Metabolic syndrome and solid-organ transplantation.

The metabolic syndrome is proposed as a cluster of known cardiovascular risk factors, interrelated by a common pathophysiological defect, that symbolize a heightened metabolic burden. Advocates of the concept argue that it is a predictor for both diabetes and cardiovascular disease, complications of great importance posttransplantation. The abundant medical literature on the topic is now expanding into the field of transplantation with evidence linking the metabolic syndrome to adverse patient and graft outcomes. Although the implications posttransplantation are significant, controversy surrounds the concept and the topic has not previously been reviewed in the context of solid-organ transplantation. The purpose of this review is to update transplant clinicians with our current understanding of the metabolic syndrome, review the transplantation literature and examine the controversies surrounding the concept.

The effect of rosuvastatin on insulin sensitivity and pancreatic beta-cell function in nondiabetic renal transplant recipients.

Interventions to attenuate abnormal glycemia posttransplantation are required. In addition, surrogate markers of declining glycemic control are valuable. Statins may have pleiotropic properties that attenuate abnormal glucose metabolism. We hypothesized statins would improve glucose metabolism and HbA1c would be advantageous as a surrogate for worsening glycemia. We conducted a prospective, randomized, placebo controlled, crossover study in 20 nondiabetic renal transplant recipients at low risk for NODAT and compared effects of rosuvastatin on insulin secretion/sensitivity. Mathematical model analysis of an intravenous glucose tolerance test determined first-phase insulin secretion, insulin sensitivity and disposition index. Second-phase insulin secretion was determined with a meal tolerance test. Biochemical/clinical parameters were also assessed. Rosuvastatin significantly improved total cholesterol (-30%, p < 0.001), LDL cholesterol (-44%, p < 0.001) and triglycerides (-19%, p = 0.013). C-reactive protein decreased but failed to achieve statistical significance (-31%, p = 0.097). Rosuvastatin failed to influence any glycemic physiological parameter, although an inadequate timeframe to allow pleiotropic mechanisms to clinically manifest raises the possibility of a type II statistical error. On multivariate analysis, glycated hemoglobin (HbA1c) correlated with disposition index (R(2)= 0.201, p = 0.006), first-phase insulin secretion (R(2)= 0.106, p = 0.049) and insulin sensitivity (R(2)= 0.136, p = 0.029). Rosuvastatin fails to modify glucose metabolism in low-risk patients posttransplantation but HbA1c is a useful surrogate for declining glycemic control.

Interpreting regulatory authority guidance on immunosuppressive therapy for renal transplantation: a response to the UK's National Institute for Clinical Excellence (NICE).

AIMS: A group of UK consultant transplant physicians and surgeons (the Consensus Group) met to consider the implications and interpretation of the National Institute for Clinical Excellence's (NICE) Technology Appraisal No. 85 on the use of immunosuppressive therapy for renal transplantation in adults. METHODS: This group considered what the implications of these guidelines might be for clinical practice and consensus was developed on those areas which were potentially open to different interpretations. A wider survey of nephrologists and transplant surgeons throughout the UK was also performed to gauge the impact of the NICE recommendations. RESULTS AND CONCLUSIONS: The outcome of the discussions of the Consensus Group are presented with particular reference to the recommendations of how to respond to calcineurin inhibitor (CNI) intolerance. The survey suggested that the publication of this NICE guidance has resulted in relatively few changes in prescribing practice: UK transplant centers continue to use a wide range of locally developed protocols for immunosuppressive therapy. These include the use of agents such as mycophenolate mofetil (MMF) and sirolimus, despite the fact that both drugs appeared to receive only conditional acceptance in the NICE Guidelines.

Cyclosporin A-induced gingival overgrowth is unrelated to allograft function in renal transplant recipients.

