Peter J. Dupont

Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symptoms or vesicoureteric reflux.

Background. The significance of late urinary tract infections (UTIs) after renal transplantation and their association with scarring and graft dysfunction remains controversial. We sought to define the prevalence of renal scarring in allograft recipients with a history of late recurrent UTIs, to determine whether the presence of vesicoureteric reflux (VUR) confers an increased risk of scarring and to establish whether scarring correlates with graft dysfunction. Methods. Among 307 renal allograft recipients, we identified 56 (18%) with late recurrent UTIs (≥3/year). A total of 32 patients had undergone further investigation by both 2,3 dimercapto-succinic acid single-photon emission computed tomography (99mTc-DMSA SPECT) scan and micturating cystourethrogram (MCUG). Results. Of the 32 patients, 24 (75%) had scars on 99mTc-DMSA SPECT and 15 (47%) had reflux on MCUG. Thirteen of these 15 patients with reflux (87%) had scars, although there was no significant correlation between number of scars and degree of reflux. Eleven of 17 patients (65%) with UTIs but without VUR had scars, as did 12 of 14 (86%) with previous graft pyelonephritis. The pattern of scarring (typically multiple focal cortical defects) suggested infection as the cause. This pattern was not seen in a contemporary cohort with vascular occlusions and was rarely seen in patients with chronic allograft nephropathy. Scarring was not associated with inferior graft survival (median follow-up, 15 years). Conclusions. In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux.

Fas ligand exerts its pro-inflammatory effects via neutrophil recruitment but not activation

Fas ligand (FasL) expression induces apoptosis of activated T cells and has been suggested as a strategy to inhibit graft rejection. Unfortunately, the use of FasL to confer ‘immune privilege’ in this setting has been hampered by the finding that it may also provoke a destructive granulocytic response. While the Fas/FasL‐mediated apoptotic pathways are well defined, the pro‐inflammatory effects of FasL are poorly understood. Our aim in this study was to define in vitro the biological effects of FasL on neutrophil recruitment and activation. DAP‐3 cells expressing human FasL on the cell membrane (mFasL) potently induced apoptosis in human neutrophils and in activated T lymphocytes. Recombinant human soluble FasL (sFasL), by contrast, was a very weak inducer of apoptosis, even at high concentrations. This latter observation suggests that cleavage of mFasL by naturally occurring matrix metalloproteinases may serve to down‐regulate FasL activity in vivo. However, in the presence of a cross‐linking antibody, the efficiency of apoptosis‐induction by sFasL was greatly increased, suggesting that the lesser pro‐apoptotic potency of sFasL reflects an inability to induce trimerization of the Fas receptor. With regard to pro‐inflammatory effects, we found that sFasL is a potent neutrophil chemoattractant and, given that it induces little apoptosis, the dominance of sFasL over mFasL may mean that graft‐infiltrating neutrophils will survive to mediate inflammation. Neither sFasL nor mFasL produced neutrophil activation as assessed by chemiluminescence assay. This suggests that neutrophils recruited to an inflammatory site by FasL will be activated by mechanisms other than Fas–FasL signalling.

Skewing of pretransplant anti-HLA class I antibodies of immunoglobulin G isotype solely toward immunoglobulin G1 subclass is associated with poorer renal allograft survival.

Sensitized patients with lymphocytotoxic immunoglobulin (Ig)G anti-human leukocyte antigen (HLA) antibodies have an increased risk of rejection and poorer graft survival. Little is known, however, about the correlation between IgG antibody subclass and clinical outcomes. We identified 20 sensitized renal transplant recipients (panel reactive antibody >15%), all of whom had anti-HLA class I antibodies of an IgG isotype with known specificity before transplantation but who received a crossmatch negative graft. We analyzed the degree of skewing solely toward IgG1 (n=11) or to other IgG subclasses with or without IgG1 (n=9) and correlated these findings with graft survival. At last follow-up (median follow-up 28 months), 6 of 11 patients (55%) with anti-HLA antibodies skewed toward IgG1 had lost their grafts compared with 0 of 9 patients (0%) with anti-HLA antibodies not skewed toward IgG1 (P =0.01 log-rank test). Anti-HLA antibodies of an IgG1 subclass may be a novel marker predicting poor graft outcome.

Lesson of the week: cholesterol emboli syndrome.

Cholesterol embolism is a common but underrecognised complication arising from a variety of vascular insults

Renal Transplantation in Indo-Asian Patients in the UK

Membership of some ethnic groups has an effect on renal transplant outcome but little is known about the impact of Indo‐Asian ethnicity, despite this groups high incidence of renal disease. We compared outcomes in Indo‐Asians and Caucasians at the Hammersmith Hospital (Indo‐Asians, N = 46; Caucasians, N = 90), in the Long‐Term Efficacy and Safety Surveillance (LOTESS) database of cyclosporin‐treated renal transplant recipients (Indo‐Asians, N = 254; Caucasians, N = 4262) and the National Transplant Database held by UK Transplant (Indo‐Asians, N = 459; Caucasians, N = 4831). The baseline demographic and co‐morbid characteristics of the two ethnic groups were comparable, save for more diabetes in the Indo‐Asian community. Following transplantation, the incidence of delayed graft function and steroid‐resistant acute rejection were also comparable, as were graft and patient survival (out to 5 years) and graft function. In addition, post‐transplant blood pressure, levels of cholesterol and triglycerides and exposure to corticosteroids and cyclosporin were comparable. However, when patients who were not diabetic before transplantation were studied separately, there was an increased incidence of diabetes in the Indo‐Asian community (Hammersmith data: Indo‐Asians 10.9% vs. Caucasians 3.3%, p = 0.02; LOTESS data Indo‐Asians 5.5% vs. Caucasians 1.6%, p < 0.0001). Subsequent management of this group should pursue immunosuppressive regimens less likely to impair post‐transplant glucose tolerance.

