Kidney Disease


Condition


Urinary ACR (mg/g)


Terms


Normoalbuminuria


<30


Normally to mildly increased


Microalbuminuria


30–300


Moderately increased


Macroalbuminuria/overt proteinuria


>300


Severely increased



ACR albumin-to-creatinine ratio




Proteinuria, first characterized by Kimmelstiel and Wilson in a pathological report, results from complex damage in the glomerular filtration barrier, including the endothelial cells, basement membrane, and podocytes [5]. Proteinuria not only is a marker of glomerular injury but also implicates tubular injury. The natural course of DKD, proposed by Mogensen, including changes in proteinuria and GFR, as well as stages of preventive treatment, is shown in Fig. 3.1 [6]. In patients with type 1 diabetes, the average time from diagnosis of diabetes to onset of proteinuria is 19 years; in contrast, it is shorter and variable in patients with type 2 diabetes, as the disease may have already been present for several years prior to the establishment of diagnosis. Renal function may loss progressively over several years in patients with type 1 diabetes without intervention. Despite advances in interventions that slow down the progression of DKD, the number of patients progressing to renal failure is still increasing, making diabetes the major cause of ESRD [2].

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Fig. 3.1

Nature course of diabetic kidney disease. GFR glomerular filtration rate; DKD diabetic kidney disease; GBM glomerular basement membrane; BP blood pressure


3.3 Renal Pathology in DKD


After the onset of diabetes, kidney weight and size keep increasing until the establishment of overt nephropathy. Glomerular basement membrane (GBM) thickening is the first change that can be measured. Mesangial expansion (Fig. 3.2) develops later due to increased matrix accumulation in the mesangial region [7]. When renal dysfunction occurs, increased mesangial expansion and marked GBM thickening can be observed. Diffuse mesangial expansion can be linked with nodular lesions containing areas of marked mesangial expansion forming large round fibrillar mesangial zones with palisading of mesangial nuclei around the nodules and compression of the associated glomerular capillaries (Kimmelstiel–Wilson nodules) (Fig. 3.3). The severity of glomerular damage is associated with GFR and albuminuria.

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Fig. 3.2

Histopathological manifestations in diabetic kidney disease. Mesangial expansion and mesangial matrix accumulation are presented. (periodic acid-Schiff staining, ×400)


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Fig. 3.3

Histopathological manifestations in diabetic kidney disease. Typical Kimmelstiel-Wilson nodule (arrowhead), dissolve of mesangium (star) and thickening of TBM (arrow) are presented. (methenamine silver staining, ×400)


Renal tubules and interstitium may also undergo structural changes, particularly in the later stages of DKD. The thickening of the tubular basement membrane (Fig. 3.2) closely correlates with the thickening of the GBM. Tubulointerstitial fibrosis and tubular atrophy may be the best pathologic predictors of progressive loss of GFR, which are more universal in patients with type 2 diabetes. In fact, the renal pathologic change is heterogeneous in patients with type 2 diabetes; only a subset of patients with type 2 diabetes has typical diabetic glomerulopathy, whereas a considerable proportion has more advanced tubulointerstitial and vascular damage [8]. Furthermore, the appearance of the kidney in some patients with type 2 diabetes is more suggestive of glomerular ischemia or tubulointerstitial disease.


3.4 Diagnosis of DKD


The main basis of the diagnosis of DKD is the test values of urinary protein excretion and estimated GFR (eGFR). Renal injury may be considered to be caused by diabetes in most patients with diabetes who have any of the following features [9]:



  • Macroalbuminuria



  • Diabetic retinopathy accompanied with microalbuminuria



  • Microalbuminuria in patients diagnosed with type 1 diabetes for more than 10 years


Screening for DKD should begin at 5 years after the diagnosis of type 1 diabetes and at the diagnosis of type 2 diabetes. Patients with diabetes may annually undergo screening for DKD, which should include measurement of urinary ACR and serum creatinine concentration, estimation of GFR, and ophthalmologic examination (Fig. 3.4).

