David Levy, MD, FRCP
Overview of Diabetic Kidney Disease
End-stage renal disease (ESRD) is a common and terrible outcome of diabetes. However, recent data in both type 1 and type 2 diabetes are encouraging. In type 1 diabetes, where not long ago diabetic nephropathy was almost inevitable after 20–30 years, fewer than 1% of patients diagnosed in Sweden between 1977 and 1985 developed ESRD, and rates of dialysis take-on throughout Europe were stable during the 1990s, despite rising prevalence and longer survival in type 1 diabetes. Even in type 2 diabetes, at least in the USA, the rising incidence of ESRD between 1990 and 1996 in people over 45 years has now been replaced by a consistent decrease up to 2006 in all age groups, amounting to 2–4% per year. This must reflect improved multimodal management of type 2 diabetes . However, the challenge remains formidable, and reducing this costly end-stage complication requires widespread action at primary-care level to diagnose and intercept increasing albuminuria and falling eGFR as early as possible and to treat them vigorously with the best evidence- based means….
Renal disease in type 1 diabetes
Any degree of albuminuria caused by diabetes is very unusual within 5 years of diagnosis, and should be thoroughly investigated (for example, I have seen a teenage type 1 patient with early-onset microalbuminuria and hypertension who turned out to have Cushing’s disease). Nevertheless, functional renal changes do occur shortly after diagnosis, including renal hypertrophy (increased kidney volume) and hyperfiltration, associated with elevated GFR (> 135–150 mL/min). Early renal hypertrophy may increase the risk of developing microalbuminuria, though hyperfiltration does not. Changes on renal biopsy occur within a decade of diagnosis in young people and are associated with lack of nocturnal dipping on ambulatory blood pressure testing. Microalbuminuria may appear or temporarily worsen during periods of very poor glycemic control, but this may be due to the hyperglycemia or to the medical problems, especially systemic infection, that precipitated the poor control.
In a typical population of type 1 patients, about 15% will have microalbuminuria, 5% macroalbuminuria, and 3% will be in renal failure. Prepubertal duration of type 1 diabetes may contribute less than post-pubertal duration to the development of renal disease, and onset under the age of 5 years seems to delay the development of nephropathy. Regression from microalbuminuria to normoalbuminuria is very common (up to one-third of cases), but annually about 2% of microalbuminuric patients progress to macroalbuminuria, cumulatively significant in this young population.
Non-modifiable risks for progression of diabetic renal disease
- Diabetes duration
- Initial albumin excretion rate (AER)
Modifiable or partly modifiable risks
- Blood pressure
- Insulin resistance characteristics (e.g. low HDL-cholesterol, elevated triglycerides, degree of abdominal obesity, inflammatory markers such as white blood count and fibrinogen)
- Total cholesterol
Renal disease in type 2 diabetes
In contrast with type 1 diabetes, at diagnosis up to 10% of type 2 patients already have microalbuminuria and a small proportion overt proteinuria. A global study found microalbuminuria in 40% and macroalbuminuria in 10%. As in type 1 diabetes, hyperfiltration is common, occurring in 10–20%, depending on the measurement method used, and can occur even in patients with IGT. In UKPDS, progression from microalbuminuria to macroalbuminuria was only slightly more frequent in type 2 diabetes than type 1, about 3% annually, though other estimates are a little higher, around 5%; another 2% progress annually from microalbuminuria to macroalbuminuria, and from macroalbuminuria to significant renal impairment or renal replacement therapy. Dyslipidemia (low HDL, elevated apolipoprotein B) and other factors associated with the metabolic syndrome (e.g. elevated fibrinogen) predict progression to overt nephropathy, again as in type 1 diabetes. The dyslipidemia (and worse hypertension) may partly account for the higher rate of diabetic nephropathy found in ethnic minority African, African-Caribbean and South Asian patients, in the UK and elsewhere. While the fear of renal failure is always present, the reality is that the likelihood of death from cardiovascular disease, is greater than the risk of progressing nephropathy, especially when there is renal impairment (serum creatinine > 175 µmol/L, 2 mg/dL), at which level the annual mortality is about 12% .
