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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2006  |  Volume : 17  |  Issue : 4  |  Page : 481-490
Diabetic Nephropathy

Department Internal Medicine, Ruperto-Carola-University, Heidelberg, Germany

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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

How to cite this URL:
Ritz E. Diabetic Nephropathy. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2022 Jan 18];17:481-90. Available from: https://www.sjkdt.org/text.asp?2006/17/4/481/32484

   Introduction Top

Renal failure in diabetes, particularly in type 2 diabetes, has become "a medical catastrophy of worldwide dimension". [1] 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. [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, [3] a prognosis comparable to that of a patient with metastasizing gastro­intestinal carcinoma.

The renal risk is similar in type 1 and type 2 diabetes [4] and may even be somewhat more adverse in type 2. [5] 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. [2] 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) Top

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. [6] Also, more pronounced insulin resistance and metabolic syndrome are found in type 1 and 2 diabetic patients with micro­vascular complications. [7],[8] One important cause of microalbuminuria is selective loss of nephrin expression by podocytes which is reversible with blockade of the renin angiotensin system (RAS). [9]

It is clear, however, that the threshold for the diagnosis of MA is arbitrary. Rachmani [10] 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; [11] 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 Top

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 [12] and type 2 diabetes. [13] If the mother was diabetic, i.e. hyperglycemic, at the time of pregnancy, the risk of DN in the offspring is further increased [14] and this may be related to diminished nephron number. [15] 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). [16] 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. [17] In a model of normotensive hyperglycemic rats with type 2 diabetes (Goto Kakizaki) Janssen [ [18] found no proteinuria and glomerulosclerosis, whilst superimposition of DOCA-salt hyper­tension caused rapid development of renal disease. [18] In humans as well, the risk of hyperglycemia (HbA1 c ) amplifies the risk of microalbuminuria conferred by increased systolic blood pressure. [19]

It has been postulated that there is a genetic predisposition to DN and recently Janssen [20] 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) [21] and oxidative stress [2] 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 [23] and the reduction of protein­uria by treatment is associated with slower progress. [24] 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 Top

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 [25] and type 2 diabetes, [26],[27] 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. [28]

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. [29]

It appears that microalbuminuria can be prevented in type 2 diabetics (at least in part) by blockade of the RAS [30] and possibly, at least in animal experiments, by RAS blockade even in the pre-diabetic stage. [31]

There is abundant evidence documenting that in type 1 [32] as well in type 2 diabetes [30],[33] angiotensin converting enzyme (ACE) inhibitors, and more recently angiotensin receptor blockers (ARB), [34],[35] 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 [36] or type 2 diabetes [37] and the rate of loss of glomerular filtration rate (GFR) is almost doubled by smoking. [38] ACE inhibitors attenuate the risk but do not abrogate it. [39] The renal risk is less in ex-smokers compared to current smokers, [40] 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 [41] 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 [42] 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 Top

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. [43] 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; [44],[45] 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. [40] Unfortunately, compliance to the advice of the physician is notoriously poor although the blood pressure­independent deleterious effect of smoking is beyond any doubt. [46]

   Why is Blood Pressure Lowering so Important? Top

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%). [47] 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. [44],[45] 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. [48]

In the DETAIL trial, [49] 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. [50]

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; [50] 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 Top

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 [51] 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. [52],[53] 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, [54] whilst in patients on HD, the 4D study showed no significant lowering of the primary composite end point [55] 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. [56]

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 [55] as well as in a study of Koch, [57] 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. [58] 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. [59] 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 Top

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, [60] 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. [61]

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, [62],[63] 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 Top

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%, [64] 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.

