Clinical pathology of nephropathy
Approximately 30-40% of patients with type 1 or type 2 diabetes develop diabetic nephropathy. Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (> 300 mg/24 h, or 300 mg/g creatinine), a relentless decline in GFR, raised arterial blood pressure and enhanced cardiovascular morbidity and mortality. There is a characteristic histopathology. Prior to development of diabetic nephropathy a proportion of individuals with short-duration diabetes may have glomerular hyperfiltration persisting for some years after diagnosis. Whether or not this predisposes to later diabetic nephropathy remains controversial. In classical diabetic nephropathy, the first clinical sign of diabetic nephropathy is of increased urine albumin excretion into the microalbuminuric range (30-300 mg/24h, or 30-300 mg/g creatinine; albuminuria grade A2). Untreated, microalbuminuria will rise gradually, reaching the clinical proteinuric range (albuminuria grade A3) over 5- 15 years. Glomerular filtration then begins to decline and end-stage renal failure is reached without treatment in 5-7 years. Although albuminuria is the first sign, the first symptom of diabetic nephropathy is usually peripheral oedema which occurs at a very late stage.
A broader term, kidney disease in diabetes, is used for patients with chronic kidney disease (impaired renal function or proteinuria) regardless of the background. Although impaired renal function without albuminuria is prevalent in particular in elderly subjects, it is much less likely to progress if albuminuria is not present.
The phases of diabetic nephropathy
Figure 1 [click to enlarge]A preclinical phase of diabetic nephropathy consisting of a normoalbuminuric (albuminuria grade A1) and a microalbuminuric (albuminuria grade A2) stage and a clinical phase characterized by albuminuria grade A3, hypertension and declining renal function are well documented in both type 1 and type 2 diabetic patients (Figure 1).
Prior to development of increasing albuminuria approximately one third of type 1 diabetic patients will have a glomerular filtration rate (GFR) above the upper normal range for age-matched healthy nondiabetic subjects. The degree of hyperfiltration is less in type 2 diabetic patients and hyperfiltration is even reported to be absent in some studies.
Longitudinal studies suggest that hyperfiltration is a risk factor for subsequent increase in urinary albumin excretion and development of diabetic nephropathy in type 1 diabetic patients, but conflicting results have also been reported. A recent meta analysis based on 10 cohort studies following 780 patients found a hazard ratio of 2.71 (95% confidence interval 1.20 to 6.11) for progression to microalbuminuria (albuminuria grade A2) in patients with hyperfiltration. The prognostic significance of hyperfiltration in type 2 diabetic patients is still debated.
Microalbuminuria (Albuminuria grade A2)
In 1969, Keen and colleagues  demonstrated elevated urinary albumin excretion (UAE) in patients with newly diagnosed type 2 diabetes. This abnormal but subclinical UAE has been termed microalbuminuria. Recently it was suggested for chronic kidney disease in general to use the term ”moderately increased albuminuria” (albuminuria grade A2) instead of microalbuminuria . In addition to hyperglycaemia, many other factors can induce microalbuminuria in diabetic patients such as hypertension, massive obesity, heavy exercise, various acute or chronic illnesses and cardiac failure. The day-to-day variation in UAE is high, 30 to 50%. Consequently more than one urine sample is needed to determine whether an individual patient has persistent microalbuminuria. Urinary albumin excretion within the microalbuminuric range (30 mg - 300 mg/24 h) in at least two out of three consecutive non-ketotic sterile urine samples is the generally accepted definition of persistent microalbuminuria (albuminuria grade A2). For convenience it has been recommended to use (early morning) spot urine samples for screening and monitoring. There is less day to day variability in morning compared to random spot urine samples. Urinary albumin creatinine ratio is measured, and microalbuminuria is defined as 30 to 300 mg /g creatinine (x 0.1131 for mg/mmol). It has been suggested that adjusting the urinary albumin concentration for urinary creatinine concentration not only may correct for diuresis, but elevated ratios may reflect two independent risk factors: elevated albumin excretion reflecting renal and vascular damage, and reduced creatinine excretion associated to reduced muscle mass .
Persistent microalbuminuria has not been detected in children with type 1 diabetes younger than 12 years of age and, in general, is exceptional in the first 5 years of type 1 diabetes, whereas it may be present from onset in type 2 diabetes. The annual rate of increase in urinary albumin excretion is about 20% in both type 2 and type 1 diabetic patients with persistent microalbuminuria.
GFR measured using the single injection technique with plasma clearance of a tracer (for example (51Cr-EDTA), iohexol) or the renal clearance of inulin is normal or slightly elevated in type 1 diabetic patients with microalbuminuria. Prospective studies have demonstrated that GFR remains stable at normal or supranormal levels for at least 5 years if clinical nephropathy does not develop. Nephromegaly is still present and is even more pronounced in microalbuminuric than in normoalbuminuric type 1 diabetic patients. In microalbuminuric type 2 patients GFR declines at rates approximating 3 to 4 mL/min/year.
