Thermoreversible hyaluronan-hydrogel and autologous nucleus pulposus cell delivery regenerates human intervertebral discs in an ex vivo, physiological organ culture model.

Numerous studies show promise for cell-based tissue engineering strategies aiming to repair painful intervertebral disc (IVD) degeneration. However, clinical translation to human IVD repair is slow. In the present study, the regenerative potential of an autologous nucleus pulposus (NP)-cell-seeded thermoresponsive hyaluronic acid hydrogel in human lumbar IVDs was assessed under physiological conditions. First, agarose-encased in vitro constructs were developed, showing greater than 90 % NP cell viability and high proteoglycan deposition within HA-pNIPAM hydrogels following 3 weeks of dynamic loading. Second, a bovine-induced IVD degeneration model was used to optimise and validate T1ρ magnetic resonance imaging (MRI) for detection of changes in proteoglycan content in isolated intact IVDs. Finally, isolated intact human lumbar IVDs were pre-scanned using the established MRI sequence. Then, IVDs were injected with HA-pNIPAM hydrogel alone or autologous NP-cell-seeded. Next, the treated IVDs were cultured under cyclic dynamic loading for 5 weeks. Post-treatment T1ρ values were significantly higher as compared to pre-treatment scans within the same IVD and region of interest. Histological evaluation of treated human IVDs showed that the implanted hydrogel alone accumulated proteoglycans, while those that contained NP cells also displayed neo-matrix-surrounded cells within the gel. The study indicated a clinical potential for repairing early degenerative human IVDs using autologous cells/hydrogel suspensions. This unique IVD culture set-up, combined with the long-term physiological culture of intact human IVDs, allowed for a more clinically relevant evaluation of human tissue repair and regeneration, which otherwise could not be replicated using the available in vitro and in vivo models.

The revised Tokuhashi score; analysis of parameters and assessment of its accuracy in determining survival in patients afflicted with spinal metastasis.

PURPOSE: To determine the significance of each parameter of the revised Tokuhashi score and identify which is associated with survival. BACKGROUND: Spinal metastases are common and can be a challenging medical issue. Treatment options depend on patients' prognosis. Many scoring systems in the literature help estimate prognosis, such as the Tokuhashi, revised Tokuhashi, and Tomita scoring systems. METHODS: A retrospective review of all patients from 2003 to 2012 treated for spinal metastases in one center was conducted. Imaging, pathology, and charts were reviewed to determine the modified Tokuhashi scores. Scores were then compared to the actual documented survival. Univariate and multiple regression analyses were used to assess the importance of each individual parameter and survival time. Linear regression was used to determine the relationship between the Tokuhashi score and weighted Tokuhashi score with survival time. RESULTS: A total of 126 patients were reviewed. All parameters in the revised Tokuhashi score were significantly associated with survival time except for primary site using univariate analysis. Only the number of spinal metastases and metastasis to major organs showed statistical significance when multiple variable analysis was used. CONCLUSION: A number of spinal metastases and metastasis to major organs were the most important predictors of actual survival. Modification to the score based on population characteristics would help better identify patients with spinal metastases that can benefit from surgery.

Comparative analysis in continuous expansion of bovine and human primary nucleus pulposus cells for tissue repair applications.

Autologous NP cell implantation is a potential therapeutic avenue for intervertebral disc (IVD) degeneration. However, monolayer expansion of cells isolated from surgical samples may negatively impact matrix production by way of dedifferentiation. Previously, we have used a continuous expansion culture system to successfully preserve a chondrocyte phenotype. In this work, we hypothesised that continuous expansion culture could also preserve nucleus pulposus (NP) phenotype. We confirmed that serial passaging drove NP dedifferentiation by significantly decreasing collagen type II, aggrecan and chondroadherin (CHAD) gene expression, compared to freshly isolated cells. Proliferation, gene expression profile and matrix production in both culture conditions were compared using primary bovine NP cells. Both standard culture and continuous culture produced clinically relevant cell populations. However, continuous culture cells maintained significantly higher collagen type II, aggrecan and CHAD transcript expression levels. Also, continuous expansion cells generated greater amounts of proteoglycan, collagen type II and aggrecan protein deposition in pellet cultures. To our surprise, continuous expansion of human intervertebral disc cells - isolated from acute herniation tissue - produced less collagen type II, aggrecan and CHAD genes and proteins, compared to standard culture. Also, continuous culture of cells isolated from young non-degenerate tissue did not preserve gene and protein expression, compared to standard culture. These data indicated that primary bovine and human NP cells responded differently to continuous culture, where the positive effects observed for bovine cells did not translate to human cells. Therefore, caution must be exercised when choosing animal models and cell sources for pre-clinical studies.

