Guest guest Posted April 5, 2005 Report Share Posted April 5, 2005 Proteinuria JoAnn Guest Apr 05, 2005 11:15 PDT Author: Cheryl Curtis, MSN, RN, CNN http://web.ask.com/redir?u=http%3a%2f%2ftm.wc.ask.com%2fr%3ft%3dan%26s%3da7%26ui\ d% Proteinuria is a condition in which urine contains an " excess " amount of protein. Proteinuria is often one of the first signs of renal disease and is often asymptomatic. Proteinuria is a finding in almost every form of glomerular disease. Protein Handling in Normal Kidneys In a healthy kidney, the glomerular capillary wall acts as a barrier to prevent proteins from entering the urine based on size and electrical charge of the proteins. This is dependent on the integrity of the capillary wall. The glomerular capillary wall consists of three layers: the fenestrated endothelium, the glomerular basement membrane, and the epithelial cells attached to the glomerular basement membrane. The primary barrier to the filtration of protein is the glomerular basement membrane. (1) If the glomerulus is intact, only trace amounts of albumin escape in the glomerular filtrate. Proteins that are smaller than albumin (< 68,000 daltons) are filtered and reabsorbed by the proximal tubule. In most circumstances, up to 1500 mg of protein is filtered every 24 hours. Most of this is reabsorbed by the proximal tubule, where the protein undergoes catabolism. As a result, as much as 150 mg of protein is excreted daily in the urine. Tubular proteinuria occurs when the proximal tubule is damaged and interferes with the reabsorption of protein. (2) In glomerular injury, the size and the charge-selective barriers of the glomerular capillary wall may be altered. The glomerular capillary wall normally has a fixed negative charge. This allows the wall to repel negatively charged plasma proteins. (2) In normal kidneys, low molecular-weight proteins and small amounts of albumin are filtered. These proteins are reabsorbed by the proximal tubule and are catabolized. This results in a daily protein excretion of approximately 40-80 mg. (1) Definition and Measurement of Proteinuria Proteinuria is described as urinary excretion of more than 150 mg of protein in a 24-hour period. Presence or absence of proteinuria is usually first detected by dipstick evaluation of urine. A dipstick reading is normally read as zero to 4+. This corresponds to concentrations of zero to more than 500mg/dL of protein. A more accurate quantitative result of protein is obtained with a 24-hour urine collection. In most situations, the results of the dipstick will correlate fairly well with the quantitative urine collection. The dipstick method, however, is most sensitive to albumin, where the quantitative method detects all proteins. The dipstick may be negative when low molecular-weight proteins, and not albumin, are present in the urine. This can occur in some tubular diseases where the proximal tubule catabolism of filtered protein is impaired. It can also happen in diseases where there is excessive production and filtration of low-molecular-weight proteins, exceeding the proximal tubule's ability to catabolize filtered proteins. An important clinical example of this is multiple myeloma, where the urine might contain large amounts of protein detected by quantitative measurement, but test as negative or only trace positive by urine dipstick. (1) Laboratory evaluation of proteinuria first quantifies the amount of protein being excreted. Generally, if the amount is found to be > 3 gm/day, it is almost always of glomerular origin. Proteinuria < 3 gm/day is nondiagnostic. This could represent a pre-renal, tubular or glormerular origin. If the origin is unclear, the next step is to evaluate by urine protein electrophoresis. If the protein is found to be >70% albumin, the source is glomerular. A tubular source will cause excretion of globulins more than albumin. A pre-renal source usually has a single globulin peak, which represents the protein with the highest plasma concentration. (1) Microalbuminuria Microalbuminuria is defined as daily urinary albumin excretion of 30 - 300 mg/day. Diseases such as diabetes and essential hypertension can manifest microalbuminuria. This level of albumin excretion is above the normal range, yet is undetectable by dipstick. Microalbuminuria is thought to be the earliest sign of nephropathy in diabetes mellitus, and is a good predictor of cardiovascular risk in diabetes and hypertension. Microalbuminuria can only be detected using sensitive laboratory techniques, and only when specifically requested. It is recommended that patients with diabetes mellitus undergo yearly screening for microalbuminuria. (1) Mechanisms of Proteinuria Proteinuria can be classified according to four major mechanisms: Functional proteinuria Overproduction or prerenal proteinuria Glomerular proteinuria Tubular proteinuria Functional proteinuria. Functional proteinuria describes a transient increase in protein excretion. This can sometimes occur without the presence of renal disease. Fever, emotional or physical stress, and acute illness can cause significant, but transient, increases in urinary protein excretion. Urinary protein excretion is increased two-to three-fold after periods of heavy exercise. The mechanism for this type of proteinuria most likely relates to changes in the glomerular pore size rather than alterations in the glomerular basement membrane. (1) Orthostatic proteinuria is another benign condition. This refers to abnormally elevated protein excretion in the upright position, but normal excretion in a recumbent position. This condition is found in 2-5% of adolescents, but rarely noted in persons 30 years of age or older. (1) Overproduction or prerenal proteinuria. Overproduction or pre-renal proteinuria occurs with the existence of an increased plasma concentration of one or more filterable proteins. This increases the filtered protein load, thereby increasing excretion. There may be due to increased excretion of heavy chains, light chains or other immunoglobulin fragments. (1) Glomerular proteinuria. Glomerular loss of proteins can result from many different mechanisms. The three most common are: Loss of the negative charges of the glomerular basement membrane An increase in effective pore size or number due to damage to the glomerular basement membrane Disease-related changes in glomerular hemodynamics. All glomerular diseases fall into this category. Some examples are focal glomerulonephritis, post streptococcal glomerulonephritis, minimal change disease, focal sclerosis, membranous glomerulonephritis, and diabetic nephropathy. (1) Tabular proteinuria. The fourth classification of proteinuria is tubular proteinuria. This occurs when there is impaired tubular reabsorption of normally filtered proteins. This area includes some hereditary diseases such as Wilson disease, and some toxic injuries such as lead poisoning. (1) Populations at Risk for Proteinuria People with diabetes, hypertension and family history of renal disease may be at risk for proteinuria. In the United States, diabetes is the leading cause of renal failure. In diabetic patients, the first sign of deteriorating kidney function may be the presence of small amounts of protein in the urine. As kidney function deteriorates, the amount of protein increases. African Americans are more likely than Caucasian Americans to have hypertension and develop kidney problems from it. Other groups at risk for proteinuria are American Indians, Hispanics, Pacific Islanders, the elderly, and the obese. (5) Common Causes of Proteinuria Primary glomerular disorders: Orthostatic or postural proteinuria Membranous glomerulonephritis Idiopathic membranoproliferative glomerulonephritis Focal segmental glomerulonephritis IgA nephropathy Minimal change disease Proliferative glomerulonephritis Secondary disorders: Hereditary/familial: diabetes mellitus, Alport syndrome, sickle cell disease Autoimmune: systemic lupus erythematosus (SLE), Goodpasture's syndrome, Wegener's granulomatosis, polyarteritis