The diagnosis of DN is considered in a diabetic patient that has undergone a routine urinalysis (UA) that includes screening for microalbuminuria and has physical exam findings that are associated with diabetes mellitus. These can be:
- Fourth heart sound
- Diminished deep tendon reflexes and sensations such as fine touch (signs of diabetic neuropathy)
- Non-healing skin ulcers or osteomyelitis
Signs and symptoms
In diabetic patients, early signs and symptoms for kidney disease are non-specific and rare. The more common presentation of kidney disease is after it has progressed significantly . Clinical features include:
- Ankle and/or pedal edema
- Elevated blood pressure
- Elevated blood urea nitrogen (BUN) and serum creatinine
- Fatigue, pallor, anemia
- Reduction in dose/frequency of insulin or other anti-diabetic medication
The differential diagnosis for DN in a patient with diabetes mellitus includes:
Entire Body System
A 56-year-old female patient was clinically characterized by heavy proteinuria, anemia, hypertension, and no detectable monoclonal protein in serum or urine. She had a history of diabetes with retinopathy and hypertension. [ncbi.nlm.nih.gov]
Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. The deleterious effects of hypertension are likely directed at the vasculature and microvasculature. [emedicine.medscape.com]
Arterial hypertension Arterial hypertension is known to be correlated with the progression of DN, in addition to being a major risk factor for the same. [symptoma.com]
Both systolic and diastolic hypertension markedly accelerate the progression of diabetic nephropathy, and aggressive antihypertensive management is able to greatly decrease the rate of fall of GFR. [care.diabetesjournals.org]
An increasing prevalence of diabetes without improved treatment of its complications will mean a rise of kidney failure due to diabetic nephropathy. [nordforsk.org]
It is important to identify appropriate foods when you have kidney failure. [livestrong.com]
Chronic kidney disease can progress even further to kidney failure. People with kidney failure need treatment with dialysis or a kidney transplant. [mydr.com.au]
If left untreated, this can lead to kidney failure. [health.cvs.com]
Now you see why diabetic kidney failure is such a real danger for diabetics over the long term. Diabetic Kidney Failure: Early Stages Diabetic kidney failure is a very real threat. [sepalika.com]
[…] associated with an increased risk of death in general, particularly from cardiovascular disease. Signs and symptoms The onset of symptoms is 5 to 10 years after the disease begins. A usual first symptom is frequent urination at night: nocturia [en.wikipedia.org]
Clinical features include: Albuminuria/proteinuria Ankle and/or pedal edema Elevated blood pressure Elevated blood urea nitrogen (BUN) and serum creatinine Nocturia Polyuria Nausea/vomiting Fatigue, pallor, anemia Pruritus Reduction in dose/frequency [symptoma.com]
A 24-hour urine collection is used for estimating glomerular filtration rate (GFR) and analysis of protein, creatinine and urea levels in the urine. UA of a DN patient usually shows glycosuria and proteinuria (150 to >300mg/dl). Though uncommon, but hyaline casts may also be found.
Estimating the GFR (by using equations like the MDRD formula), are useful to monitor the progression of kidney disease.
Serum and urinary electrophoresis
These are useful for excluding multiple myeloma as the cause for DN in suitable case scenarios. They also help in the classification of proteinuria (usually glomerular type in DN).
In the initial course of the disease, the kidney is either slightly enlarged or normal in size. With chronic renal disease, the kidney shrinks in size. Ultrasound sound is helpful in excluding obstruction. It is preferrable to have echogenicity studies in chronic renal disease.
A renal biopsy is indicated only if the diagnosis of DN is in doubt or an alternative diagnosis is more likely. A renal biopsy is not required to diagnose DN in a case presenting with typical history, physical exam and lab findings suggestive of a progressive renal disease.
These cases were diagnosed as diabetic nodular glomerulosclerosis, although there was no obvious evidence for diabetes. [ncbi.nlm.nih.gov]
Dose should be decreased if symptoms of orthostatic hypotension develop or serum creatinine increases by more than 30%. [msdmanuals.com]
Abnormal Renal Function
DN is considered the case when there is macroalbuminuria alone or macroalbuminuria together with abnormal renal function. [news-medical.net]
A strict glycemic control is essential in DN since evidence indicates that in patients with diabetes mellitus (type 1 and type 2, both), hyperglycemia plays a major role in contributing to the progression of the disease. There is strong evidence supporting the aforementioned recommendation, especially for type 1 diabetes.