Infection and chronic allograft dysfunction

With the advent of more potent immunosuppressive regimens, the incidence of acute rejection following renal transplantation has declined sharply in recent years. In spite of this, long-term graft outcomes remain suboptimal because of relentless attrition by cumulated insults to the allograft. As acute rejection rates have declined, other causes of graft injury and loss have recently emerged. Among these, infectious diseases remain a persistent threat and can be associated with allograft dysfunction. This group includes nephropathy due to polyoma (BK) virus infection, cytomegalovirus disease, and bacterial infection (the latter most commonly arising from the urinary tract). Rarer infectious causes of chronic allograft dysfunction include cryoglobulinemia associated with hepatitis C, Epstein-Barr virus-associated posttransplant lymphoproliferative disease, and direct cytotoxicity from adenoviral infection or parvovirus B19.

Early changes in scores of chronic damage on transplant kidney protocol biopsies reflect donor characteristics, but not future graft function

The amount of irreversible injury on renal allograft biopsy predicts function, but little is known about the early evolution of this damage. In a single‐center cohort, we examined the relationship between donor‐, recipient‐, and transplantation‐associated factors and change in a morphometric index of chronic damage (ICD) between protocol biopsies performed at implantation and at 2–3 months. We then investigated whether early delta ICD predicted subsequent biochemical outcomes. We found little evidence to support differences between the study group, who had undergone serial biopsies, and a contemporaneous control group, who had not. In allografts with serial biopsies (n = 162), there was an increase in ICD between implantation (median: 2%, IQR:0–8) and 2–3 months post‐transplant (median 8% IQR:4–15; p < 0.0001). Donation from younger or live donors was independently associated with smaller early post‐transplant increases in ICD. There was no evidence for a difference in delta ICD between donation after cardiac death vs. donation after brain death, nor association with length of cold ischemia. After adjustment for GFR at the time of the second biopsy, delta ICD after three months did not predict allograft function at one yr. These findings suggest that graft damage develops shortly after transplantation and reflects donor factors, but does not predict future biochemical outcomes.

Intracranial hypotension secondary to spinal arachnoid cyst rupture presenting with acute severe headache: a case report

IntroductionHeadache is a common presenting complaint and has a wide differential diagnosis. Clinicians need to be alert to clues that may suggest an underlying secondary aetiology. We describe a novel case of headache secondary to intracranial hypotension which was precipitated by the rupture of a spinal arachnoid cyst.Case reportA 51-year-old Indian female presented with sudden onset severe headache suggestive of a subarachnoid haemorrage. Investigations including a computed tomography brain scan, cerebrospinal fluid examination and a magnetic resonance angiogram were normal. The headache persisted and magnetic resonance imaging revealed bilateral thin subdural collections, a spinal subarachnoid cyst and a right-sided pleural effusion. This was consistent with a diagnosis of headache secondary to intracranial hypotension resulting from spinal arachnoid cyst rupture.ConclusionsSpinal arachnoid cyst rupture is a rare cause of spontaneous intracranial hypotension. Spontaneous intracranial hypotension is a common yet under-diagnosed heterogeneous condition. It should feature significantly in the differential diagnosis of patients with new-onset daily persistent headache.

Assessment of the Potential Transplant Recipient

Renal transplantation transforms life expectancy in patients with end-stage renal disease (Fig. 66.1). All patients who are considered for renal transplantation require rigorous preoperative assessment in order to ensure their fitness to undergo surgery under general anaesthesia and to optimise the therapeutic impact of a scarce and precious resource. This chapter will review the practical aspects of delivering such an assessment with reference to available evidence and guidelines [1, 2].

Tissue Typing, Crossmatch and Antibody Incompatibility in Kidney Transplantation

For the majority of suitable patients with end-stage renal disease (ESRD), transplantation offers a significant survival advantage, improved quality of life and a substantial saving in terms of annual medical care. In countries with limited or no chronic dialysis provision, transplantation may offer the only hope of survival for patients with ESRD. However in every country with a transplant programme, the demand for kidney transplants continues to outstrip supply with the consequence that many patients fail to be transplanted in a timely fashion or at all. The two principal immunological barriers to solid organ transplantation (SOT); blood group incompatibility and HLA incompatibility have restricted access to transplantation. In the last two decades, strategies to expand the pool of donors have become increasingly commonplace and include the use of blood group-incompatible (ABOi) transplants, HLA-incompatible transplants (HLAi), acceptable mismatch schemes and paired-exchange programmes.