Disseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin.

Disseminated adenovirus (ADV) infection in solid organ transplant patients is associated with high mortality. Limited studies have shown benefit from using cidofovir (CDV), as well as intravenous immunoglobulin (IVIG). In this study, we report 2 renal transplant patients who presented with fever and pulmonary infiltrates. Both patients continued to worsen despite antibiotic therapy. Bronchoalveolar lavage viral culture and serum polymerase chain reaction (PCR) were positive for ADV. Patients were treated with CDV, IVIG, and reduction in immunosuppression. A progressive decline in serum ADV DNA by PCR correlated with clinical improvement and pulmonary infiltrates improved. Both patients recovered. Allograft function was preserved although reversible acute kidney injury was observed in both patients. To the best of our knowledge, this is the first successful use of CDV and IVIG in renal transplant patients with disseminated ADV infection.

Primum non Nocere: is chronic kidney disease staging appropriate in living kidney transplant donors?

The aphorism of Primum non Nocere ('first do no harm') was introduced to guide physicians in making difficult and potentially hazardous decisions. The application of estimating equations for glomerular filtration rate (GFR) and classification schema for chronic kidney disease (CKD) has inadvertently led to 'labeling' of many living donors as having CKD postdonation. This review examines this issue and its possible consequences. Although complete long-term studies are lacking, it appears that the 'labeling' of such donors as having CKD postdonation is common but not associated with a major effect on morbidity or mortality.

Iatrogenic emphysematous pyelonephritis in a renal transplant patient.

Emphysematous pyelonephritis (EPN) is a rare condition that typically occurs in patients with diabetes mellitus, urinary tract obstruction, or immunosuppression such as solid organ transplant recipients. It has high mortality and frequently requires nephrectomy to achieve cure, although percutaneous drainage has been reported to be successful in some patients. We report a renal transplant recipient with underlying diabetes mellitus who developed iatrogenic EPN. The patient initially presented with dyspnea and was admitted for cardiac evaluation. There was no evidence of urinary tract infection at the time of admission. The patient developed high-grade fever 3 days after admission. Despite intravenous (IV) antibiotic therapy, the patient developed acute renal failure requiring hemodialysis. Studies revealed Klebsiella bacteremia and EPN. We believe that urinary tract infection was precipitated by urinary bladder catheterization performed on the day of admission. Despite 2 weeks of IV antibiotic therapy, infection persisted with progressive extension of gas into the perinephric space on repeat imaging. The patient underwent a transplant nephrectomy with subsequent clinical recovery. This case illustrates that antibiotics alone are often inadequate to cure and preserve renal function in EPN despite immediate therapy. Furthermore, this patient underscores the risk of serious infection precipitated by urinary bladder catheterization in immunocompromised patients.

Polyoma viral infection in renal transplantation: the role of immunosuppressive therapy.

BACKGROUND: Polyoma virus infection in renal transplant recipients has been observed with increasing frequency in recent years. Renal allograft involvement in this condition may occur as a result of primary infection or secondary to reactivation of the latent virus. Interstitial nephritis, ureteric stenosis, rise in serum creatinine and allograft function loss have been attributed to this viral infection. METHODS: In this study we reviewed our experience with 8 patients who developed polyoma viral infection confirmed by allograft biopsy. All patients were receiving mycophenolate mofetil as part of the immunosuppression and 7 of the 8 patients were on tacrolimus. All patients have biopsy proven polyoma viral infection. The following therapeutic maneuvers were carried out following the diagnosis of polyoma viral infection: 1) stopping mycophenolate and 2) switching tacrolimus to cyclosporine or reducing the tacrolimus dose to adjust it at a lower therapeutic trough level. The clinical course and outcome of our patients were reviewed in relation to manipulation of immunosuppressive medications. RESULTS: The incidence of this infection in our transplant program in the last 3 yr was 5.3%. Seventy-five percent of the patients had at least one rejection episode and 63% had more than one rejection episode. The main risk factor for the development of polyoma viral infection was related to the intensity of immunosuppression. The use of antirejection therapy after histological diagnosis of polyoma virus infection was not associated with improvement of renal function despite the histological appearance of acute rejection. Thus, the interstitial nephritis associated with polyoma viral infection appears to be an inflammatory response to the virus rather than acute rejection. Six out of the 8 patients stabilized renal function with reduction in immunosuppression. CONCLUSIONS: Reduction in immunosuppression was associated with the stabilization of renal function when instituted early. However, these patients were left with a degree of allograft dysfunction and their outcome may be significantly compromised. The lack of effective antiviral therapy for polyoma virus may limit the use of newer and more potent immunosuppressive medications.