Control of hypertension
An effective control of blood pressure delays the progression of diabetic glomerulopathy. It has been demonstrated that rate of decline in renal function is retarded by effective control of hypertension in cases with type 1 DM, proteinuria and hypertension , especially when a fall in SBP occurs together with a reduction in glomerular capillary pressure. The appropriate lower limit for SBP is yet to be ascertained .
Angiotensin-converting enzyme (ACE) inhibitors
Evidence indicates that ACE inhibition can significantly delay the progression and development of DN.
Angiotensin receptor blockers (ARBs) for renin-angiotensin system (RAS) inhibition
There is evidence suggesting that ARBs are a good option for treating DN .
Renal replacement therapy
Renal replacement can be presented as an option for diabetic patients with ESRD, especially those who are chronically ill. The details pertaining to renal replacement therapy should preferably be discussed with the patient at an early stage of the disease. It is advisable to initiate treatment at a creatinine clearance / estimated GFR(eGFR) of 10-15 ml/min for cases diagnosed with DN. Treatment can be initiated at an early stage for diabetics in the following circumstances:
- Uncontrollable blood pressure secondary to hypervolemia
- Presence of uremic symptoms as anorexia and cachexia
- Severe vomiting due to presence of uremia in addition to gastroparesis
Several recommendations that focus on providing an outline of a diet for different caloric requirements, suited to various case scenarios have been made available by the American Diabetic Association. Protein restricted diet (0.8-1 g/kg/day) may be helpful in delaying the progression of DN in advanced cases. Phosphorus and potassium restriction is recommended for cases with advanced nephropathy, which may require the use of agents like phosphate binders.
DN is associated with significant morbidity and mortality. A reliable predictor for the morbidity and mortality associated with DN for both type 1 and type 2 DM is proteinuria. The prevalence of albuminuria in DM is 30-35%. In patients diagnosed with diabetes mellitus, microalbuminuria and macroalbuminuria, both increase the all cause mortality. Cardiovascular morbidity can be predicted by Microalbuminuria is known to be associated with cardiovascular morbidity and mortality. It is also known to increase the risk of coronary artery disease (CAD) and peripheral vascular disease (PVD).
ESRD accounts for 59-66% of mortalities in type 1 DM patients that have concurrent nephropathy. A prospective study from Germany reported a survival rate of <40% in the younger age group diagnosed with type 1 DM and <10% in the elderly with type 2 DM. ESRD can be caused by type 1 and type 2 DM, both. However, majority of the cases are the ones diagnosed with type 2 DM. Although an approximate 20-40% of type 1 DM cases develop ESRD, there has been a steady decline in the fraction of cases that developed ESRD due to type 1 DM. Comparing it with statistics for type 2 DM, in spite of having only 10-20% cases that develop uremia secondary to diabetes, they almost equate the total number of diabetics developing ESRD due to 5-10 fold greater prevalence of type 2 diabetes. In patients with type 1 DM and DN, cardiovascular disease is a significant cause of mortality (15-25%).
In patients diagnosed with either type 1 or type 2 diabetes mellitus (DM), one of the major risk factors for developing microalbuminuria is hyperglycemia   . A 37% reduction in microvascular endpoints has been associated with 1% decrease in HbA1c . A recently published trial also emphasized on aggressive treatment of DM to decrease microvascular sequelae . It has also been shown that mild to moderate renal injury secondary to DN in cases with type 1 DM was reversed after pancreatic transplantation . Although there are a few studies that have demonstrated a reduction in GFR with high glucose levels  , the role of metabolic control in presence of albuminuria needs to be further investigated to define any significance.
Arterial hypertension is known to be correlated with the progression of DN, in addition to being a major risk factor   for the same. Upon analysis of UKPDS, it was observed that for every 10 mmHg decrease in systolic blood pressure (SBP), the risk of microvascular complications was reduced by 13%. Also, patients having a SBP<120 mmHg in the same group had the smallest risk for microvascular complications .
Smoking is a known risk factor for DN  . Although the speculation of smoking being a contributing factor in the progression of DN is unconfirmed   , patients are advised to quit smoking irrespective of the phase of DN. This intervention aims at decreasing the associated cancer and cardiovascular risk as well.