Acute mechanical injury of the human intervertebral disc: link to degeneration and pain.

Excessive mechanical loading or acute trauma to intervertebral discs (IVDs) is thought to contribute to degeneration and pain. However, the exact mechanisms by which mechanical injury initiates and promotes degeneration remain unclear. This study investigates biochemical changes and extracellular matrix disruption in whole-organ human IVD cultures following acute mechanical injury. Isolated healthy human IVDs were rapidly compressed by 5% (non-injured) or 30% (injured) of disc height. 30% strain consistently cracked cartilage endplates, confirming disc trauma. Three days post-loading, conditioned media were assessed for proteoglycan content and released cytokines. Tissue extracts were assessed for proteoglycan content and for aggrecan integrity. Conditioned media were applied to PC12 cells to evaluate if factors inducing neurite growth were released. Compared to controls, IVD injury caused significant cell death. Injury also caused significantly reduced tissue proteoglycan content with a reciprocal increase of proteoglycan content in culture media. Increased aggrecan fragmentation was observed in injured tissue due to increased matrix metalloproteinase and aggrecanase activity. Injured-IVD conditioned media contained significantly elevated interleukin (IL)-5, IL-6, IL-7, IL-8, MCP-2, GROα, and MIG, and ELISA analysis showed significantly increased nerve growth factor levels compared to non-injured media. Injured-disc media caused significant neurite sprouting in PC12 cells compared to non-injured media. Acute mechanical injury of human IVDs ex vivo initiates release of factors and enzyme activity associated with degeneration and back pain. This work provides direct evidence linking acute trauma, inflammatory factors, neo-innervation and potential degeneration and discogenic pain in vivo.

Postoperative recovery patterns following discectomy surgery in patients with lumbar radiculopathy.

This retrospective study of prospectively collected data aimed to identify unique pain and disability trajectories in patients following lumbar discectomy surgery. Patients of this study population presented chiefly with lumbar radiculopathy and underwent discectomy surgery from thirteen sites enrolled in the CSORN registry. Outcome variables of interest included numeric rating scales for leg/back pain and modified Oswestry disability index scores at baseline, 3, 12, and 24 months post-operatively. Latent class growth analysis was used to identify distinct courses in each outcome. Data from 524 patients revealed three unique trajectories for leg pain (excellent = 18.4%, good = 55.4%, poor = 26.3%), disability (excellent = 59.7%, fair = 35.6%, poor = 4.7%) and back pain (excellent = 13.0%, good = 56.4%, poor = 30.6%). Construct validity was supported by statistically significant differences in the proportions of patients attaining the criteria for minimal important change (MIC; 30%) or clinical success in disability (50% or Oswestry score ≤ 22) (p < 0.001). The variable proportions of patients belonging to poor outcome trajectories shows a disconnect between improved disability and persistence of pain. It will be beneficial to incorporate this information into the realm of patient expectation setting in concert with future findings of potential factors predictive of subgroup membership.

Nitrogen inputs drive nitrogen concentrations in U.S. streams and rivers during summer low flow conditions.

Ecological and human health impairments related to excess nitrogen (N) in streams and rivers remain widespread in the United States (U.S.) despite recent efforts to reduce N pollution. Many studies have quantified the relationship between N loads to streams in terms of N mass and N inputs to watersheds; however, N concentrations, rather than loads, are more closely related to impacts on human health and aquatic life. Additionally, concentrations, rather than loads, trigger regulatory responses. In this study, we examined how N concentrations are related to N inputs to watersheds (atmospheric deposition, synthetic fertilizer, manure applied to agricultural land, cultivated biological N fixation, and point sources), land cover characteristics, and stream network characteristics, including stream size and the extent of lakes and reservoirs. N concentration data were collected across the conterminous U.S. during the U.S. Environmental Protection Agency's 2008-09 National Rivers and Streams Assessment (n = 1966). Median watershed N inputs were 15.7 kg N ha-1 yr-1. Atmospheric deposition accounted for over half the N inputs in 49% of watersheds, but watersheds with the highest N input rates were dominated by agriculture-related sources. Total N input to watersheds explained 42% and 38% of the variability in total N and dissolved inorganic N concentrations, respectively. Land cover characteristics were also important predictors, with wetland cover muting the effect of agricultural N inputs on N concentrations and riparian disturbance exacerbating it. In contrast, stream variables showed little correlation with N concentrations. This suggests that terrestrial factors that can be managed, such as agricultural N use practices and wetland or riparian areas, control the spatial variability in stream N concentrations across the conterminous U.S.

