The Journal — July 2016
By Patricio A. Pazmiño, PhD, MD
Send correspondence to Patricio A. Pazmiño, PhD, MD, Nephrology, Internal Medicine Hypertension Center, 1701 N Mesa, El Paso, TX 79902-3503; email: drppazmino[at]gmail[dot]com.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States and other developed countries. In 1982, diabetes accounted for 27% of patients with ESRD in the United States and rose to 36% by 1992 and to 47% in 2012. Currently, the number of prevalent cases of ESRD in the country (dialysis and transplant) exceeds more than 636,900. Primary care practitioners (PCP) provide more than 90% of the diabetic care and are well-positioned to identify, prevent, and treat initially DN. PCPs should identify DN with a urine microalbumin test, obtain a serum creatinine and glomerular filtration rate, monitor hemoglobin A1c, and treat hypertension and dyslipidemia according to current guidelines. This article reviews basic concepts and goals for DN as well as the 2014 data for diabetic renal failure in the most populous counties in Texas. The Texas counties bordering Mexico show an excessive prevalence of diabetic renal failure.
Diabetic nephropathy (DN), also called diabetic kidney disease (DKD),1 is one of the most common renal disorders seen in Texas. A grave complication of diabetes mellitus (DM), DN is also the leading cause of end-stage renal disease (ESRD) in the United States and other developed countries.2,3 Today in the United States, approximately 75% of men and 67% of women are either overweight or obese (using a body mass index of >25),4 and 50% of US adults have diabetes or prediabetes.5 The prevalence of DM in the United States has risen from 5.5% to 9.3%, paralleling the rise of obesity.6 Over the past three decades, we have witnessed an epidemic increase in obesity, metabolic syndrome, and type 2 DM (T2DM). This is also reflected in a significant increase in the number of patients with DN in Texas.
DN or DKD is a progressive disorder caused by damage to the glomerular capillaries and associated renal structures; DN is preventable, and progression may be delayed if treated on a timely basis. DN has five stages. The overt clinical phase is preceded by many decades of microalbuminuria.7 This is, in turn, a predictor of future microvascular and macrovascular diseases. The final stage of DN is ESRD. When patients reach ESRD, the disease becomes a significant socioeconomic burden to the patients, their families, and the health care system. The morbidity and mortality caused by DN are almost twice as high as those of the nondiabetic with ESRD, and the overall prognosis for diabetics is the worst of all patients with ESRD.2,8
This review encompasses basic information about DN: epidemiology and 2014 data of diabetic renal failure in Texas, the natural history and stages of diabetic nephropathy, pathogenesis, risk factors, diagnosis, clinical manifestations, treatment essentials including the Rule of 100's, and conclusions.
The Centers for Disease Control and Prevention (CDC) estimated that in 2012 about 29.1 million Americans, or 9.3% of the population, had DM. About 8.1 million persons with DM were undiagnosed.9 Type 1 DM (T1DM), formerly known as insulin-dependent diabetes mellitus, is due to minimal or absent pancreatic insulin secretion. It accounts for about 10% of diabetics and occurs most often in children and young adults. T2DM, previously known as non-insulin–dependent diabetes mellitus, is characterized by insulin resistance. Usually occurring in overweight adults older than 30 years, T2DM is the most common type of diabetes. More than 13 million Americans have glucose intolerance, and about one-third to one-half of them remain undiagnosed. One in two people with diabetes do not know they have it.10
Diabetes and its associated microvascular and macrovascular complications represent a major public health problem worldwide. DM is associated with an excessive risk for cardiovascular morbidity and mortality. DM is the seventh leading cause of death in the United States. Every 7 seconds, 1 person dies from DM. Direct and indirect costs of DM exceed $245 billion a year.10 A recent study from Sweden involving more than 400,000 patients with diabetes showed an excess mortality with worsening glycemic control, severe renal complications, impaired renal function, and death at a younger age.11
In 1982, DN accounted for 27% of US patients with ESRD and rose to 36% by 1992 and to about 44% in 2011.2 On December 12, 1995, the United States had 257,266 Medicare patients with ESRD, and 31.4% of them were diabetic, with a point prevalence rate of 303 per million. The incidence rate during 1995 was 68,870, and 40.4% were diabetic, with an incidence rate of 104 per million. In the same year, 40.4% of Texans with ESRD had diabetes as the primary diagnosis. In 1998, the number of Texans with ESRD was 19,474, and 9136 (46.9%) were diabetic.2 In 2012, the number of prevalent cases of ESRD in the United States was 619,097 (hemodialysis, 402,514; peritoneal dialysis 40,605; and transplant, 175,978).3 The incidence of ESRD in the United States in 2012 was 359 per million and the prevalence (number of ESRD patients per million population on December 31, 2012) was 1976. For example, the El Paso County 2014 point prevalence was 2145 patients with ESRD, 63% or 1357 due to DN (1302 type 2 and 55 type 1)2,3,12 (also P.A. Pazmiño, MD, unpublished observations, Diabetic renal failure in Texas along the border with Mexico).
We previously reported data of 19,336 patients from 80 counties in Texas in 2003 and also analyzed the influence of ethnicity and household income on diabetic renal failure.12 Table 1 presents the 2014 data obtained from the 2014-2015 Texas Almanac and from the ESRD Texas network for the 20 most populous counties in Texas. This table includes the county's population, the number of ESRD patients in each county, and the calculated number and percentage of ESRD due to diabetes and hypertension.
Table 2 shows the same data in the 8 Texas counties bordering Mexico with an unusually high prevalence of diabetic renal failure, which is under further study. This is followed by an update of current concepts on DN.
