The Challenges of Distinguishing Different Causes of TMA in a Pregnant Kidney Transplant Recipient.

Thrombotic microangiopathy (TMA) reflects a syndrome of endothelial injury characterised by microangiopathic haemolytic anaemia (nonimmune), thrombocytopenia, and often end-organ dysfunction. TMA disorders are well-recognised in kidney transplant recipients, often due to an underlying genetic predisposition related to complement dysregulation, or de novo due to infection, immunosuppression toxicity, or antibody-mediated rejection. In pregnancy, TMA disorders are most commonly due to severe pre-eclampsia or HELLP, but may also be due to thrombotic thrombocytopenic purpura (TTP) or complement-mediated (atypical) haemolytic uremic syndrome (aHUS). Complement dysregulation is being recognised as playing a role in the development of preeclampsia and HELLP syndrome in addition to aHUS. Due to overlapping clinical and laboratory features, diagnosis can be difficult and delays in treatment can be life-threatening for both mother and fetus. This report describes a 32 year-old female who had two successive wanted pregnancies. The first pregnancy was terminated at 22 weeks gestation due to presumed severe preeclampsia and fetal growth restriction in the context of known chronic kidney failure due to reflux nephropathy. A living-related kidney transplant was performed to improve the chances of pregnancy resulting in a live birth. A subsequent pregnancy was complicated by progressive kidney impairment and hypertension at 22 weeks gestation. Kidney biopsy showed TMA, but the etiology was unclear. This report highlights the diagnostic dilemma of TMA in a pregnant kidney transplant recipient and a role for the anti-C5 terminal complement blockade monoclonal antibody eculizumab, in pregnancy-associated TMA, especially at a peri-viable gestation.

Caffeine potentiation of mefenamic acid-induced lesions in the rat renal medulla.

The effect of caffeine given in combination with mefenamic acid on the renal medulla was examined. Sprague-Dawley rats were divided into four groups and gavage fed either vehicle suspension (control), mefenamic acid, mefenamic acid+caffeine or caffeine only for 4 months. Renal tissue taken from the corticomedullary junction was processed for electron microscopy. Ultrathin sections were cut after identification of vasa rectae on survey sections. On subsequent morphometric analysis, percentage interstitial tissue was calculated from the total area of vasa recta less the non-interstitial tissue. The median percentage of interstitial tissue in the mefenamic acid and caffeine group was 41 (range 33-50; n = 15) compared with 34 (20-48; n = 20) in mefenamic acid (P less than 0.01), 29 (15-42; n = 15) in caffeine only (P less than 0.001) and 32 (20-46; n = 18) in vehicle-treated animals (P less than 0.001). There were no significant differences between mefenamic acid alone and vehicle or caffeine-only groups or between caffeine-only and vehicle-treated controls. This suggests that caffeine potentiates the effect of the non-steroidal anti-inflammatory drug, mefenamic acid, on the rat renal medulla, resulting in a quantitative increase in the interstitial tissue between adjacent afferent and efferent vasa recta.

Effects of the angiotensin converting enzyme inhibitor, benazepril, on the sino-aortic baroreceptor heart rate reflex.

The effects of monotherapy with the angiotensin converting enzyme inhibitor benazepril (10 mg once daily) on cardiovascular baroreceptor reflexes were determined in 10 patients with essential hypertension using a randomized, double-blind, placebo-controlled, cross-over protocol. Early sino-aortic baroreceptor/heart rate reflex resetting was apparent with acute treatment; this effect persisted throughout the active treatment period. Changes in baroreflex sensitivity did not appear to mediate the hypotensive effect of benazepril.

Caffeine potentiates the nephrotoxicity of mefenamic acid on the rat renal papilla.

The effect of caffeine given in combination with mefenamic acid on the renal papilla was studied. Sprague-Dawley rats were divided into four groups and gavage fed either control suspension, mefenamic acid, mefenamic acid and caffeine or caffeine alone for 4 months. Semiquantitative urinalysis was performed at 3 months and showed increased haematuria in the mefenamic acid and caffeine group. There were no significant differences in serum creatinine at sacrifice. Renal histology revealed more advanced papillary necrosis in rats gavage fed mefenamic acid and caffeine compared with all other groups (p less than 0.0001). Rats fed mefenamic acid alone showed more damage than control and caffeine-fed groups (p less than 0.0001, p less than 0.0002, respectively). This suggests that caffeine potentiates the nephrotoxicity of the non-steroidal anti-inflammatory drug, mefenamic acid, on the rat renal papilla. The mechanism of this potentiation by caffeine is yet to be defined.

Renal failure and nephrotic syndrome associated with sulindac.

Four elderly patients developed nephrotic syndrome while receiving sulindac. Sulindac treatment had commenced 4-12 months prior to presentation with the nephrotic syndrome. Two patients also developed oliguric renal failure. Renal biopsy in one showed minimal change nephropathy and in three cases membranous nephropathy. Interstitial nephritis was present on renal biopsy in all cases. The nephrotic syndrome and renal failure resolved in all cases after withdrawal of sulindac. Two patients received steroid therapy and improvement in renal function and disappearance of proteinuria seemed to be temporarily related to steroid therapy in both cases. Despite the fact that sulindac is less likely to cause renal failure due to inhibition of renal prostaglandin secretion this report shows that sulindac treatment can be associated with renal failure and the nephrotic syndrome.