Early Treatment of Risk Factors
Early treatment of risk factors for diabetic nephropathy will slow and/or prevent its progression. These risk factors include hyperglycemia, hypertension, smoking, and dyslipidemia. These are also risk factors for cardiovascular disease that should be vigorously treated.
Intensive Glycemic Control
The importance of strict glycemic control in preventing diabetic nephropathy has been confirmed by large clinical trials in both type 1 and type 2 diabetes. In the Diabetes Control and Complications Trial (DCCT), intensive treatment of diabetes reduced the incidence of microalbuminuria by 39%. Furthermore, patients randomized to strict glycemic control had a long-lasting reduction of 40% in the risk for development of microalbuminuria and hypertension 7–8 years after the end of the DCCT. Similarly, the UK Prospective Diabetes Study (UKPDS) of type 2 diabetes reported a 30% reduction in the risk of developing microalbuminuria in the intensively treated group as compared to the conventionally treated group.
The effect of strict glycemic control on the progression from microalbuminuria to macroalbuminuria and on the rate of renal function decline in macroalbuminuric patients is still controversial.
In the DCCT study, intensified glycemic control did not decrease the rate of progression to macroalbuminuria in patients with type 1 diabetes who were microalbuminuric at the beginning of the study. In another prospective study of 115 patients with diabetes and renal impairment, 50 with type 1 diabetes and 65 with type 2 diabetes, no relationship between HbA1c and fall in creatinine clearance was seen over a 7-year period. However, in two-combined analysis of the large Steno study better glycemic control was associated with a fall in the urinary albumin excretion rate and a decreased decline in the GFR. Similarly, in 18 patients with type 1 diabetes and diabetic nephropathy prospectively followed for 21 months, a direct relationship was noted between fall in the GFR and HbA1c, with the greatest fall in the GFR occurring in those with the highest HbA1c.
There are fewer details on the natural history of treated type 2 diabetes, although one study based in Japan randomized 110 patients with type 2 diabetes and 55 patients with retinopathy and microalbuminuria to receive either multiple injection therapy or conventional insulin therapy over a 6-year period. The cumulative percentage of progression of nephropathy in the multiple insulin therapy group was 11.5% as compared to 32.0% in the conventional insulin therapy group.
To date, no large trial of intensive therapy has been reported in overt nephropathy in either type 1 or type 2 diabetes. This lack of evidence of efficacy might be due to the complexity of delivering tight glycemic control and the increased risk of hypoglycemia in patients with impaired renal function. Therefore, intensive treatment of diabetes aiming at a HbA1c <7% (The American Diabetes Association standard) should be pursued as early as possible to prevent the development of microalbuminuria.
Intensive Blood Pressure Control
Multiple studies on the effect of pharmacologic induction of normotension in type 1 and type 2 diabetic patients with persistent microalbuminuria indicate that urinary albumin excretion may be reduced while clinically evident nephropathy is postponed and perhaps prevented. Hypertension is common in diabetic patients, even when renal involvement is not present. About 40% of type 1 and 70% of type 2 diabetic patients with normoalbuminuria have blood pressure levels <140/90 mm Hg.
In both type 1 and type 2 diabetic patients with overt diabetic nephropathy, blood pressure reduction, whether with angiotensin-converting enzyme (ACE) inhibitors or non-ACE inhibitors, reduces albuminuria, delays progression of nephropathy, postpones renal insufficiency, and improves survival. As a key example in UKPDS, a reduction in systolic blood pressure from 154 mm Hg to 144 mm Hg reduced the risk for the development of microalbuminuria by 29%.
Although retardation of the decline in the GFR has been shown with other antihypertensive medications, blockade of the renin–angiotensin system (RAS) with ACE inhibitors or angiotensin receptor blockers (ARBs) is thought to confer an additional “renoprotective” benefit on preserving renal function.
