Yousri M. Barri

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 μmol/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 × 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 × 109/l and to platelets > 50 × 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.

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.

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.

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.

Definition of chronic kidney disease after uninephrectomy in living donors: what are the implications?

Background. Living kidney transplant donors generally have a favorable renal functional outcome postuninephrectomy, but concern remains that a reduced glomerular filtration rate (GFR) postuninephrectomy might have harmful effects. This study examines the short-term (3 months) effect of donor nephrectomy on GFR and the occurrence of stage 3 chronic kidney disease (CKD) postuninephrectomy. Methods. The prevalence of stage 3 CKD (Kidney Disease Quality Outcome Initiative [GFR<60 mL/min/1.73 m2]) was examined in 196 living donors by comparing preuninephrectomy and 3-month postuninephrectomy values of GFR using 125I-iothalamate GFR (iGFR), modification of diet in renal disease estimated GFR (eGFR), Cockcroft-Gault estimated creatinine clearance, and endogenous 24-hr creatinine clearance. The accuracy of GFR estimations for predicting iGFR was also studied. Results. The mean GFR before and after donation were iGFR, 105±18 and 68±13 mL/min/1.73 m2; eGFR, 98±19 and 63±12 mL/min/1.73 m2; Cockcroft-Gault estimated creatinine clearance, 125±33 and 85±22 mL/min/1.73 m2, and endogenous 24-hr creatinine clearance, 133±38 and 86±24 mL/min/1.73 m2, respectively. Stage 3 CKD was found postuninephrectomy in 53 donors (27%) by iGFR and in 73 donors (38%) by eGFR. The prevalence of stage 3 CKD was greater with older age. GFR estimation equations did not accurately predict iGFR, particularly postuninephrectomy. Conclusions. Stage 3 CKD is commonly observed after living kidney donation, particularly in older donors. The long-term impact of stage 3 CKD postuninephrectomy is poorly understood and may not have the same implications as stage 3 CKD in other conditions. eGFR is a poor predictor of true GFR in kidney donors.

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.

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.

Systolic blood pressure is the main etiology for poorly controlled hypertension.

BACKGROUND Isolated systolic hypertension is an important risk factor for cardiovascular events. The purpose of this study was to detect the prevalence of and to evaluate the effectiveness of currently available medications in the treatment of uncontrolled isolated systolic hypertension. METHODS We randomly selected a total of 585 patients with hypertension from our database. The two most recent blood pressure (BP) readings and other data were obtained by chart review. RESULTS Of 585 patients, 340 (58%) had controlled BP. Of 245 patients with uncontrolled hypertension, 77.1% had uncontrolled isolated systolic hypertension and the remaining 22.9% had uncontrolled diastolic hypertension. Patients with uncontrolled systolic hypertension were on average taking more antihypertensive medications than patients with controlled BP (2.10 +/- 0.09; P = .034). CONCLUSIONS Systolic hypertension is the etiology of uncontrolled hypertension in the majority of patients. Currently available antihypertensive medications are less effective in controlling systolic hypertension.

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.