Natural History and Stages of Diabetic Nephropathy
Mogensen and associates13 have described five stages of the progression of DN in T1DM (Table 3).2 The evolution of DN in T2DM is less well defined but in general may follow a similar course.14 The stages may be blurred as microalbuminuria or proteinuria is often present in many type 2 diabetic patients at the time of the initial diagnosis, including 3% of newly diagnosed T2DM patients who have macroalbuminuria.13 An understanding of the five stages of DN helps the PCP make informed medical and therapeutic decisions
Stage I: Early Hypertrophy and Hyperfunction
An increase in size of the kidneys is accompanied by hyperfiltration. The glomerular filtration rate (GFR) is above normal, up to 140%. Intensive insulin therapy normalizes hyperglycemia and corrects glomerular hyperfiltration.
Stage II: Early Glomerular Lesions
About 30% of T1DM cases progress to stage 2. Two to five years after the onset of T1DM, the renal histology becomes abnormal, and a gradual expansion of the mesangium and matrix is detected plus subtle thickening of the glomerular basement membrane (GBM). Transient microalbuminuria may be noted. Clinically, stages 1 and 2 are usually silent.
Stage III: Microalbuminuria
Stage III is characterized by the presence of fixed microalbuminuria, defined as increased urine albumin excretion (UAE) of 30 to 300 mg/24 hours or 20 to 200 mcg/minute. Over 7 to 10 years, about 30% to 45% of microalbuminuric patients progress to overt proteinuria. Blood pressure tends to be higher in patients with microalbuminuria. The combination of microalbuminuria and higher blood pressure, if not treated properly, gradually leads to progressive GFR deterioration and clinical nephropathy.
Stage IV: Clinical Nephropathy
Clinical nephropathy is manifested by overt proteinuria of more than 300 mg/day. Over several years, a progressive decrease in the GFR of about 10 mL/min/year occurs in patients with T1DM as well as an insidious progression to nephrotic-range proteinuria (more than 3.5 g/day) associated with hypoalbuminemia, hyperlipidemia, and gradual anasarca. Systemic hypertension is noted frequently, and manifestation of renal insufficiency may appear. About 95 % of T1DM patients have coincident retinopathy, but it is present only in about 65% of T2DM patients. Renal biopsy may reveal diffuse or nodular Kimmelstiel-Wilson glomerulosclerosis, plus afferent and efferent arteriolar hyalinosis and progressive tubulointerstitial fibrosis.
Stage V: End-Stage Renal Disease
The lapse between diagnosis of T2DM and ESRD may range from 5 to 30 years. Typically, ESRD may occur decades after the onset of microalbuminuria. The frequency of ESRD and diabetic nephropathy depends strongly on the duration of diabetes and the level of proteinuria. Worsening hypertension and renal insufficiency develop and are associated with glomerular sclerosis and fibrosis. The prevalence of ESRD is about 40% in T1DM versus 20% to 30% in T2DM. Approximately half of patients with T2DM develop proteinuria 20 to 40 years after diagnosis of diabetes but not everyone ends up in ESRD; some succumb to other microvascular and macrovascular disorders, for reasons that are unknown.
Four main theories have been proposed to explain the pathogenesis of diabetic nephropathy:2,13-18
- Hyperglycemia is one of the factors in the development of DN. This may involve a number of mechanisms including hyperfiltration, intraglomerular hypertension, and hypertrophy. DN may also be initiated by alterations in the hexosamine pathway with the formation of advanced glycosylation end (AGE) products and might induce reactive oxygen species, monokines, chemokines, increased protein kinase C activity, changes in metalloproteinases, and growth factors, all of which mediate tissue injury.
- Hormonal imbalances caused by hyperglycemia involve alterations in insulin, growth hormones, glucagon, and, perhaps, abnormal intracellular signaling pathways.
- Renal hemodynamic changes are induced by disturbances in glomerular hypertension and glomerular hyperfiltration. Hyperfiltration is mediated by greater relaxation of the afferent arterioles in the glomeruli and leads to increased glomerular blood flow and elevated glomerular capillary pressure. Hypertension may increase transglomerular protein filtration, inducing proteinuria and mesangial deposition of circulating proteins. As a consequence, mesangial expansion and glomerulosclerosis result in gradual destruction of surviving nephrons. A positive feedback stimulus for compensatory hyperfiltration is then initiated, which leads to a further increase in GFR and progressive renal injury.
- Genetics is the fourth factor as both type 1 and type 2 tend to cluster in families. At present, we cannot predict which patients will develop DN. Type 1 diabetic patients with siblings who have DN have more than a 70% risk for developing DN. Type 2 diabetics have a hereditary predisposition for or against development of DN. However, DN is likely a polygenic disease, and its progression is probably related to multiple polymorphisms with variable effect sizes.
Multiple factors have been identified or proposed that place people at increased risk for development and progression of DN. The most important factors are poor glycemic control, uncontrolled hypertension, family history of DM, racial factors, and smoking. Other putative factors are shown in Table 4; however, they are not consistently present in all cases.2,13-18
The diagnosis and staging are based upon the evaluation of kidney function given by the creatinine and estimated glomerular filtration rate (eGFR) and by the presence of kidney damage or injury as detected in the urinary albumin-to-creatinine ratio (ACR). Most patients are asymptomatic throughout the early stages of DN. The typical features of the 5 stages of DN are summarized in Table 3. The initial diagnostic tests should focus on early detection of kidney injury and the development of incipient nephropathy (Table 5). This has been simplified and replaced in the latest American Diabetes Association (ADA) guidelines to two categories using a spot urine collection to determine a urine ACR. A normal ACR is less than 30 mg/g of creatinine, and increased albumin excretion occurs when the ACR is equal to or more than 30 mg/g of creatinine (Table 6).