Changes in tubular function take place early in diabetes and are related to the degree of glycaemic control. The proximal tubular reabsorption of fluid, sodium and glucose is enhanced. This process could diminish distal sodium delivery and thereby modify tubuloglomerular feedback signals, which would result in enhancement of GFR. There are suggestions that this could be a target for intervention with SGLT2 inhibitors . A direct effect of insulin in increasing distal sodium reabsorption has also been demonstrated. The consequences of these alterations in tubular transport for overall kidney function are unknown. Markers of acute tubular damage have also been investigated in relation to prediction and progression of diabetic nephropathy. In some studies elevated markers such as liver fatty acid binding protein or KIM 1 were slightly elevated in normo or microalbuminuric patients later progressing to diabetic nephropathy.
Several studies have demonstrated blood pressure elevation in children and adults with type 1 diabetes and microalbuminuria. The prevalence of arterial hypertension (≥ 140/90 mm Hg) in adult patients with type 1 diabetes increases with urine albumin level. Prevalence rates are 42%, 52%, and 79% in individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively. The prevalence of hypertension in those with type 2 diabetes (mean age 60 years) is higher: 71%, 90%, and 93% in the normoalbuminuria, microalbuminuria, and macroalbuminuric groups, respectively. A genetic predisposition to hypertension in type 1 diabetic patients who develop diabetic nephropathy has been suggested but other studies did not confirm the concept. Several studies have reported that sodium and water retention play a dominant role in the initiation and maintenance of systemic hypertension in patients with microalbuminuria and diabetic nephropathy, whereas the contribution of the renin-angiotensin-aldosterone system (RAAS) is smaller .
Diabetic nephropathy is characterized by persistent albuminuria (> 300 mg/24 h, or 300 mg/g creatinine), a relentless decline in GFR, raised arterial blood pressure and enhanced cardiovascular morbidity and mortality. Although albuminuria is the first sign, peripheral edema is often the first symptom of diabetic nephropathy. Anaemia seems to occur at an earlier stage in diabetic nephropathy than in other kidney diseases, so that anaemia is a frequent finding in patients with diabetic nephropathy and moderately reduced renal function. Furthermore, the degree of anaemia is an independent risk factor associated with the decline in GFR or development of ESRD in type 2 diabetic patients with diabetic nephropathy although intervention with erythropoietin was not helpful.
Diabetic nephropathy rarely develops in patients with type 1 diabetes before 10 years after diagnosis, whereas approximately 3% of patients with newly diagnosed type 2 diabetes already have overt nephropathy. The incidence peak (3% per year) is usually found in those who have had diabetes for 10 to 20 years, thereafter a progressive decline in incidence takes place. Most studies dealing with the natural history of diabetic nephropathy have demonstrated a relentless, often linear rate of decline in GFR. Importantly, this rate of decline is highly variable across individuals, ranging from 2 to 20 mL/min/year, with a mean approximating 12 mL/min/year. Type 2 diabetic patients with nephropathy display the same degree of loss in filtration function and in variability of GFR. With aggressive treatment of risk factors for loss of renal function, particularly blood pressure with blockers of the RAAS, hyperglycaemia, dyslipidaemia and smoking cessation, the median survival has improved significantly and the rate decline in GFR is now 2-5 ml/min/year .
The Diabetic Person with Advanced Renal Failure
The diabetic patient with advanced renal failure (CKD stage 4 and 5), has a much higher burden of microvascular and macrovascular complications than the diabetic patient without proteinuria or in the earlier stages of diabetic nephropathy. The morbidity of diabetic patients with CKD is usually more severe than that of the average patient seen in the diabetes outpatient clinic. Consequently, even when such patients are asymptomatic, they must be monitored at regular intervals for timely detection of complications (ophthalmologic examination at half-yearly intervals, cardiovascular status yearly, foot inspection at each visit) and they must be closely monitored for need of conservative intervention against anaemia and calcium metabolic abnormalities.
The physician in charge of the care of a diabetic patient with impaired renal function has to face a spectrum of therapeutic challenges, such as fluid retention, hypertension, anaemia, glycaemic control, and bacterial infections. The most vexing clinical problems are related to coronary heart disease and autonomic polyneuropathy.
Kidney disease in Diabetes
Recent studies have demonstrated impaired renal function (CKD stage 3: estimated GFR<60 ml/min/1.73m2) in many patients with normoalbuminuria. Discussion continues as to whether this is due to ageing, rather than kidney disease, as this phenotype is often seen in elderly women and is often non-progressive. Alternative suggestions are that the phenotype is due to treatment-induced remission of albuminuria in patients with diabetic nephropathy, or even a non-albuminuric phenotype of diabetic nephropathy. In a 19 year follow up of the Diabetes Control and Complications Study in type 1 diabetic patients 24% of patients developing eGFR below 60 ml/min/1.73 m2 had normoalbuminuria on all prior measurements. Presently we lack sufficient longitudinal data to clarify the aetiology of this clinical phenotype. The recent focus of work from the Joslin Institute in Boston USA has been on early progressive renal decline, where early decline in eGFR is found to be present in subjects without elevated albuminuria, but with a long-term high risk of ESRD . This has led the researchers to look for other markers associated with this phenotype. For example, TNF receptor 1and 2 have been found to be associated with loss of renal function in such patients .