High serum cholesterol level is a known risk factor for developing DN in patients diagnosed with type 2 DM  . Albuminuria in type 1 DM cases has been asociated with elevated serum triglycerides, LDL cholesterol and total cholesterol  . In type 1 DM cases with macroalbuminuria, an elevated serum cholesterol level may likely be a risk factor for developing loss of GFR .
Proteinuria can itself cause DN to progress. A proteinuria greater than 2 g/24 hrs has been associated with an increased risk of ESRD . The leakage of albumin may activate inflammatory cascades, which in-turn can lead to glomerular damage . Therefore, decreasing urinary albumin excretion may well be a reasonable approach for the treatment of DN.
Glomerular hyperfiltration has a minor role, if any, as a causative of DN . In approximately one-third of patients diagnosed with type 2 DM, GFR is elevated  . Theoretically, this may lead to glomerular damage, which in-turn can result in DN . Presently, the evidence for classifying glomerular hyperfiltration as a risk factor of DN is controversial   . Elevated urine albumin excretion (UAE) is frequently observed in type 2 DM cases with one kidney  , whereas aggressive disease has not been observed in patients with type 1 DM with a single kidney .
In patients with type 1 DM, it has been found that high UAE values are associated with an increased dietary protein consumption . There is no evidence for the same association in cases with type 2 DM. It has also been found that in cases with type 1 DM, consuming fish protein in higher amounts is associated with a smaller risk of microalbuminuria . The presence of microalbuminuria has also been associated with a high consumption of saturated fats in cases with type 1 DM . It is speculated that the underlying mechanism for these effects may be related to hemodynamic factors .
Genetic risk factors
It has been theorized that the interaction of certain genes with the environment may cause DN   . So far, there is no known gene that could exert a major effect for causation of DN. A better understanding of the genes that act as predisposing factors to DN may allow development of screening techniques and preventive measures to benefit the high risk cases.
It is rare to find DN in patients who incurred type 1 DM (insulin dependent diabetes mellitus, IDDM) for a period that is less than ten years. Concurrent overt nephropathy is found in nearly 3% of cases newly diagnosed with type 2 DM (non-insulin dependent diabetes mellitus, NIDDM). The highest incidence of 3% per year is most often found in patients with a history of diabetes for approximately 10 to 20 years, beyond which there is a progressive decline in the incidence.
There is considerable variation in the epidemiological data on DN from various European countries. The proportion of cases for renal replacement therapy in Germany is higher than United States. In the year 1995, a study conducted in Heidelberg, Germany, reported that among the admission cases for renal replacement therapy, 59% had diabetes and of these, 90% had type 2 DM. The incidence of ESRD from type 2 DM was reported to be increasing in Denmark and Australia, countries which have been known to have a low incidence of type 2 DM. The data from Asian countries has been difficult to retrieve.
Males and females are equally affected from DN.
It is rare to find DN in patients who incurred type 1 DM for a period that is less than ten years. The highest incidence of 3% per year is most often found in patients with a history of diabetes for approximately 10 to 20 years. Patients that are diagnosed with end-stage kidney disease have a mean age of approximately 60 years.
Prevalence by race
The incidence and severity of DN is higher in blacks (3-6 times greater than whites), Pima Indians and Mexican Americans who have type 2 DM. It may be possible that the higher incidence of DN reported in these races could be associated with multiple factors that are influenced by socioeconomic considerations like diet, hypertension, poor control of hyperglycemia and obesity. This may also be an indication of familial clustering of the disease in these particular populations.
From 1997-2002, the incidence of ESRD-DM did not decrease in men, Hipanics, blacks and people in the age group of 65-74 years. Another study evaluating the period 1990-2002 reported that the incidence of ESRD-DM increased in people over the age of 75 years. The goal of decreasing the incidence of ESRD-DM in persons over the age of 75 years can be challenging since the survival of diabetic patients is increasing and ESRD typically occurs in cases having a 15-20 years long history of diabetes . Additionally, as the number of diabetics in the United States increases along with continued ageing of the population, the number of cases for ESRD will continue to rise. The present trend of a decline in the incidence of ESRD in diabetics may change if the mean age for developing diabetes decreases, or those diagnosed with diabetes live for a longer period of time.
There are three significant changes that are observed on histological examination of a kidney tissue sample obtained from a patient having diabetic nephropathy. These include glomerular basement membrane (GBM) thickening, mesangial expansion (secondary to hyperglycemia, possibly through glycosylation or increase in matrix protein production) and glomerular sclerosis (secondary to intraglomerular hypertension, caused by afferent renal artery dilatation or ischemic injury due to narrowing of glomerular vasculature by hyaline deposition). There is no major difference in the prognostic significance with any of these histological patterns.