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Fig. 3.4

Flowchart for the evaluation of DKD in patients with diabetes. ACR albumin-to-creatinine ratio; eGFR estimated glomerular filtration rate; DR diabetic retinopathy; GN glomerulonephritis; DKD diabetic kidney disease; ANCA anti-neutrophil cytoplasmic antibody; C3 complement 3; C4 complement 4


3.4.1 Measurement of Urinary ACR


Microalbuminuria is accepted as an independent risk factor associated with the progression of chronic kidney disease (CKD) and GFR loss. Measurement of microalbuminuria is currently widely available and easy to perform with relatively low cost. As the interpretation of results for albumin concentration alone may be unreliable due to variations in urinary concentration and timed collections are inconvenient, the ACR in a spot urine sample (preferably the first morning specimen) is recommended. Metabolic perturbation, hemodynamic factors, and presence of urinary tract infection may affect the appearance of albumin in the urine [10]. Hence, the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend that elevated ACR be confirmed in the absence of marked hypertension, urinary tract infection, and cardiac failure with two additional tests during the next 3–6 months [9].


3.4.2 Measurement of Serum Creatinine Concentration and eGFR


In clinical practice, the serum creatinine concentration is the most frequently used index to evaluate renal function. However, it is not sensitive enough and may be highly misleading when patients have low muscle mass, especially in elderly patients with diabetes. Therefore, the KDOQI guidelines recommend that the GFR be estimated with the Modification of Diet in Renal Disease Study equation; however, the evidence shows that the usefulness of eGFR alone as a regular screening test for CKD in diabetes is less secure [9].


3.4.3 Ophthalmologic Examination


A study including a cohort of patients with type 1 diabetes and with type 2 diabetes revealed that a large proportion of patients with type 1 diabetes and macroalbuminuria also showed signs of diabetic retinopathy, whereas nearly half of the patients with hypertension and type 2 diabetes who had macroalbuminuria did not have concomitant retinopathy [11]. Thus, the presence of retinopathy and macroalbuminuria in patients with type 1 diabetes strongly suggests DKD. In contrast, as for patients with type 2 diabetes, the accompanied presence of retinopathy is only partly useful in the discrimination of renal pathology, and the absence of retinopathy does not rule out the presence of DKD.


3.4.4 Indications for Renal Biopsy


Due to the variability in clinical course and complexity of clinical manifestation, renal biopsy is required for some patients with both diabetes and CKD to discriminate the potential cause of the kidney disease. Renal biopsy should be considered in the following patient situations:


  1. 1.

    eGFR rapidly declines, or renal dysfunction without significant proteinuria is observed.


     

  2. 2.

    The onset of proteinuria is sudden and progresses rapidly, particularly in patients with duration of type 1 diabetes <5 years. Alternatively, the evolution of proteinuria is atypical (e.g., nephrotic syndrome develops in the absence of persistent microalbuminuria).


     

  3. 3.

    The presence of macroscopic hematuria or active nephritic urinary sediment containing acanthocytes and red blood cell casts, which suggests glomerulonephritis, is detected.


     

3.5 Management of Patients with Diabetes and CKD


For patients with diabetes, when GFR <60 mL/min/1.73 m2, complications of CKD should be evaluated, which commonly include electrolyte imbalance, metabolic acidosis, anemia, secondary hyperparathyroidism, and CKD–mineral bone disorder. Adjustment of drugs’ dosage is necessary (Table 3.2).


Table 3.2

Management of patients with diabetes and CKD according to GFR







































GFR (mL/min/1.73 m2)

Recommendation

All patients with diabetes

Screen for serum creatinine, ACR, eGFR, and serum potassium every 12 months


45–60

Consideration of dose adjustment of drugs in use


Screen for eGFR every 6 months


Screen for serum electrolyte (Ca, P included), acid alkali balance, hemoglobin, and parathyroid hormone


Evaluation of vitamin D


Consideration of test for bone mineral density


Nutritional consultation


Referral to nephrologist when diabetes with non-DKD or the cause of CKD is unknown


30–44

Screen for eGFR every 3 months


Screen for serum electrolyte (Ca, P included), acid alkali balance, hemoglobin, parathyroid hormone, albumin, and weight


Consideration of dose adjustment of drugs in use


<30

Referral to nephrologist



GFR glomerular filtration rate; ACR urinary albumin-to-creatinine ratio; eGFR estimated glomerular filtration rate; CKD chronic kidney disease; DKD diabetic kidney disease


3.5.1 Treatment of DKD


Interventions deemed useful in preventing the progression of DKD include lifestyle improvement, strict glycemic and blood pressure (BP) control, control of dyslipidemia, and renin–angiotensin–aldosterone system (RAAS) blockade. Patients who develop ESRD may require renal replacement therapy (Fig. 3.4).


