Physiopathology of proteinuria and laboratory diagnostic strategy based on single protein analysis

A quantification of proteins of different molecular size has been shown to be useful in characterizing the mechanism and medical causes of proteinuria. By analyzing urine albumin, alpha1-microglobulin, immunoglobulin G and alpha2-macroglobulin together with total protein, prerenal, glomerular, tubular and postrenal causes of proteinuria can be detected and differentiated by their specific urine protein patterns. Using automated turbidimetric procedures, prerenal proteinurias are characterized by an albumin/total protein ratio below 0.4. Tubulo-interstitial diseases which are negative in the protein test strip procedure are detected and clearly differentiated from other causes of proteinuria by their high alpha1-microglobulin/albumin ratios. In post-renal proteinuria, alpha2-macroglobulin proved to be a useful marker, when albumin excretion exceeds 100 mg/l urine. This protein exhibits plasma-like ratios to albumin in postrenal causes, whereas it is much lower in renal proteinurias. The new strategy, which has been evaluated in more than 500 clinically and partly histologically proven cases of renal diseases, more sensitively detects glomerular and tubulo-interstitial diseases when applied in urine screening and allows us to distinguish all clinically important causes from analysis of a morning spot urine sample.     

Proteinuria: diagnostic principles and procedures

Proteinuria has been thought of as the first sign of serious renal disease. However, in some patients proteinuria may last for years without other evidence of kidney damage, and in other patients it may only be an insignificant and transient laboratory finding. The nature and severity of renal involvement in a particular patient are often suggested by the clinical picture, and the pattern and amount of proteinuria. The physician should use this information in evaluating the severity of the patient's disease. An approach for such evaluations is offered by briefly reviewing the causes and prognosis of the various types of proteinuria and by suggesting steps to take in treating patients with increased protein excretion.     

ACE inhibitors and proteinuria

This review discusses the clinical consequences of urinary protein loss and the effects of inhibitors of the angiotensin converting enzyme (ACE) on this clinical finding. Proteinuria appears to be an important risk factor for renal function deterioration and for cardiovascular mortality. ACE inhibitors have been shown to reduce proteinuria more effectively than other antihypertensives. Their antiproteinuric effect seems to be independent of the underlying renal disease, and is mediated by a specific, not yet fully elucidated mechanism. Urinary protein loss related phenomena, such as hypoalbuminemia and aberrant lipoprotein profile, tend to improve also during ACE inhibitor treatment. Furthermore, ACE inhibition has been shown to prevent the renal function deterioration that is frequently observed in patients with renal disease. Interestingly, it has recently been shown that in proteinuric patients with renal disease the initial proteinuria lowering response to ACE inhibition predicts long-term renal function outcome during this treatment the more proteinuna is lowered during the first months, the better renal function will be preserved over the following years. Because of these favorable effects ACE inhibitors have become a widely used class of agents in nephrology. They are not only prescribed for lowering blood pressure in the hypertensive renal patient, but also as symptomatic treatment of patients with proteinuria, and to prevent renal function loss in patients with both diabetic and non-diabetic renal disease.     

Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes

OBJECTIVE: To evaluate whether the protein:creatinine ratio in spot morning urine samples is a reliable indicator of 24 hour urinary protein excretion and predicts the rate of decline of glomerular filtration rate and progression to end stage renal failure in non-diabetic patients with chronic nephropathy. DESIGN: Cross sectional correlation between the ratio and urinary protein excretion rate. Univariate and multivariate analysis of baseline predictors, including the ratio and 24 hour urinary protein, of decline in glomerular filtration rate and end stage renal failure in the long term. SETTING: Research centre in Italy. SUBJECTS: 177 non-diabetic outpatients with chronic renal disease screened for participation in the ramipril efficacy in nephropathy study. MAIN OUTCOME MEASURES: Rate of decline in filtration rate evaluated by repeated measurements of unlabelled iohexol plasma clearance and rate of progression to renal failure. RESULTS: Protein:creatinine ratio was significantly correlated with absolute and log transformed 24 hour urinary protein values (P = 0.0001 and P < 0.0001, respectively.) Ratios also had high predictive value for rate of decline of the glomerular filtration rate (univariate P = 0.0003, multivariate P = 0.004) and end stage renal failure (P = 0.002 and P = 0.04). Baseline protein:creatinine ratios and rate of decline of the glomerular filtration rate were also significantly correlated (P < 0.0005). In the lowest third of the protein:creatinine ratio (< 1.7) there was 3% renal failure compared with 21.2% in the highest third (> 2.7) (P < 0.05). CONCLUSIONS: Protein:creatinine ratio in spot morning urine samples is a precise indicator of proteinuria and a reliable predictor of progression of disease in non-diabetic patients with chronic nephropathies and represents a simple and inexpensive procedure in establishing severity of renal disease and prognosis.     