The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure first published the recommendation that the target level of blood pressure in diabetes be reduced to at or below 130/85 mm Hg. Similarly, the American Diabetes Association adapted the recommendation in 1999. Continuing this theme, a consensus report of the National Kidney Foundation (NKF) advises that the blood pressure goal should be less than 130/80 mm Hg for nonproteinuric patients and 125/70 mm Hg for those with proteinuria. To achieve this degree of blood pressure reduction usually necessitates more than one antihypertensive drug plus a willing patient. The ideal drug combination is far from clear. Few data compare combination drugs with single agents. One study examined the added antihypertensive effect of 12.5 mg of hydrochlorothiazide (HCTZ) in patients with diabetic nephropathy and GFR values within normal ranges. These patients were initially treated with an ACE inhibitor (cilazapril) or an α-blocker (doxazosin). A mean decline of 15 mm Hg in systolic blood pressure (SBP) and 8 mm Hg in diastolic blood pressure (DBP) was obtained. Addition of HCTZ induced a further decline in SBP of 8 mm Hg and in DBP of 5 mm Hg. The combination also gained a greater reduction in the urinary albumin excretion rate.
ACE inhibitors are the drugs of choice for the treatment of hypertension and for retarding the decline in renal function in diabetic patients. Evidence that ACE inhibitors are indeed renoprotective against deterioration of renal failure was afforded by a study that demonstrated a significant decline in primary endpoints (doubling of serum creatinine and the development of ESRD) in the cohort treated with captopril. Seven years later, the EUCLID study, which was done in 18 European centers, randomized type 1 diabetic patients with normoalbuminuria or microalbuminuria to treatment with an ACE inhibitor (lisinopril) or a placebo. After 24 months, there was a significant difference favoring the lisinopril cohort both in terms of mean UAE and in the ratio of transition from normoalbuminuria to microalbuminuria. Similar benefits of ACE inhibitors have also been seen in patients with type 2 diabetes. The MICRO-HOPE study involved 1140 patients with type 2 diabetes and microalbuminuria randomized to ramipril 10 mg/day or a placebo. The blood pressure of all patients was to be kept at normal (target) values permitting the addition of other medications. The study aim was to determine whether ACE inhibition has organ protective effects independent of its antihypertensive action. Sustaining this thesis, at 4.5 years ramipril-treated patients had a combined primary outcome risk reduction of 25%, with myocardial infarction being decreased by 22%, stroke by 33%, cardiovascular death by 37%, and total mortality by 24%. There was a slower rise in UAE in ramipril-treated patients while fewer patients on ramipril progressed from microalbuminuria to macroalbuminuria.
ARBs are antihypertensive agents that inhibit the renin–angiotensin system by selectively blocking the AT1 subtype of A11 receptors. A renoprotective effect of ARBs was proven by the results of three large international prospective controlled studies published in one issue of the New England Journal of Medicine. These three studies enrolled type 2 diabetic patients with microalbuminuria or overt proteinuria and renal impairment. The renoprotective effect of irbesartan and losartan was established as these agents not only reduced albuminuria but also, over period of 2–4 years, significantly retarded the decline in the GFR and decreased the proportion of patients progressing to end-stage renal failure.
These three studies, in addition to the MICRO-HOPE and EUCLID studies, provide a strong rationale for the use of ACE inhibitors and/or ARBs in diabetic patients with nephropathy. The present standard of care for proteinuric diabetic patients is based on the inclusion of ACE inhibitors or ARBs. Recently, several studies have indicated benefits from dual blockade of the renin–angiotensin system by ACE inhibitors plus ARBs as noted by a greater reduction in albuminuria and blood pressure in combination-treated diabetic patients compared to the maximal dose of an ACE inhibitor alone.
Dietary Protein Restriction
In health and in diabetes, dietary protein intake modulates renal hemodynamics. Several reports suggest that in type 1 diabetes, ingestion of a high protein diet increases the risk of nephropathy. It is also known that protein restriction is effective in alleviating the symptoms of uremia and may delay the need for dialysis. Beyond symptomatic relief, a reduced protein intake is advocated to slow or/and prevent a decline in renal function. The proposed mechanism for halting progression is the reduction in hyperfiltration that occurs in the remaining nephrons after renal injury is established. A benefit from dietary protein restriction was noted in a small prospective randomized controlled study of 35 patients with type 1 diabetes and clinical nephropathy. The low-protein diet contained 0.6 mg/kg/day and patients were followed for a mean period of 35 months. A 4-fold decrease in the rate of fall of the GFR was found in the low-protein diet group compared to controls after 3 months. The mean urinary protein excretion fell by 24% in the study group but rose by 22% in the control group. At the end of the study, the reduction in proteinuria in the study population was only 6%, whereas the controls had a 24% increase. Adding to the case for dietary protein restriction, it was found that albumin excretion rates decreased when patients with microalbuminuria were fed a predominantly vegetarian diet in the absence of significant change in either blood glucose control or arterial blood pressure. Although a clear benefit of dietary restriction has not been shown in a large randomized prospective trial, based on these small positive clinical studies a protein intake of <0.8 g/kg is a reasonable regimen for patients with macroalbuminuria with further restriction as the GFR falls.
