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The CHOIR trial in anemic patients with chronic kidney disease compared epoetin-alfa treatment with low (11.3 g/l) and high (13.5 g/l) hemoglobin targets on the composite end point of death, hospitalization for heart failure, stroke, and myocardial infarction. However, other anemia management trials in patients with chronic kidney disease found there was increased risk when hemoglobin is targeted above 13 g/dl. In this secondary analysis of the CHOIR trial, we compared outcomes among the subgroups of patients with diabetes and heart failure to describe the comparative relationship of treatment to these two different hemoglobin goals. By Cox regression analysis, there was no increased risk associated with the higher hemoglobin target among patients with heart failure. In patients without heart failure, however, the hazard ratio (1.86) associated with the higher target was significant. Comparing survival curves in an unadjusted model, patients with diabetes did not have a greater hazard associated with the higher target. Subjects without diabetes had a significantly greater hazard in the high as compared to the low target, but the interaction between diabetes and the target was not significant. We suggest that the increased risks associated with higher hemoglobin targets are not clinically apparent among subgroups with greater mortality risk. These differential outcomes underscore the need for dedicated trials in these subpopulations. Kidney International (2010) 77, 239-246; doi:10.1038/ki.2009.415; published online 4 November 2009

Using the American Diabetes Association Diabetes Personal Health Decisions calculator 2 to incorporate the potential donor's personal and family history, his 10- and 30-year risk of developing T2DM were estimated at 75 and 81%, respectively.

Posttransplant anemia is a common problem that may hinder patients’ quality of life. It occurs in 12 to 76% of patients, and is most common in the immediate posttransplant period. A variety of factors have been identified that increase the risk of posttransplant anemia, of which the level of renal function is most important. Sirolimus, a mammalian target of rapamycin inhibitor, has been implicated as playing a special role in posttransplant anemia. This review considers anemia associated with sirolimus, including its presentation, mechanisms, and management.

CASE PRESENTATION A 55-year-old male with end-stage renal disease (ESRD) secondary to diabetic nephropathy on hemodialysis for 2 years via a tunneled catheter line was admitted to the Brigham & Women’s Hospital with chest pain. The chest pain was localized to the midline, radiated to the left arm, and was present at rest with no diaphoresis. His cardiac enzymes were elevated (troponin-I of 11.46 ng/ml and creatinine kinase-MB of 30.7 ng/ml) and his electrocardiogram (EKG) showed nonspecific ST–T wave changes that were unchanged from previous EKG 6 months earlier. He had a history of coronary artery disease (CAD) status post coronary artery bypass graft (CABG) 10 months earlier, type 1 diabetes mellitus since the age of 6 years, and peripheral neuropathy, blindness secondary to proliferative retinopathy, gastroparesis, neurogenic bladder, peripheral vascular disease (above-knee amputation of right limb), hypertension, and hypercholesterolemia. He had a failed living-related renal transplant because of recurrent diabetic nephropathy and chronic allograft nephropathy after 15 years. He had no history of stroke. His medications included aspirin, metoprolol, simvastatin, gemfibrozil, insulin, calcium acetate, sevelamer, epoeitin alfa, methadone, and hydromorphone hydrochloride. There was no significant family history of cardiovascular or renal disease. On physical examination, he was alert and afebrile, with a blood pressure of 135/60 mmHg, heart rate of 70 beats per minute, respiratory rate of 14 breaths per minute, with an oxygen saturation of 100% on room air and jugular venous pressure of 7 cm. His tunneled catheter site on the right side of the neck was clean, with no tenderness or erythema. Cardiac examination revealed distant heart sounds with no murmurs. The rest of the examination was unremarkable. CLINICAL DIAGNOSIS A clinical diagnosis of acute coronary syndrome (ACS) (a non-ST-elevation myocardial infarction (MI)) was made.

CASE PRESENTATION A 67-year-old African American female with end-stage renal disease secondary to renal artery stenosis and ischemic nephropathy presents with increased somnolence of 1-day duration. Past medical history is notable for depression, mild dementia, glaucoma, gastroesophageal reflux disease, Graves disease that is inactive, diastolic heart failure, atrial fibrillation, and peripheral vascular disease. Two years prior to admission, the patient had undergone a dobutamine stress test for the work-up of dyspnea that was reported normal. The patient had a left brachio-cephalic arteriovenous graft inserted in February 2004. In November 2006, 2 months before the present admission, the graft required a declotting procedure and angioplasty and stenting of two lesions in the cephalic vein. At the same time, large pseudoaneurysms of the mid-venous and mid-arterial limbs were also identified. Medications included aspirin, diltiazem, amiodarone, esomeprazole, salmeterol, sevelamer, paricalcitol, and metoprolol. The patient was receiving epoetin at each dialysis treatment using an anemia protocol (10 000 U every dialysis treatment, three times each week, that had been intensified over the prior 3 months; Figure 1). Approximately 1 month prior to admission, the patient had received iron gluconate 125 mg x 1 dose. Social history was significant for the patient living at home with a nephew as her principal caregiver. There was no significant family history. Review of systems was not possible as patient was too somnolent. On examination the patient was drowsy. Blood pressure was 120/70 mm Hg and heart rate was 61 beats per min. She was afebrile and had normal respiratory rate. Pupils bilaterally were equal and reactive to light. Other cranial nerves, motor, and sensory examination was grossly normal. The examination of other systems was otherwise unremarkable except for 1 + edema bilaterally and the absence of a thrill or bruit over the left brachiocephalic arteriovenous graft. Laboratory testing on admission revealed a serum sodium of 140mEq/l, potassium 5.6 mEq/l, chloride 90 mEq/l, bicarbonate 33mEq/l, blood urea nitrogen 30 mg/dl, creatinine 5.9 mg/dl, glucose 42 mg/dl. Calcium, phosphate, and liver function tests, including transaminases and bilirubin, were within normal limits, except for alkaline phosphatase of 120 lU and serum albumin, 3 mg/dl (normal range 3-5 mg/dl); hematocrit was 55.9%; hemoglobin (Hgb) 16.8 mg/dl, white blood cell count was 6.42 x 10 6 l -1 (normal range 4.5-11 x10 6 l -1 ), platelets 219000. Her laboratory records from 2 weeks previously, as checked in her outpatient dialysis unit, showed Hgb level of 13.1 mg/dl, transferrin saturation of 23%, serum ferritin level of 283 ng ml -1 , and serum albumin level of 3.1 g/dl.