Factors relating to urinary protein excretion in children with autosomal dominant polycystic kidney disease

Adults with autosomal dominant polycystic kidney disease (ADPKD) who have overt proteinuria (>300 mg/d) have higher mean arterial pressures, lower creatinine clearances, larger renal volumes, and a more aggressive course of renal disease than ADPKD patients without proteinuria. This study examines the relationship between proteinuria and microalbuminuria and similar factors in ADPKD children. A total of 189 children from 81 ADPKD families was included in the analysis. The ADPKD children (n = 103) had significantly greater urine protein excretion rates than the non-ADPKD children (n = 86) (3.9+/-0.3 versus 2.8+/-0.2 mg/m2 per h, P < 0.001). Children with severe renal cystic disease (> 10 cysts; n = 54) had greater protein excretion than those with moderate disease (< or = 10 cysts; n = 49) (4.4+/-0.5 versus 3.3+/-0.2 mg/m2 per h, P < 0.05). The ADPKD children had significantly greater albumin excretion rates than the non-ADPKD children (32+/-6 versus 10+/-2 mg/m2 per 24 h, P < 0.001), and a higher percentage of ADPKD children had significant microalbuminuria (>15 mg/m2 per 24 h in boys and >23 mg/m2 per 24 h in girls) than their unaffected siblings (30% versus 10%, P < 0.05). Thirty percent of ADPKD children had albuminuria and 23% had overt proteinuria. For all ADPKD children, there was no correlation between proteinuria and hypertension. However, there was a significant correlation between urinary protein excretion and diastolic BP among children diagnosed after the first year of life (r = 0.23, P < 0.05). Therefore, proteinuria and albuminuria occur early in the course of ADPKD and may be markers of more severe renal disease.     

Clinical studies of the prognosis in cases of chance proteinuria and/or hematuria]

A total of 174 cases that consulted due to chance proteinuria and/or hematuria (CPH) were studied as to its clinical course, in particular patients' prognosis. They were selected from 311 patients on whom renal biopsy was performed from December, 1975 to December, 1985 in our institute. Furthermore, IgA nephropathy which occupied the major part of the CPH group was also studied as a prognostic factor. The CPH group showed 81% of disease stabilizing rate in 10 years' follow-up. In various data such as chemical analysis of blood and urine, immunoglobulin levels, and renal function at the time of biopsy, daily urinary protein excretion (greater than 1 g/day) statistically showed a significant correlation to deterioration of the renal function during the follow up. However, hematuria was not found correlated. Of CPH group, 48% was diagnosed to be with IgA nephropathy. The patients with IgA nephropathy with CPH, comparing with the cases without CPH, were younger and had better renal function and milder change of renal mesangial proliferation. The 10 years-disease stabilizing rates of the disease were 81% in CPH and 63% in non CHP group. In conclusion, prognostic factors affecting renal function in the CPH group was found to be daily urinary protein excretion and, if diagnosed as IgA nephropathy by biopsy, pathological changes were also shown to be prognostic factors. Therefore, CPH patients having proteinuria over 1 g/day must be examined by renal biopsy and when IgA nephropathy is diagnosed, long time follow-up is necessary and re-biopsy for examination of pathological change during the interval is recommended.     

Cerebral venous thrombosis and acquired protein S deficiency: an uncommon cause of headache in systemic lupus erythematosus

A 42-yr-old woman with hypertension and renal involvement due to systemic lupus erythematosus (SLE) developed unilateral headache followed by the sudden onset of confusion and a grand mal convulsion. Cerebral computed tomography was normal. A magnetic resonance imaging angiogram revealed cerebral venous thrombosis and a venous infarct. Nephrotic syndrome had resulted in an acquired protein S deficiency. A review of previous cases suggests that either renal disease with proteinuria or features of the antiphospholipid syndrome are prerequisites for the development of cerebral venous thrombosis in SLE. Low free-protein S levels may be an additional risk factor. Furthermore it is likely that this condition is underdiagnosed.     

