History of the preanalytical phase: a personal view.

In the 70ies of the last century, ther term "preanalytical phase" was introduced in the literature. This term describes all actions and aspects of the "brain to brain circle" of the medical laboratory diagnostic procedure happening before the analytical phase. The author describes his personal experiences in the early seventies and the following history of increasing awareness of this phase as the main cause of "laboratory errors". This includes the definitions of influence and interference factors as well as the first publications in book, internet, CD-Rom and recent App form over the past 40 years. In addition, a short summary of previous developments as prerequesits of laboratory diagnostic actions is described from the middle age matula for urine collection to the blood collection tubes, anticoagulants and centrifuges. The short review gives a personal view on the possible causes of missing awareness of preanalytical causes of error and future aspects of new techniques in regulation of requests to introduction of quality assurance programs for preanalytical factors.

NGAL, L-FABP, and KIM-1 in comparison to established markers of renal dysfunction.

BACKGROUND: New urinary biomarkers like neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid binding protein (L-FABP), and kidney injury molecule-1 (KIM-1) open the opportunity to detect kidney injuries in early stages. Our study aimed at evaluating NGAL, L-FABP, and KIM-1 in comparison to established markers of urine protein differentiation for detection of renal dysfunction. METHODS: On the basis of the PROTIS expert system (for differentiation of glomerulo-/tubulopathy) urine and plasma samples of 263 randomly selected patients were routinely examined (urine: total protein, albumin, IgG, α1-microglobulin, creatinine, and dip stick results for leukocytes, blood, protein, glucose, pH, and nitrite; plasma: creatinine and cystatin C) followed by the analysis of the new urine biomarkers NGAL (CMIA), L-FABP (ECLIA), and KIM-1 (ELISA). RESULTS: Of the three new markers L-FABP showed the highest correlation with α1-microglobulin (r=0.76, p<0.01) and was closest associated with the degree of tubular proteinuria assessed by the PROTIS system. NGAL distinguished the PROTIS proteinuria groups with distinctive tubular proteinurias from the controls as well, but revealed a marked diagnostic influence by leukocyturia. Urinary KIM-1 revealed only a weak diagnostic value for the detection of renal injury. CONCLUSIONS: Urinary NGAL and L-FABP proved to be promising candidates for detecting injuries of the renal tubular system over a broad range of clinical conditions. L-FABP showed a better diagnostic performance and a lower interference by leukocyturia and hematuria than NGAL. Both markers may serve as sensitive tissue injury markers in addition to the established markers of renal functional impairment.

Diagnostic pathways for exclusion and diagnosis of kidney diseases.

In 2006, the German Society for Clinical Chemistry and Laboratory Medicine together with the Society of Nephrology founded a working group with the aim to develop diagnostic pathways for the detection and differentiation of renal diseases. Based on existing recommendations, these pathways may be structured to be a basis for implementation into hospital and laboratory information systems. The present paper describes the contents of these pathways regarding glomerular filtration rate, hematuria, leukocyturia and proteinuria.

Clinical role of urinary low molecular weight proteins: their diagnostic and prognostic implications.

In traditional urinalysis, casts in the urinary sediment are the only specific signs of renal tubular injury. When tubulo-interstitial fibrosis became the most predictive sign of renal outcome, tubular enzymes derived from proximal tubular brush border or lysosomes were used as early markers of nephrotoxicity and other tubular dysfunctions. More recently, the increase in low molecular weight proteins in urine, assumed to be freely filtered, was reported to reflect tubular dysfunction. This can have pre-renal, renal and post-renal causes. Among the pre-renal causes, Bence Jones protein (immunoglobulin light chains), myoglobin and haemoglobin are signs of extra-renal diseases. On the other hand, beta(2)-microglobulin, alpha(1)-microglobulin, retinol binding protein and lysozyme were recommended as tubular markers. Because of its lower pre-renal variability and higher stability in urine during storage in the bladder and urinary vessel, alpha(1)-microglobulin proved to be the most valuable in early detection, renal outcome prediction and easy inclusion in routine analytical programmes. In addition, other markers of intra-renal inflammatory processes may help to mirror histological changes occurring in the kidney. Future guidelines should therefore include low molecular protein as a tubular marker.

A new concept for detection of Bence Jones proteinuria in patients with monoclonal gammopathy.

Bence Jones (free light chain-FLC) proteinuria is usually detected by immunofixation electrophoresis (IFE) of urine. With a new, automated immunoassay, it is now possible to quantify FLC in serum and urine. In the present study, we compared different routine methods for monoclonal FLC screening. From our results we conclude that the measurement of FLC in serum is highly sensitive and should replace urine tests. Additionally, possible kidney dysfunction, caused by nephrotoxicity of FLC, should be assessed by urine protein analysis and cystatin C measurements.

Preanalytical Variables and Their Influence on the Quality of Laboratory Results.

While analytical standards have been developed by established quality control criteria, there has been a paucity in the development of standards for the preanalytical phase. Only recently recommendations have been published regarding the quality of samples including the definition of the optimal sample size, the use of anticoagulants and stabilizers, stability criteria regarding transport and storage and handling of hemolytic, lipemic and icteric samples. Technical recommendations regarding sampling, transport and identification have been developed by national and international consensus organizations. The development of a preanalytical quality manual takes on an urgency in the goal towards achieving total quality control. Every day the laboratory is confronted with data arising out of preanalytical errors. Ability to recognize such data is critical to maintaining total laboratory quality and will be illustrated with case studies.