K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13-18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

https://care.diabetesjournals.org/content/diacare/33/10/2285.full.pdf

Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity, and Treatments

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastro- paresis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brit- tle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal (GI), genitourinary, and cardiovascular). GI distur- bances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal inconti- nence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to con- sideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunc- tion should be performed for individuals with diabetes who have recurrent urinary tract infec- tions, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; mea- surement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve func- tion; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an in- creased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of auto- nomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing) be used for longitudi- nal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing re- quires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recom- mended tests for assessing CAN is readily per- formed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of au- tonomic dysfunction earlier) serves to estab- lish a baseline, with which 1-year interval tests can be compared. Regular HRV testing pro- vides early detection and thereby promotes timely diagnostic and therapeutic interven- tions. HRV testing may also facilitate differen- tial diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and diz- ziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to im- prove metabolic control and to use therapies such as ACE inhibitors and -blockers, proven to be effective for patients with CAN. Diabetes Care 26:1553-1579, 2003

/pdf/diabetic-autonomic-neuropathy-4kabtayo3d.pdf

Diabetic Autonomic Neuropathy

Here we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4-8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

Sex steroids and the construction and conservation of the adult skeleton.

Context.—Pain is the most disturbing symptom of
diabetic peripheral neuropathy. As many as 45% of patients with
diabetes mellitus develop peripheral neuropathies.Objective.—To evaluate the effect of gabapentin monotherapy
on pain associated with diabetic peripheral neuropathy.Design.—Randomized, double-blind, placebo-controlled,
8-week trial conducted between July 1996 and March 1997.Setting.—Outpatient clinics at 20 sites.Patients.—The 165 patients enrolled had a 1- to 5-year
history of pain attributed to diabetic neuropathy and a minimum 40-mm
pain score on the Short-Form McGill Pain Questionnaire visual analogue
scale.Intervention.—Gabapentin (titrated from 900 to 3600
mg/d or maximum tolerated dosage) or placebo.Main Outcome Measures.—The primary efficacy measure was
daily pain severity as measured on an 11-point Likert scale (0, no
pain; 10, worst possible pain). Secondary measures included sleep
interference scores, the Short-Form McGill Pain Questionnaire scores,
Patient Global Impression of Change and Clinical Global Impression of
Change, the Short Form–36 Quality of Life Questionnaire scores, and
the Profile of Mood States results.Results.—Eighty-four patients received gabapentin and 70
(83%) completed the study; 81 received placebo and 65 (80%) completed
the study. By intent-to-treat analysis, gabapentin-treated patients'
mean daily pain score at the study end point (baseline, 6.4; end point,
3.9; n = 82) was significantly lower (P<.001) compared with
the placebo-treated patients' end-point score (baseline, 6.5; end
point, 5.1; n = 80). All secondary outcome measures of pain were
significantly better in the gabapentin group than in the placebo group.
Additional statistically significant differences favoring gabapentin
treatment were observed in measures of quality of life (Short Form–36
Quality of Life Questionnaire and Profile of Mood States). Adverse
events experienced significantly more frequently in the gabapentin
group were dizziness (20 [24%] in the gabapentin group vs 4
[4.9%] in the control group; P<.001) and somnolence (19
[23%] in the gabapentin group vs 5 [6%] in the control group;
P = .003). Confusion was also more frequent in the gabapentin
group (7 [8%] vs 1 [1.2%]; P = .06).Conclusion.—Gabapentin monotherapy appears to be
efficacious for the treatment of pain and sleep interference associated
with diabetic peripheral neuropathy and exhibits positive effects on
mood and quality of life.

/pdf/gabapentin-for-the-symptomatic-treatment-of-painful-3hioh8gzer.pdf

Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients With Diabetes Mellitus: A Randomized Controlled Trial

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%; and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently–6% of IDDM and 1% of NIDDM patients. Overall, two thirds of diabetic patients have objective evidence for some variety of neuropathy, but only about 20% have symptoms, and only 6% of IDDM and only 1% of NIDDM patients have sufficiently severe polyneuropathy to be graded stage 2b, and none were graded stage 3. Approximately one quarter of patients had subclinical carpal tunnel syndrome, but only 7.7% had symptomatic carpal tunnel syndrome. Thus, diabetic peripheral neuropathy is frequent but less severe than generally thought. As generally believed, however, neuropathy, retinopathy, and nephropathy are significantly associated.

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%, and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently--6% of IDDM and 1% of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population‐based cohort The Rochester Diabetic Neuropathy Study

Renal stone epidemiology: A 25-year study in Rochester, Minnesota

Plasma bone Gla-protein (BGP) is a sensitive and specific marker for metabolic bone disease. Because BGP is removed from the circulation mainly by kidney clearance, increased plasma BGP in subjects with impaired renal function could be due to decreased renal clearance, increased bone metabolism, or both. These factors were evaluated in 62 patients with various degrees of renal failure in whom we measured plasma BGP, [125I]iothalamate clearance [a measure of glomerular filtration rate (GFR)], and [131I]o-iodohippurate clearance (a measure of effective renal plasma flow). In all patients with GFR greater than 30 ml/min·1.73 m2, plasm a BGP was within the normal range for age- and sex-comparable control subjects, and large increases in plasma BGP did not occur until GFR was below 20 ml/min·1.73 m2. Nonlinear regression analysis showed that the variation in plasma BGP was substantially accounted for using the exponential of GFR. Similarly, plasma BGP was normal for values of effective renal plasma flow above ...

David M. Wilson

Papers

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population‐based cohort The Rochester Diabetic Neuropathy Study

Renal stone epidemiology: A 25-year study in Rochester, Minnesota

Effect of renal function on plasma levels of bone Gla-protein.

The Stone Clinic Effect in Patients With Idiopathic Calcium Urolithiasis