Microalbuminuria is diagnosed when the albumin excretion rate is 20 to 200 mcg/min, mg/mL, or mg/L detected in two out of three different determinations of spot or overnight samples done over a 3- to 6-month interval, or an equivalent 24-hour urine excretion of 30 to 300 mg/day (Table 5). Macroalbuminuria, or overt nephropathy, is present when the ACR is more than 200 mcg/min, reproducible in two out of three separate spot collections over 6 months, or more than 300 mg/day.2,19
Recently, the National Kidney Foundation, ADA, Levey et al, and others have updated previous Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines and nomenclature for diabetes and chronic kidney disease (CKD).1,18-23 These guidelines replace prior albuminuria categories based on the ACR (in mg/g) with 3 categories: A1: ≤30 mg/g, normal to mildly increased; A2: ≥30-300 mg/g, moderately increased (formerly microalbuminuria); and A3: ≥300 mg/g, severely increased (includes nephrotic syndrome, ACR ≥2000 mg/g) (Table 6). The 2016 updated ADA guidelines also replaced the term "diabetic nephropathy" with "diabetic kidney disease."1 The GFR categories are now labeled as G1 to G6 expressed in mL/min/1.73 m2 (Table 6). For example, a patient can be classified as G3aA3. This corresponds to a GFR of 45 to 59 with severely increased albuminuria that causes ACR greater than 300 mg/g of creatinine.
Several studies have shown that the onset and course of DN or DKD can be significantly delayed by early intervention. The first 3 CKD stages are usually asymptomatic and requires laboratory testing. Therefore, recommendations call for the albuminuria level to be checked at diagnosis and annually in patients with T2DM. In patients with T1DM, microalbuminuria should be checked at puberty and annually after a 5-year duration of diabetes.1,2,13,19-23 Confirmatory tests are recommended, as false positive tests may occur with urinary tract infections, hypertension, massive obesity, excessive physical exercise, stress, severe hyperglycemia, congestive heart failure, and fever. In the office setting, microalbuminuria can be checked easily with two commercially available tests: the Roche's Micral Test immunoassay and the Miles' tablet Micro-Bumintest. The Micral Test immunoassay uses a strip that is immersed in the urine sample for 5 seconds, producing a color reaction after 1 to 5 minutes. This result is compared with color blocks on the vial label corresponding to the albumin concentration found in mg/L.2
The recommended test for albumin in the urine is a spot urinalysis for microalbumin and creatinine ratio. If microalbuminuria is present, a 24-hour urine collection may be done to check for protein and creatinine clearance. If more than 300 mg of albumin is found or if the serum creatinine is >1.8 mg/dL, a nephrological evaluation is suggested to exclude other causes of proteinuria. If no other causes are present and if microalbuminuria persists, the patient should be treated for DN or DKD with intensified glycemic control, risk reduction, and normalization of blood pressure if applicable. But once microalbuminuria is documented, irrespective of blood pressure, treatment with an angiotensin-converting enzyme (ACE) inhibitor is recommended or an angiotensin receptor blocker (ARB) if the patient has side effects.1,2,19-23
Overt DN is characterized by proteinuria, hypertension, edema, and renal insufficiency. About 40% of type 1 diabetic patients develop significant nephropathy. However, in type 2 diabetes, DN occurs only in around 5% to 20%, depending mostly on ethnic factors. Renal histopathological changes may include minimal or no glomerular changes, glomerular mesangial expansion, nodular glomerulosclerosis, the classic lesions of the Kimmelstiel-Wilson syndrome, or nonspecific vascular changes and tubulointerstitial disease.1,2,13-19 The earliest evidence of nephropathy is microalbuminuria.13 This later progresses to clinical proteinuria or macroalbuminuria, overt or gross proteinuria (dipstick positive >300 mg/day or more than 200 mcg/min), which is often accompanied by hypertension and progression to a nephrotoxic nephrotic range proteinuria (>3.5 g/day). Eventually, macroalbuminuria leads to decreasing GFR, about 1 mL/min per month, with an inexorable increase in serum creatinine until ESRD appears.1,2,13,14
Several renal function tests can be used to follow the progression of DN or DKD. The creatinine clearance (Ccr) is a widely used direct method of estimating GFR. It is based on results of a carefully timed urine collection, a period usually of 24 hours. Invalid studies may result from an incomplete collection or failure to achieve bladder emptying at the start and end of the collection period. Serum creatinine (Scr) and blood urea nitrogen tests are indirect measures of GFR; however, they are less sensitive markers of renal function than the creatinine clearance. In early DN or DKD, the reported normal range may not show an increase until approximately half of the renal function is lost and overt nephropathy is established.2 Other nuclear medicine studies, such as 125Iothalamate, 51Cr-EDTA, and 99mTC-DTPA, can be used to estimate the GFR, but these are not widely available and are expensive. In a patient with nonfluctuating renal function, a rough assessment of the creatinine clearance can be obtained from plasma without urine measurements by using the Cockcroft-Gault formula:24
[140-age] x [body weight (kg)]
Cr Clearance or Ccr (mL/min) = -----------------------------------------
72 x Scr (mg/dL)