   References Top

1.Ritz E, Rychlik I, Locatelli F, Halimi S. End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimen­sions. Am J Kidney Dis 1999;34:795-808.  Back to cited text no. 1  [PUBMED]  
2.Schwenger V, Mussig C, Hergesell O, Zeier M, Ritz E. Incidence and clinical characteristics of renal insufficiency in diabetic patients. Dtsch Med Wochenschr 2001;126:1322-6.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Koch M, Kutkuhn B, Grabensee B, Ritz E. Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Trans­plant 1997;12:2603-11.  Back to cited text no. 3    
4.Hasslacher C, Ritz E, Wahl P, Michael C. Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant 1989;4:859-63.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Yokoyama H, Okudaira M, Otani T, et al. Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Kidney Int 2000;58:302-11.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004;140:167-74.  Back to cited text no. 6    
7.Parvanova A, Iliev I, Filipponi M, et al. Insulin resistance and proliferative retino­pathy: a cross-sectional, case-control study in 115 patients with type 2 diabetes. J Clin Endocrinol Metab 2004;89:4371-6.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Thorn LM, Forsblom C, Fagerudd J, et al. Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care 2005;28:2019-24.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Benigni A, Gagliardini E, Tomasoni S, et al. Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy. Kidney Int 2004;65:2193-200.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Rachmani R, Levi Z, Lidar M, Slavachevski I, Half-Onn E, Ravid M. Considerations about the threshold value of microalbumin­uria in patients with diabetes mellitus: lessons from an 8-year follow-up study of 599 patients. Diabetes Res Clin Pract 2000;49:187-94.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225-32.  Back to cited text no. 11    
12.Seaquist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989;320:1161-5.  Back to cited text no. 12    
13.Nelson RG, Knowler WC, Pettitt DJ, Saad MF, Bennett PH. Diabetic kidney disease in Pima Indians. Diabetes Care 1993;16:335-41.  Back to cited text no. 13  [PUBMED]  
14.Nelson RG, Morgenstern H, Bennett PH. Intrauterine diabetes exposure and the risk of renal disease in diabetic Pima Indians. Diabetes 1998;47:1489-93.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Amri K, Freund N, Van Huyen JP, Merlet­Benichou C, Lelievre-Pegorier M. Altered nephrogenesis due to maternal diabetes is associated with increased expression of IGF-II/mannose-6-phosphate receptor in the fetal kidney. Diabetes 2001;50:1069-75.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med 2005;165:923-8.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Gnudi L, Viberti G, Raij L, et al. GLUT-1 overexpression: Link between hemodyna­mic and metabolic factors in glomerular injury? Hypertension 2003;42:19-24.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Janssen U, Riley SG, Vassiliadou A, Floege J, Phillips AO. Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy. Kidney Int 2003;63:2162-70.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Tapp RJ, Shaw JE, Zimmet PZ, et al. Albuminuria is evident in the early stages of diabetes onset: results from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Am J Kidney Dis 2004;44:792-8.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Janssen B, Hohenadel D, Brinkkoetter P, et al. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 2005;54:2320-7.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun 1998;248:28-32.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Kohen R, Yamamoto Y, Cundy KC, Ames BN. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci U S A 1988;85:3175-9.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Atkins RC, Briganti EM, Lewis JB, et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005;45:281-7.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhi­bition: a patient-level meta-analysis. Ann Intern Med 2003;139:244-52.  Back to cited text no. 24  [PUBMED]  [FULLTEXT]
25.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.  Back to cited text no. 25    
26.Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23 Suppl 2:B21-9.  Back to cited text no. 26  [PUBMED]  
27.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of compli­cations in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-53.  Back to cited text no. 27    
28.Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardio­vascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643-53.  Back to cited text no. 28  [PUBMED]  [FULLTEXT]
29.Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002;61:1086-97.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]
30.Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-51.  Back to cited text no. 30  [PUBMED]  [FULLTEXT]
31.Nagai Y, Yao L, Kobori H, et al. Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats. J Am Soc Nephrol 2005;16:574-5.  Back to cited text no. 31    
32.Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbu­minuria or microalbuminuria. The EUCLID Study Group. Lancet 1997;349:1787-92.  Back to cited text no. 32    
33.Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 1996;156:6-289.  Back to cited text no. 33    