There are several mechanisms that contribute to the pathogenesis of DN, which include polyol pathway activation, effect of high glucose, activation of renin-angiotensin system, formation of reactive oxygen species (ROS), glomerular hyperfiltration, protein kinase C pathway activation and increase in advanced glycation end-products (AGEs)  . These mechanisms bring about various downstream changes at the cellular level that eventually lead to disruption of the glomerular filtration barrier, visualized on histologocal examination as mesangial expansion, tubulointerstitial fibrosis and nodualr glomerular sclerosis .
Glomerular endothelial cells
These are highly fenestrated cells that have minute pores (50-80 nm in size) through their cytoplasm . Glycocalyx (consisting proteoglycans [PG] like versican, glypican, syndecan and perlecan), glycosaminoglycans (GAG), chondroitin sulfate and heparan sulfate cover the luminal surface of endothelial cells .
They form an important component of the glomerular filtration barrier. As the size of the pores is larger than the circulating proteins like albumin, the glomerular endothelial cells are considered non-contributory for macromolecule filtration. Recent studies, however, have demonstrated that these cells play an important role in glomerular filtration barrier. GAG digestion by chondroitinase, hyaluronidase, and heparanase damage the glycocalyx layer and decrease the density of negative charge at the glomerular filtration barrier, thus increasing fractional clearance of albumin  . It has been observed that the fractional clearance of albumin increases 12 folds without any changes in the ultrastructure when non-covalently bounds components of endothelial glycocalyx are eluded by infusing hypersonic sodium chloride in the renal artery .
The tubulointersitium consists of interstitial cells, tubular system and the vascular system of the kidney . There is significant amount of evidence indicating that tubulointerstitial changes are associated with progression of DN  .
Morphology of podocytes
Loss of podocytes within the glomeruli occurs early in the the progression of DN. Pagtalunan et al., using renal biopsies obtained from Pima Indian patients diagnosed with type 2 diabetes with macroproteinuria, demonstrated a decrease in the number of podocytes per glomeruli . The flattening of podocyte foot processes was found to be associated with the loss of podocytes . A reduction in the number of podocytes has been found to be a good predictor for the progression of albuminuria . The nephropathy found in type 1 DM patients has been shown to have similar changes  .
The measures to prevent or retard the progression of diabetic nephropathy include:
- Control of blood pressure with a target SBP of <130 mmHg and diastolic blood pressure of <80 mmHg using ACE inhibitors (preferred for type 1 DM) or ARBs (preferred in type 2 DM patients)
- Restrict salt intake to <6 grams per day
- Dietary protein restriction (0.8 - 1.0 g/kg body weight)
- Tight control of hyperglycemia, with a target HbA1c <7.0
- Smoking cessation
- Consider initiating the patient on statins
- Weight loss in obese patients
- Avoid minor analgesics
- Avoid use of nephrotoxic drugs such as NSAIDs, certain antibiotics and contrast media
Diabetic nephropathy (DN) is a clinical syndrome, characterized by the presence of persistent albuminuria (>300 mg/day or >200 μg/min confirmed by testing at least twice, 3-6 months apart), elevated arterial blood pressure and progressive decline in glomerular filtration rate (GFR). Approximately 20-40% of diabetic patients are eventually diagnosed with DN. It is the most common etiology for end-stage renal disease (ESRD) and the most frequent indication for chronic dialysis. The major risk factors include hypertension, hyperglycemia, glomerular hyperfiltration, proteinuria, disorders of renal renin-angiotension system, genetic predisposition and presence of advanced glycation end-products. Other possible risk factors include dyslipidemia and numeric depletion of nephrons.
Diabetes can lead to kidney disease by causing injury to the nephrons due to excess glucose (a type of sugar). Diabetes does not allow the body to use the glucose present in blood. When the glucose builds up in the blood, it starts damaging the nephrons. Nephrons are a part of the kidney that filter out the waste and fluid from blood to make urine. Diabetes is a major cause of kidney disease. Controlling the blood sugar levels is important in order to prevent and treat kidney disease.
- Predictors of the development of microalbuminuria in patients with Type 1 diabetes mellitus: a seven-year prospective study. The Microalbuminuria Collaborative Study Group Diabet Med 1999, 16:918-925.