If the patient is a woman, the same formula is used, and the result is multiplied by 0.85 to adjust for smaller muscle mass. The formula overestimates CCr in obese patients and those on a low-protein diet. For the past two decades, the Modification of Diet in Renal Disease (MDRD) formula that uses serum creatinine or its modifications has been used to estimate the GFR and CKD staging. Other formulas proposed use cystatin or a combination with creatinine, and for many investigators, the CKD EPI (Chronic Kidney Disease Epidemiology Collaboration) equation is preferred. This was just reviewed by Levey et al.22 Other experts argue that CKD should be adjusted according to age and that an artificial increase is seen in patients reported as having CKD.25 Adding to this confusion, the KDOQI and ADA groups have reviewed the staging of CKD and have replaced the nomenclature and prior concepts of microalbuminuria and macroalbuminuria with moderately increased albuminuria and severely increased albuminuria, respectively.2,18-23 The author prefers the prior conceptual staging outlined in Table 3.2,13
The risk for cardiovascular disease increases as the stage of DN progresses. Once albuminuria is detected, the risk increases at earlier stages. When the patient has advanced renal insufficiency approaching ESRD, a closer estimate of the GFR may be done with a simultaneous 24-hour urine collection to check for creatinine and urea clearances. Usually in ESRD, the creatinine clearance overestimates, whereas the urea clearance underestimates the actual GFR. Thus, the arithmetic mean of the two clearance values gives an approximate estimate of the actual GFR. When this value is approaching 15 mL/min/1.73 m2, patient education, extensive counseling, and preparation for renal replacement therapy should be done without delay.2,18-23
As renal function deteriorates, a pattern of signs and symptoms may become evident. Symptoms can take 5 to 10 years to appear after the kidney damage begins. Usually the symptoms are apparent when the GFR is 35% or less and when patients become nephrotic. As the kidney conditions worsen, the uremic syndrome gradually becomes apparent due to the progressive accumulation of metabolic waste products. Late symptoms at this stage include tiredness, malaise, nausea, vomiting, anorexia, itchy skin, and peripheral edema.2,13-23
Cardiovascular and pulmonary manifestations may include hypertension, pericarditis, arrhythmias, congestive heart failure, and pulmonary edema. Endocrine and metabolic abnormalities may include renal osteodystrophy, carbohydrate intolerance, infertility, and malnutrition. Fluid and electrolyte abnormalities include weight gain, edema, metabolic acidosis, calcium, phosphorus, and electrolyte imbalances. Gastrointestinal signs and symptoms may include anorexia, hiccups, nausea, vomiting, gastrointestinal bleeding, gastroenteritis, and even uremic breath. Hematologic and immunologic abnormalities encompass fatigue, anemia, leukopenia, and increased risk of bleeding and infection. Neuromuscular abnormalities range in severity from retinopathy, muscular irritability, polyneuropathy, and fatigue to subtle changes in concentration and level of consciousness, including stupor, seizures, and coma. When the GFR falls below 20 mL/min, the patient with DKD or DN gradually is at a greater risk for developing concomitant illnesses. Finally, when creatinine clearance falls to 10 mL/min or less, the patient with DN is often too ill to perform any work or maintain any livelihood without renal replacement therapies.2,13-23
The treatment of DN is based on the clinical stage of DN or DKD. The approaches directed to each different stage of DN include nonpharmacologic and pharmacologic therapies.2,18-23,26-31
The nonpharmacologic therapy includes patient education, risk reduction, identification and management of comorbid conditions, and lifestyle modifications including diet and exercise. When a patient reaches stage 5 diabetic nephropathy, ESRD, or end-stage kidney disease, the options for renal replacement therapy include hemodialysis, peritoneal dialysis, and transplantation. In the elderly, conservative non-dialytic care may be advisable, as studies have shown no real survival or medical advantages of dialytic therapies. In the 1970s in the United States and United Kingdom, patients older than 65 years were not started on dialysis.
In the United States, several types of oral agents and combinations thereof plus several types of insulins have been approved for the pharmacological treatment of diabetes mellitus (Table 7).26-31 Many of these agents are not indicated in patients with CKD stages 3-5 due to adverse side effects.
As for preventative measures, three can be taken to slow the development of DN. The primary prevention aims to forestall or delay the progression from normoalbuminuria to microalbuminuria. The arrest or postponement of the progression from microalbuminuria to macroalbuminuria is the aim of secondary prevention. Tertiary prevention hinders or defers the progression of overt DN or macroalbuminuria to ESRD and cuts morbidity and mortality by delaying the time lag from macroalbuminuria to dialysis or transplant.
Renal and cardiovascular morbidity and mortality are markedly increased in patients with T2DM, and the level of albuminuria or proteinuria predicts outcomes. Thus, we shall review the main strategies used to prevent DN or DKD progression, including intensive glycemic control, effective albuminuria management, aggressive blood pressure control, the Pazmiño Rule of 100's, smoking cessation, protein restriction, cholesterol reduction, and reversal of endothelial dysfunction.2,16,18,21,26-31
Intensive Glycemic Control
Compelling evidence from the medical literature shows that long-term glucose control is essential. We should strive to maintain the glycosylated hemoglobin A1c (HbA1c) level at or below 7 percent. The lowest possible HbA1c is the target, but exceptions or an HbA1c goal around 8% should be sought in older and frail patients who have low life expectancy, are demented, or have hypoglycemia unawareness.