Hyperlipidemia is a risk factor for the development of vascular disease including nephropathy in both rat models of diabetes and human type 1 and type 2 diabetes. The effect of lipid reduction by antihyperlipidemic agents on the progression of diabetic nephropathy has not been established. Although large prospective trials of the effect of treatment of dyslipidemia on the progression of diabetic nephropathy have not been reported, some evidence indicates that lipid reduction by antihyperlipidemic agents preserves the GFR and decreases proteinuria in diabetic patients.
A recent randomized, double-blind placebo-controlled study compared simvastatin and diet versus placebo and diet on albuminuria in 39 patients with type 1 diabetes and nephropathy. Although not attaining significance, the rise in albuminuria was slower in the simvastatin-treated cohort compared to placebo over 2 years. A meta-analysis on lipid-lowering therapy on progression of renal disease assessed 13 prospective controlled trials, seven of which were exclusively in diabetic patients. Lipid lowering was associated with a lower rate of decline in renal function compared to controls (p = 0.008) inducing beneficial effects equivalent to ACE inhibition in the preservation of renal function. The discerned effect on the GFR did not correlate with either the type of lipid-lowering agent or the etiology of renal disease. As for other components of renoprotection, large prospective clinical trials with longer follow-up are needed to validate the value of lipid-lowering agents.
However, as cardiovascular disease is the number one cause of death in diabetic patients with nephropathy, optimizing lipid control is now a standard of care.
Cessation of Cigarette Smoking
Convincingly, a linkage between cigarette smoking and progression of diabetic nephropathy has been established. The effect of cigarette smoking on diabetic renal and retinal complications in 359 type 1 diabetic patients was assessed. The prevalence of an increased rate of albumin excretion was 2.8 times higher in smokers than in those who do not smoke. Even after correction for glycohemoglobin level and duration of diabetes, smoking was a significant factor in their logistic regression model for albuminuria. Significant improvement in urinary albumin excretion was noted when subjects ceased smoking. Similar findings were reported in patients with type 2 diabetes and nephropathy. As is true for preventing pulmonary and cardiovascular disease, reducing or quitting smoking should be part of all regimes for renoprotection in diabetic patients.
Although normalizing blood pressure, optimizing glycemic control, and adhering to a low-protein diet may retard the development and progression of diabetic nephropathy, many diabetic patients still progress to ESRD. Continuing empathetic interactions as renal function deteriorates builds confidence and minimizes panic, despair, and frantic behavior as the need for ESRD therapy becomes pressing. Patients with diabetic nephropathy should be referred to a nephrologist early in the course of their disease in order to optimize their pre-ESRD care. Reports from both Europe and the United States found that a high proportion of patients with diabetic nephropathy are referred to a nephrologist late in the course of their disease, resulting in suboptimal treatment.
Management of diabetic patients with progressive renal insufficiency is a challenge because of comorbid conditions that accompany the nephropathy. These preexisting comorbid conditions (cardiovascular disease, retinopathy, cerebrovascular and peripheral vascular disease) play a major role in the decreased survival of diabetic patients on renal replacement therapy. In practice, a team of collaborating specialists optimize the pre-ESRD diabetic care. This team should include a nephrologist, diabetologist, nutritionist, cardiologist, ophthalmologist, podiatrist, and other specialists when necessary. Pre-ESRD management of diabetic patients with advanced renal failure includes sustaining a hemoglobin level above 11 g/dL by administering erythropoietin and supplemental iron, minimizing metabolic bone disease due to secondary hyperparathyroidism by use of phosphate binders, along with use of synthetic vitamin D and/or calcimimetics. Potential familial kidney donors should be interviewed and tissue typed; when hemodialysis appears to be likely, preserving forearm cutaneous veins by avoiding venous punctures and intravenous catheters and maintaining good nutritional status are essential.