nodosa, rheumatoid arthritis Infectious: postinfectious glomerulonephritis, endocarditis, hepatitis B Drug-induced: non-steroidal anti-inflammatory drugs, heroin, gold, mercury Neoplastic: Hodgkin's disease, lymphomas, leukemia, multiple myeloma Miscellaneous: amyloidosis, pre-eclampsia / eclampsia, renovascular hypertension, interstitial nephritis, fever, exercise (2) Symptoms of Proteinuria Proteinuria is usually detected initially on routine urinalysis or dipstick. Often it is an unexpected finding. Patients may be completely asymptomatic, or may have many symptoms depending on the magnitude of the proteinuria and/or the level of renal function. Nephrotic syndrome is characterized by protein excretion of greater than 3.5 grams/day. Classic presentation of nephrotic syndrome includes edema, hypertension, hypoalbuminemia, and hypercholesterolemia. Patients with glomerulonephritis may be asymptomatic or have hematuria, edema of new onset, or pulmonary symptoms. (3) Complications of Proteinuria Proteins are essential for all body processes. Excessive loss of proteins can damage different systems resulting in diverse complications. Some clinical complications are as follows: Hypoalbuminemia Edema Increased hepatic lipoprotein synthesis Increased platelet aggregability Increased tubular protein reabsorption Possible tubular dysfunction Tubular damage Loss of proteins carrying vitamins, hormones and minerals Trace mineral deficiencies Vitamin D deficiency Loss of immunoglobulins Reduced cellular immunity Increased susceptibility to infection Alterations in coagulation factors Spontaneous thromboembolism Renal vein thrombosis Negative nitrogen balance Malnutrition Alteration in drug metabolism (1) Hypocalcemia Management of Proteinuria Successful treatment of the underlying glomerular disease is the primary goal of therapy. Some forms of glomerular disease have no specific treatment and others are not always successfully treated. In some cases the presence of severe proteinuria necessitates therapy to reduce the protein excretion specifically. Dietary restriction of protein, the use of angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs may be effective in some cases. (1) Dietary protein restriction may lower proteinuria in some, though not all, patients. The lowest allowable protein restriction is 0.6g/kg/day plus protein added to match urinary losses. This therapy may also help slow the progression of renal disease, but should only be used in close collaboration with a renal dietician in order to avoid problems with negative nitrogen balance. (1) Angiotension-converting enzyme (ACE) inhibitors have also proven to be useful in some cases of proteinuria. While reduction of the blood pressure with any agent is of some use, ACE inhibitors seem to be the most consistently effective with regards to renal disease and proteinuria. They reduce protein by lowering efferent arteriolar resistance. Other mechanisms may also be involved, including a direct affect on glomerular permselectivity. For maximum benefit, ACE inhibitors should be used in conjunction with diuretic therapy and a low sodium diet. Close follow-up is required in patients with moderate to severe renal insufficiency, since ACE inhibitors could cause a rise in the patient's serum creatinine, rise in potassium levels, and acute renal failure. (1) Non-steroidal anti-inflammatory medications in high doses may also be useful in the treatment of proteinuria. These drugs have a tendency to reduce the glomerular filtration rate. They can only be used, however, when the glomerular filtration rate is not severely impaired to avoid the risks of hyperkalemia and acute renal failure. These medications also have a high incidence of gastrointestinal side effects, especially in high doses, therefore are not used as frequently as the other treatments discussed. (1) Patients with nephrotic syndrome generally require the most aggressive management to minimize complications such as edema, ascites and hypercoaguable state. Nephrotic syndrome is characterized by severe proteinuria of more than 3.5gms/day. Edema can be defined as an excess of fluid within the interstitial or nonvascular extracellular space that is detectable by visual or other clinical means. Edema is usually found in the lower extremities, but can also be found periorbital, sacral, fingers, lungs or within a body cavity such as abdominal ascities. (4) The protein loss in nephrotic syndrome patients is managed with dietary restriction of protein, ACE inhibitors and possibly non-steroidal anti-inflammatory drugs. The patient's peripheral edema is managed by dietary salt restriction. Gentle diuresis is indicated for severe edema, especially if there is skin breakdown or weeping. (2) Severe nephrotic syndrome predisposes to thrombus due to the loss of hemostasis control proteins such as anti-thrombin, protein S and protein C. This hypercoagulable state can lead to renal vein thrombosis as well as deep vein thrombosis of the lower extremities especially in patients with sedentary lifestyles. (2) Hyperlipidemia is also common in patients with nephrotic syndrome. Elevated cholesterol and triglyceride levels place the patient at high risk for cardiovascular disease due to accelerated atherosclerosis. Dietary management should be instituted when the serum cholesterol exceeds 200 mg/dL, or the triglyceride level exceeds 300 mg/dL. Lipid lowering agents as well as dietary interventions may be necessary. (2) Nutritional Management of Proteinuria Nephrotic range proteinuria or nephrotic syndrome is characterized by excessively high rates of protein excretion. An increase in dietary protein would stimulate albumin synthesis, but may also increase glomerular permeability. That would result in a urinary loss of the albumin that was synthesized. Therefore, current recommendations are for a dietary intake of 0.8 to 1 gram/kg/day of protein in patients with normal serum creatinine levels. There are some exceptions to this. In patients with good renal function who have more than 15 grams of protein excretion daily, develop protein calorie malnutrition, or receive high doses of corticosteroids, as trial period of moderately increased protein intake might be recommended. (6) Caloric intake for patients with nephrotic syndrome should be calculated according to the individual needs of the patient using a nutritional assessment and screening tool. It is important to avoid insufficient calorie intake in these patients, since this might result in catabolism of lean tissue. Weight reduction in this population should be approached cautiously and closely monitored. (6) Another common characteristic of patients with nephrotic syndrome is hyperlipidemia. Elevated serum lipid levels are thought to be due to increases in lipoprotein production. Serum albumin levels are typically inversely related to serum lipid concentrations. Dietary treatment of hyperlipidemia in patients with nephrotic syndrome is a secondary goal. (6) Summary Proteinuria is described as urinary protein excretion greater than 150 mg/24-hours. Nephrotic range proteinuria is an excretion of greater than 3.5 gm/24-hours. The etiology of proteinuria is diverse. It may reflect renal manifestations of a systemic disease or a primary renal disease. It may also occur without a recognized disease process. Four recognized classifications of proteinuria are functional, overproduction or pre-renal, glomerular, and tubular. The objective of initial evaluation of proteinuria is to identify the quantity, type, and reproducibility of the protein. Treatment options vary according to the underlying disease process. Case Study Sally A. is a 53 year-old female marketing director. She presents for consult with the following laboratory results and symptoms: Serum creatinine level of 1.9 Serum albumin of 2.6 Cholesterol level of 303 24-hour urine protein of 8 gm/ 24 hours 3+ edema bilateral lower extremities to knees Blood pressure of 154/96 Claims a weight loss of 12 pounds in past two months Take the Test References Anderson, S. Proteinuria. In: Greenburg, A. editor. Primer On Kidney Diseases (2nd edition). Boston: National Kidney Foundation; Academic Press. 