Mechanisms of tumor metastasis to bone.

Bone metastases occur in approximately 80% of patients with advanced cancer. They are characterized by cancer cell growth and bone destruction that cause pain, fractures, anemia, and hypercalcemia. At diagnosis, bone metastases are usually incurable owing to their advanced development. However, the early stages in their formation are asymptomatic and begin as single micrometastatic cells from the blood stream. These cells can be detected by molecular analysis of bone marrow in approximately 30% of patients at the time of cancer diagnosis, but not all single micrometastatic cells develop into clinically significant bone metastases. A synergistic relationship exists between the micometastasis and the bone environment creating favorable conditions for the development and growth of disseminated tumor cells. Such bone metastases induce osteolysis or new bone formation, releasing growth factors and cytokines, which in turn amplify this pathological mechanism. The underling hypothesis, first proposed by Paget in 1889, is that the growth of disseminated tumor cells in bone is dependent on the fertility of the soil or bone itself. This article explores the most current opinions in this area of study and presents a comprehensive summary of the major factors involved.

Expression of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P in epithelial tumors of the kidney and the urinary bladder.

The differential expression of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P was investigated in 11 renal cell carcinomas and 11 urinary bladder carcinomas and compared with their expression in non-neoplastic tissue preparations from the kidney (n = 9) and urinary bladder (n = 12). The glycoproteins were demonstrated immunohistologically in frozen sections and additionally, in some cases, in paraffin sections. MCA and BW 495/36-P positive cells were present in all preparations except for a grade I transitional cell carcinoma of the bladder, in which no MCA-expression could be detected. In the non-neoplastic renal tissue mainly the cells of the distal tubuli were stained by the antibodies against these two glycoproteins. Carcinoma cells of the kidney and of the urinary bladder showed an increased expression of both epitopes. CA 125, in comparison, was strongly expressed in 3 of the 11 urinary bladder carcinomas investigated but could only be shown in a few cells of a single renal cell carcinoma. Normal renal tissue showed no and the urinary bladder only very isolated CA 125 positive epithelial cells. Apart from this distribution, strong staining of the connective tissue fibers with CA 125 antibody was seen in all paraffin sections, but not in the frozen sections. This leads to the supposition that in these structures there is a CA 125 cryptantigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunocytochemical determination of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P in urine of patients with epithelial tumors of the kidney and urinary bladder.

Pre-operative and, in some cases, post-operative urine samples from 29 patients with renal cell or urinary bladder carcinoma were compared to samples from 24 healthy persons and 10 patients with nephrolithiasis and 9 patients with other benign disorders of the efferent urinary tract. The specimens were examined for the presence of MCA, CA 125 and BW 495/36-P expressing epithelial cells. The urine concentrations of the soluble antigens MCA and CA 125 were determined simultaneously in urine samples from 35 patients with renal cell or urinary bladder carcinoma, 10 patients with cystitis and 30 healthy individuals. MCA and BW 495/36-P expressing epithelial cells were significantly increased in all pre-operative urine samples of the tumor patients compared to the group of healthy persons. This increase was also seen with CA 125-positive cells in patients with bladder carcinoma, not however in patients with renal cell carcinoma. BW 495/36-P positive cells were also found in both groups of tumor patients in greater numbers than in the patients with nephrolithiasis or other benign urinary tract disorders. Based on a specificity of 97% when compared to the control urine samples, the cytological determination of the antigens MCA, CA 125 and BW 495/36-P in urinary tract cells of all tumor patients revealed a sensitivity of 48%, 33% and 79% as well as a positive predictive value of 92%, 89% and 95%, respectively. The sensitivity of CA 125 increased to 67% upon isolated analysis of patients with bladder carcinoma. The majority of labelled cells were not identifiable as tumor cells morphologically and appeared as normal transitional epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Prenatal diagnosis of congenital nephrosis of the Finnish type (CNF) in the second trimester.

