| Abstract|| |
In most Western countries, diabetic nephropathy (DN) has become the single most common condition found in patients with end-stage renal disease (ESRD). This is to some extent due to better survival of diabetic patients with renal failure, but mostly due to the dramatic increase in the prevalence of type 2 diabetes. The majority of type 2 diabetic patients with renal failure suffer from nodular glomerulosclerosis (Kimmelstiel-Wilson); but ischemic nephropathy, irreversible acute renal failure (mostly acute on chronic) and diabetes co-existing with primary renal diseases are common as well. Classical DN evolves in a sequence of stages. After a period of glomerular hyperfiltration, increased urinary albumin excretion [microalbuminuria (MA)] i.e. 30-300 mg/day or 20 - 200 µg/minute indicates the onset of overt DN. Risk factors for development of DN are positive family history, hyperglycemia in the mother during pregnancy, high blood pressure, obesity and insulin resistance. Poor glycemic control (HbA1c) and elevated systolic blood pressure (> 135 mm Hg) interact in enhancing the risk of DN. Proteinuria and smoking are major promoters of progression. The risk of onset of microalbuminuria can be reduced by lowering of blood pressure and specifically by blockade of the renin angiotensin system (RAS). In patients with established DN, the target systolic blood pressure should be <130 mm Hg and RAS blockade is obligatory. Treating all cardiovascular risk factors is a high priority. Antihypertensive management is rendered difficult by extreme volume sensitivity, pronounced activation of the RAS and autonomic neuropathy. Cardiac events are excessively frequent, glycemic control becomes difficult and autonomic diabetic neuropathy with gastroparesis and diabetic foot are additional problems. Hemodialysis or continuous ambulatory peritoneal dialysis should be started relatively early. In the absence of contraindications, transplantation (renal transplantation, combined kidney/pancreas transplantation or pancreas after kidney transplantation) is the treatment of choice.
Keywords: Diabetes mellitus, Type II diabetes, Diabetic nephropathy, Hypertension, Renal failure, Uremia, Progression, Antihypertensive therapy
|How to cite this article:|
Ritz E. Diabetic Nephropathy. Saudi J Kidney Dis Transpl 2006;17:481-90
| Introduction|| |
Renal failure in diabetes, particularly in type 2 diabetes, has become "a medical catastrophy of worldwide dimension".  According to the USRDS report 2003, 43% of incident diabetic patients [334 per million population (pmp) per year] had diabetes ( ). This figure is an underestimate because a sizable proportion of patients develop diabetes while on dialysis. Our local experience shows that 49% of incident patients (98 ppm) have diabetes, 6% of whom have type 1 and 94% type 2.  Although there has been some recent improvement, life expectancy on hemodialysis (HD) continues to be poor. In a German prospective study, the 5-year survival was 40% in younger type 1 and 8% in the elderly type 2 diabetics,  a prognosis comparable to that of a patient with metastasizing gastrointestinal carcinoma.
The renal risk is similar in type 1 and type 2 diabetes  and may even be somewhat more adverse in type 2.  Apart from classical diabetic glomerulosclerosis (KimmelstielWilson), which we found in 70 % of our patients, presentation with small kidneys and no proteinuria, presumably ischemic nephropathy, was found in 10 to 20% and other primary renal diseases in approximately 20% of the patients.  A novel mode of presentation is irreversible acute renal failure, mostly in the form of acute on chronic renal failure.
| Diagnosis of Diabetic Nephropathy (DN)|| |
The first clinical evidence of DN is microalbuminuria (MA) defined as excretion in urine of 30 to 300 mg albumin/day or 20 to 200 µg/ml. Because of the high day-to-day variability, the diagnosis of microalbuminuria should only be made if two out of three urine samples have been positive and if primary renal causes have been excluded. Even in nondiabetic patients with the metabolic syndrome, the risk of microalbuminuria increases with the number of components of the metabolic syndrome.  Also, more pronounced insulin resistance and metabolic syndrome are found in type 1 and 2 diabetic patients with microvascular complications. , One important cause of microalbuminuria is selective loss of nephrin expression by podocytes which is reversible with blockade of the renin angiotensin system (RAS). 