3.5.1.1 Lifestyle Improvement


The KDOQI guidelines recommend a dietary protein intake of 0.8 g/kg body weight per day for individuals with diabetes and stage 1–4 CKD [9]. For patients with diabetes on hemodialysis (HD), 1.3 g/kg weight per day is suggested. Smoking should immediately be stopped upon the diagnosis of diabetes.


3.5.1.2 Glycemic Control


Hyperglycemia is the primary cause of DKD. Strict glycemic control through insulin or islet cell transplantation improves hyperfiltration, hyperperfusion, and glomerular capillary hypertension and decreases urinary albumin excretion in experimental diabetic animals. Moreover, strict glycemic control slows the development and progression of DKD in patients with diabetes.


In the Diabetes Control and Complications Trial (DCCT), patients with type 1 diabetes who received intensive therapy (average hemoglobin A1c [HbA1c] level of 7.2%) showed a 39% lower risk of developing microalbuminuria when compared to patients who received conventional therapy (average HbA1c level of 9.1%) at 6.5-year follow-up. Furthermore, patients receiving intensive therapy showed a 54% reduction in progression from microalbuminuria to macroalbuminuria [12]. At the end of the DCCT, all patients in the previous two groups received intensive therapy, and nephropathy was evaluated based on urine specimens at 3 and 4 years after the original DCCT. The average HbA1c level was 8.2% in the previous conventional therapy group, and 7.9% in the previous intensive therapy arm. However, the intensive therapy group still has advantage over the former conventional therapy group with an 86% lower risk of new-onset albuminuria. More recently, data from the DCCT and Epidemiology of Diabetes Interventions and Complications (EDIC) study suggested a 50% reduction of the long-term risk of impaired GFR in patients undergoing intensive therapy as compared to their counterparts receiving conventional therapy [13].


A number of major studies have also reported a lower risk of DKD in patients with type 2 diabetes undergoing stricter glycemic control. As shown in the United Kingdom Prospective Diabetes Study (UKPDS), newly diagnosed patients with type 2 diabetes were randomly divided into intensive therapy (HbA1c level of 7.0%) treated with sulfonylurea or insulin and conventional therapy (HbA1c level of 7.9%) with diet alone [14]. The reduction in the risk of developing microalbuminuria over 9 years and of progression from microalbuminuria to proteinuria was 24% and 42%, respectively, in the intensive therapy group. After study termination, patients were observed for another 10 years. Although the HbA1c level between the two groups was comparable within 1 year, lower risk of microvascular disease and myocardial infarction persisted. This phenomenon of prolonged beneficial effects on complications of diabetes achieved through strict glycemic control even being followed by less intensive glycemic control has been described as “metabolic memory” or “legacy effect.”


Considering the impressive results from several major clinical trials, the American Diabetes Association (ADA) suggests an HbA1c level of <7% for all patients with diabetes in order to reduce their risk of developing DKD [15]. The target blood glucose level can be achieved through treatment with insulin, oral hypoglycemic drugs, or a combination of both. Insulin can be used at any stage of DKD. However, oral hypoglycemic drugs should be carefully used according to one’s renal function (Table 3.3) [16]. The use of most first- and second-generation sulfonylureas should be avoided when the eGFR is ˂60 mL/min/1.73 m2. Biguanides (metformin) should not be used if GFR is <30 mL/min/1.73 m2 or the serum creatinine concentration is >1.5 mg/dL in men and >1.4 mg/dL in women. Thiazolidinediones can be safely used in patients with DKD.
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Oct 20, 2020 | Posted by in NEPHROLOGY | Comments Off on Kidney Disease

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