- Gall MA, Hougaard P, Borch-Johnsen K, Parving HH: Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study. BMJ 1997, 314:783-788.
- Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000, 321:405-412.
- Alaveras AE, Thomas SM, Sagriotis A, Viberti GC: Promoters of progression of diabetic nephropathy: the relative roles of blood glucose and blood pressure control. Nephrol Dial Transplant 1997, 12(Suppl 2):71-74.
- Hovind P, Rossing P, Tarnow L, Parving HH: Smoking and progression of diabetic nephropathy in type 1 diabetes. Diabetes Care 2003, 26:911-916.
- Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998, 339:69-75.
- Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008, 358:2560-2572.
- Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R: Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med 1998, 158:998-1004.
- Park JY, Kim HK, Chung YE, Kim SW, Hong SK, Lee KU: Incidence and determinants of microalbuminuria in Koreans with type 2 diabetes. Diabetes Care 1998, 21:530-534.
- Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000, 321:412-419.
- Forsblom CM, Groop PH, Ekstrand A, Totterman KJ, Sane T, Saloranta C, Groop L:Predictors of progression from normoalbuminuria to microalbuminuria in NIDDM. Diabetes Care 1998, 21:1932-1938
- Smulders YM, Rakic M, Stehouwer CD, Weijers RN, Slaats EH, Silberbusch J: Determinants of progression of microalbuminuria in patients with NIDDM. A prospective study. Diabetes Care 1997, 20:999-1005.
- Chaturvedi N, Fuller JH, Taskinen MR: Differing associations of lipid and lipoprotein disturbances with the macrovascular and microvascular complications of type 1 diabetes. Diabetes Care 2001, 24:2071-2077
- Jenkins AJ, Lyons TJ, Zheng D, Otvos JD, Lackland DT, McGee D, Garvey WT, Klein RL:Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy. Kidney Int 2003, 64:817-828.
- Mulec H, Johnsen SA, Wiklund O, Bjorck S: Cholesterol: a renal risk factor in diabetic nephropathy? Am J Kidney Dis 1993, 22:196-201.
- Ruggenenti P, Remuzzi G: Nephropathy of type-2 diabetes mellitus. J Am Soc Nephrol 1998, 9:2157-2169.
- Remuzzi G, Ruggenenti P, Benigni A: Understanding the nature of renal disease progression. Kidney Int 1997, 51:2-15.
- Caramori ML, Gross JL, Pecis M, de Azevedo MJ: Glomerular filtration rate, urinary albumin excretion rate, and blood pressure changes in normoalbuminuric normotensive type 1 diabetic patients: an 8-year follow-up study. Diabetes Care 1999, 22:1512-1516.
- Silveiro SP, Friedman R, Gross JL: Glomerular hyperfiltration in NIDDM patients without overt proteinuria. Diabetes Care 1993, 16:115-119
- Brenner BM, Lawler EV, Mackenzie HS: The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int 1996, 49:1774-1777.
- Murussi M, Baglio P, Gross JL, Silveiro SP: Risk factors for microalbuminuria and macroalbuminuria in type 2 diabetic patients: a 9-year follow-up study. Diabetes Care 2002, 25:1101-1103.
- Caramori ML, Gross JL, Pecis M, de Azevedo MJ: Glomerular filtration rate, urinary albumin excretion rate, and blood pressure changes in normoalbuminuric normotensive type 1 diabetic patients: an 8-year follow-up study. Diabetes Care 1999, 22:1512-1516.
- Dahlquist G, Stattin EL, Rudberg S: Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients. Nephrol Dial Transplant 2001, 16:1382-1386.
- Silveiro SP, da Costa LA, Beck MO, Gross JL: Urinary albumin excretion rate and glomerular filtration rate in single-kidney type 2 diabetic patients. Diabetes Care 1998, 21:1521-1524.
- Ficociello LH, Perkins BA, Roshan B, Weinberg JM, Aschengrau A, Warram JH, Krolewski AS:Renal hyperfiltration and the development of microalbuminuria in type 1 diabetes. Diabetes Care 2009, 32:889-893.
- Chang S, Caramori ML, Moriya R, Mauer M: Having one kidney does not accelerate the rate of development of diabetic nephropathy lesions in type 1 diabetic patients. Diabetes 2008, 57:1707-1711.