It is clear, however, that the threshold for the diagnosis of MA is arbitrary. Rachmani  found that individuals in the upper tertile of normal albumin excretion had a 12.4 times higher risk to develop overt microalbuminuria and a 9.8 fold higher risk to develop a cardiovascular end point [Table - 1].
The natural history of microalbuminuria in type 2 diabetics has been defined by the UK Prospective Diabetes Study;  progression from normoalbuminuria to microalbuminuria, from microalbuminuria to macroalbuminuria and from macroalbuminuria to impaired renal function, each of which increases by 2 to 3% per year. It is important that once the patient has macroalbuminuria, he or she is more likely to die from cardiovascular causes, than to develop renal failure.
| Pathophysiology of Diabetic Nephropathy|| |
Despite hyperglycemia, not all, but only between 20 to 40 % of the diabetic patients develop DN. Several predisposing factors have been defined. An important one is the family history both in type 1  and type 2 diabetes.  If the mother was diabetic, i.e. hyperglycemic, at the time of pregnancy, the risk of DN in the offspring is further increased  and this may be related to diminished nephron number.  An important risk factor is blood pressure; even pressure values within the normal range are related to the risk of developing endstage renal disease (ESRD).  Glomerular hypertension and in vitro cyclic stretch are linked to increased cellular glucose uptake and production of chemokines (MCP1); this can be reversed by rosiglitazone.  In a model of normotensive hyperglycemic rats with type 2 diabetes (Goto Kakizaki) Janssen [  found no proteinuria and glomerulosclerosis, whilst superimposition of DOCA-salt hypertension caused rapid development of renal disease.  In humans as well, the risk of hyperglycemia (HbA1 c ) amplifies the risk of microalbuminuria conferred by increased systolic blood pressure. 
It has been postulated that there is a genetic predisposition to DN and recently Janssen  identified, in a limited number of type 2 diabetics with DN, a predisposing polymorphism in the gene coding for carnosinase. Individuals with less active carnosinase and lower carnosine levels had a lower renal risk, which may be explained by the known protection against AGE (advanced glycation end products)  and oxidative stress  of carnosine. This finding has not been confirmed in all populations of type 2 diabetics and there are undoubtedly multiple genes that code for increased renal risk.
An important factor promoting the progression of diabetic nephropathy is proteinuria. High protein excretion is predictive of the rate of progression  and the reduction of proteinuria by treatment is associated with slower progress.  We could recently show that albumin is rendered more toxic to tubular epithelial cells by glycation, which explains the great sensitivity of the kidney to proteinuria in diabetes.
| Prevention of Diabetic Nephropathy|| |
To prevent the onset of early phases of DN, four interventions are particularly useful:
- near normoglycemia
- lowering blood pressure
- blockade of the renin angiotensin system
- cessation of smoking.
In the absence of hyperglycemia, there is no DN. It is therefore not surprising that both in type 1  and type 2 diabetes, , tight glycemic control reduced the renal risk. The EDIC trial showed that, at least with respect to cardiovascular (CV) events, glycemic control in the early years of diabetes caused persistent reduction of the risk. 
The ABCD study (Appropriate Blood Pressure Control in Diabetes) showed that blood pressure lowering per se reduced the risk of microalbuminuria, independent of the blood pressure lowering agent when nisoldipine and enalapril were compared. 
It appears that microalbuminuria can be prevented in type 2 diabetics (at least in part) by blockade of the RAS  and possibly, at least in animal experiments, by RAS blockade even in the pre-diabetic stage. 
There is abundant evidence documenting that in type 1  as well in type 2 diabetes , angiotensin converting enzyme (ACE) inhibitors, and more recently angiotensin receptor blockers (ARB), , reduced the risk of progression of microalbuminuria and in the Benedict trial, even the onset of microalbuminuria.