Results of autologous stem cell transplant in multiple myeloma patients with renal failure.

Data are presented on 81 multiple myeloma (MM) patients with renal failure (creatinine > 176.8 micromol/l) at the time of autologous stem cell transplantation (auto-SCT), including 38 patients on dialysis. The median age was 53 years (range: 29-69) and 26% had received more than 12 months of prior chemotherapy. CD34+ cells were mobilized with granulocyte colony-stimulating factor (G-CSF) alone (n = 51) or chemotherapy plus G-CSF (n = 27), yielding medians of 10 and 16 x 106 CD34+ cells/kg respectively (P = 0.003). Sixty patients (27 on dialysis) received melphalan 200 mg/m2 (MEL-200). Because of excessive toxicity, the subsequent 21 patients (11 on dialysis) received MEL 140 mg/m2 (MEL-140). Thirty-one patients (38%) completed tandem auto-SCT, including 11 on dialysis. Treatment-related mortality (TRM) was 6% and 13% after the first and second auto-SCT. Median times to absolute neutrophil count (ANC) > 0.5 x 109/l and to platelets > 50 x 109/l were 11 and 41 d respectively. Non-haematological toxicities included mucositis, pneumonitis, dysrhythmias and encephalopathy. At a median follow up of 31 months, 30 patients have died. Complete remission (CR) was achieved in 21 patients (26%) after first SCT and 31 patients (38%) after tandem SCT. Two patients discontinued dialysis after SCT. Median durations of complete remission (CR) and overall survival (OS) have not been reached; probabilities of event-free survival (EFS) and OS at 3 years were 48% and 55% respectively. Dialysis dependence and MEL dose did not affect EFS or OS. Sensitive disease prior to SCT, normal albumin level and younger age were independent prognostic factors for better OS. In conclusion, renal failure had no impact on the quality of stem cell collections and did not affect engraftment. MEL-140 had an acceptable toxicity and appeared equally effective as MEL-200. In the setting of renal failure, the role of auto-SCT early in the disease course and benefits of tandem SCT require further evaluation.

Acute rejection presenting as nephrotic syndrome.

BACKGROUND: Early diagnosis and treatment of acute rejection is important to prevent continued renal injury. Acute rejection most commonly presents with asymptomatic rise in serum creatinine. Proteinuria associated with acute rejection is well established; however, there is limited documentation of the presentation of acute rejection as nephrotic syndrome in the literature. METHODS AND RESULTS: We report a renal transplant patient who presented with early onset nephrotic syndrome without change in serum creatinine, whose allograft biopsy confirmed acute glomerulitis and vascular rejection. Treatment of the acute rejection was accompanied by resolution of the nephrotic syndrome. A second episode of acute rejection was also manifested as nephrotic range proteinuria. CONCLUSION: The nephrotic syndrome in early post-transplantation period should prompt a work-up for acute rejection even in the absence of the common findings of this complication.

Renal allograft dysfunction associated with cytomegalovirus infection.

Renal transplant recipients are at an increased risk for cytomegalovirus (CMV) infection, which occurs as a primary infection or as a result of reactivation of a latent virus. The main risk factors for symptomatic CMV disease include a CMV-negative recipient of a kidney from a CMV-positive donor (primary infection) and treatment of rejection with monoclonal or polyclonal antibodies. In this study, we report a renal transplant recipient with multiple risk factors for the development of CMV infection. He developed three episodes of CMV disease; the first was associated with gastrointestinal tract involvement, and the second episode was diagnosed according to surveillance laboratory test results in the absence of symptoms. The third episode was associated with acute allograft dysfunction. The renal transplant biopsy specimen showed viral inclusions without acute rejection or glomerular abnormality. Despite the absence of morphological injury on biopsy, treatment of CMV with ganciclovir was accompanied by an improvement in renal function. Further studies are needed to establish the mechanism of allograft dysfunction in the absence of inflammatory changes.

Oxidant mechanisms in gentamicin nephrotoxicity.