T2DM is a progressive disorder, and all treatments show secondary failure over time. Insulin therapy is often recommended when oral agents or combinations are no longer successful or not indicated. In most patients, the failure of two or three oral agents used together calls for the use of insulin alone or in addition to oral agents, and these are not reviewed here.2,27-31
Of major importance are the results of the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Research Group, which have shown the benefits of intensive therapy in delaying the onset of diabetic complications.25-33 The United Kingdom Prospective Diabetes Study34 shows a variety of results including a 26% reduction of microvascular complications, a 21% lowering of retinopathy progression, a 34% decrease in microalbuminuria, a 16% decline of myocardial infarction, and a 10% diminution of diabetes-related death, as compared with conventional therapy. Thus, intensive pharmacotherapy is effective in reducing microvascular complications. For every percentage point decrease in HbA1c, the risk of complications is reduced by 35%, and, more importantly, any reduction in HbA1c is beneficial.2,18,21,26-34
Glucose control is probably a key determinant for ESRD risk. The ADVANCE trial, the largest clinical trial that includes follow-up of 8494 patients, showed that intensive glucose control leads to long-term reductions in the risk for developing ESRD.35
The latest ADA guidelines endorse optimization of glucose and blood pressure control to reduce the risks or to slow the progression of DN.1,19,28,30 Table 8 shows the parameters and goals for patients with diabetes mellitus.2,21,28-31
Currently, a dozen and half societies or organizations offer guidelines for patients with diabetes (Table 9). The annual ADA guidelines are recommended;1,2,26-31 however, few practitioners read them. Thus, I suggest the Rule of 100's as noted on the parameters shown on the right side of Table 8. This rule is based on evidence gathered from recent trials, ADA and National Kidney Foundation recommendations, clinical experience, and current guidelines.36 This rule is a practical, effective, and simple guideline proposed to enhance the management of the diabetic patient. The objective of this rule is to integrate into clinical practice the results of clinical trials and evidence-based medicine. The Rule of 100's should be applied to the mean glycemic control, mean arterial blood pressure, mean low-density lipoprotein cholesterol (LDL-C), and mean microalbuminuria, and can be extended to other parameters (eg, triglycerides, ideal body weight, salt intake, smoking abstinence, and exercise). The Rule of 100's simplifies the main ADA recommendations for the busy clinician, and its implementation will ultimately achieve risk reduction and decrease the prevalence of diabetes-related complications.36
Effective Albuminuria Management
Microalbuminuria control is of paramount importance. Again, microalbuminuria is now called moderately increased albuminuria.1,18,20 At this stage, intensive diabetic control is critical. Type 1 diabetic patients with microalbuminuria have a 15- to 20-fold predisposition to develop macroalbuminuria (now called severely increased albuminuria) after 10 years, whereas in type 2 diabetic patients, the risk is only a 5- to 10-fold increase. Microalbuminuria is a marker of endothelial dysfunction and is also a strong predictor of myocardial infarction and stroke. Thus, a routine urinalysis is recommended in type 2 diabetic patients at the time of diagnosis. If the urinalysis is positive for protein, a 24-hour collection for protein and creatinine clearance is advisable for follow-up and treatment. If the urinalysis is negative for protein, a test for microalbuminuria is needed and, depending on the results, an algorithm can be followed (Figure), as previously suggested by ADA.2,19
If the test for microalbuminuria is positive, it needs to be validated one more time, and thereafter treatment with any ACE inhibitors is initiated. The microalbuminuria test should be repeated in 4 to 6 weeks. If, on one hand, no microalbuminuria is detectable, the ACE inhibitor is continued. If, on the other hand, microalbuminuria is still present, the dose of the ACE inhibitors should be increased. This is followed up by another determination of microalbuminuria in 4 to 6 weeks, and the dose of the ACE inhibitor should be increased (unless contraindicated) until the microalbuminuria disappears or is stable in three consecutive urine samples.2,19
Aggressive Blood Pressure Control
Aggressive blood pressure control for a patient with DN or DKD is crucial. Hypertension is the most important factor that accelerates the progression of DN. The blood pressure should be lowered gradually after significant carotid stenotic lesions have been excluded, especially in the elderly, to avoid potential complications.2 There is significant association between blood pressure and insulin sensitivity. The antihypertensive therapy is very important in patients with T2DM but is beyond the scope of this discussion and has been reviewed recently.37 Note the findings of a 50% reduction of major cardiovascular events in type 2 diabetic patients whose target diastolic pressures were 80 mm Hg; this was not seen among patients whose diastolic blood pressures were 90 mm Hg. Thus, it is recommended that the blood pressure in patients with DN and proteinuria of less than 1 gram should be 130/85 mm Hg. However, if the patient with DN has more than 1 gram of protein per 24 hours, the recommended blood pressure should be 125/75 mm Hg. These goals are a bit controversial and have been recently modified.1,2,18,19,34-39
Microalbuminuria should signal the need for antihypertensive therapy. ACE inhibitors should be the first line of therapy for DN. If side effects appear or if blood pressure control is not adequate, ARBs may be used instead of or, in some cases, in addition to ACE inhibitors.1,2,19,34-39 An ACE or an ARB is not indicated if the patient is normotensive and has no albuminuria. Independent of the systemic blood pressure changes, ACE inhibitors have a beneficial effect on proteinuria, GFR, vasculature, heart, and kidneys. However, because of the small risk for hyperkalemia and unrecognized renal artery stenosis (<5%), serum creatinine and potassium should be monitored at the start of the treatment and 1 week thereafter.2
Use of the renin-angiotensin-aldosterone system blockade before the development of DN appears to be of little advantage, as suggested by the study of Mauer et al, which found no benefit in preserving renal function or preventing proteinuria over a 5-year period.38
The long-acting calcium channel blockers are commonly prescribed and are generally well-tolerated. They are used generally in combination with other agents, but they are less effective than ACE inhibitors in reducing albuminuria and with respect to cardiac endpoints. Thereby, they should not be used as monotherapy but in combination with ACE inhibitors. Diuretics and beta blockers are also commonly prescribed, and they may have undesirable side effects and are inferior in reducing proteinuria.1,2,19,36-39
The choice of agents in hypertensive diabetic patients is mostly based on two factors: the prevention of adverse cardiovascular events and the effects of slowing or reversing the progression from one stage of DN to the next. For example, the ALLHAT trial found a lower onset of heart failure with chlorthalidone compared with amlodipine and lisinopril.40 In the ACCOMPLISH trial, an ACE inhibitor combined with amlodipine provided better protection against cardiovascular outcomes than the combination of an ACE inhibitor and low dose of hydrochlorothiazide.41
As noted above, ACE inhibitors or ARBs are the preferred initial therapy in patients with microalbuminuria or macroalbuminuria or even in hypertensive patients without albuminuria or proteinuria. ACE inhibitors or ARBs are associated with improvement and stabilization in renal function and a decrease in albuminuria. At present, about a dozen ACE inhibitors and more than half-a-dozen ARBs are available. The reader is suggested to become thoroughly familiar with one or two agents in each group.