It has been known for more than two decades that the renal risk is higher in smokers with type 1  or type 2 diabetes  and the rate of loss of glomerular filtration rate (GFR) is almost doubled by smoking.  ACE inhibitors attenuate the risk but do not abrogate it.  The renal risk is less in ex-smokers compared to current smokers,  suggesting that intense efforts to motivate patients to stop smoking are justified. At this point, one may ask whether there is evidence that fewer diabetics develop DN today. The Steno Hospital in Copenhagen reported recently  that between 1965 and 1984, the cumulative incidence of DN decreased progressively pointing to the efficacy of prevention. Recent data from Denmark and the USA (USRDS) also indicate that the incidence of type 2 diabetics reaching ESRD gradually flattens out. One important concept in preventing or halting DN is that of "Intensified multifactorial treatment". Gaede  randomized 80 patients randomly to be treated by general practitioners according to national guidelines or to be treated by intensified multifactorial intervention aiming for optimal control of hyperglycemia, hypertension and dyslipidemia with cardiovascular disease and microalbuminuria as end points. As shown in [Table - 2], after eight years, there was a dramatic reduction not only in the risk of nephropathy but also of autonomic polyneuropathy, retinopathy and cardiovascular disease.
| Management of the Diabetic Patient with Nephropathy|| |
Once the diabetic patient has developed DN, by far the most important intervention is lowering of blood pressure. Different guidelines propose systolic blood pressure values (systolic pressures are more important for progression than diastolic pressures) below 130 or 125 mm Hg with the patient seated. Performing ambulatory blood pressure measurements substantially increases precision, because diabetics, particularly those with DN, have an attenuated decrease of nighttime blood pressure and often even exhibit a paradoxical increase in nighttime blood pressure.
There has been much recent discussion whether pharmacological blockade of the RAS provides additional benefit.  The comparison of type 2 diabetic patients with DN, treated either with alternative antihypertensive agents or RAS blockade, clearly shows a blood pressure-independent benefit from RAS blockade; , the discussion is relatively academic, since for optimal management of blood pressure four to five classes of antihypertensive agents are necessary anyway and also since the target is very difficult to achieve unless the RAS is blocked.
A highly successful intervention is again cessation of smoking.  Unfortunately, compliance to the advice of the physician is notoriously poor although the blood pressureindependent deleterious effect of smoking is beyond any doubt. 
| Why is Blood Pressure Lowering so Important?|| |
At the time of diagnosis of type 2 diabetes, we found by ambulatory blood pressure measurement, that 80% of the patients had either normally elevated blood pressure values (> 130/80 mm Hg) or inadequate night time decrease (dipping < 15%).  The first priority is therefore lowering of blood pressure.
The superiority of RAS blockade in addition to blood pressure lowering alone has been shown in studies on type 2 diabetics with advanced DN. , In type I diabetes also, intervention with captopril caused a substantial reduction of progression, but in this study the blood pressures were not identical in the two arms of the trial. 
In the DETAIL trial,  the ACE inhibitor enalapril and the ARB telmisartan, attenuated in a similar fashion the rate of loss of GFR in diabetic patients with early DN. After five years, the loss of GFR had become minimal. This compares very favourably with interventions in later stages of DN (IDNT, RENAAL) where renal end points could be reduced only by approximately 30%.
It is obvious that ACE inhibitors and ARB are equally effective. Recent work shows that the combination of ACE inhibitors and ARB in sub-maximal doses causes more potent reduction of GFR loss even if blood pressure values are identical in the groups of comparison. 
It is important that apart from lowering blood pressure, reduction of proteinuria per se is an independent target for treatment and if proteinuria is not reduced below 1 gm/day, dose escalation, combination of ACE inhibitors and ARB, or addition of a minerallocorticoid receptor inhibitor (spironolactone or eplerenon) is indicated;  because of the substantial risk of hyperkalemia, we consider the latter safe only if there is no major reduction in the renal function.
| The Uremic Patient with Diabetes Mellitus|| |
In the management of the uremic patient with diabetes mellitus, one of the most important problems is hypertension. Hypertension is extremely volume sensitive so that reduction of dietary salt intake and administration of diuretics is highly recommended. The blood pressure amplitude is usually high as a consequence of increased aortic stiffness. There are indications that excessive lowering of diastolic blood pressure below values of 65 to 70 mm Hg increases cardiovascular risk because of reduced coronary perfusion  so that certain prudence is required. A challenging situation is the syndrome of supine hypertension/ orthostatic hypotension caused by autonomic polyneuropathy with disturbance of the baroreceptor reflex. There is no panacea for this situation.