Cholelithiasis and jaundice]

A case of significant proteinuria occurred as a result of bilateral renal vein thrombosis secondary to dehydration, which resolved after treatment with urokinase. The patient developed nausea and vomiting from viral gastroenteritis with subsequent volume contraction. He later noted the onset of aching lower abdominal and flank pain. On admission, he was noted to have a serum creatinine of 1.7 mg/dL, and 4+ proteinuria on urinalysis. A 24-hour urine collection showed 2.34 g protein. A renal venogram showed bilateral renal vein thrombosis (RVT) without involvement of the inferior vena cava. Therapy was initiated with heparin at 1,000 U/hr, followed by intravenous (IV) urokinase, 4,400 U/kg bolus, followed by 4,400 U/kg/hr with continuous infusion for 12 hours. A repeat renal venogram done at this time showed partial resolution of thrombosis bilaterally. A second 12-hour infusion of urokinase at 5,000 U/kg/hr was performed; at this time, the patient reported resolution of his flank and abdominal pain. A repeat 24-hour urine collection showed 60 mg protein with a normal creatinine clearance. Levels of antithrombin III, protein C, and protein S were all normal. A renal biopsy was performed and showed normal histology on light, immunofluorescent, and electron microscopic evaluation. The patient has done well on no therapy and has had no recurrence of thrombosis or proteinuria after 2.5 years. This is a US government work. There are no restrictions on its use.     

Urinary fibrin-fibrinogen degradation products in nephrotic syndrome

The urinary concentration of fibrin-fibrinogen degradation products (F.D.P.) was measured in 90 patients with proteinuria above 2 g/1 and correlated with proteinuria, differential protein clearances, serum urea and creatinine, and renal biopsy findings. There was a linear correlation (r equals 0-7; P less than 0-001) between the urinary F.D.P. excretion and the selectivity of the proteinuria such that patients with highly selective proteinuria excreted only small amounts of F.D.P. whereas those with non-selective proteinuria excreted much higher levels. There was a significant correlation between the urinary F.D.P. excretion and the urine:serum (U:S) ratio of IgG excretion but not with the U:S ratio or urinary excretion of albumin or transferrin. Sephadex G200 column chromatography of the concentrated urine in 26 cases showed that patients with highly selective proteinuria excreted predominantly F.D.P. of low molecular weight in the urine whereas those with non-selective proteinuria excreted mainly fibrinogen and products of high molecular weight. Hence the type and quantity of F.D.P. in the urine are determined primarily by the differential filtration of fibrinogen and the various degradation products from the plasma through the glomerular basement membrane, which in turn is determined by the "pore size" of the basement membrane. In clinical nephrology measurement of the urinary F.D.P. level provides a rapid and convenient means of estimating the differential protein clearance.     

The role of T cell receptor dimerization for T cell antagonism and T cell specificity

Endemic nephropathy is a chronic renal disease with a high prevalence in a geographically limited area of Croatia. It has also been recorded in some parts of Bosnia, Serbia, Bulgaria and Romania. Despite numerous studies conducted to date, the etiology of this disease has not been clarified. Pathological studies of the kidney in the early stage of endemic nephropathy have shown renal tubules to be the primary sites of the pathologic process with an interstitial tissue reaction, whereas glomerular alterations are of a secondary character. Tubulointerstitial lesions can thus account for the symptoms of the disease, i.e. tubular proteinuria and reduced urine concentration capacity and urine acidification. Also, an increased incidence of malignant tumours of the urinary tract was found in the same geographic area.     

Criterion validity and the utility of reactive and proactive aggression: comparisons to attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, and other measures of functioning

Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is a clinicopathologic entity that includes proteinuria, azotemia, focal segmental glomerulosclerosis or mesangial hyperplasia, and tubulointerstitial disease. The incidence of HIVAN is increased in black patients and variable depending on the age and geographic area. The objective of this study was to describe relevant clinical and pathological findings in 30 children with HIVAN followed at the Children's National Medical Center in Washington, D.C. Our experience of the last 12 years showed a spectrum of HIVAN that seems to be coincident with the degree of acquired immunodeficiency syndrome (AIDS) symptomatology. By renal sonograms and frequent urinalysis, we identified children undergoing the early stages of HIVAN with enlarged echogenic kidneys, proteinuria, and "urine microcysts". HIVAN did not necessarily progress rapidly to end-stage renal disease. Nephrotic syndrome or chronic renal insufficiency were late manifestations of HIVAN. Children with HIVAN were likely to develop transient electrolyte disorders, heavy proteinuria, and acute renal failure due to systemic infectious episodes or nephrotoxic drugs. HIVAN was associated with other HIV-induced illnesses and high mortality rates. Early detection and careful clinical follow-up of children with HIVAN may reduce the incidence of renal-cardiovascular complications and improve their quality of life.     