BACKGROUND: Severe gingival hyperplasia (GH) is one of the most frequent side-effects associated with the prescription of Cyclosporine-A (CsA). AIM: This study statistically modeled the medical and dental risk factors for the development of GH following CsA administration to determine whether renal function post-transplantation was related to the incidence or extent of GH in 236 consecutive renal transplant patients. METHOD: All patients were at least 6 months post-transplant and medicated with both traditional oral CsA (n=220 individuals) and the new microemulsion form CsA-Me (n=229 individuals). Patients had either received CsA alone (n=45 individuals) or cyclosporine and nifedipine (n=191 individuals). Gingival overgrowth was assessed and computerized data, available for all patients included; pre- and post-transplant medical history and post-transplant renal function, i.e., serum creatinine levels, documented rejection episodes and glomerular filtration rates (GFR). These data together with CsA serum levels and last-recorded dose of CsA, CsA-Me, nifedipine, azathioprine and prednisolone, were analysed by multivariate regression analysis using SPSS. RESULTS: The extent and severity of hyperplasia was significantly correlated with the dosage and serum level of CsA at 3, 6 and 12 months post-transplantation; last recorded dosage, however (p<0.0001), was the most accurate predictor of hyperplasia. Gingivitis (p<0.0001) and plaque (p<0.002), were associated with hyperplasia. Duration of renal replacement therapy, age at transplantation, post-transplant interval serum creatinine levels and documented rejection episodes were unrelated with the extent and severity of GH. Of all the renal variables only the correlation of GFR with last recorded doses of CsA and CsA-Me, approached significance; this was then considered for inclusion in the model. CONCLUSION: In a multiple regression analysis including GFR, however, only last CsA (and CsA-Me) doses and gingivitis score were selected for inclusion in the final model. These data demonstrate that inter-patient variation in the extent and severity of GH and renal function post-transplantation are unrelated and are mediated independently.

Association of prolonged hyperglycemia with glomerular hypertrophy and renal basement membrane thickening in the Goto Kakizaki model of non-insulin-dependent diabetes mellitus.

The aim of the current study was to characterize the effects of prolonged hyperglycemia on renal structure and function using a model of non-insulin-dependent diabetes mellitus: the Goto Kakizaki (GK) rat, which does not have confounding variables, such as hyperlipidemia, obesity, or elevated blood pressure. The data show that hyperglycemia in this model was not associated with the development of significant proteinuria, but it was associated with the development of definitive age-dependent renal structural changes. These changes consisted of thickening of glomerular basement membrane at 35 weeks and tubular basement membrane. This thickening was accompanied by marked glomerular hypertrophy resulting from a parallel increase in total capillary luminal volume and mesangial volume, but fractional capillary and mesangial volumes remained unchanged. There was evidence of podocyte injury, as assessed by de novo expression of desmin. In contrast, there was no evidence of mesangial cell activation, as assessed by their de novo expression of alpha-SMA. Interstitial monocyte/macrophage influx increased significantly in GK rats at 12 weeks compared with Wistar controls. Glomerular macrophage infiltration was elevated significantly in 35-week GK rats. The structural changes described in the GK rat are similar to those described in prolonged non-insulin-dependent diabetes mellitus patients who have not developed overt renal disease. This model allows us to investigate further the mechanisms involved in the pathogenesis of the consequences of prolonged hyperglycemia.

Conversion from cyclosporin (Neoral) to tacrolimus (Prograf) in renal allograft recipients with chronic graft nephropathy: results of an observational study.

To evaluate the role of tacrolimus in the treatment of Chronic Graft Nephropathy (CGN), a pilot cross-sectional study was performed on 14 patients with deteriorating renal function and biopsy-proven CGN. Maintenance therapy was switched from cyclosporin to tacrolimus, and results of conversion on allograft function were assessed by estimated glomerular filtration rate (GFR) and clinical outcome. Minimum follow-up was 15 months. Two distinctive response patterns emerged: (i) continuing deterioration of renal function with no apparent benefit over the projected trend of GFR (nine patients), and (ii) unequivocal change in the GFR trend line equation with reduced rate of deterioration in one patient and sustained improvement of GFR in four patients (reversal of downward trend). Five out of 14 patients (36 %) benefited from replacing Neoral with Prograf. All five patients exceeded their estimated time of return to dialysis by a median of 41 weeks (range: 29-52) and their grafts continue to function.

Conversion of renal transplant recipients from cyclosporin to low-dose tacrolimus for refractory rejection.

Twenty-five patients with refractory rejection following renal transplantation were converted from cyclosporin to tacrolimus in an attempt to salvage the allografts. All patients had received two or three pulses of methylprednisolone, 6 had OKT3, 14 had antithymocyte globulin (ATG) and 2 had both OKT3 and ATG prior to conversion. The median time from transplantation to conversion to tacrolimus was 32 days (range 12-322). Patients underwent a simple switch from cyclosporin- to tacrolimusbased therapy with tacrolimus administered at a median dose of 0.15 mg/kg per day. Doses were adjusted according to clinical response and trough blood levels. Twenty-one of the 25 patients (84%) with refractory rejection showed evidence of reversal of rejection as indicated by a significant reduction in serum creatinine (Student's paired t-test, P < 0.05) following conversion to tacrolimus. None of these patients had further episodes of rejection. Three patients had ongoing rejection and returned to dialysis, and 1 patient showed deteriorating renal function associated with a cytomegalovirus infection. Of 18 patients currently on tacrolimus, 15 have improved renal function and 3 have shown no further deterioration. We conclude that low-dose tacrolimus appears to be effective in salvaging renal allografts with resistant rejection.