Congenital nephrosis of the Finnish type is an hereditary, autosomal recessive disease which leads to death in early infancy. This is a case report concerning an affected fetus with legal interruption in the 24th week of gestation on the basis of certain sonographic changes in the fetal kidneys and changes in the protein profile in amniotic fluid, which were consistent with nephrotic damage of the kidneys. Light and electron microscopy showed evidence of CNF, i.e. increase of mesangial matrix and cells in glomeruli, dilated tubular segments, and effaced and plumb foot-processes of the glomerular epithelial cells. Antenatal diagnosis of CNF therefore seems feasible in the second trimester of gestation by means of AFP determinations in maternal serum and amniotic fluid as well as by using sonographic criteria and determination of proteins in amniotic fluid.

[Microproteinuria and enzymuria in fever and pyelonephritis in childhood. A prospective study of 180 children]. / Mikroproteinurie und Enzymurie bei Fieber und Pyelonephritis im Kindesalter. Eine prospektive Untersuchung an 180 Kindern.

In 180 children (87 children belonging to a control group, 68 with fever of non-renal origin, and 25 with pyelonephritis) albumin and immunoglobulin G (markers for glomerular dysfunction), alpha-1-microglobulin and beta-NAG (markers for proximal tubular dysfunction) and apolipoprotein A1 (marker of "postrenal' dysfunction) were measured in second-voided morning urine. In children with fever of non-renal origin, glomerular dysfunction was encountered in 8.8%, tubular dysfunction in 17.6% and mixed glomerular-tubular dysfunction in 14.7% of cases. Among children with pyelonephritis, 28% revealed glomerular dysfunction and 44% mixed glomerular-tubular dysfunction. No case of solitary proximal tubular dysfunction was observed in children with pyelonephritis. There were highly significant differences in presence and expression of glomerular dysfunction between children with fever of non-renal origin and children with pyelonephritis (P < 0.0001), whereas with regard to proximal tubular dysfunction, the differences were only moderately significant (beta-NAG: P < 0.01) or of low significance (alpha-1-microglobulin: P < 0.05). This may indicate that morphologic changes occur during interstitial pyelonephritis due to inflammation of glomeruli, resulting in glomerular dysfunction, while proximal tubular dysfunction may additionally be due to fever-associated function processes.

[Localization and extent of tissue damage caused by extracorporeal lithotripsy (ESWL)]. / Lokalisation und Ausmass einer Gewebeschädigung durch die extrakorporale Lithotrypsie (ESWL).

Extracorporeal shock wave lithotripsy (ESWL) causes proteinuria. In our study we investigated the protein fractions and the electrolyte composition of the urine in patients who had been treated with ESWL. The aim was to obtain information on the degree and the localisation of the glomerular, tubular or vascular destruction caused by ESWL in humans. A total of 34 patients with stones had been treated with ESWL. As parameters we used: urine output, creatinine clearance, total protein, albumin, immunoglobulin G, N-acetyl-beta-D-glucosaminidase (beta-NAG), alpha-1-microglobulin, the fractional excretion of Na+ and apolipoprotein-A-1. After ESWL treatment proteinuria and albuminuria are found. Our parameters show no deterioration of the glomerula or the tubulus. The increase in apolipoprotein-A-1, a postglomerular parameter, however, is interpreted as a manifestation of vascular destruction after ESWL; this is normally temporary, leaving no permanent damage.

[Imaging and functional parameters in diagnosis of obstructive nephropathy]. / Bildgebende und funktionelle Parameter in der Diagnostik der obstruktiven Nephropathie.