Renal Replacement Therapy
Diabetic patients with ESRD have options for renal replacement therapy similar to nondiabetic patients. For diabetic ESRD patients those options include hemodialysis, peritoneal dialysis, kidney transplant alone, and a combined pancreas and kidney transplant, which is unique to diabetic patients. Before a patient is assigned a specific modality of renal replacement therapy, it is important that patients and their families be properly informed about the advantages and disadvantages of each treatment option.
Selecting the treatment that is best for a particular patient is made by considering the patient's age, level of education, severity of comorbid conditions, social and family support, and geographic location. Once the decision for a preferred option is made, preparation for renal replacement therapy should be started. For instance, an arteriovenous fistula should be established in patients who will be undergoing hemodialysis, and a peritoneal catheter should be inserted in those who will be treated with peritoneal dialysis. As a general guide, renal replacement therapy is initiated when the GFR of a diabetic patient falls to 10–15 mL/minute.
As reported in the USRDS 2004 registry, 75% of all diabetic patients with ESRD are treated with hemodialysis (center or home), 7.4% with peritoneal dialysis [continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD)], and 17% receive a functioning kidney transplant. Hemodialysis treatment for diabetic patients is similar to that for nondiabetic patients. An ideal hemodialysis regimen consists of three weekly dialysis sessions, each lasting 3.5–4.5 hours, as determined by individual blood chemistry and clinical response during which extracorporeal blood flow is maintained at 300–500 mL/minute.
The survival and rehabilitation of diabetic patients on maintenance hemodialysis are distinctly inferior to those of nondiabetic patients, mainly because of preexisting severe vascular disease. Peripheral vascular calcification in middle-sized arteries plus atherosclerosis of small vessels may pose a challenge for the vascular surgeon attempting to construct a vascular access in a diabetic patient. Although the preferred vascular access is an arteriovenous fistula, preexisting vascular disease limits its utility in diabetic patient, who have a primary fistula failure rate of 30–40%. A less desirable, but necessary alternative vascular access can be constructed using a polytetrafluoroethylene graft, which has a half-life in excess of 1 year.
The proportion of arteriovenous fistulas compared to grafts can be increased in diabetic patients by careful preoperative investigation to select an adequate location for initial placement to the fistula. Large-diameter arteries and veins, frequently requiring use of the elbow region, are employed, thereby avoiding an initial polytetrafluoroethylene graft. Continuous surveillance by a nephrologist and the dialysis staff concerning early elective access revision and avoidance of thrombosis improves the viability of the primary fistulas. Complications of vascular access are the leading cause of hospitalization in diabetic patients with ESRD undergoing hemodialysis.
Glycemic control in diabetic patients undergoing dialysis is difficult. Insulin dosage is more complex because of unrecognized gastroparesis, which disconnects absorption of ingested food from timed insulin administration and because of reduced renal insulin catabolism, which results in the prolonged action of exogenous insulin. This combination causes erratic glucose regulation complicated by frequent hypoglycemic episodes, a potentially serious complication. Glycemic control should remain a priority in the dialyzed diabetic patient as it may retard further complications of microvascular disease. Survival during the long-term management of ESRD in diabetes has been linked to the quality of glycemic control achieved.
Although the survival of diabetic patients on dialysis has been improving over the past decade, morbidity and mortality remain significantly higher than in those without diabetes. This grim reality is mostly attributed to the progression of comorbid conditions. Cardiovascular disease, infections, and withdrawal from dialysis are the leading cause of mortality in patients with diabetes and ESRD.
Peritoneal dialysis is a satisfactory alternative mode of dialytic therapy available for diabetic ESRD patients. In the United States, peritoneal dialysis is applied to only 7% of all diabetic patients on renal replacement therapy. As is true for hemodialysis, preparation of the patient for CAPD, the most frequently utilized form of peritoneal dialysis, necessitates education, repetitive explanation, and facilitating surgery to insert an intraperitoneal permanent catheter. CAPD can be mastered as a home regimen in about 4 weeks. An alternative to manual cycling of the dialysate is the use of a mechanical cycling device in a CCPD regimen, which can be performed during sleep.