34.Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbumin­uria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbumin­uria (CALM) study. BMJ 2000;321:1440-4.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]
35.Parving HH, Lehnert H, Brochner­Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the develop­ment of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345:870-8.  Back to cited text no. 35    
36.Christiansen JS. Cigarette smoking and prevalence of microangiopathy in juvenile­onset insulin-dependent diabetes mellitus. Diabetes Care 1978;1:146-9.  Back to cited text no. 36  [PUBMED]  
37.Klein R, Klein BE, Moss SE, Cruickshanks KJ. Ten-year incidence of gross proteinuria in people with diabetes. Diabetes 1995;44: 916-23.  Back to cited text no. 37  [PUBMED]  
38.Biesenbach G, Grafinger P, Janko O, Zazgornik J. Influence of cigarette-smoking on the progression of clinical diabetic nephropathy in type 2 diabetic patients. Clin Nephrol 1997;48:146-50.  Back to cited text no. 38  [PUBMED]  
39.Chuahirun T, Wesson DE. Cigarette smoking predicts faster progression of type 2 esta­blished diabetic nephropathy despite ACE inhibition. Am J Kidney Dis 2002;39:376-82.  Back to cited text no. 39  [PUBMED]  [FULLTEXT]
40.Sawicki PT, Didjurgeit U, Muhlhauser I, Bender R, Heinemann L, Berger M. Smoking is associated with progression of diabetic nephropathy. Diabetes Care 1994;17:126-31.  Back to cited text no. 40  [PUBMED]  
41.Hovind P, Tarnow L, Rossing K, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care 2003;26:1258-64.  Back to cited text no. 41  [PUBMED]  [FULLTEXT]
42.Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.  Back to cited text no. 42  [PUBMED]  [FULLTEXT]
43.Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005;366:2026-33.  Back to cited text no. 43  [PUBMED]  [FULLTEXT]
44.Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin­receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60.  Back to cited text no. 44  [PUBMED]  [FULLTEXT]
45.Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9.  Back to cited text no. 45  [PUBMED]  [FULLTEXT]
46.Orth SR, Ritz E, Schrier RW. The renal risks of smoking. Kidney Int 1997;51:1669-77.  Back to cited text no. 46  [PUBMED]  
47.Keller CK, Bergis KH, Fliser D, Ritz E. Renal findings in patients with short-term type 2 diabetes. J Am Soc Nephrol 1996; 7:2627-35.  Back to cited text no. 47  [PUBMED]  
48.Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting­enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329:1456-62.  Back to cited text no. 48    
49.Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952-61.  Back to cited text no. 49  [PUBMED]  [FULLTEXT]
50.Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 2005;67:799-812.  Back to cited text no. 50  [PUBMED]  [FULLTEXT]
51.Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006;144:884-93.  Back to cited text no. 51  [PUBMED]  [FULLTEXT]
52.Foley RN, Culleton BF, Parfrey PS, et al. Cardiac disease in diabetic end-stage renal disease. Diabetologia 1997;40:1307-12.  Back to cited text no. 52  [PUBMED]  [FULLTEXT]
53.Foley RN, Parfrey PS. Cardiac disease in the diabetic dialysis patient. Nephrol Dial Transplant 1998;13:1112-3.  Back to cited text no. 53  [PUBMED]  [FULLTEXT]
54.Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96.  Back to cited text no. 54  [PUBMED]  [FULLTEXT]
55.Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-48.  Back to cited text no. 55  [PUBMED]  [FULLTEXT]
56.Morioka T, Emoto M, Tabata T, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care 2001;24:909-13.  Back to cited text no. 56  [PUBMED]  [FULLTEXT]
57.Koch M, Trapp R, Kulas W, Grabensee B. Critical limb ischaemia as a main cause of death in patients with end-stage renal disease: a single-centre study. Nephrol Dial Transplant 2004;19:2547-52.  Back to cited text no. 57  [PUBMED]  [FULLTEXT]
58.Schomig M, Ritz E, Standl E, Allenberg J. The diabetic foot in the dialyzed patient. J Am Soc Nephrol 2000;11:1153-9.  Back to cited text no. 58  [PUBMED]  [FULLTEXT]
59.Dikow R, Schwenger V, Schomig M, Ritz E. How should we manage anaemia in patients with diabetes? Nephrol Dial Transplant 2002;17 Suppl 1:67-72.  Back to cited text no. 59  [PUBMED]  [FULLTEXT]
60.Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a gluco­corticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-8.  Back to cited text no. 60  [PUBMED]  [FULLTEXT]
61.Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting trans­plantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725-30.  Back to cited text no. 61  [PUBMED]  [FULLTEXT]
62.Becker BN, Brazy PC, Becker YT, et al. Simultaneous pancreas-kidney transplantation reduces excess mortality in type 1 diabetic patients with end-stage renal disease. Kidney Int 2000;57:2129-35.  Back to cited text no. 62  [PUBMED]  [FULLTEXT]
63.Becker BN, Rush SH, Dykstra DM, Becker YT, Port FK. Preemptive transplantation for patients with diabetes-related kidney disease. Arch Intern Med 2006;166:44-8.  Back to cited text no. 63  [PUBMED]  [FULLTEXT]
64.Ghavamian M, Gutch CF, Kopp KF, Kolff WJ. The sad truth about hemodialysis in diabetic nephropathy. JAMA 1972;222:1386-9.  Back to cited text no. 64  [PUBMED]  

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