Acute renal failure is a major complication of aminoglycoside antibiotics, which are widely used in the treatment of gram-negative infections. Sequential reduction of oxygen along the univalent pathway leads to the generation of superoxide anion, hydrogen peroxide, hydroxyl radical, and water. A large body of in vitro and in vivo evidence indicates that these partially reduced oxygen metabolites are important mediators of gentamicin nephrotoxicity. Gentamicin has been shown to enhance the generation of superoxide anion and hydrogen peroxide by renal cortical mitochondria. The interaction between superoxide anion and hydrogen peroxide in the presence of metal catalyst can lead to the generation of hydroxyl radical. Gentamicin has been shown to lead to release of iron from renal cortical mitochondria and to enhance generation of hydroxyl radical. These in vitro observations have been supported by in vivo studies in which scavengers of reactive oxygen metabolites and iron chelators have shown to be protective in gentamicin induced acute renal failure. There is evidence to suggest that studies may have broader implication in being relevant to other aminoglycosides including streptomycin and being applicable to other major toxicity of aminoglycoside such as ototoxicity.

Acute renal failure following bone marrow transplantation.

Acute renal failure (ARF) is one of the most frequent and potentially life threatening complications following bone marrow transplantation (BMT). Several renal syndromes that occur are either unique or occur with a disproportionate frequency post-BMT. Clinically ARF can be classified according to the time of onset post-BMT. Immediate ARF syndromes include tumor lysis syndrome and marrow-infusion associated toxicity, which usually occur within 5 days post-BMT. Hepatorenal-like syndrome secondary to venoocclusive disease occur within one month and is the most common cause of early ARF syndrome. The late renal syndromes, more than 4 weeks post-BMT, include BMT-associated nephropathy, which may be acute or chronic, and cyclosporin nephrotoxicity. Other non-specific causes of ARF such as sepsis, hypotension, volume depletion, nephrotoxic agents and obstructive uropathy can also occur at any time period. Frequently ARF is multifactorial in these patients with complicated clinical course. Therapeutic approach depend on the underlying etiology. Supportive treatment such as optimization of volume status and dialysis when indicated are important steps as specific therapy is rarely available. Therefore, efforts should be targeted to the prevention of ARF. This includes prophylaxis for tumor lysis syndrome and marrow infusion toxicity by hydration and alkaline diuresis, avoiding nephrotoxic agents, early recognition and treatment of infection and correction of volume depletion.

Salt intake determines the renal response to L-arginine infusion in normal human subjects.

Studies in experimental animals have shown that nitric oxide (NO) generation in the kidney from L-arginine participates in adapting renal function to changes in salt intake, but similar studies in human subjects are lacking. Therefore, we compared the infusion of 30 g of L-arginine to 30 g of branched chain amino acids (control), in eight normal human subjects after 5 to 7 days of equilibration to a low salt (LS; 20 mumol.24 hr-1) or high salt (HS; 200 mumol.24 hr-1) intake. Lithium clearance was used as a marker of proximal tubular reabsorption. Compared to the control infusion, L-arginine did not significantly alter blood pressure, inulin or paraaminohippurate clearance, but significantly increased (P < 0.05) the excretion of NO2 + NO3 (NOx) (LS, 157 +/- 46 to 210 +/- 48 mumol.min-1; HS, 138 +/- 30 to 182 +/- 70) and cGMP (LS, 253 +/- 63 to 337 +/- 76 pmol.min-1; HS, 311 +/- 68 to 563 +/- 52). Renal sodium excretion was decreased by L-arginine infusion during the low salt intake (45 +/- 5 to 21 +/- 3 mumol.min-1; P < 0.05) but was increased by L-arginine during the high salt intake (298 +/- 56 to 537 +/- 84 mumol.min-1; P < 0.05). The calculated fractional reabsorption of sodium in the proximal and distal nephrons, as assessed from lithium and sodium clearances, was increased by L-arginine during the low salt intake but was decreased by L-arginine during the high salt intake. L-arginine increased plasma insulin concentration significantly (P < 0.05). This effect was independent of salt intake (LS, 67 +/- 7 to 92 +/- 13 ng.ml-1; HS, 66 +/- 7 to 76 +/- 9 ng.ml-1). L-arginine did not significantly after plasma renin activity. In conclusion, L-arginine increases the excretion of NOx and cGMP and increases plasma insulin, but the effect on sodium excretion depends upon salt intake. L-arginine enhances Na reabsorption in the proximal and distal nephrons during the low salt intake, but inhibits it during the high salt intake. Effects of L-arginine on NO and cGMP may contribute to its effects on Na reabsorption.

The effects of potassium depletion and supplementation on blood pressure: a clinical review.