CAPD offers some advantages over hemodialysis, such as freedom from a machine, performance at home, reduced cardiovascular stress, better preservation of renal function, avoidance of heparin, and less dietary restrictions. However, the disadvantages of peritoneal dialysis include the risk of peritonitis, the high rate of technical failure, and less adequate dialysis when residual renal function is low.
Some nephrologists consider peritoneal dialysis as the preferred choice of treatment for diabetic ESRD patients. Indeed, the CAPD or CCPD may be life sustaining when vascular access sites for hemodialysis have been exhausted, or in those with severe congestive heart failure, angina, or severe dialysis-related hypotension. Peritoneal dialysis involves less vascular stress because of its relatively slow ultrafiltration rate coupled with less rapid solute removal.
During the course of both CAPD and CCPD, there is a constant risk of peritonitis as well as a gradual decrease in peritoneal surface area, which may ultimately prove to be insufficient for adequate dialysis. Diabetic patients on CAPD experience twice as many hospitalization days as nondiabetic patients: peritonitis accounts for 30–50% of these hospital days.
Of the two major options in dialytic therapy for ESRD in diabetes, the USRDS consistently reports superior survival in those treated by hemodialysis, except in those under age 45 years, compared to peritoneal dialysis. However, there are few studies reporting equivalent patient survival for peritoneal dialysis versus hemodialysis in the first 2 years of treatment. The two leading causes of death in diabetic CAPD patients are cardiovascular events and infection.
In the 1970s and early 1980s many transplant programs excluded diabetic ESRD patients from consideration for renal transplantation. However, in centers that performed transplants during this period, the survival of diabetic patients receiving transplants exceeded that of diabetic patients remaining on dialysis. Today, the improved management of diabetic and uremic complications established kidney transplantation as the preferred form of treatment for diabetic ESRD patients.
Although the survival of diabetic ESRD patients after renal transplantation is continuously improving, over a 5-year period it is 10–20% below that of patients with other causes of renal disease. A further decrease in survival of diabetic renal transplant recipients after 5 or more years is the consequence of coronary, cerebral, and other macrovascular diseases. The most recent analysis of patient survival in diabetic kidney transplant recipients indicated 93.7% 1-year and 85.5% 3-year survival for recipients of grafts from deceased donors and 95.4% 1-year and 91.3% 3-year survival for those receiving living donor transplants. The annual death rates of transplant recipients are approximately one-third those of diabetic patients remaining on dialysis. In fairness, it must be noted that a strong selection bias extracts the fittest patients for kidney transplants leaving a residual pool of dialysis patients with extensive life-threatening comorbidities.
To respond to the real risk of cardiac events in diabetic renal transplant recipients and to assess the extent of cardiovascular disease present prior to transplantation, at least annual reassessment with noninvasive studies in asymptomatic high-risk patients should be performed.
Over the past decade, highly successful results have been reported in type 1 diabetic patients for pancreatic transplants inserted concurrently with a renal allograft. Although combined pancreas and kidney transplants do not result in an increase in immediate perioperative mortality, perioperative morbidity is markedly increased over that of a kidney transplant alone. Almost 13,000 pancreas transplants were reported to the international Pancreas Transplant Registry from 1966 through September 1999, with 75% of them performed in the United States. The majority of pancreas transplants in the United States have been combined kidney–pancreas transplants (SPK). One year patient survival has improved from 90% for 1987–1988 cases to 95% for 1995–1996 cases. In addition, pancreas graft survival has improved from 74% to 85% at 1 year for the same time period; kidney graft survival improved from 83% to 91%. Solitary pancreas transplants, either pancreas alone (PTA) or pancreas after kidney transplant (PAK), constitute only a small proportion of the total pancreas transplants in the United States. Graft survival of PTA or PAK is worse compared to SPK. Early reports have surprisingly found a substantial survival benefit for pancreas plus kidney transplants in type 2 diabetic ESRD patients.
Chuahirun T et al: Cigarette smoking exacerbation and its cessation ameliorates renal injury in type 2 diabetes. Am J Kidney Dis 2004;327:57.