Current therapy of chronic renal failure

The course of chronic renal failure is generally progressive and mediated by several factors that operate in combination. Several extrarenal events which may cause transient or permanent deterioration of renal function, are important, because their correction may slow the progression of renal disease e.g. volume disorders, infection, nephrotoxic agents. In progression of chronic renal disease leading factors are hypertension, proteinuria and high protein/phosphorus intake. Number of evidence suggests that ameliorating hypertension, reducing proteinuria slow the progression of chronic renal failure. Clinical studies in diabetic nephropathy demonstrated that the renoprotective effect of ACE inhibitors was independent of their effect of systemic blood pressure. In ESRD patients access for renal replacement therapy should be obtained as early as possible. An A-V fistula may take several weeks to mature especially in diabetic or elderly patients. Early dialysis has been advocated in diabetic patients. In general, patients can start ESRD therapy when residual kidney function drops to 5-10% of normal value. High quality of dialysis should be provided to the uremic patient with respect of successful renal transplantation.     

Detection, significance and treatment of paraprotein in patients presenting with 'idiopathic' proteinuria without myeloma

This paper describes the detection of a paraprotein in blood or urine in 12 of 260 patients with 'idiopathic' proteinuria, most of whom presented with the nephrotic syndrome. None had myeloma at presentation and only two have developed it. Initial clinical and biochemical findings did not suggest paraprotein-associated disease, total serum globulins and individual immunoglobulin levels usually being in the normal range. In seven of the 12 cases the paraprotein was detected only after repeated analysis of serum and urine specimens over months or years. Renal histopathology varied from case to case and is described in detail; amyloid deposition did not occur in patients who excreted kappa chain Bence Jones protein and was extensive in only three. One of these eventually developed myeloma. Patients were aged 27--69 years at onset and were observed without specific therapy for up to 56 months. Glomerular filtration rate tended to decline and proteinuria persisted. All patients have now been treated by a chemotherapeutic regimen consisting of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cyclophosphamide, melphalan, and prednisolone, in repeated short courses. In some patients, particularly those who had kappa Bence Jones protein, there was striking improvement. Overall survival is good, eight patients being alive 17--90 months after the onset of symptoms. The importance of repeated search for paraprotein in apparently idiopathic renal disease in adults is emphasized.     

Overt proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease

The amount of proteinuria is a prognostic indicator in a variety of glomerular disorders. To examine the importance of urinary protein excretion in autosomal dominant polycystic kidney disease, this study determined the clinical characteristics of autosomal dominant polycystic kidney disease patients with established proteinuria and the frequency of microalbuminuria in hypertensive autosomal dominant polycystic kidney disease patients without proteinuria. In 270 autosomal dominant polycystic kidney disease patients, mean 24-h urinary protein excretion was 259 +/- 22 mg/day. Forty-eight of 270 autosomal dominant poly-cystic kidney disease patients had over proteinuria (> 300 mg/day). The patients with established proteinuria had higher mean arterial pressures, larger renal volumes, and lower creatinine clearances than did their nonproteinuric counterparts (all P < 0.0001), a greater pack year smoking history (P < 0.05), and the projection of a more aggressive course of renal disease (P < 0.05). All autosomal dominant polycystic kidney disease patients with established proteinuria were hypertensive, as compared with 67% without established proteinuria (P < 0.001). Forty-nine patients with hypertension and left ventricular hypertrophy without established proteinuria were examined for microalbuminuria; 41% demonstrated microalbuminuria. Those with microalbuminuria had higher mean arterial pressure, larger renal volumes and increased filtration fraction. Therefore, established proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease patients are associated with increased mean arterial pressure and more severe renal cystic involvement.     

Nephrotic syndrome in autosomal dominant polycystic kidney disease

Urinary protein excretion is generally less than 1 g/24 h in autosomal dominant polycystic kidney disease (ADPKD), and the association of the nephrotic syndrome with this condition is considered rare. A patient with ADPKD associated with nephrotic-range proteinuria is described. She exhibited a relatively rapid impairment of her renal function. An open renal biopsy revealed focal segmental glomerulosclerosis (FGS) with features consistent with secondary FGS. Twenty-one patients with ADPKD and nephrotic syndrome were retrieved from the literature. Fourteen of them (including this case) had a histopathologic evaluation, and FGS was the dominant diagnoses (five patients). Next in frequency were minimal-change disease and membranous nephropathy, with two patients each. Five other patients had a variety of diagnoses. Thus, it is difficult to ascertain if these associations are coincidental or represent a specific pathogenetic relationship. The evaluation of the data also suggests that the presence of proteinuria and nephrotic syndrome accelerates the course of ADPKD toward ESRD.     