In general, as DN progresses, combination therapy is usually required in most patients. Carvedilol (Coreg) is a preferred beta blocker when compared with metoprolol because of potential benefits on glycemic control and a lower rate of progression of DN or DKD. If the patient has renal disease or heart failure, a loop diuretic should be added. The goal blood pressure should be lower than 140/90 mm Hg in most diabetics and ideally 130/80 mm Hg in DN or DKD patients with proteinuria exceeding 500 mg/day. Occasionally, a systolic pressure below 120 mm Hg may be considered to decrease stroke risks, but the absolute benefit attained is 1 in 89 patients at 5 years and is counterbalanced by more adverse side effects, extra visits, and increased cost, as noted in the ACCORD blood pressure trial.42 In general, we prefer to avoid a diastolic pressure below 55 to 60 mm Hg to avoid potential cardiological side effects.43
Recently, the Systolic Blood Pressure Intervention Trial showed a 30% drop in cardiovascular events, stroke, and death in a group treated to a systolic target of 120 mm Hg rather than 140 mm Hg and prompted the Study Data Safety Monitoring Board to end the study early. However, this study did not include patients with DM.44
To sum up, ACE inhibitors and ARBs should be used as first-line therapies in T1DM and T2DM if hypertension and albuminuria or proteinuria is present. ACE inhibitors or ARBs slow the progression to ESRD. They are not curative or preventative once DN or DKD is established. Currently, no major evidence supports ACE inhibitors and ARBs for the primary prevention of microalbuminuria, and the target blood pressure should be lower than 130/80 mm Hg, especially in those patients with proteinuria. A simple guideline for the primary care practitioner is the Rule of 100's, but for the interested reader, the yearly updated ADA guidelines are suggested.1,18,19.34,36
Regarding the possible use of an ACE/ARB combination to maximally block the renin-angiotensin-aldosterone system, it can be done but needs to be monitored closely for adverse side effects. The CALM study looked at candesartan and lisinopril endpoints in terms of blood pressure control and proteinuria, and although a benefit was shown, no improvement occurred in mortality and disease outcomes.45 The NEPHRON-D study found the combination of ACE inhibitors and ARBs was associated with increased risk for adverse side effects in patients with DN,46 and the ONTARGET study showed that the combination group had worse renal function and adverse outcomes compared with the group that received a single agent.47
Progression of DN to ESRD is closely correlated with the degree of proteinuria, affecting less than 10% of patients with <1 g/day of proteinuria, as compared with almost 3 times higher in patients with 2 to 4 g of proteinuria per day.48 As noted before, nephrotic range proteinuria is toxic (nephrotoxic) to the kidneys.
Concerning the use of ACE inhibitors and ARBs for renoprotection in the context of major surgery, the decisionmaking should be done individually. If the indication is for renal benefit, a short-term discontinuation seems reasonable. If it is for hypertension or myopathic heart disease, it is preferable to continue these agents and monitor the renal function postoperatively.
Because an "aldosterone escape" may exist in patients treated with an ACE inhibitor or ARB, aldosterone receptor antagonists such as spironolactone (Aldactone) or eplerenone (Inspra) have been studied for use in conjunction with ACE inhibitors or ARBs. For example, spironolactone can reduce significantly the proteinuria excretion49 but needs to be monitored closely for hyperkalemia. Similarly, direct renin inhibitors like aliskiren (Tekturna) may also play a role in the treatment of DN,50 but again, patients need to be followed closely to avoid side effects of the combined renin-angiotensin-aldosterone system blockade.2,27,37,51
An issue that frequently arises is hyperkalemia in patients taking ACE inhibitors, ARBs, or a combination of agents. In this situation, a reduction of the doses should be tried, potassium restriction should be started, and loop diuretics can be used, as well as avoidance of potassium-sparing diuretics. Kayexalate can be used temporarily. However, if the potassium level does not return to baseline levels in 2 to 4 weeks, ACE inhibitors and ARBs should be discontinued. Patiromer, a new nonabsorbable polymer that binds potassium in exchange for calcium, may be a helpful adjunctive therapy.52 This agent was recently approved by the Food and Drug Administration as Veltassa.
Smoking is a risk factor for cardiovascular disease, and diabetics are at increased risk of premature death from cardiovascular disorders. Evidence suggests that smoking can hasten the progression of DN.53,54 Smoking cessation should be strongly encouraged.
Protein restriction remains subject to controversy as shown by the MDRD study group.34,38,39,55 However, there does appear to be the benefit of a modest reduction in dietary protein. Based on current data, a protein restriction of about 1 g/kg/day (approximately 10% of daily calories) is recommended for patients with clinical nephropathy, with a further restriction to 0.8 g/kg/day once GFR begins to fall.1,2,18-21,55,56 Instructions and counseling by a renal dietitian is desirable to avoid protein-calorie malnutrition.