The major clinical problem and major cause of death in these patients is cardiac disease as shown in [Table - 3]. The prevalence of left ventricular hypertrophy, heart failure and ischemic heart disease is substantially higher in diabetic as compared to non-diabetic patients starting HD. The odds ratio to develop de novo heart failure is particularly increased. , The situation has improved, however, because in the ACORD study we recently found that a prevalence of LVH was substantially lower than 50%. The high prevalence of cardiac disease necessitates risk factor management. Fortunately, the interventions that retard progression are exactly the ones, which improve cardiac risk: blood pressure lowering, beta blockade, blockade of the RAS and reversal of hypervolemia by loop diuretics.
In non-uremic diabetic individuals, statins are highly effective in reducing cardiac end points as shown in the CARDS study,  whilst in patients on HD, the 4D study showed no significant lowering of the primary composite end point  mainly because coronary death was no longer the most frequent cause of death compared to sudden death and death from heart failure. The conclusion is that treatment with statins should be started early. A difficult issue is glycemic control: in diabetic patients with impaired renal function. Insulin half life is prolonged and sulfonylurea compounds (or their active metabolites) cumulate with few exceptions (gliquidone, glimepirid); at the same time there is resistance to the glucose lowering action of insulin, presumably due to circulating inhibitory factors, because insulin resistance is improved by HD. It is important that the new glinides and glitazones do not cumulate and do not cause specific pharmacokinetic problems in uremic patients.
In my opinion, the major problem in the uremic diabetic patient is wasting and anorexia. Insulin antagonizes hypercatabolism. Therefore, the indication for insulin treatment should be handled liberally. In the patient on dialysis, hyperglycemia is problematic because it causes hypervolemia and hyperkalemia. Poor glycemic control is also associated with poorer survival on dialysis. 
A major clinical problem is also autonomic neuropathy; the consequences are gastroparesis (vomiting, temporal dissociation between insulin absorption and food absorption), alternating diarrhea and obstipation, detrusor paresis, painless myocardial infarction, supine hypertension and orthostatic hypotension as well as the neuropathic diabetic foot.
The importance of foot lesions on survival has been grossly underestimated in the past. In the 4D study  as well as in a study of Koch,  foot lesions were the most potent predictors of death, potentially because inflammation aggravates the cardiovascular risk. [Table - 4] shows the clinical differences between neuropathic and ischemic foot, the management of which differs substantially.  A relatively new problem is the recognition that anemia is more prevalent and more severe in diabetic as compared to non-diabetic patients at any given level of GFR.  In the controlled prospective ACORD trial, we found no further benefit when the hemoglobin was raised above the recommended target level (10.5 to 11.5 vs 13 to 15gm/dl).
| The Diabetic Patient and Terminal Renal Failure|| |
In my opinion, dialysis should be started earlier in diabetic compared to non-diabetic patients, i.e. at an approximate GFR of 15 ml/minute. Frequently, dialysis is required even earlier for reasons other than low GFR, e.g. recurred pulmonary edema with or without left ventricular malfunction, vomiting from combined gastroparesis and uremia and, most importantly progressive cachexia. The principles for selecting hemodialysis versus CAPD do not differ from those in nondiabetic patients.
The improving results of renal transplantation offer a note of hope. Islet transplantation, although attracting much interest,  is currently not a widely practiced and uniformly successful procedure.
Although mortality in transplanted diabetics is higher than in non-diabetics, it is substantially better than in hemodialyzed diabetics. 
At least in type 1 diabetics, (possibly in the future in type 2 diabetics also), combined kidney and pancreas transplantation is the treatment of choice, , particularly since graft survival and also patient survival has considerably increased in recent years with quite acceptable results. With the increasing frequency of live kidney donation, a common practice is to first transplant the live donor kidney and in a second step transplant the pancreas (pancreas after kidney).
| Outlook|| |
Compared to the situation in the early seventies, when one of the pioneers of dialysis wrote a paper on "The sad truth about hemodialysis in diabetic nephropathy" because oneyear survival was only 22%,  treatment of the uremic diabetic with dialysis and particularly with kidney and pancreas transplantation, has revolutionized the outcome.
Still morbidity and mortality are substantially higher than in non-diabetics. The challenge in the future will be to prevent diabetic nephropathy. This will necessitate screening, early detection and determinant intervention.
There are many hurdles to this goal, but it is my personal conviction that the goal is achievable, at least in the majority of patients.
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Nierenzentrum, Im Neuenheimer Feld 162, D-69120 Heidelberg
[Table - 1], [Table - 2], [Table - 3], [Table - 4]