Immediate ipsilateral fibular transfer in a large tibial defect using a ring fixator. A case report

A 57-year-old man with monoclonal gamma-globulinemia was admitted because of edema and proteinuria. A renal biopsy specimen showed lobular glomerulonephritis associated with deposition of material that was positive for IgG, C3, C1q, fibrin, kappa light chain, and lambda light chain but was not stained by Congo red. Glomeruli showed massive electron-dense deposits with two kinds of unusual, highly organized crystalline structures in the mesangial matrix and peripheral capillary loops. Clinically, the patient had nephrotic syndrome, microscopic hematuria, and hypertension. No Bence-Jones protein or cryoglobulin was found in the urine or serum. Immunoelectrophoresis of blood and urine revealed increased IgG-lambda paraprotein, but no free light chains were found. This case was not associated with amyloidosis, systemic lupus erythematosus, light chain deposition disease, cryoglobulinemia, or multiple myeloma. Immunotactoid glomerulopathy was diagnosed. Treatment with oral prednisone was effective for the management of nephrotic syndrome and renal dysfunction. Glomerular deposition of two kinds of microtubular structure in immunotactoid glomerulopathy has rarely been reported.     

The effect of tonsillectomy on the level of circulating immune complexes and urine changes in patients with glomerulonephritis

The influence of tonsillectomy on circulating immune complexes (C.I.C.) level, proteinuria and erythrocyturia was studied in 42 patients with chronic tonsillitis (Ch.T.) and urine abnormalities. The level of C.I.C. was examined by two methods: the 3.5% polyethyleneglycol (PEG) precipitation method and the 125I-C1q binding method. After tonsillectomy, bacteriological analysis of removes facial tonsilla was performed in 7 patients and morphological analysis in 11. Renal biopsy was done in 28 patients. The control group was consisted of 18 patients with Ch.T. without urine abnormalities. The presence of C.I.C. was established in 48% of patients with urine abnormalities using PEG method and in 33% with 125I-C1q binding method. Mean values of C.I.C. in patients with proteinuria or erythrocyturia were statistically higher than in the control group. After tonsillectomy, transitory increase of C.I.C. level was observed in 60% of patients, accompanied by augmentation in urine changes, especially proteinuria. During one year of observation, significant decrease in C.I.C. levels detected by PEG method, as well as in proteinuria and in erythrocyturia was found. In 10 patients urine abnormalities disappeared. No differences between both groups of patients were found in the results of bacteriological and morphological studies of removed tonsilla. However, the normalisation of urine changes was noticed in patients without hypertension and in whom renal disease did not exceed two years. Renal histology revealed mesangocapillary proliferative Gn in 14, mesangial proliferative Gn in 11, and focal/segmental glomerulosclerosis in 3 patients. In one patient with mesangial proliferative Gn complete retreat of urine changes was observed. We suggest that the presence of Ch.T. influences on the C.I.C. detectability in patients with chronic glomerulonephritis. The tonsillectomy can lead do the decrease of C.I.C. levels, as well as to the decrease of proteinuria and/or erythrocyturia. Serum C.I.C. examination seems to be helpful in qualifying patients with Ch.T. for tonsillectomy, in immunological monitoring after the operation and in later prognosis in case of chronic glomerulonephritis.     

Clinical application of capillary electrophoresis to unconcentrated human urine proteins

Urine protein electrophoresis can be performed by capillary electrophoresis using spun unconcentrated urine diluted with running buffer. The separation which utilises the excellent sensitivity of capillary electrophoresis gives electropherograms similar to those obtained by diluting concentrated urine with buffer. A 72 cm x 50 microns internal diameter (ID) fused silica capillary was used for the analysis which took less than 15 min. Bence Jones protein can be detected from unconcentrated urine over urine protein concentrations ranging from 9.7 g/L to 0.04 g/L. Other clinical patterns, such as glomerular proteinuria, the presence of intact immunoglobulin and Tamm Horsfall protein can also be detected. The benefit of using unconcentrated urine is the time and cost saved by not concentrating the urine.     

Age and sex differences in health beliefs and behaviours

BACKGROUND: Mushroom poisoning by some species of the Cortinarius (Agaricales) often lead to irreversible renal failure caused by the nephrotoxin orellanine. In 1994 and 1995, six poisoning outbreaks involving ten individuals in Northern Italy and in Austria were investigated. METHODS: A total of 87 clinical samples (urine and blood samples including renal biopsy material of three patients) were examined for the presence of orellanine by thin layer chromatography. RESULTS: Orellanine can be detected after a relatively long period following poisoning by performing a simple thin layer chromatography technique using small quantities of renal biopsy material. No toxin was found in urine or blood samples. CONCLUSIONS: Orellanine is rapidly concentrated in the kidneys in a relatively soluble form and cannot be detected in urine, blood and dialysis fluids at the time when first symptoms appear.