1998. p. 42-46. Mars, D. R. Proteinuria and the Nephrotic Syndrome. In: Tisher, C.C. & Wilcox, C.S. editors. Nephrology (2nd edition). Philadelphia: Williams & Wilkins; 1993. p. 20-26. Cooper, M. Proteinuria. In: Fihn, S.D. & DeWitt, D.E. editors. Outpatient Medicine. Philadelphia: W. B. Saunders Company; 1998. p. 607-610. Levy, M. Edematous States and Hepatorenal Syndrome. In: Levine, D.Z. editor. Caring For The Renal Patient (3rd edition). Philadelphia: W.B. Saunders Company; 1997. p. 126-127. National Kidney and Urologic Diseases Information Clearinghouse. Updated: December, 2000. (cited 2001, Jan 20), Available from: URL; http://www.niddk.nih.gov/health/kidney/bups/protienuria/proteinuria.htm Nelson, J. K., Moxness, K. E., Jensen, M. D., & Gastineau, C. F. Mayo Clinic Diet Manual: A Handbook of Nutritional Practices (7th edition). Boston: Mosby. 1994. p. 333 - 334. 2002 Wild Iris Medical Education ===================================================================== Post subject: Causes of Proteinuria -- Causes of Proteinuria http://web.ask.com/redir?u=http%3a%2f%2ftm.wc.ask.com%2fr%3ft%3dan%26s%3da7%26ui\ d% Cause details for Proteinuria: As blood passes through healthy kidneys, they filter the waste products out and leave in the things the body needs, like proteins. Most proteins are too big to pass through the kidneys' filters into the urine, unless the kidneys are damaged. The two proteins that are most likely to appear in urine are albumin and globulin. Albumin is smaller and therefore more likely to escape through the filters of the kidney, called glomeruli. Albumin's function in the body includes retention of fluid in the blood. It acts like a sponge, soaking up fluid from body tissues. Inflammation in the glomeruli is called glomerulonephritis, or simply nephritis. Many diseases can cause this inflammation, which leads to proteinuria. Additional processes that can damage the glomeruli and cause proteinuria include diabetes, hypertension, and other forms of kidney diseases. 1 In some cases, prostatitis is caused by bacterial infection and can be treated with antibiotics. But the more common forms of prostatitis are not associated with any known infecting organism.2 Underlying condition causes of Proteinuria: The list of possible underlying conditions (see also Misdiagnosis of underlying causes of Proteinuria) mentioned in various sources as possible causes of Proteinuria includes: Kidney disease Kidney conditions High blood pressure Hypertension-related kidney failure Proteinuria as a symptom: Conditions listing Proteinuria as a symptom may also be potential underlying causes of Proteinuria. The list of conditions listing Proteinuria as a symptom in our database includes: Acute kidney failure Childhood nephrotic syndrome Diabetic Nephropathy Eclampsia Glomerulonephritis Kidney conditions Kidney disease Lupus Nephrotic syndrome Preeclampsia Primary amyloidosis Typhoid fever Related information for causes of Proteinuria: Further relevant information on causes of Proteinuria may be found in the risk factors for Proteinuria and underlying causes of Proteinuria. Footnotes: 1. excerpt from Proteinuria: NIDDK 2. excerpt from Your Urinary System and How It Works: NIDDK -- Printable | Next: Risk Factors for Proteinuria -- By using this site you agree to our Terms of Use. Information provided on this site is for informational purposes only; it is not intended as a substitute for advice from your own medical team. The information on this site is not to be used for diagnosing or treating any health concerns you may have - please contact your physician or health care professional for all your medical needs. Please see our Terms of Use. ________________ ===================================================================== Post subject: Proteinuria Predicts Stroke and Other Atherosclerotic Vascular --- Stroke. 1996;27:2033-2039.) © 1996 American Heart Association, Inc. -http://stroke.ahajournals.org/cgi/content/full/27/11/2033 - Articles Proteinuria Predicts Stroke and Other Atherosclerotic Vascular Disease Events in Nondiabetic and Non–Insulin-Dependent Diabetic Subjects Heikki Miettinen, MD; Steven M. Haffner, MD; Seppo Lehto, MD; Tapani Ronnemaa, MD; Kalevi Pyorala, MD; Markku Laakso, MD the Department of Medicine, University of Kuopio (H.M., S.L., K.P., M.L.), the Department of Medicine, University of Turku (T.R.), and the Research and Development Centre, Social Insurance Institution, Turku (T.R.), Finland; and the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center (San Antonio) (H.M., S.M.H.). Correspondence to Heikki Miettinen, MD, University of Texas Health Science Center at San Antonio, Department of Medicine, Division of Clinical Epidemiology, 7703 Floyd Curl Dr, San Antonio, TX 78284-7873. E-mail miet-. Reprint requests to Markku Laakso, MD, University of Kuopio, Department of Medicine, PO Box 1627, 70211 Kuopio, Finland. Abstract Top Abstract Introduction Subjects and Methods Results Discussion References Background and Purpose Increased urinary albumin and protein excretion is associated with cardiovascular disease mortality independent of other cardiovascular risk factors in subjects with non–insulin-dependent diabetes mellitus (NIDDM). We assessed the relationship between the different degrees of proteinuria at baseline and the incidence of stroke, as well as other atherosclerotic vascular disease events, in a prospective study of nondiabetic and NIDDM subjects. Methods Our study was based on the 7-year follow-up of cohorts of nondiabetic (n=1375) and NIDDM (n=1056) subjects in Finland. The urinary protein concentration at baseline was stratified into three categories: no proteinuria (<150 mg/L), borderline (150 to 300 mg/L), and clinical proteinuria (>300 mg/L). Results The association between the different degrees of proteinuria and the atherosclerotic vascular events was similar in nondiabetic and NIDDM subjects. Cardiovascular disease mortality was higher both in nondiabetic and NIDDM subjects with clinical proteinuria than in those without proteinuria. The incidence of stroke was 1.6% in nondiabetic subjects without proteinuria, 3.2% in subjects with borderline proteinuria, and 8.5% in subjects with clinical proteinuria (P<.001 for trend). In NIDDM patients, the corresponding rates were 7.2%, 11.1%, and 23.0%, respectively (P<.001 for trend). The association between clinical proteinuria and the incidence of stroke remained significant both in nondiabetic and in NIDDM subjects after adjustment for other cardiovascular risk factors. Clinical proteinuria was also associated with the incidence of coronary heart disease events and that of lower-extremity amputation. NIDDM independently increased the risk of atherosclerotic vascular disease events regardless of the proteinuria status. Conclusions Clinical proteinuria significantly predicted stroke and other atherosclerotic vascular disease events independent of other cardiovascular risk factors. This finding is compatible with the view that increased urinary protein excretion rate may be associated with widespread vascular damage. Key Words: atherosclerosis • coronary heart disease • diabetes mellitus • mortality • proteinuria Introduction Top Abstract Introduction Subjects and Methods Results Discussion References It is well established that the incidences of atherosclerotic vascular diseases such as CHD, stroke, and arterial disease of lower extremities are higher in patients with NIDDM than in nondiabetic subjects,1 which is only in part explained by the adverse effects of diabetes on the classic cardiovascular risk factors.1 The risk of CVD death has been found to be associated with an increased urinary albumin and protein excretion rate independent of classic cardiovascular risk factors in patients with NIDDM2 3 4 5 6 7 8 9 10 and nondiabetic subjects.5 11 12 The mechanisms of the association between albuminuria and increased