Conversion of renal transplant recipients from cyclosporin (neoral) to tacrolimus (prograf) for haemolytic uraemic syndrome.

Five patients with cyclosporin-related haemolytic uraemic syndrome (HUS) following cadaveric renal transplantation were converted from cyclosporin- to tacrolimus-based immunosuppression. All patients had biochemical, haematological and biopsy evidence of HUS at the time of conversion. Four of the patients showed complete resolution of the syndrome within 1 week of conversion with normalisation of haemoglobin, platelets and lactate dehydrogenase levels. In the fifth patient renal function stabilised with slow resolution of the haematological and biochemical parameters. Four of the five patients are still taking tacrolimus, one having converted back to cyclosporin due to marked hair loss. We conclude that conversion to tacrolimus appears to be an effective treatment for cyclosporin-related HUS following renal transplantation.

Incidence of end-stage renal disease in medically treated patients with severe bilateral atherosclerotic renovascular disease.

Incidence of end-stage renal disease in medically treated patients with severe bilateral atherosclerotic renovascular disease. Atherosclerotic renovascular disease is an important cause of end-stage renal disease (ESRD). The exact incidence of ESRD and the rate of decline in glomerular filtration rate (GFR) in patients with this condition is unknown. We report the mortality, the rate of decline in renal function, and incidence of ESRD in 51 patients with bilateral atherosclerotic renovascular disease followed-up for a median period of 52 months. None of these patients had undergone any surgical or radiological intervention. Renal function was determined by serial measurements of serum creatinine. Bilateral atherosclerotic renovascular disease was associated with a high mortality rate; the crude mortality rate at 60 months was 45%. Assessment of renal function showed impaired renal function at time of angiography and a nonuniform and variable decline in renal function during the period of observation. The median GFR decreased from 39 mL/min (range, 15 to 80 mL/min) at time of angiography to 31 mL/min (range, 10 to 70 mL/min) and 24 mL/min (range, 10 to 40 mL/min) at 24 and 60 months, respectively (P < 0.05). The calculated mean rate of decline in GFR for all patients was 4 mL/min/yr (range, 1 to 16 mL/min/yr). Over the 5 years, there was a progressive increase in the incidence of ESRD. Of the original 51 patients who underwent angiography, six patients reached ESRD. The crude incidence of ESRD was, therefore, 12%. Patients who reached ESRD were characterized by advanced azotemia at the time of angiography (median GFR, 25 mL/min) and a rapid decline in GFR (8 mL/min) compared with patients who did not reach ESRD during the observation period (median GFR, 43 mL/min and an average rate of decline GFR of 3 mL/min).

Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease.

To determine the effect of the ACE gene insertion/deletion (I/D) polymorphism, angiotensinogen gene M235T polymorphism and the angiotensin 1 receptor gene A1166C polymorphism on the age of onset of end-stage renal failure (ESRF) in PKD1 adult autosomal-dominant polycystic kidney disease (ADPKD), 189 individuals from 46 families with PKD1 were genotyped for each polymorphism. Of the 189 patients 52 (28%) reached ESRF at an average age of 48 +/- 1 year. In patients genotyped for the ACE gene insertion/deletion polymorphism the frequencies of the DD, ID and II genotypes were similar to those expected from Hardy Weinberg equilibrium. In patients with ESRF there was an excess of patients homozygous for the deletion allele (DD: 48% chi2 = 9.97 (1df) P = 0.002). Cumulative renal survival was significantly reduced among those with DD genotype compared to ID and II genotypes. The estimated mean renal survival (95% confidence intervals) were: DD, 52 years [48, 57]; II, 59 years [54, 63]; ID, 64 years [56, 72]; chi2 = 6.13 (1df) P = 0.013, DD versus ID/II. The mean age of renal failure was significantly younger in the DD genotype compared to ID and II genotypes (DD, ID, and II: 44 +/- 2, 49 +/- 2 and 54 +/- 3 years, respectively; P < 0.05 DD vs. ID, P < 0.05 DD vs. II). Ten of the eleven patients who reached ESRF before the age of 40 were homozygous for the deletion allele. The relative risk for ESRF below the age 40 for DD genotype was 17. For all ages there was an overall increased risk of 1.4 for ESRF with the DD genotype. There was no interaction between age of onset of ESRF and either the angiotensinogen M235T allele or angiotensin 1 receptor A1166C polymorphism. This study strongly suggests that PKD 1 patients homozygous for the deletion allele of the ACE gene are at increased risk of developing ESRF at a early age.

