcome. In that study, which was designed more than a decade ago, a target blood pressure of less than 150/85 mm Hg had been adopted for "tight blood pressure control". By today's standards, this is no longer considered adequate control. Nevertheless, the modest 10 mm Hg difference in systolic blood pressure between "tight" and "less tight" control was associated with an impressive 30% reduction of the rate of death. Based on these and other observations, a number of authorities consider a blood pressure < 130/85 mm Hg , as optimal for the diabetic patient and the National Kidney Foundation recommends even lower pressures, i.e. 125/75 mm Hg in patients with chronic renal insufficiency. 
A particular bone of contention is the selection of the appropriate antihypertensive agent. Based on the observation that reduction of proteinuria is the single most important predictor of success in halting progression of diabetic disease,  it has been recommended that for antihypertensive treatment one should start by using an ACE inhibitor.  ACE inhibitors were superior to placebo in patients with advanced diabetic nephropathy and type 1 diabetes  and the same has been shown in type 2 diabetic patients, at least in the early stages of the disease.  Whether this is true for advanced diabetic nephropathy in type 2 diabetes is currently under study in two large multicenter international trials. These trials are designed to study the effect of irbesartan and losartan on progression of advanced nephropathy in type 2 diabetes. So far, no controlled evidence for a beneficial effect of angiotensin receptor blockers is available, but given the evidence for a role of angiotensin in progression  the use of these drugs appears to be rational.
There is much less evidence concerning calcium channel blockers.  At least nondihydropyridine calcium channel blockers reduced proteinuria and attenuated progression better than did beta-blockers in the study of Bakris et al.  There are also good arguments for combining calcium channel blockers and ACE inhibitors.  There has been great concern about potential cardiovascular side effects of calcium channel blockers in diabetic patients. Estacio found a higher rate of myocardial infarction in diabetic patients on calcium channel blockers compared to patients on ACE inhibitors. Presumably, this finding does not indicate an excess cardiovascular risk with calcium channel blockers but rather inferiority to ACE inhibitors in the prevention of cardiovascular events. This interpretation is supported by the observation, in the SystEur study, that with respect to the reduction of cardiovascular events, diabetic patients derived more benefit from treatment with calcium channel blockers than did non-diabetic patients.
When the diabetic patient has reached the stage of renal failure, he usually suffers from a multitude of medical problems caused by diabetic microvascular and macrovascular complications. These are summarized in [Table - 8]. Because of the co-morbidity caused by multi-organ involvement, optimal management of these patients requires an effective interdisciplinary approach.
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Department of Nephrology, University of Heidelberg, Bergheimer Str. 58 D-69115 Heidelberg,
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8]