Other (non-diabetic) nephropathies
The reported frequency of non-diabetic nephropathy in patients with proteinuria varies with the criteria used to justify renal biopsy. Perhaps up to one-third of proteinuric type 1 patients have non-diabetic glomerular disease, but in type 2 patients, selected on the basis of absent retinopathy, the rate is lower, around 10%. Many renal units screen for non-diabetic renal diseases using standard serological tests (e.g. ANF, ANCA, complement), but renal biopsy is very rarely performed these days unless these tests are strongly indicative or there are unusual clinical features, for example:
- rapid deterioration in renal function;
- suspicious urinary sediment, red cell casts;
- sudden development of nephrotic syndrome (see below);
- short duration (e.g. less than 5 years) of otherwise uncomplicated type 1 diabetes.
Even when these features occur, biopsy usually shows typical diabetic renal disease. The clinical benefit of identifying alternative or additional renal parenchymal disease has not been established, but these are subtle matters and patients with any of these unusual features need a nephrology opinion. The full range of non-diabetic renal disease can be encountered on biopsy, but a large retrospective study in the USA  found, in decreasing order of prevalence, focal segmental glomerulosclerosis, minimal-change disease, IgA nephropathy, and membranous glomerulonephritis.
Do not forget renal stone disease, which is more common in people with the metabolic syndrome (increasing risk with increasing numbers of defined components) and type 2 diabetes, and which is associated with chronic kidney disease (CKD).
ESR and CRP in diabetic nephropathy
A high erythrocyte sedimentation rate (ESR) due to elevated fibrinogen synthesis is a non-specific indicator of CKD, and values between 25 and 55 mm/hour would be expected, with a weak upward trend with advancing stage of CKD. In contrast, CRP is normal or only slightly elevated (e.g. about 12 mg/L in CKD stage 5), and barely increases even in hemodialysis patients (about 7 mg/L). CRP is therefore a reliable marker of infection in patients with CKD .
Microscopic hematuria, sometimes heavy, occurs in about 70% of patients with macroalbuminuria, and is not a reliable indicator of non-diabetic renal disease; however, all patients with macroalbuminuria need a renal tract ultrasound scan.
Stages of CKD: estimated glomerular filtration rate
Serum creatinine is no longer regarded as a sufficiently accurate estimate of renal function, since a normal or near-normal serum creatinine may mask markedly impaired renal function, especially in the elderly. eGFR is now routinely reported, nearly always using the MDRD equation, which takes into account age, gender, serum creatinine and ethnic origin (black vs. other ethnicities). Since serum creatinine is a term in the calculation, its variability and effect on the resulting eGFR must be taken into account, especially with eGFR values above 60 mL/min, where precision is particularly poor. The resulting stages of CKD should be used as a broad guide only, and rate of change of eGFR, as well as its absolute value, is very important (Table 8.1). There is concern about the rigid use of referral criteria based on CKD stage. Most people, even those with diabetes, who have CKD stage 3 are elderly and may not have risk factors for progression to ESRD, compared with risk factors for a moderately increased cardiovascular risk. The benefit of nephrology referral in many of these patients, as opposed to careful control of vascular risk factors, which could be more efficiently done in primary care, is questionable.
An important term for a syndrome comprising macroalbuminuria, hypertension, and reduced eGFR (i.e. CKD stage 2 or worse, and deteriorating). It should be used precisely, because it defines a group with a very high risk of cardiorenal events. Data from ADVANCE show that in patients with type 2 diabetes (the same probably applies to type 1 diabetes) with macroalbuminuria (ACR > 34 mg/mmol, 300 mg/g) and eGFR below 60 mL/min, cardiovascular events are increased threefold and renal events 22-fold.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)