Conversion from cyclosporin to tacrolimus in a patient with prolonged acute tubular necrosis.

Acute tubular necrosis (ATN) is a common condition of following cadaveric renal transplantation with an incidence in many series of nearly 50%. The aetiology is uncertain; however, it would appear to be related to damage to the transplant kidney either prior to retrieval, During cold preservation or during re-warming of the kidney at the time of anastamotic construction. There is no specific therapy for ATN and treatment is comprised of an expectant policy with supportive dialysis and fluid restriction. Renal function improves in the majority of cases, though there may be delayed function for several weeks. We report a case of dialysis-dependent ATN that had persisted for 5 months following transplantation. Following conversion to tacrolimus there was immediate improvement in renal function, and after a month of tacrolimus therapy the patient was dialysis-independent.

Tubulointerstitial injury and impaired renal function after recovery from acute puromycin nephrosis.

Renal function was assessed at 2 and 8 wk after infusion of puromycin into the left renal artery of Munich Wistar rats. At 2 wk, albumin excretion averaged 90 +/- 12 micrograms/min in the left kidney and 4 +/- 1 microgram/min in the right kidney. Unilateral nephrosis was accompanied by reduction in the glomerular filtration rate (GFR) (left, 0.71 +/- 0.04; right, 1.31 +/- 0.02 ml/min) and by impaired excretion of sodium (FENa; left, 0.025 +/- 0.004; right, 0.064 +/- 0.006%). Reductions in GFR and FENa in the nephrotic kidney were not reversed by acute angiotensin II receptor blockade with losartan. At 8 wk, albumin excretion averaged 6 +/- 1 in the left kidney and 8 +/- 1 microgram/min in the right kidney. Recovery from nephrosis was accompanied by persistent reduction in GFR (left, 1.05 +/- 0.05; right, 1.41 +/- 0.05 ml/min) and impairment of sodium excretion in the previously nephrotic left kidney (left, 0.031 +/- 0.004; right, 0.051 +/- 0.004%). Losartan again did not return GFR and FENa toward normal. The reductions in GFR and FENa in the previously nephrotic left kidney were associated with structural changes, including intratubular casts, an increased fractional volume of the interstitium (left, 25 +/- 1; right, 15 +/- 1%), decreased fractional volume of tubules (left, 66 +/- 2; right, 77 +/- 1%), and glomerular collapse (left, 15 +/- 2; right, 1 +/- 1%). These findings suggest that tubulointerstitial injury can cause persistent reduction in GFR and impairment of sodium excretion after recovery from acute nephrosis.

The effect of acute angiotensin II blockade on renal function in rats with reduced renal mass.

The effect of acute Ang II blockade on renal function in rats with reduced nephron number was assessed in micropuncture studies. The Ang II receptor blocker, losartan, was administered at a dose of 10 mg i.v. at two intervals following five-sixths renal ablation. At eight weeks following ablation, Ang II blockade (Ang IIX) increased sodium excretion [UNa V, Ang IIX 2.2 +/- 0.4 microEq/min; time control (TC) 1.0 +/- 0.3 microEq/min; P < 0.05] but did not reduce mean arterial pressure (AP, Ang IIX 142 +/- 6 mm Hg; TC 151 +/- 6 mmHg), glomerular transcapillary pressure (delta P, Ang IIX 50 +/- 1 mm Hg; TC 50 +/- 1 mm Hg), or urine albumin excretion (UAlb V: Ang IIX 149 +/- 18 micrograms/min; TC 168 +/- 20 micrograms/min). Similarly, at two weeks following ablation, Ang II blockade increased UNa V (Ang IIX 2.8 +/- 0.4 microEq/min; TC 0.5 +/- 0.2 microEq/min; P < 0.05) without reducing AP (Ang IIX 132 +/- 6 mm Hg; TC 140 +/- 7 mm Hg), delta P (Ang IIX 50 +/- 3 mm Hg; TC 48 +/- 2 mm Hg), or UAlb V (Ang IIX 32 +/- 3 micrograms/min; TC 36 +/- 10 micrograms/min). These findings indicate that within the remant kidney, Ang II promotes sodium retention but does not have an acutely reversible effect on glomerular pressure or permselectivity.