Kidney transplants, antibodies and rejection: is C4d a magic marker?

The immunohistochemical detection of the complement degradation product C4d in renal allograft biopsies has gained considerable clinical interest in recent years. The accumulation of C4d along peritubular capillaries is generally regarded as a marker for an antibody-mediated allo-response and is associated with poor graft survival. The aim of this review is to discuss histological findings associated with the deposition of C4d. Emphasis is placed on diagnostic and therapeutic implications. Unanswered questions regarding C4d and graft injury are highlighte

Renal amyloidosis revisited: amyloid distribution, dynamics and biochemical type

Background. Renal amyloidosis results from protein misfolding and leads to progressive renal insufficiency. Few data are available concerning the relevance of the histomorphological patterns and the dynamics of the disease process. Methods. Cases of renal amyloidosis in native kidney biopsies (n = 203) were retrospectively evaluated for the pattern of amyloid distribution, the extent of glomerular amyloid deposition and the amount of interstitial fibrosis and tubular atrophy. One hundred and fifty-eight cases were characterized by immunohistochemistry to determine the biochemical amyloid type. Morphological findings were correlated with available clinical data. Results. According to the predominant site of amyloid deposition, 84.6% showed a glomerular, 9.4% a vascular and 6% a tubulointerstitial distribution pattern. Within the glomeruli, amyloid was initially deposited in a focal segmental fashion that became diffuse and global in later stages. Most cases were identified as AL lambda (84/158) or AA (68/158). There was no correlation between the biochemical type and the distribution pattern. Serum creatinine correlated well with interstitial fibrosis and tubular atrophy and proteinuria with the glomerular amyloid load. Conclusions. The relevance of the different distribution patterns is unclear at the moment, but they may be due to the physicochemical properties of the amyloid fibrils in a given patient. This may become important in future anti-fibrillar therapie

Long-term Treatment of Minimal-change Nephrotic Syndrome with Cyclosporin: A Control Biopsy Study

Seven patients with minimal-change nephrotic syndrome confirmed by renal biopsy were treated with cyclosporin (CsA). Four patients had frequent relapses and three others had primary steroid resistant nephrotic syndrome. Corticosteroids were discontinued as soon as CsA whole blood trough values of 200-500 ng/ml (RIA method) were reached. A full remission, defined as complete disappearance of proteinuria, was achieved in five patients under this treatment. In the two other patients proteinuria was reduced. Two patients experienced an acute episode of dose-dependent nephrotoxicity; however, overall renal function, as determined by the creatinine clearance, was stable. Control biopsies in five patients after a mean treatment period of 10 months showed no significant vascular or interstitial toxicit

Obituary to analgesic nephropathy—an autopsy study

Background. To determine whether classic analgesic nephropathy with renal papillary and urothelial capillary sclerosis could still be detected at autopsy in the beginning of the 21st century, the present study which is similar to a previous one performed in 1980 was undertaken as suggested by the Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy. Methods. Consecutive autopsies of 616 adults performed at the Basle Institute of Pathology between November 2000 and February 2002 were analysed. Tissue samples of renal cortex and papilla of 1220 kidneys and of each ureter and main renal artery available were subjected to a very careful and meticulous study using classical histopathological methodology. Results. A number of lesions was found macroscopically but not a single case of papillary necrosis or analgesic nephropathy could be detected preceding histological analysis. Histologically, the most frequent lesions were vascular in 57.8% of kidneys followed by glomerular lesions in 13.1% (mostly diabetic glomerulosclerosis). Tubulo-interstitial lesions, mostly pyelonephritis were detected in 9.3% with only a single case of classic analgesic nephropathy with bilateral complete papillary necrosis and ureteral capillary sclerosis in a female who had received a renal transplant 14 years before her demise at the age of 67. In another five cases, complete papillary necrosis was detected associated with pyelonephritis, hydronephrosis or in completely shrunken kidneys. However, in the absence of capillary sclerosis, a histopathological diagnosis of classic analgesic nephropathy could not be made in any of these five cases. Conclusions. The Basle autopsy prevalence of analgesic nephropathy decreased continuously from some 3% in 1980 to 0.2% in 2000 as shown by the present study. Similarly, capillary sclerosis of the urinary tract, the initiating event in the pathophysiology of papillary necrosis and analgesic nephropathy and the histological hallmark of the effect of toxic metabolites of phenacetin in analgesic abusers decreased from 4% of autopsy cases between 1978 and 1980 to the single case of the present study observed at the end of 2000. Thus, the classic analgesic nephropathy has disappeared some 20 years after the removal of phenacetin from the analgesic market despite the fact that mixed analgesics containing paracetamol, the main metabolite of phenacetin, have continued to be popular and widely used drug

C4d staining of renal allograft biopsies: a comparative analysis of different staining techniques