CVD risk are poorly understood, and several explanations have been proposed. Increased urinary albumin excretion may be associated with adverse changes in cardiovascular risk factors,4 13 14 15 16 or alternatively, it may be a marker of widespread vascular damage,17 endothelial dysfunction enhancing atherogenesis,18 19 or a marker of CVD itself.16 Although the relationship between microalbuminuria and CVD mortality is well established in patients with NIDDM, less is known about the association between clinical proteinuria and the incidence of atherosclerotic vascular disease events, particularly in nondiabetic subjects. In particular, very few data are available regarding the relationship between proteinuria and stroke or peripheral arterial disease.20 21 The purpose of our study was to assess the relationship between different degrees of proteinuria at baseline and atherosclerotic vascular disease events during the 7-year follow-up of population-based cohorts of nondiabetic and NIDDM subjects. If the relationship between proteinuria and atherosclerotic vascular disease events is independent of conventional cardiovascular risk factors, the hypothesis that proteinuria is an indicator of underlying vascular damage is strengthened. We also analyzed the association between increased urinary protein concentration and non-CVD mortality because recently published observations suggest that proteinuria may also be related to non-CVD mortality in NIDDM patients.8 10 Subjects and Methods Top Abstract Introduction Subjects and Methods Results Discussion References Patients With NIDDM All diabetic patients in Finland who need drug therapy receive it free of charge according to the Sickness Insurance Act. These subjects are registered in a computerized central registry maintained by the Social Insurance Institution. On the basis of information from this registry, we identified all diabetic patients aged 45 to 64 years who were born and living in the Kuopio University Hospital district in East Finland or in the Turku University Central Hospital district in West Finland. The formation of this patient population consisting of 510 diabetic patients in East Finland (participation rate, 89%) and 549 patients in West Finland (participation rate, 79%) has been described in detail previously.22 23 Insulin-dependent diabetes was excluded in all patients treated with insulin by C-peptide measurements as previously described.24 None of the diabetic patients in the final study population classified as having NIDDM according to the WHO criteria25 had a history of ketoacidosis. For the purposes of this article, three NIDDM patients with serum creatinine higher than 200 mmol/L were excluded. The final study group included 252 diabetic men and 257 women in East Finland and 328 diabetic men and 219 women in West Finland. Nondiabetic Subjects A random control population sample of subjects whose place of birth was in the Kuopio University Hospital district or in the Turku University Central Hospital district and who were living in these areas was taken from the population registry containing all subjects aged 45 to 64 years. The study population consisted of 651 (participation rate, 79%) East Finland and 730 (participation rate, 85%) West Finland nondiabetic control subjects. After the exclusion of 10 nondiabetic subjects with serum creatinine higher than 200 mmol/L, the final nondiabetic study group included 312 nondiabetic men and 336 nondiabetic women in East Finland and 328 nondiabetic men and 399 nondiabetic women in West Finland. Study Methods The baseline examination of nondiabetic and NIDDM subjects was carried out from 1982 through 1984. The examination included an interview on previous medical history, history of smoking, and use of drugs, as well as the drawing of blood samples for laboratory examinations and measurements of height, weight, and blood pressure. All medical records of subjects who reported in the interview that they had been admitted to the hospital because of symptoms suggestive of stroke or MI were reviewed by two experienced internists (M.L. in Kuopio and T.R. in Turku). The WHO criteria for verified definite or possible stroke were used in the ascertainment of the diagnosis of previous stroke, which was defined as a clinical syndrome consisting of definite neurological symptoms persisting for more than 24 hours.26 Thromboembolic and hemorrhagic stroke, but not subarachnoid hemorrhage, were included in the diagnosis of stroke. The modified WHO MONICA criteria for verified definite or possible MI based on chest pain symptoms, electrocardiographic changes, and enzyme determinations were used in the ascertainment of the diagnosis of previous MI.27 Subjects were classified as having hypertension if they were receiving drug treatment for hypertension or if systolic blood pressure was 160 mm Hg or diastolic blood pressure was 95 mm Hg measured in the sitting position after a 5-minute rest. Serum lipids were determined from fresh serum samples drawn after a 12-hour overnight fast. Serum total cholesterol and triglyceride levels were determined enzymatically (Boehringer Mannheim GmbH). Serum HDL cholesterol was determined directly after precipitation of apolipoprotein B–containing lipoproteins with dextran sulfate and magnesium chloride. Apolipoproteins A1 and B were determined by radioimmunoassay. HbA1 was estimated by ion exchange affinity chromatography (Isolab Inc; reference range, 5.5% to 8.5%). Plasma glucose was determined with the glucose oxidase method (Boehringer). Total urinary protein concentration was measured from the morning spot urine specimen with the Coomassie brilliant blue method (Bio-Rad Laboratories). For the purposes of this study, the subjects were classified into three categories according to the degree of proteinuria: no proteinuria (<150 mg/L), borderline proteinuria (150 to 299 mg/L), and clinical proteinuria (300 mg/L). Collection of Follow-up Data In 1990, a postal questionnaire containing questions about the hospitalization due to stroke, acute chest pain, or lower-extremity amputation was sent to every surviving patient of the original study. All medical records of the subjects who reported in the questionnaire that they had been admitted to the hospital because of stroke, chest pain symptoms, or amputation were reviewed. To complete the end point data collection and review of medical records, we used computerized hospital discharge registers to identify the hospitalizations due to stroke, CHD, and amputation for those participants who did not respond to the questionnaire, as well as the hospitalizations of those participants who had died between the baseline examination and December 31, 1989. Copies of death certificates of subjects who had died were obtained from the Central Statistical Office of Finland. In the final classification of the causes of death, hospital and autopsy records were also used if available. In the ascertainment of the diagnosis of stroke we used the WHO MONICA criteria for verified definite or possible stroke.26 Thromboembolic and hemorrhagic stroke, but not subarachnoid hemorrhage, were included in the diagnosis of stroke. In the ascertainment of the diagnosis of MI, the modified WHO MONICA criteria for verified definite or possible MI were used.27 Lower-extremity amputations due to trauma and other nonvascular causes were excluded. Statistical Methods Statistical analyses were conducted with the SAS program, version 6.10.28 Differences between the groups were assessed by 2 test or ANCOVA by using age, sex, and area as covariates. Because of skewed distribution, triglyceride values were log transformed for statistical analyses. Stratified analyses by using the median split for different variables were performed by 2 test. For these analyses, subjects with borderline and clinical proteinuria were combined into one class. Interaction between urinary protein and each stratification variable was tested with the test of homogeneity. The associations between the different stages of proteinuria