Obstruction of the kidney leads to terminal kidney failure within a few years. Therefore, early recognition of such obstruction is of importance. Non-invasive diagnostic ultrasound examination now allows intrauterine visualization of a suspected obstruction. However, the implications of such a dilated ureteral pelvic system are obscure. Whether there is obstruction or dilatation can only be evaluated postnatally by a nuclear technique. The aim of our study was to measure the recovery of kidney function. We investigated 13 kidneys of 9 newborns or small infants (up to 2 years). The follow-up was continuous for up to 29 days. The parameters were: urine output (24-h clearance), glomerular filtration rate, fractional excretion of sodium and potassium, free water clearance, total protein excretion, albumin and alpha 1 microglobulin excretion. The urine output fell from 0.3 to 0.12 ml/min within 14 days after relief of obstruction. The glomerular filtration rate rose from nearly 30 ml/min to about 50 ml/min within a week. The fractional excretion of sodium and potassium indicated recovery of the proximal tubli. The fractional sodium excretion fell below 1% within 4 days. The free water clearance reflects the concentrating ability of the kidney, and in kidneys from newborns it had only positive values, while in kidneys of children older than 6 months there were also negative values. The protein excretion and the albuminuria showed recovery of the glomerular as well as the tubular system.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure telemonitoring is useful to achieve blood pressure control in inadequately treated patients with arterial hypertension.

Failing to reach blood pressure (BP) goals is one of the main problems in hypertension management. Especially in high-risk patients, intensive monitoring including frequently office visits or new techniques to monitor home BP is required. A total of 60 patients with uncontrolled hypertension were included and randomized into a group with telemetric BP monitoring (TBPM) (n=30) and a control group receiving standard care (n=30). During the 3-month study period, patients received in addition to their antihypertensive pre-treatment up to 2 × 300 mg irbesartan to achieve the required target BP. All patients were instructed to measure their BP once daily in the morning. In the TBPM group automatic alerts were generated by the central database server using pre-defined algorithms and patients were subsequently contacted by the physician. At baseline mean 24-h ambulant BP monitoring (ABPM) was 143.3±11.1/82.6±9.9 mm Hg in the TBPM group and 141.4±12.6/82.1±6.5 mm Hg in the standard care group. During treatment mean systolic BP showed a more intensive decrease in the TBPM vs control group (-17.0±11.1 mm Hg vs -9.8±13.7 mm Hg; P=0.032). Patients in the TBPM group had a more pronounced night dipping and a higher reduction of mean pulse pressure than controls (-8.1±5.9 mm Hg vs -2.8±7.4 mm Hg, P=0.004). After 3 months, TBPM-treated patients were given a higher mean daily dose of irbesartan (375±187 mg vs 222±147 mg in controls; P=<0.001). We demonstrated that with TBPM a more effective and faster titration of the antihypertensive agent is possible. The alarm criteria chosen were useful to improve BP control.

Nature of native defects in ZnO.

This study revealed the nature of native defects and their roles in ZnO through positron annihilation and optical transmission measurements. It showed oxygen vacancies are the origin for the shift in the optical absorption band that causes the red or orange coloration. It also revealed experimental evidence that the donor nature of oxygen vacancy is approximately 0.7 eV. In addition, this work showed the Zn interstitial was not the donor in the as-grown ZnO and supported recent calculations that predicted hydrogen in an oxygen vacancy forms multicenter bonds and acts as a shallow donor.

[Body weight telemetry in patients with endstage renal failure on hemodialysis: preliminary data]. / Körpergewichts-Telemetrie bei Hämodialysepatienten--vorläufige Daten.

BACKGROUND AND OBJECTIVE: Non-adherence to fluid intake restrictions is one of the leading problems in hemodialysis patients. The consequences of chronic volume overload and massive hypotensive episodes resulting from enhanced ultrafiltration lead to an increased mortality and incidence of vascular events. Telemetric body weight monitoring (TBWM) suggests itself as a successful way to reduce daily fluid intake PATIENTS AND METHODS: This monocentric, prospective, randomized open study includes 120 patients with end-stage renal failure undergoing chronic hemodialysis (for at least two months) three times a week. The mean interdialytic weight gain (IWG) was more than 1.5 kg/2 days over the four weeks immediately before start of the study. The effect of daily body weight telemonitoring on IWG, blood pressure, haemoglobin variability, hospital stay, vascular events and mortality were observed for three months. All monitored patients (group 1, n = 60) received a weekly report of their weight changes, the number of alarms (automatically sent by email to the study center when daily IWG was greater than 0.75 kg/d) and of the interventions by phone (conducted by the responsible nephrologist when IWG was > 2 kg/day). Hemodynamics (each hemodialysis procedure) and weekly laboratory data were recorded for all patients. RESULTS: Preliminary data of 44 patients showed a significant reduction of daily IWG (weekly average, p = 0.0187) and a smaller number of alarm reports after the whole study period in group 1. Blood pressure monitoring during hemodialysis showed less hyper- and hypotensive episodes in patients with an IWG of less than 1.5 kg/2 days. In the control group there have so far been no changes of the analysed parameters. CONCLUSIONS: TBWM seems to be an effective method for optimizing adherence to fluid intake restrictions in patients on hemodialysis. Hemoglobin variability, mortality rates and the number of vascular events will still have to be analysed in detail for all patients once the entire study period has been completed.