- Yip JW, Jones SL, Wiseman MJ, Hill C, Viberti G: Glomerular hyperfiltration in the prediction of nephropathy in IDDM: a 10-year follow-up study. Diabetes 1996, 45:1729-1733.
- Toeller M, Buyken A, Heitkamp G, Bramswig S, Mann J, Milne R, Gries FA, Keen H: Protein intake and urinary albumin excretion rates in the EURODIAB IDDM Complications Study.Diabetologia 1997, 40:1219-1226.
- Mollsten AV, Dahlquist GG, Stattin EL, Rudberg S: Higher intakes of fish protein are related to a lower risk of microalbuminuria in young Swedish type 1 diabetic patients. Diabetes Care 2001, 24:805-810.
- Pecis M, de Azevedo MJ, Gross JL: Chicken and fish diet reduces glomerular hyperfiltration in IDDM patients. Diabetes Care 1994, 17:665-672.
- Riley MD, Dwyer T: Microalbuminuria is positively associated with usual dietary saturated fat intake and negatively associated with usual dietary protein intake in people with insulin-dependent diabetes mellitus. Am J Clin Nutr 1998, 67:50-57.
- Krolewski AS: Genetics of diabetic nephropathy: evidence for major and minor gene effects. Kidney Int 1999, 55:1582-1596.
- Krolewski AS, Ng DP, Canani LH, Warram JH: Genetics of diabetic nephropathy: how far are we from finding susceptibility genes? Adv Nephrol Necker Hosp 2001, 31:295-315.
- Nelson RG, Knowler WC, Pettitt DJ, Bennett PH. Kidney diseases in diabetes. In: Diabetes in America. 2nd ed. Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, eds. Washington, DC: US Department of Health and Human Services, National Institutes of Health; 1995. DHHS publication no. (NIH)95-1468; 361--6.
- Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013; 93: 137–188
- Rask-Madsen C, King GL. Vascular complications of diabetes: Mechanisms of injury and protective factors. Cell Metab 2013; 17: 20–33
- Kolset SO, Reinholt FP, Jenssen T. Diabetic nephropathy and extracellular matrix. J Histochem Cytochem 2012; 60: 976–986.
- Maezawa Y, Cina D, Quaggin SE. Chapter 22 Glomerular Cell Biology. Seldin and Giebisch's the Kidney: Physiology & Pathophysiology. Elsevier Inc., Academic Press, Amsterdam, Boston, 2012
- Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 2008; 88: 451–487
- eansson M, Haraldsson B. Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier. Am J Physiol Renal Physiol 2006; 290:F111–F116
- Jeansson M, Haraldsson B. Glomerular size and charge selectivity in the mouse after exposure to glucosaminoglycan-degrading enzymes. J Am Soc Nephrol 2003; 14: 1756–1765.
- Friden V, Oveland E, Tenstad O, et al. The glomerular endothelial cell coat is essential for glomerular filtration. Kidney Int 2011; 79: 1322–1330
- Bonventre JV. Can we target tubular damage to prevent renal function decline in diabetes? Semin Nephrol 2012; 32: 452–462
- Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury? Kidney Int 1999; 56: 1627–1637.
- Pagtalunan ME, Miller PL, Jumping-Eagle S, et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997; 99: 342–348.
- Meyer TW, Bennett PH, Nelson RG. Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria. Diabetologia 1999; 42:1341–1344.
- Toyoda M, Najafian B, Kim Y, et al. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes 2007; 56: 2155–2160.
- White KE, Bilous RW, Marshall SM, et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002; 51: 3083–3089.
- Rosolowsky ET, Skupien J, Smiles AM, et al. Risk for ESRD in type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol. 2011 Mar. 22(3):545-53.
- National Kidney Foundation: Diabetes and Kidney Disease. Available at http://www.kidney.org/atoz/atozItem.cfm?id=37
- Mogensen CE. The effect of blood pressure intervention on renal function in insulin-dependent diabetes.Diabete Metab. 1989. 15(5 Pt 2):343-51
- Diabetes Guidelines. Royal Free Hampstead NHS Trust. Available at http://royalfree.org.uk/default.aspx?top_nav_id=1&sel_left_nav=25&tab_id=403. Accessed: 7/2/09.
- Laight DW. Therapeutic inhibition of the renin angiotensin aldosterone system. Expert Opin Ther Pat. 2009 Jun. 19(6):753-9