and stroke, serious CHD events (CHD death or nonfatal MI), and amputation were studied with multiple logistic regression analysis. Kaplan-Meier estimates for the survival curves for each level of the urinary protein concentration were obtained and compared using the log-rank test. Kaplan-Meier estimates for serious CHD events were not analyzed because the dates of the first nonfatal CHD events were not available. We also performed Cox regression analysis for fatal events. The results, however, were similar to those obtained by multiple logistic regression, and only the results of logistic regression analyses are presented. This study was approved by the ethics committees of Kuopio University Hospital and Turku University Central Hospital. Results Top Abstract Introduction Subjects and Methods Results Discussion References Baseline Characteristics Elevated urinary protein excretion (borderline and clinical proteinuria together) was found in East Finland in 25% of nondiabetic and 58% of NIDDM subjects and in West Finland in 16% of nondiabetic and 46% of NIDDM subjects. Borderline and clinical proteinuria were more common in East Finland than in West Finland and also in men than in women. NIDDM patients with borderline or clinical proteinuria were slightly older than NIDDM patients without proteinuria (mean±SEM, 58.6±0.2 versus 57.6±0.2 years, P<.01). Table 1 presents clinical characteristics of nondiabetic and NIDDM subjects by the degree of proteinuria at baseline adjusted for age, sex, and area. The prevalence of hypertension was higher both in nondiabetic and NIDDM subjects with borderline or clinical proteinuria than in subjects without proteinuria. Previous MI at baseline was more common in NIDDM patients with clinical proteinuria than in those without proteinuria or with borderline proteinuria. In nondiabetic subjects, the prevalence of previous MI was similar regardless of the degree of proteinuria. The lipid profile in NIDDM patients with borderline or clinical proteinuria tended to be worse than in patients without proteinuria. Total cholesterol and triglyceride levels in NIDDM patients with proteinuria were higher, and HDL cholesterol levels lower, than in patients without proteinuria. In nondiabetic subjects, we found no difference in total or HDL cholesterol levels between different categories of proteinuria. The degree of proteinuria was not significantly associated with the duration of diabetes, but it was highly significantly related to poor metabolic control of diabetes measured either as fasting plasma glucose level or glycosylated hemoglobin. View this table: [in this window] [in a new window] Table 1. Characteristics of Nondiabetic and Diabetic Subjects by Different Degrees of Proteinuria at Baseline Adjusted for Study Area, Age, and Sex Proteinuria and Mortality Fig 1 shows the survival curves for all-cause mortality in three proteinuria categories in nondiabetic and NIDDM subjects. All-cause mortality was higher both in nondiabetic and NIDDM subjects with borderline or clinical proteinuria than in those without proteinuria. View larger version (17K): [in this window] [in a new window] Figure 1. Survival curves for all-cause mortality by urinary protein concentration (U-Prot) in NIDDM and nondiabetic patients. The mortality from CVD in NIDDM patients with clinical proteinuria was significantly higher than in patients with borderline proteinuria or without proteinuria (Fig 2). The CVD mortality of NIDDM patients with borderline proteinuria was also significantly higher than in NIDDM patients without proteinuria. CVD mortality tended also to be higher in nondiabetic subjects with borderline or clinical proteinuria than in those without proteinuria. However, the differences between the groups were smaller than in NIDDM patients. The results of the survival analysis for CHD mortality were similar to those for total CVD mortality (data not shown). View larger version (18K): [in this window] [in a new window] Figure 2. Survival curves for CVD mortality by urinary protein concentration (U-Prot) in NIDDM and nondiabetic patients. In NIDDM patients with borderline or clinical proteinuria, the non-CVD mortality was higher than in those without proteinuria (data not shown). In nondiabetic subjects, we found no statistically significant differences in mortality from non-CVD among different proteinuria groups. The most important causes for non-CVD deaths (n=97) in NIDDM patients were neoplasms (41%), diabetes and its complications (25%), gastrointestinal and liver diseases (15%), and traumas (6%). In nondiabetic subjects, the most important reasons for non-CVD deaths (n=43) were neoplasms (56%), traumas (23%), and gastrointestinal and liver diseases (12%). Proteinuria and Incidence of Stroke and Other Atherosclerotic Vascular Disease Events During the 7-year follow-up, 376 NIDDM patients (36%) and 84 nondiabetic subjects (6.1%) developed an atherosclerotic vascular disease event. The corresponding numbers for stroke were 125 (12%) and 30 (2%) and for serious CHD events 255 (24%) and 57 (4%), respectively. There were no amputations in nondiabetic subjects, but in 58 of the NIDDM patients (10%) a lower-extremity amputation was performed during the 7-year follow-up. The incidence of atherosclerotic vascular disease events during the follow-up was almost two times higher in NIDDM patients with clinical proteinuria than in those without proteinuria (Fig 3). The incidence of atherosclerotic vascular disease events increased stepwise with the degree of proteinuria in both nondiabetic and NIDDM subjects. A similar stepwise trend was found between proteinuria and stroke and CHD events both in NIDDM and nondiabetic subjects, as well as between proteinuria and amputation in NIDDM patients. View larger version (40K): [in this window] [in a new window] Figure 3. Incidence of CHD events (CHD death or nonfatal MI), stroke, lower-extremity amputation, and all atherosclerotic vascular disease (ASVD) events (any one of the three previous categories of events) in nondiabetic or NIDDM subjects by urinary protein concentration (U-Prot), both areas and sexes combined (probability values for trends as shown). Table 2 shows the results of multivariate logistic regression analyses for the association between proteinuria and stroke, CHD events, and lower-extremity amputation comparing borderline or clinical proteinuria separately with the group without proteinuria. The strength of the association between borderline proteinuria and stroke as indicated by the odds ratios was similar in nondiabetic and NIDDM subjects. However, this association was not statistically significant. The association of clinical proteinuria with stroke was stronger than that of borderline proteinuria with stroke, and the strength of the association did not differ in nondiabetic and NIDDM subjects. View this table: [in this window] [in a new window] Table 2. Adjusted Odds Ratios and 95% Confidence Intervals for Borderline (150-300 mg/L) or Clinical (>300 mg/L) Proteinuria With Regard to CHD Events, Stroke, Amputation, and All Atherosclerotic Vascular Events Obtained Using Different Models in Logistic Regression Analysis in Nondiabetic and NIDDM Subjects The association between borderline proteinuria and CHD events both in nondiabetic and NIDDM subjects was similar to that between borderline proteinuria and stroke (Table 2). However, the association between clinical proteinuria and stroke was even stronger than that between clinical proteinuria and CHD events. When analyses were restricted only to subjects without a previous history of MI at baseline, the strength of the association between proteinuria and CHD events did not change (odds ratios for clinical proteinuria versus group without proteinuria were 2.04 to 2.61 in nondiabetic subjects and 1.92 to 2.27 in NIDDM patients). Further adjustment for apolipoproteins A1 and B did not change the results of multivariate logistic regression analysis (data not shown). Furthermore, we found an association between proteinuria and