Urinary protein analysis.

The differentiation and analysis of urinary proteins has substantially contributed to our knowledge of physiological and pathophysiological processes during glomerular filtration and tubular catabolism of plasma constituents. By use of high-resolution biochemical separation techniques, several urinary polypeptides could be identified as plasma proteins, tissue antigens, tubular enzymes and protein breakdown products. With regard to clinical application, the separation results of conventional gel chromatography and agarose electrophoresis were surpassed by fast protein liquid chromatography and polyacrylamide electrophoresis in one- and two-dimensional systems. In contrast to early one-dimensional polyacrylamide gel electrophoresis (PAGE) methods using homogeneous gels on a macro scale, modern gradient slab gels achieve better resolution over the entire relative molecular mass range of urinary proteins. For clinical demands, the use of micro-scale gradient gels, either laboratory-made or pre-cast, together with an improved Coomassie Brillant Blue staining, offers several advantages, including rapidity, sensitivity and economy. Isoelectric focusing and two-dimensional PAGE, combined with sensitive silver staining and immunoblotting methods, have proved to be valuable tools for the identification and characterization of urinary proteins in defined renal and extra-renal diseases. The quantitative determination of urinary indicator proteins such as albumin and alpha 1- and beta 2-microglobulin can be regarded as a reasonable complement to the pattern diagnosis, especially in the long-term course of renal diseases.

[Urinary proteins as indicators of diabetic nephropathy]. / Harnproteine als Indikatoren der diabetischen Nephropathie.

During the last ten years, several studies proved the applicability of urinary albumin quantification in the early diagnosis of diabetic nephropathy. Owing to its high accuracy and its comparable low methodological effort, only the albumin determination was emphasised. Parallel studies of urinary protein patterns, however, using sodium dodecylsulfate-polyacrylamide gel-electrophoresis demonstrated the increased excretion of other high- and low-molecular mass proteins in different stages of diabetic nephropathy. Consequently an extension of the mere albumin assay including a macromolecular (e.g. transferrin) and a micromolecular (e.g. alpha-1-microglobulin) protein seems meaningful. According to this study, both methodological lines (combined quantitative and qualitative analysis, respectively) are useful tools in the early detection and the follow up of diabetic nephropathy.

[Clinical aspects of renal ischemia and acute renal failure]. / Klinik der renalen Ischämie und des akuten Nierenversagens.

The rapid breakdown of renal excretory function termed "acute renal failure" (ARF) is accompanied by an increase in nitrogenous substances in the blood, usually eliminated with the urine (azotemia). Important causes of renal injury are renal ischaemia and the application of nephrotoxic drugs. The period of increasing symptoms (initiation) may be reversed by early therapeutic interventions, while the advanced stage with persistent oligo-/anuria (maintenance) requires haemodialysis treatment. The phase of repair (recovery) is initiated by the polyuric stage of ARF. Even in uncomplicated cases, one should expect only partial restoration of renal concentration ability.

Alpha 1-microglobulin (protein HC): features of a promising indicator of proximal tubular dysfunction.

alpha 1-Microglobulin (protein HC) is a stable urinary indicator protein which reflects acute and chronic dysfunctions of the proximal renal tubule. High urinary concentrations were found to be indicative of tubular drug toxicity, interstitial nephritis or chronic renal failure. The protein is synthesized by liver cells and readily associates with serum immunoglobulin A. Only the free form is filtered through the glomerulus and is reabsorbed by proximal tubular cells. The exact physiological function of this member of the new superfamily of lipocalins is still unknown, but there are indications that alpha 1-microglobulin (protein HC) may serve as an excretion vehicle for fluorescent, charge-heterogeneous substances of unknown nature. Additionally, it seems to be associated with the humoral and cellular immune response.