Patients with DN are at high risk for cardiovascular disease and premature death. Lipid management is important in the prevention of atherosclerosis. About 2% of patients with CKD progress to ESRD. Most patients with DN will die of a cardiovascular event before they progress to ESRD. The risk increases significantly after stage CKD 3b; the risk can be lowered with the use of lipid-lowering therapy. Results of the Heart Protection Study using simvastatin demonstrated that a 30% to 40% reduction from baseline LDL cholesterol is most beneficial for people with kidney disease.57 Type 1 and type 2 diabetic patients should be screened for cardiovascular risk factors and treated accordingly. Ideally, lipid-lowering therapy should be based on assessing cardiovascular disease risk instead of an elevated LDL-C level.58 The American College of Cardiology and the American Heart Association Task Force updated guidelines 3 years ago. For patients with DM and LDL-C levels of 70-189 mg/dL, we need to calculate the 10-year risk of atherosclerotic cardiovascular disease. If risk is <7.5%, moderate-intensity statin therapy is suggested. If risk is >7.5%, high-intensity statin therapy is needed. The latter include patients with an acute coronary syndrome; prior myocardial infarction; stable or unstable angina; coronary or other arterial revascularization; or stroke, transient ischemic attacks, or peripheral arterial disease.59 A risk calculator is available at http://my.americanheart.org/cvriskcalculator. If a calculator is not available, the Rule of 100's is an easy and simple alternative that includes an LDL-C of 100 and preferably a level of 70.36
Reversal of Endothelial Dysfunction
Under normal conditions, the glomerular endothelium actively regulates vascular tone, permeability to molecules and macrophages, the composition of the endothelial matrix, and the proliferation of smooth muscle cells. The renin angiotensin system plays also an important role in regulating vascular fibrinolysis, growth factors, and matrix accumulation. This system interacts with the fibrinolytic system at the level of the endothelium. The endothelium is a critically important regulator of blood flow. ACE is a crucial mediator of this interaction. About 90% of ACE is tissue bound (blood vessels, heart, kidneys, and central nervous system), and 10% is in the circulation. This enzyme is present on the surface of endothelial cells. Therefore, ACE regulates the expression of the fibrinolytic proteins tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Angiotensin II regulates endothelial type 1 PAI-1 production and secretion while bradykinin promotes vasodilation by enhancing the production of t-PA. The PAI-1 is particularly increased in the vasculature of patients with diabetes. Endothelial dysfunction is undoubtedly a factor in the development of the microvascular and macrovascular complications seen in T1DM and T2DM.2,18,37-39
The ACE inhibitors protect the vessel wall and produce a decrease in angiotensin II level and accumulation of bradykinin. This in turn promotes the release of nitric oxide, which results in vasodilation and relaxation of vascular smooth muscle. The ACE inhibitors blunt the production of superoxide anions, decrease vascular smooth muscle cell growth and migration, and decrease platelet aggregation. They also help maintain the fibrinolytic balance by decreasing PAI-1 and increasing t-PA levels. Thus, they may contribute to the effect of these agents in preventing ischemic cardiovascular events in patients with T2DM. Also, angiotensin II is involved in matrix accumulation and induction of glomerular cell growth. Therefore, the reversal of endothelial dysfunction with ACE inhibitors, statins, aspirin, and thiazolidinediones helps slow the progression of DN and is an area of active investigation.2,16-21,34-39
CKD is preventable and, if recognized early, progression can be delayed. However, when a patient reaches ESRD, the appropriate steps must be taken for dialysis or transplantation or both for the patient's survival. The patient should be referred to a nephrologist on a timely basis. In general, the nephrologist will provide patient education about choices available and will initiate and supervise renal replacement therapy. The choices of renal replacement therapy are tailored to the patient's desires and abilities.2
Avoid a late referral of the patient with DN and renal failure. Some of these patients may present as uremic emergencies, which are often associated with high morbidity and mortality. Late referrals should be avoided because they provoke a major setback to the patient with DN or DKD, who frequently has difficulty accepting the options available for ESRD. These late referrals also have a worse prognosis, and they may have to rely on a temporary or inadequate angioaccess and associated complications. Many of these DN patients are affected, as they may lose their jobs due to the prolonged absence from work.2,16,19,33,41,59-61
In the United States, Medicare has provided major support to the ESRD patient's care since the enactment of a special law in 1972. Nonetheless, the purpose of the management of the patient with DN should be to provide patient education and intensive and appropriate medical, lipid, and antihypertensive therapy. We should aim to maintain near euglycemia and normoalbuminuria, achieve risk reduction, and ideally stop or reverse the progression of DN. Our ultimate goal should be to decrease the prevalence of diabetic complications in the 21st century.2
Glenda Harbert, RN, COQH, and Nathan Muzos, information management director, ESRD Network of Texas, assisted in providing 2014 ESRD information.
Grant Support: Nephrology, Internal Medicine & Hypertension Center (NIH Center), El Paso.
- American Diabetes Association. Standards of medical care in diabetes-2016: summary of revisions. Diabetes Care. 2016;39(Suppl 1):S4-S5.
- Pazmiño PA, Pazmiño AK. Diabetic nephropathy. El Paso Physician. 2000;23(3):12-17.
- US Renal Data System. United States Renal Data System 2014. Annual Data Report. Bethesda, MD. National Institute of Health; 2014.
- Yan L, Colditz GA. Prevalence of overweight and obesity in the United Sates, 2007-2012. JAMA Intern Med. 2015;175(8):1412-1413.
- Menke A, Casagrande S, Geiss L, Cowe CC. Prevalence of and trends in diabetes among in adults in the United States, 1988-2012. JAMA. 2015;314(10):1021-1029.
- Selvin E, Parrinello CM, Sacks DB, Coresh J, Trends in prevalence and control of diabetes in the United States. 1988-1994 and 1999-2010. Ann Intern Med. 2014;160(8):517-525.
- Messent JW, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study. Kidney Int. 1992;41(4):836-839.
- Chantrel F, Enache I, Bouiller M, et al. Abysmal prognosis of patients with type 2 diabetes entering dialysis. Nephrol Dial Transplant. 1999;14(1):129-136.
- Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed August 10, 2015.
- IDF Diabetes Atlas. 6th ed. 2014 Update. http://www.idf.org/diabetesatlas. Accessed August 10, 2015.
- Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720-1732.
- Pazmiño PA, Pazmiño AK. Diabetic renal Failure in Texas: Influence of ethnicity and household income. Tex Med. 2003;99(10):57-65.
- Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease with emphasis on the stage of incipient diabetic nephropathy. Diabetes. 1983;32(Suppl 2):64-78.
- Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med. 1999;341(15):1127-1133.
- Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med. 1982;72(3):375-380.
- Tuttle KR, DeFronzo RA, Stein JH. Treatment of diabetic nephropathy: a rational approach based on its pathophysiology. Semin Nephrol. 1991;11(2):220-235.
- Anderson S, Brenner BM. Pathogenesis of diabetic glomerulopathy: hemodynamic considerations. Diabetes Metab Rev. 1998;4:163-177.
- Bakris GL. UpToDate: Wolters Kluwer Health website. Overview of diabetic nephropathy. http://www.uptodate.com. Accessed August 10, 2015.
- American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2000;23(Suppl 1):S32-S42.
- American Diabetes Association. Microvascular complications and foot care. In: Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38(Suppl 1):S558-S566.
- National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60(5):850-886.
- Levey AS, Becker C, Inker LA. Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review. JAMA. 2015;313(8):837-846.
- Vassalotti JA, Centor R, Turner BJ, Greer RC, Choi M, Sequist TD; National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Practical approach to detection and management of chronic kidney disease for the primary care clinician. Am J Med. 2016;129(2):153-162.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-34.
- Glassock R, Delanaye P, El Nahas M. An age-calibrated classification of chronic kidney disease. JAMA. 2015;314(6):559-560.
- Tong L, Adler S. Prevention and treatment of diabetic nephropathy. In: Johnson RJ, Feehally J, Floege J. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, Elsevier Saunders; 2015:372-380.
- Bakris GL. Treatment of diabetic nephropathy. Wolters Kluwer Health: UpToDate. http://www.uptodate.com. Accessed August 10, 2015.
- American Diabetes Association. Glycemic Targets. Sec 6. In: Standards of Medical Care in Diabetes-2015. Diabetes Care. 2015;38(Suppl 1):S33-S40.
- Vijan S. In the clinic. Type 2 diabetes. Ann Intern Med. 2015;162(5);ITC1-16.
- American Diabetes Association Approaches to Glycemic Control. Sect. 7. In: Standards of Medical Care in Diabetes–2015. Diabetes Care. 2015;38(Suppl 1):S41-S48.
- Inzucchi S, Bergenstad RM, Buse, JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
- The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1983;329(14):977-986.
- Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653.
- United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317(7160):703-713.
- Perkovic V, Heerspink Hl, Chalmers J, et al; ADVANCE Collaborative Group. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013;83(3):517-523.
- Pazmiño PA. The Rule of 100s: clinical targets in diabetes mellitus. Practical Diabetology. 2001;20(3):34-37. http://www.bmj.com/rapid-response/2011/11/02/p-pazminos-diabetes-mellitus-rule-100s. Accessed February 20, 2016.
- Bakris GL. Treatment of hypertension in patients with diabetes. Wolters Kluwer Health: UpToDate. http://www.uptodate.com. Accessed August 10, 2015.
- Mauer M, Zinman B, Gardner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361(1):40-51.
- Parving H-H, Mauer M, Ritz E. Diabetic nephropathy. In: Brenner BM, ed. Brenner & Rector's The Kidney. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1265-1298.
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attacks Trial (ALLHAT). JAMA. 2002;288(23):2981-2997.
- Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-2428.
- ACCORD Study Group. Cushman WC, Evans GW, Byington RP et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
- Weiss JW, Petrik AF, Thorp ML. Identification and management of chronic kidney disease in older adults. Clin Geriatr. 2011;19(2):33-37.
- Wright JT Jr, Williamson JD, Whelton PK, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.
- 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(7274):1440-1444.
- Fried LF, Emanuele N, Zhang JH, et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903.
- Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study: a multicentre, randomized, double-blind, controlled trial. Lancet. 2008;372(9638):547-553.
- Atkins RL, 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(2):281-287.
- Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systemic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):543-551.
- Parving HH, Persson F, Lewis JB, et al; AVOID study investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358(23):2433-2446.
- Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol. 2010;56(1):77-85.
- Ingelfinger JR. A new era for the treatment of hyperkalemia? N Engl J Med. 2015;372(3):275-277.
- Sawicki P, Didjugeit U, Mulhauser I, et al. Smoking is associated with progression of diabetic nephropathy. Diabetes Care. 1994;17(2):126-131.
- Hovind D, Rossing P, Tarnow L, Parving HH. Smoking and progression of diabetic nephropathy in type 1 diabetic. Diabetes Care. 2003;26(3):911-916.
- Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330(13):877-884.
- Woredekai Y, Friedman EA. Clinical aspects of diabetic nephropathy. In: Schrier RW. Diseases of the Kidney & Urinary Tract. 8th ed. Philadelphia, PA: Wolters Kluwer & Lippincott; 2007:1894-1908.
- Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet. 2003;361(3974):2005-2016.
- Sarnak MJ, Bloom R, Munter C, et al. KDOQUI US Commentary on the 2013 KDIGO clinical practice guideline for lipid management in CKD. Am J Kidney Dis. 2015;65(33):354-366.
- Keaney JF Jr, Curfman GD, Jarcho JA. A pragmatic view of the new cholesterol treatment guidelines. N Engl J Med. 2014;370(3):275-278.
- Chan MR, Dall AT, Fletcher KE, Lu N, Trivedi H. Outcomes in patients with chronic kidney disease referred late to nephrologists: a meta-analysis. Am J Med. 2007;120(12):1063-1070.
- Jones SC, Marshall SM, Bilous RW. Diabetic nephropathy. In: DeFronzo RA, Ferranini E, Keen H, Zimmet P, eds. International Textbook of Diabetes Mellitus. 3rd ed. Chichester, United Kingdom: J Wiley & Sons Ltd; 2004:1219-1251.
July 2016 Texas Medicine Contents
Texas Medicine Main Page