lower-extremity amputation in NIDDM patients similar to the associations between proteinuria and stroke or proteinuria and CHD events (Table 2). Discussion Top Abstract Introduction Subjects and Methods Results Discussion References We have shown for the first time in the same prospective study that clinical proteinuria predicts the incidence of stroke, as well as serious CHD events (CHD death or nonfatal MI), both in nondiabetic and NIDDM subjects and the incidence of lower-extremity amputation in NIDDM patients. Furthermore, both the all-cause and CVD mortality were higher in nondiabetic and NIDDM subjects with clinical proteinuria (>300 mg/L) than in those without proteinuria. NIDDM independently increased the risk of atherosclerotic vascular disease events regardless of proteinuria status. Nevertheless, the association between the different degrees of proteinuria and the risk of stroke, CHD events, or lower-extremity amputation was stepwise and basically similar in nondiabetic and NIDDM subjects. The association of clinical proteinuria with the risk of stroke, as well as with the risk of CHD events or amputation, was independent of other cardiovascular risk factors in NIDDM patients. The risk of ischemic stroke is undoubtedly higher in diabetic patients than in nondiabetic subjects.1 23 29 30 31 32 33 Hypertension is the strongest risk factor for stroke both in nondiabetic and diabetic subjects.31 34 Only a few studies have been published previously regarding the association between proteinuria and the risk of stroke. In Japanese and European prospective studies on diabetic patients, proteinuria predicted cerebrovascular diseases during the follow-up.20 21 On the other hand, Gall et al,8 in their study based on 5-year follow-up of NIDDM patients, found no significant relationship between baseline albuminuria and the mortality from stroke. However, their study included only very few subjects who developed stroke. Our findings showing that clinical proteinuria predicts all-cause and CVD mortality are compatible with those of previous studies suggesting that increased urinary albumin2 3 4 7 8 35 36 or protein9 10 excretion is associated with increased mortality. Several studies have shown that the mortality risk is 2.3 to 4 times higher in NIDDM patients with microalbuminuria than in those without microalbuminuria.2 3 35 36 However, Mattock et al4 reported recently that the mortality risk in NIDDM patients with microalbuminuria was almost 10 times higher than in NIDDM patients without albuminuria. In these studies, CVD has been the most important cause of death.3 4 36 Gall et al8 reported recently the results of a prospective 5-year follow-up study in which the risk of cardiovascular death was 2.5-fold in NIDDM patients with macroalbuminuria (300 mg/24 h) but not in those with microalbuminuria (30 to 299 mg/24 h). Less is known about the association of albuminuria or proteinuria and all-cause or CVD mortality in nondiabetic subjects. In prospective studies, microalbuminuria has predicted both total and CVD mortality,3 5 11 12 in some studies independent of other cardiovascular risk factors.5 12 Our results also showed that adjustment for other cardiovascular risk factors and apolipoproteins does not markedly alter the odds ratios for proteinuria with regard to different manifestations of atherosclerotic vascular disease. The implication of these findings in nondiabetic subjects and NIDDM patients is that increased urinary protein excretion rate may be the reflection of widespread vascular damage, as suggested by the Steno hypothesis (Deckert et al17 ). Damsgaard et al37 showed in nondiabetic subjects that the increase in all-cause mortality during the 8- to 9-year follow-up associated with albuminuria was mostly due to an increased mortality of albuminuric nondiabetic subjects during the first years after the baseline examination. No difference in mortality between subjects with and without albuminuria was found among those who survived the first 5 years of the follow-up. Contrary to the findings of Damsgaard et al,37 in our study the mortality of both nondiabetic subjects and NIDDM patients with clinical proteinuria continued to be higher than that in corresponding subjects without proteinuria during the last years of follow-up also. Similar results have been published by other investigators.7 36 The implication of these findings is that proteinuria is not solely the complication of any preclinical serious disease but the reflection of underlying disorder itself. Although the etiology of lower-extremity amputation is multifactorial, including combinations of ischemia, neuropathy, trauma, and infection, the ischemia often plays a major role in pathways leading to amputation.38 As far as we know, no studies regarding the association between proteinuria and the risk of amputation have been published previously. The prevalence of peripheral arterial disease has been shown to be higher in NIDDM patients with albuminuria,39 40 but no association between proteinuria and the incidence of peripheral arterial disease was found in a prospective study.21 In our study, the association between clinical proteinuria and incidence of lower-extremity amputation in NIDDM patients was significant even though slightly weaker than that between proteinuria and incidence of stroke. Instead of the measurement of urinary albumin excretion rate, we determined the total urinary protein concentration from the morning spot urine. In patients with increased urinary protein excretion rate due to diabetic glomerular injury, the proportion of albumin to total urinary protein is higher than in subjects without diabetic nephropathy. The commonly used cutoff point for urinary albumin excretion rate of 200 to 300 mg/24 h has been estimated to correspond to a total urinary protein excretion rate of 500 mg/24 h.41 Our cutoff point for clinical proteinuria (300 mg/L) is close to this, assuming that the mean daily volume of urine is approximately 1.5 L. Urinary protein concentration measured from spot urine has been shown to correlate very well with 24-hour urinary protein excretion.42 43 In our study, measurement of urinary protein concentration from spot urine instead of 24-hour urine may increase random variation and decrease the strength of the association between proteinuria and atherosclerotic vascular events. Furthermore, if we had measured urinary albumin, which is more specific to diabetic nephropathy than total urinary protein, our findings concerning associations between proteinuria and atherosclerotic vascular disease events might have been even stronger than those we now report. The mechanisms of the association between proteinuria and CVD are poorly understood, and several explanations have been proposed. Albuminuria has been proposed to be associated with adverse changes in other known cardiovascular risk factors,4 13 14 15 16 a marker of established CVD itself,16 widespread vascular damage,17 or endothelial dysfunction.18 19 Furthermore, albuminuria has been shown to be related to the abnormalities in thrombogenic factors favoring the development of cardiovascular complications in patients with NIDDM.16 18 In our study, proteinuria in NIDDM patients was associated with adverse changes in most of the classic cardiovascular risk factors except smoking. Statistically significant associations were found between proteinuria and history of hypertension and elevated levels of triglycerides and total and decreased levels of HDL cholesterol. Furthermore, in NIDDM patients the metabolic control of diabetes was worse in the subjects with borderline or clinical proteinuria. However, after we controlled for all these variables, clinical proteinuria still significantly predicted the risk of stroke, as well as the risk of serious CHD events and amputation in NIDDM patients. In conclusion, increased urinary protein concentration predicted both all-cause and CVD mortality, as well as the incidence of stroke and other atherosclerotic vascular disease events, during the 7-year follow-up both in nondiabetic and NIDDM subjects. The association between clinical proteinuria and the risk of atherosclerotic vascular disease events remained statistically significant in NIDDM subjects even after controlling for other cardiovascular risk factors. Our findings are compatible with the hypothesis that increased urinary protein excretion may be associated with widespread vascular damage. Selected Abbreviations and Acronyms CHD = coronary heart disease CVD = cardiovascular disease MI = myocardial infarction NIDDM = non–insulin-dependent diabetes mellitus WHO = World Health Organization Acknowledgments This study was supported by grants from the Academy of Finland, the Aarne and Aili Turunen Foundation, and the Finnish Heart Research Foundation. Received July 2, 1996; revision received August 7, 1996; accepted August 15, 1996. References Top Abstract Introduction Subjects and Methods Results Discussion References Pyorala K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiological view. Diabetes Metab Rev. 1987;3:463-524.