Nonpharmacologic treatment currently is recognized as an important part in the treatment of hypertension, and the role of dietary potassium intake in blood pressure (BP) control is becoming quite evident. Clinical studies have examined the mechanism by which hypokalemia can increase BP and the benefit of a large potassium intake on BP control. Epidemiologic data suggest that potassium intake and BP are correlated inversely. In normotensive subjects, those who are salt sensitive or who have a family history of hypertension appear to benefit most from the hypotensive effects of potassium supplementation. The greatest hypotensive effect of potassium supplementation occurs in patients with severe hypertension. This effect is pronounced with prolonged potassium supplementation. The antihypertensive effect of increased potassium intake appears to be mediated by several factors, which include enhancing natriuresis, modulating baroreflex sensitivity, direct vasodilation, or lowering cardiovascular reactivity to norepinephrine or angiotensin II. Potassium repletion in patients with diuretic-induced hypokalemia improves BP control. An increase in potassium intake should be included in the nonpharmacologic management of patients with uncomplicated hypertension.

Calciphylaxis in a patient with Crohn's disease in the absence of end-stage renal disease.

Calciphylaxis is a rare and life-threatening condition of progressive cutaneous necrosis secondary to small and medium-sized vessel calcification previously described in patients with end-stage renal disease and hyperparathyroidism. Early diagnosis may be important in improving the poor outcome in these patients since early intervention may forestall the development of life-threatening complications. We describe a patient with Crohn's disease complicated by short-bowel syndrome and modest renal insufficiency (not requiring renal replacement therapy) who developed calciphylaxis. It appears that longstanding Crohn's disease and the short-bowel syndrome accelerated the development of calciphylaxis as the chronic renal disease was not end stage. Considering the possibility of calciphylaxis in this setting may avoid delaying the diagnosis and its consequences.

Predictors of cure of hypertension in fibromuscular renovascular disease.

Patients with fibromuscular dysplasia (FMD) and hypertension are frequently treated with percutaneous transluminal renal angioplasty (PTRA). Because the goal of this procedure is the cure of hypertension, we reviewed the outcomes of 23 consecutive patients undergoing this procedure to determine factors associated with cure. Twelve (52.2%) of the patients were taking no antihypertensive medications at 6 months and were classified as cured. Using logistic regression, we found three variables to be independently associated with cure: level of systolic blood pressure before intervention (P = 0.02), duration of hypertension (P = 0.03), and age (P = 0.03). Younger patients with milder hypertension of a shorter duration were most likely to be cured. Analysis of the regression equation predicts that some patients with an extremely low chance of cure might be managed with a trial of medical therapy, because FMD is unlikely to progress to renal failure.

Hypercalcemia and electrolyte disturbances in malignancy.

Hypercalcemia and electrolyte abnormalities are common problems in patients with malignancy. In this article we discuss the pathophysiology, clinical features, and management of hypercalcemia, which is the most common metabolic abnormality. We also analyze the electrolyte disturbances that occur in association with malignancy, including hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia, and hyperkalemia. Recognition and treatment of these disturbances are important parts of the management of patients with malignant disease.

Prediction of cure of hypertension in atherosclerotic renal artery stenosis.

We analysed the outcome of 63 consecutive, adequate interventions for atherosclerotic renal artery stenosis and hypertension: 34 patients had percutaneous transluminal renal angioplasty, and 29 had surgical correction. Hypertension was cured in 21% of patients and improved in 47%, but 32% failed to respond. We analyzed clinical variables predictive of cure. Duration of hypertension, level of diastolic blood pressure, and sex were found to be predictive of cure. The highest probability of cure was found in men with a duration of hypertension of less than 10 years and an initial diastolic blood pressure of greater than 80 mm Hg. Use of these clinical variables in a tree-based model correctly classified 80% of cases, with a sensitivity of 92% and a specificity of 77%. We conclude that a tree-based clinical algorithm based on only three clinical criteria correctly predicted cure of hypertension in most patients with renal artery stenosis and may be useful in decision making. A prospective analysis will be required to evaluate the clinical validity of the algorithm.

Cimetidine or ranitidine in renal transplant patients receiving cyclosporine.