Background. Detection of C4d along peritubular capillaries (PTC) in renal allograft biopsies is an independent prognostic marker of poor long-term graft survival. It is typically associated with circulating donor-specific antibodies. Since only little information is available on the best technique to stain C4d, we compared the two methods most often used for detecting C4d in renal allograft specimens. Methods. We investigated the expression of C4d along PTC in 64 renal allograft biopsies using a monoclonal antibody (Quidel) and immunofluorescence for frozen (F-IF) and a polyclonal antibody (Biomedica) and immunohistochemistry for formalin-fixed and paraffin-embedded (P-IHC) tissue samples. We compared the staining extent (diffuse, focal, minimal, no staining) in frozen and paraffin sections and evaluated the intra- and inter-observer concordance rates using kappa statistics. In addition, we determined the inter-observer concordance in 240 paraffin-embedded biopsies of a multi-centre study. Results. The inter- and intra-investigator concordance rate (κ = 0.9) of analysing the C4d expression by F-IF was excellent. In contrast, the detection of C4d by P-IHC demonstrated a substantially lower prevalence and extent of C4d expression with a lower intra- and inter-observer concordance rate (κ = 0.3). Only 69% of diffuse and 13% of focal C4d-expressing cases were in line classified by F-IF and P-IHC. On average, the estimated area of C4d-positive PTC in the diffuse group was 36% lower by P-IHC than by F-IF. The inter-observer concordance rate in paraffin of the 64 renal biopsies and the multi-centre study was good, but not perfect (κ = 0.57 or 0.67). Conclusions. C4d staining determined on frozen tissue samples using F-IF with a monoclonal antibody appears to be better suited for diagnostic as well as research purposes. Future studies should correlate C4d staining patterns with circulating donor-specific antibodie

The value of different resistance parameters in distinguishing biopsy-proved dysfunction of renal allografts

The data concerning the value of duplex sonography in diagnosing parenchymatous renal allograft dysfunction are controversial. Most early studies did not take into consideration the many factors influencing resistance parameters. We therefore performed a prospective, biopsy-controlled study with exclusion of all known sources of error regarding resistance parameters. Furthermore we investigated the value of a new resistance parameter, the systolic deceleration percentage. Forty-seven duplex sonographic studies were performed on 43 patients (30 male, 13 female, median age 47 years, range 7-70). Fourteen studies were done on normally functioning grafts (control group) an average of 33 days after transplantation. Thirty-three studies were performed on dysfunctional grafts immediately prior to biopsy. Grafts which had been transplanted more than a year previously or with vascular findings or any other clinical or sonographic pathology probably explaining function deterioration were excluded. In all patients, the resistive index (RI), pulsatility index (PI) and systolic deceleration percentage (DP) were calculated in the main renal artery and in the interlobar artery. Of the 33 grafts with dysfunction, nine had vascular rejection (VR), 11 interstitial rejection (IR), 11 cyclosporin A toxicity (CAT) and two other histologies (OR). The mean RI in normal grafts (NO) was 0.71±0.06 in the main artery and 0.68±0.06 in the interlobar artery, in VR 0.86±0.12 and 0.80±0.18, in IR 0.72±0.05 and 0.70±0.07, in CAT 0.67±0.06 and 0.65±0.07 and in OR 0.64±0.07 and 0.60±0.01. For PI, the values were 1.45±0.23 and 1.41±0.28 (NO), 3.5±2.13 and 2.92±2.16 (VR), 1.55±0.26 and 1.46±0.33 (IR), 1.32±0.25 and 1.27±0.26 (CAT) and 1.30±0.34 and 1.13±0.04 (OR). For DP we calculated 28±5% and 29±6% (NO), 43±14% and 36±6% (VR), 29±9% and 27±9% (IR), 31±8% and 32±7% (CAT ) and 32±4% and 28±3% (OR). The sensitivity/specificity for VR with a cutoff mean+2 SD was 0.44/1 for RI, 0.55/0.97 for PI and 0.33/0.89 for DP. It was concluded that:(1) despite the high selection of our patient group, diagnostic accuracy of duplex sonography for diagnosing parenchymatous function disorder in renal allograft remains insufficient; (2) in vascular rejection only, the resistance parameters differ significantly from the values of normal allografts; (3) the higher the cutoff of resistance parameters, the better the specificity and the worse the sensitivity for diagnosing vascular rejection; (4) of all investigated resistance parameters, the RI is the most practical due to a simple measurement techniqu

Anti-C1q autoantibodies do not correlate with the occurrence or severity of experimental lupus nephritis

Background. In systemic lupus erythematosus patients, a strong association between the occurrence of antibodies against complement C1q (anti-C1q) and lupus nephritis can be observed. However, the predictive value of anti-C1q titres for a renal flare remains to be determined. Increasing titres of anti-C1q before the occurrence of clinical apparent nephritis might not only serve as a clinical parameter but also indicate a direct pathogenic mechanism of anti-C1q. Methods. The aim of this study was to analyse the occurrence of anti-C1q before the onset of experimental lupus nephritis in MRL/MpJ +/+ mice and to correlate anti-C1q titres with the type and severity of glomerulonephritis (GN) developing at advanced age. Results. As judged by a number of morphological and immunological analyses, GN in MRL/MpJ +/+ mice resembled human lupus nephritis and occurred in variable degrees of severity. We also observed an abundant and early presence of anti-C1q. However, anti-C1q neither correlated with overall survival nor with any histological marker of severity of GN. Conclusions. The absence of a correlation between the presence of anti-C1q and the occurrence of experimental lupus nephritis contradicts the hypothesis that anti-C1q are pathogenic. However, different pathogenic mechanisms of experimental lupus nephritis and human proliferative lupus nephritis cannot be exclude