[Medline] Morgensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;310:356-360.[Abstract] Nelson RG, Pettitt DJ, Carraher MJ, Baird HR, Knowler WC. Effect of proteinuria on mortality in NIDDM. Diabetes. 1988;37:1499-1504.[Abstract] Mattock MB, Morrish NJ, Viberti GC, Keen H, Fitzgerald AP, Jackson G. Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes. 1992;41:735-741. Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Eight to nine year mortality in known non-insulin dependent diabetics and controls. Kidney Int. 1992;41:731-735.[Medline] Neil A, Hawkins M, Potok M, Thorogood M, Cohen D, Mann J. A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM. Diabetes Care. 1993;16:996-1003.[Abstract] MacLeod JM, Lutale J, Marshall SM. Albumin excretion and vascular deaths in NIDDM. Diabetologia. 1995;38:610-616.[Medline] Gall MA, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving H-H. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes. 1995;44:1303-1309.[Abstract] Ballard DJ, Humphrey LL, Melton J III, Frohnert PP, Chu C-P, O'Fallon WM, Palumbo PJ. Epidemiology of persistent proteinuria in type II diabetes mellitus: population-based study in Rochester, Minnesota. Diabetes. 1988;37:405-412.[Abstract] Stephenson JM, Kenny S, Stevens LK, Fuller JH, Lee E. Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular Disease in Diabetes. Diabetic Med. 1995;12:149-155.[Medline] Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: the Framingham study. Am Heart J. 1984;108:1347-1352.[Medline] Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects: Islington Diabetes Survey. Lancet. 1988;2:530-533.[Medline] Mattock MB, Keen H, Viberti GC, El-Gohari MR, Murrells TJ, Scott GS, Wing JR, Jackson PG. Coronary heart disease and urinary albumin excretion rate in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1988;31:82-87.[Medline] Seghieri G, Alviggi L, Caselli P, De Giorgio LA, Breschi C, Gironi A, Niccolai M, Bartolomei GC. Serum lipids and lipoproteins in type 2 diabetic patients with persistent microalbuminuria. Diabetic Med. 1990;7:810-814.[Medline] Niskanen L, Uusitupa M, Sarlund H, Siitonen O, Voutilainen E, Penttila I, Pyorala K. Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1990;33:237-243.[Medline] Winocour PH, Harland JO, Millar JP, Laker MF, Alberti KG. Microalbuminuria and associated cardiovascular risk factors in the community. Atherosclerosis. 1992;93:71-81.[Medline] Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevolsen A. Albuminuria reflects widespread vascular damage: the Steno hypothesis. Diabetologia. 1989;32:219-226.[Medline] Knobl P, Schernthaner G, Schnack C, Pietschmann P, Griesmacher A, Prager R, Muller M. Thrombogenic factors are related to urinary albumin excretion in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:1045-1050.[Medline] Stehouwer CDA, Nauta JJP, Seldenrust GC, Hackeng WHL, Donker AJM, den Ottolander GJH. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet. 1992;340:319-323.[Medline] Sasaki A, Horiuchi N, Hasegawa K, Uehara M. Mortality from coronary heart disease and cerebrovascular disease and associated risk factors in diabetic patients in Osaka District, Japan. Diabetes Res Clin Pract. 1995;27:77-83.[Medline] Morrish NJ, Stevens LK, Fuller JH, Jarrett RJ, Keen H. Risk factors for macrovascular disease in diabetes mellitus: the London follow-up to the WHO Multinational Study of Vascular Disease in Diabetics. Diabetologia. 1991;34:590-594.[Medline] Laakso M, Ronnemaa T, Pyorala K, Kallio V, Puukka P, Penttila I. Atherosclerotic vascular disease and its risk factors in non-insulin-dependent diabetic and nondiabetic subjects in Finland. Diabetes Care. 1988;11:449-463.[Abstract] Lehto S, Ronnemaa T, Pyorala K, Laakso M. Predictors of stroke in middle-aged patients with non–insulin-dependent diabetes. Stroke. 1996;27:63-68.[Abstract/Free Full Text] Madsbad S, Alberti K, Binder C, Burrin JM, Faber OK, Krarup T, Regeur L. Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetics. Br Med J. 1979;2:1257-1259.[Medline] WHO Expert Committee on Diabetes Mellitus. Technical Report Series, 246: Second Report: World Health Organization. Geneva, Switzerland: World Health Organization; 1980. WHO MONICA Project. MONICA Manual. Geneva, Switzerland: Cardiovascular Diseases Unit, World Health Organization; 1990. Tuomilehto J, Arstila M, Kaarsalo E, Kankaanpaa J, Ketonen M, Kuulasmaa K, Lehto S, Miettinen H, Mustaniemi H, Palomaki P, Puska P, Pyorala K, Salomaa V, Torppa J, Vuorenmaa T. Acute myocardial infarction (AMI) in Finland-baseline data from the FINMONICA AMI register in 1983-1985. Eur Heart J. 1992;13:577-587.[Abstract] SAS Institute Inc. SAS/Stat Users Guide, Version 6. 4th ed. Cary, NC: SAS Institute Inc; 1990:vols 1 and 2. Bell DS. Stroke in the diabetic patient. Diabetes Care. 1994;17:213-219. Review.[Abstract] Wolf PA, D'Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke. 1991;22:312-318.[Abstract] Neaton JD, Wentworth DN, Cutler J, Stamler J, Kuller L, for the Multiple Risk Factor Intervention Trial Research Group. Risk factors for death from different types of stroke. Ann Epidemiol. 1993;3:493-499.[Medline] Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Non–insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke. 1994;25:1157-1164.[Abstract] Tuomilehto J, Rastenyte D, Jousilahti P, Sarti C, Vartiainen E. Diabetes mellitus as a risk factor for death from stroke. Stroke. 1996;27:210-215.[Abstract/Free Full Text] Abbott RD, Donahue RP, MacMahon SW, Reed DM, Yano K. Diabetes and the risk of stroke: the Honolulu Heart Program. JAMA. 1987;257:949-952.[Abstract] Jarrett JR, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murrells TJ. Microalbuminuria predicts mortality in non-insulin-dependent diabetes. Diabetic Med. 1984;1:17-19.[Medline] Schmitz A, Vaeth M. Microalbuminuria: a major risk factor in non-insulin-dependent diabetes. A 10-year follow-up study of 503 patients. Diabetic Med. 1988;5:126-134.[Medline] Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Prognostic value of urinary albumin excretion rate and other risk factors in elderly diabetic patients and non-diabetic control subjects surviving the first 5 years after assessment. Diabetologia. 1993;36:1030-1036.[Medline] Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: basis for prevention. Diabetes Care. 1990;13:513-521.[Abstract] Migdalis IN, Kourti A, Voudouris G, Likoudi A, Samartzis M. The prevalence of peripheral vascular disease in sulfonylurea-treated diabetic patients with proteinuria. Int Angiol. 1990;9:271-273.[Medline] Gall MA, Rossing P, Skott P, Damsbo P, Vaag A, Bech K, Dejgaard A, Lauritzen M, Lauritzen E, Hougaard P, et al. Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1991;34:655-661.[Medline] Mogensen CE, Schmitz O. The diabetic kidney. Med Clin North Am. 1988;72:1465-1492.[Medline] Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med. 1983;309:1543-1546.[Abstract] Ralston SH, Caine N, Richards I, O'Reilly D, Sturrock RD, Capell HA. Screening of proteinuria in a rheumatology clinic: comparison of dipstick testing, 24 hour urine quantitative protein, and protein/creatinine ration in random urine samples. Ann Rheum Dis. 1988;47:759-763.[Abstract] _________________ JoAnn Guest mrsjo- DietaryTi- www.geocities.com/mrsjoguest/Genes AIM Barleygreen " Wisdom of the Past, Food of the Future " http://www.geocities.com/mrsjoguest/Diets.html Quote Link to comment Share on other sites More sharing options...