Extra-Renal complications in Diabetic Nephropathy
Diabetic retinopathy is present in virtually all type 1 diabetic patients with nephropathy, whereas only 50% to 60% of proteinuric type 2 diabetic patients have retinopathy. Absence of retinopathy should prompt further investigation for nondiabetic glomerulopathies. Blindness due to severe proliferative retinopathy or maculopathy is approximately five times more frequent in type 1 and type 2 diabetic patients with nephropathy than in normoalbuminuric patients. Macroangiopathies ( e.g., stroke, carotid artery stenosis, coronary heart disease, and peripheral vascular disease) are two to five times more common in patients with diabetic nephropathy. Peripheral neuropathy is present in almost all patients with advanced nephropathy. Foot ulcers with sepsis leading to amputation occur frequently (>25% of cases), probably due to a combination of neural and arterial disease. Autonomic neuropathy may be asymptomatic and manifest simply as abnormal cardiovascular reflexes, or it may result in debilitating symptoms. Nearly all patients with nephropathy have grossly abnormal results on autonomic function tests.
^ Magee,GM, Bilous,RW, Cardwell,CR, Hunter,SJ, Kee,F, Fogarty,DG: Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia 52:691-697, 2009
^ Keen,H, Chlouverakis,C, Fuller,JH, Jarrett,RJ: The concomitants of raised blood sugar: studies in newly-detected hyperglycaemics. II. Urinary albumin excretion, blood pressure and their relation to blood sugar levels. Guy's Hosp Rep 118:247-254, 1969
^ Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group: KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 3:1-150, 2013
^ Lambers Heerspink,HJ, Gansevoort,RT, Brenner,BM, Cooper,ME, Parving,HH, Shahinfar,S, de,ZD: Comparison of different measures of urinary protein excretion for prediction of renal events. J Am Soc Nephrol 21:1355-1360, 2010
^ Rossing,P: Assessment of kidney function: UACR--two risk markers or a 24 h collection in a minute? Nat Rev Nephrol 8:320-321, 2012
^ Cherney,DZ, Perkins,BA, Soleymanlou,N, Maione,M, Lai,V, Lee,A, Fagan,NM, Woerle,HJ, Johansen,OE, Broedl,UC, von,EM: Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129:587-597, 2014
^ Nielsen,SE, Sugaya,T, Hovind,P, Baba,T, Parving,HH, Rossing,P: Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients. Diabetes Care 33:1320-1324, 2010
^ Nielsen, S. E., Sugaya, T., Hovind, P., Baba, T., Parving, H-H., and Rossing, P. Urinary liver-type fatty acid-binding protein (u-LFABP) predicts progression to nephropathy in type 1 diabetic patients. Diabetes Care . 2010. Ref Type: In Press
^ Parving H-H: Arterial hypertension in diabetes mellitus. In International Textbook of Diabetes Mellitus. Alberti KGMM, DeFronzo RA, Keen H, Zimmet P, Eds. New York, John Wiley & Sons Ltd, 1992, p. 1521-1534
^ Fox,CS, Matsushita,K, Woodward,M, Bilo,HJ, Chalmers,J, Heerspink,HJ, Lee,BJ, Perkins,RM, Rossing,P, Sairenchi,T, Tonelli,M, Vassalotti,JA, Yamagishi,K, Coresh,J, de Jong,PE, Wen,CP, Nelson,RG: Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012
^ Thomas,MC, Cooper,ME, Rossing,K, Parving,H-H: Anaemia in diabetes: Is there a rationale to TREAT? Diabetologia 49:1151-1157, 2006
^ Pfeffer,MA, Burdmann,EA, Chen,CY, Cooper,ME, de,ZD, Eckardt,KU, Feyzi,JM, Ivanovich,P, Kewalramani,R, Levey,AS, Lewis,EF, McGill,JB, McMurray,JJ, Parfrey,P, Parving,HH, Remuzzi,G, Singh,AK, Solomon,SD, Toto,R: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361:2019-2032, 2009
^ Andresdottir,G, Jensen,ML, Carstensen,B, Parving,HH, Rossing,K, Hansen,TW, Rossing,P: Improved survival and renal prognosis of patients with type 2 diabetes and nephropathy with improved control of risk factors. Diabetes Care 37:1660-1667, 2014
^ Parving,H-H, Lewis,JB, Ravid,M, Remuzzi,G, Hunsicker,LG: Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: A global perspective. Kidney Int 69:2057-2063, 2006
^ Perkins,BA, Ficociello,LH, Ostrander,BE, Silva,KH, Weinberg,J, Warram,JH, Krolewski,AS: Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol 18:1353-1361, 2007
^ Niewczas,MA, Gohda,T, Skupien,J, Smiles,AM, Walker,WH, Rosetti,F, Cullere,X, Eckfeldt,JH, Doria,A, Mayadas,TN, Warram,JH, Krolewski,AS: Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol 23:507-515, 2012