While H2-receptor antagonists are commonly used in renal transplant patients to prevent peptic ulcer disease, they have been associated with immunostimulation, interference with cyclosporine (CsA) metabolism, and inhibition of tubular secretion of creatinine. In renal transplant patients, cimetidine in high doses has been shown to cause a sustained rise in serum creatinine (SCr) and to reduce creatinine clearance (CrCl) with no change in inulin clearance. In this short-term prospective study, we evaluated the effects of single daily doses of cimetidine or ranitidine on renal function, and CsA serum concentration. Fourteen renal transplant patients with stable renal function were assigned to receive either cimetidine 400 mg daily or ranitidine 150 mg daily for 7 days. In patients who received cimetidine, a slight rise in SCr was observed at days 2 and 5 which was not statistically significant, but no significant change in CsA trough level was noted. No changes in SCr or CsA level were noted in the patients who received ranitidine. No changes in GFR were observed in either cimetidine- or ranitidine-treated patients. We conclude that, in our short-term study, cimetidine or ranitidine in the doses used in this study did not affect the GFR or CsA level, or SCr.

Extreme blood pressure fluctuations in a patient with intact autonomic reflexes and intact sodium conservation.

A patient who had episodes of profound hypotension alternating with severe hypertension without an obvious precipitating cause is reported. The hypotensive episodes were accompanied by tiredness, syncope, bradycardia, and a low norepinephrine concentration while supine or standing. In contrast, the hypertensive episodes were associated with marked tachycardia, sweating, anxiety, abdominal pain, and very high levels of plasma norepinephrine concentration. Extensive investigations failed to support a diagnosis of pheochromocytoma. The testing of baroreceptor function and autonomic reflexes was normal. Blood pressure was not salt sensitive. It was concluded that this patient has a unique clinical syndrome of extreme fluctuation of blood pressure and sympathetic nervous activity yet intact cardiovascular reflexes and normal sodium conservation. The abnormal blood pressure regulation most likely has a central origin.

Hypomagnesemia in renal transplant patients: improvement over time and association with hypertension and cyclosporine levels.

Hypomagenesemia is frequently encountered early after kidney transplantation, especially in patients receiving cyclosporine (CsA). However, there have been no studies addressing the natural history of this disorder in adult transplant recipients. We conducted this investigation to study the change in the prevalence of hypomagnesemia over time in renal transplant patients as well as to determine the factors associated with this change. Three patient groups were studied: 24 CsA-treated patients followed longitudinally at 1, 3 and 6 months post-transplant (Group 1a, 1b, 1c); 33 CsA-treated patients at least 2 years post-transplant (Group 2; mean follow-up 55 +/- 25 months); and 31 non-CsA-treated patients at least 2 years post-transplant (Group 3; mean follow-up 132 +/- 57 months). The following parameters were monitored: serum and urine magnesium levels; serum potassium; creatinine clearance; fractional excretion of magnesium; and trough CsA levels. In group 1 patients, longitudinal follow-up showed a significant linear trend for improvement in the serum magnesium over time (1.6 +/- 0.3, 1.7 +/- 0.2, 1.8 +/- 0.2 mg/dl; p = 0.0015) as well as a decline in the whole blood CsA level (316 +/- 103, 251 +/- 82, 194 +/- 67 ng/ml; p = 0.0015) at 1, 3 and 6 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Thromboxane synthase expression in renal transplant patients with rejection.

Thromboxane synthase (TS) catalyzes the formation of thromboxane (TxA2) in monocytes/macrophages, platelets, and various tissues. TxA2 is likely to play a role in graft dysfunction due to its vasoconstrictive and platelet aggregatory properties. We studied the expression of TS in 7 normal native kidneys, 29 consecutive renal allograft biopsies (performed for rising serum creatinine, n = 23, and delayed graft function, n = 6), and one transplant nephrectomy specimen with severe acute rejection. TS expression was determined by immunocytochemistry using a monoclonal antibody against human TS, Kon-7. Histologic grading of the transplant biopsy specimens was based on the Banff classification. The degree of TS staining was graded in the glomeruli, interstitium, tubules and vessels from 0 to 3+. Of 29 biopsies, 13 had chronic nephropathy (CN), 6 had acute rejection (AR) with chronic nephropathy (AR/CN), 4 had acute rejection (AR), and 6 had acute tubular necrosis (ATN). TS staining of native kidneys showed sporadic interstitial cells. The biopsy and transplant nephrectomy specimens showed significant staining, predominantly in the glomeruli and interstitium. Positively staining cells appeared to be of macrophage/monocyte lineage by morphology. The mean glomerular staining grade was significantly increased in specimens with AR (2.3 +/- 0.9) and the mean interstitial staining was increased in specimens with AR/CN (2.2 +/- 0.9). Follow-up renal function 6 months post-biopsy showed that patients with higher TS staining grades had a faster decline in graft function. In conclusion, TS expression is increased in patients with acute rejection with or without chronic nephropathy and is associated with more rapid deterioration in function.