Guest guest Posted April 7, 2005 Report Share Posted April 7, 2005 , renato alexander <renato23451> wrote: > > Hello Ms Guest, > > My names Renato Alexander, coping with multiple > sclerosis, and, undaunted, managed to email you a > rather heartfelt 'story' of how I've been dealing > successfully with it. > > Improvements have actually been quite surreal and just > wished I could share my experience with you. I already > have hardly any self-esteem left that I'm aware of- we > tend to be hypersensitive at times- so the fact that > you didnt acknowledge my initial display of enthusiasm, surprisingly, didnt adversly affect me.. > and Im sure its by virtue of the seemingly miraculous > improvements that Ive had, even emotionally, thank > God. > > I think I may have inadvertingly offended you, in > which case I extend my most humble apologies! > > Sincerely, > Renato > Renato, My thoughts and prayers are with you during this very difficult time! There are no words in the English language to adequately express my feelings when I receive emails like yours. I truly appreciate your response! Your response is very encouraging to me. I have learned to be cautious on public forums, however if you ever need encouragement or additional help feel free to email me privately. You didn't mention your background in alternatives, or how you became aware of echinacea for MS symptoms. This is not at all surprising to me when I consider the way echinacea impacts the immune system and although I had known about the link with interferon, I always appreciate additional information and especially this regarding MS. There is a good deal of controversy on the subject... I believe MS is considered an autoimmune disease?? some say that pathogens are contraindicated for this very reason. It is very interesting to read various opinions on the subject although this just confirms to me the fact that we must all do our own research, mainly because that which is beneficial for one is not always effective for everyone else (even those who have been labeled with the same disease). Each individual is unique. Alternative medicine is largely trial and error. I do know this from my past experience as I have successfully recovered from cardiovascular disease over the past five years or more. I will say that initially I experienced a host of improvements although as time progresses the vitality and energy that I am experiencing in this new way of life is becoming almost surreal for me and especially at my age. I can honestly say that there are so many beneficial aspects of the organic diet that surpasses anything which I had ever experienced in the past. Little wonder though remembering white bread was a staple at our dinner table. Diet makes such a difference. But then we are all accustomed to the standard american diet which leaves a lot to be desired! Surreal? That is an understatement! Yet, whenever I try to explain this to those around me there is little or no comprehension. There is a lot of work to be done. There are still those who say it can't be done,so in our hearts we have the secret of health which seems hidden to the majority. I will say that Big Pharma has seemingly done their job well!!! Hugs and bright blessings, JoAnn Quote Link to comment Share on other sites More sharing options...
Guest guest Posted April 7, 2005 Report Share Posted April 7, 2005 Thank you Ms Guest, A local Va.Bch family doctor introduced me to it all; all started with a blood analysis, blood was drawn and studied.. results came back showing what food allergies one has, sensitivities and supplements 'tailor made' for ones' paticular problem are encouraged, and I just happen to be coming along great! My point in sharing all this is because, as I continue feeling better and better, I can't help feeling empathy for other 'sick' people- this is a pretty obscure 'therapy' I'm happy to provide more details, Renato PS Fatigue, cognitive difficulties etc are gone the first couple wks.. hey, I sound like a commercial, sorry, but I guess I'm more a testimonial --- JoAnn Guest <angelprincessjo wrote: > > , > renato alexander > <renato23451> wrote: > > > > Hello Ms Guest, > > > > My names Renato Alexander, coping with multiple > > sclerosis, and, undaunted, managed to email you a > > rather heartfelt 'story' of how I've been dealing > > successfully with it. > > > > Improvements have actually been quite surreal and > just > > wished I could share my experience with you. I > already > > have hardly any self-esteem left that I'm aware > of- we > > tend to be hypersensitive at times- so the fact > that > > you didnt acknowledge my initial display of > enthusiasm, > surprisingly, didnt adversly affect me.. > > and Im sure its by virtue of the seemingly > miraculous > > improvements that Ive had, even emotionally, thank > > God. > > > > I think I may have inadvertingly offended you, in > > which case I extend my most humble apologies! > > > > Sincerely, > > Renato > > > > Renato, > My thoughts and prayers are with you during this > very difficult > time! There are no words in the English language to > adequately express my feelings when I receive emails > like yours. I truly appreciate your response! Your > response is very encouraging to me. I have learned > to be cautious on public forums, however if you ever > need encouragement or additional help feel free to > email me privately. > > You didn't mention your background in alternatives, > or how you became aware of echinacea for MS > symptoms. This is not at all surprising to me when I > consider the way echinacea impacts the immune system > and although I had known about the link with > interferon, I always appreciate additional > information and especially this regarding MS. There > is a good deal of controversy on the subject... I > believe MS is considered an autoimmune disease?? > some say that pathogens are contraindicated for this > very reason. > > It is very interesting to read various opinions on > the subject although this just confirms to me the > fact that we must all do our own research, mainly > because that which is beneficial for one is not > always effective for everyone else (even those who > have been labeled with the same disease). Each > individual is unique. > > Alternative medicine is largely trial and error. > I do know this from my past experience as I have > successfully recovered from cardiovascular disease > over the past five years or more. I will say that > initially I experienced a host of improvements > although as time progresses the vitality and energy > that I am experiencing in this new way of life is > becoming almost surreal for me and especially at my > age. I can honestly say that there are so many > beneficial aspects of the organic diet that > surpasses anything which I had ever experienced in > the past. Little wonder though remembering white > bread was a staple at our dinner table. Diet makes > such a difference. But then we are all accustomed to > the standard american diet which leaves a lot to be > desired! > > Surreal? That is an understatement! Yet, whenever I > try to explain > this to those around me there is little or no > comprehension. > There is a lot of work to be done. There are still > those who say it can't be done,so in our hearts we > have the secret of health which seems hidden to the > majority. I will say that Big Pharma has seemingly > done their job well!!! > > Hugs and bright blessings, > JoAnn > > > > > > > > Quote Link to comment Share on other sites More sharing options...
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