CASE PRESENTATION A 35-year-old Hispanic male on hemodialysis for end-stage renal disease (ESRD) secondary to diabetic nephropathy was admitted with chest pain and shortness of breath. The chest pain was localized to the midline, without any radiation or diaphoresis and was present at rest. The patient was bed-bound due to bilateral below-knee amputations. He had recurrent episodes of chest pain and shortness of breath in the past 3 months for which he was hospitalized. During these admissions, his cardiac enzymes were within normal limits. A stress test performed recently was technically limited, but showed a small inferior defect with normal left ventricular function. He had a past history of type I diabetes mellitus since the age of 10. Subsequently, he developed peripheral neuropathy, blindness secondary to retinopathy, nephropathy with ESRD, and underwent below-knee amputation of left and right limbs for severe peripheral vascular disease 6 and 12 years before, respectively. He had no history of cerebrovascular accident. He also had a past history of hypertension and hypercholesterolemia. His medications included lisinopril, metoprolol, nifedipine, aspirin, clopidogrel, and insulin. He had a strong family history of diabetes, with his mother and brother being diabetes patients. On physical examination, he was lethargic, afebrile with a blood pressure of 170/86 mm Hg, heart rate of 70 beats per minute, respiratory rate of 14 breaths per minute with an oxygen saturation of 97% on 21 of supplemental oxygen, and jugular venous pressure of 14cm. Cardiac examination revealed audible S3 and S4. Respiratory examination revealed fine rales at the left lung base and decreased breath sounds at the right lung base. His tunneled catheter site on the right side of the neck was clean, with no tenderness or erythema. The remainder of the systemic examination was unremarkable.

The use of erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease has declined as randomized controlled trials have demonstrated increased risk of cardiovascular complications and mortality without a marked benefit in quality of life. Several studies have suggested that exposure to high dosages of ESA, rather than raising of the hemoglobin concentration, explains this increased risk. Cotter and colleagues report that exposure to high dosages of ESA in patients with diabetes is associated with increased risk.

The patient presented at 4.5 years of age with marked developmental delay and stunted growth. She could only walk with support and also had delayed speech development. She was born at full term to consanguineous parents with no prenatal complications. She has four healthy brothers.

A 37-year-old woman was referred to the chronic kidney disease clinic for frequent urinary tract infections since childhood. As part of her evaluation, she underwent computed tomographic urography (Figures 1, 2, 3 and 4). Complete blood count and urinalysis were normal and serum creatinine was 0.8 mg/dl. The imaging revealed the rare finding of crossed fused ectopia of the kidneys. No family history of congenital anomalies was reported.

CASE PRESENTATION A 62-year-old white male, with a bipolar disorder treated with lithium, a history of type II diabetes mellitus, and hypertension, was referred to the renal clinic for evaluation of nephrotic syndrome and stage IV chronic kidney disease (CKD) (Modification of Diet in Renal Disease glomerular filtration rate 26 cc/min/1.73 m 2 ). The patient had a history of bipolar disorder treated for over 10 years with lithium until 2 years ago when a diagnosis of KIDNEY BIOPSY On light microscopy, 16 glomeruli were observed. Seven (44%) were globally sclerosed and two revealed segmental capillary collapse, with hyaline entrapment and adhesion of the tuft to the Bowman's capsule (Figure 2). The remaining glomeruli showed a normal architecture, with mild mesangial hypercellularity associated with diffuse increase in the extracellular matrix. The glomerular basement membranes revealed focal irregularities and short segments with double contours. Tubules revealed extensive atrophy (45%) with thickening of tubular basement membranes. Many micro cysts, ranging in size from 1 to 2 mm, were noted. These were localized in the cortex and along the corticomedullary junction. The lining was of low cuboidal epithelial cells. Pericystic stromal fibrosis was apparent (Figure 3). Focal calcification and protein reabsorption granules were also noted in many tubules. The interstitium showed prominent areas of fibrosis (45%) and interstitial inflammation by mononuclear cells and very rare polymorphonuclear cells. Interlobular arteries and arterioles revealed moderate changes of arteriosclerosis. Congo-red stain was negative. No significant deposits were observed on immunofluorescence microscopy, except for nonspecific trapping of immunoglobulin M and C3 in the mesangial areas. Tubular basement membranes revealed focal deposition of C3 ( þþþ /4 þ ). A single sclerosed glomerulus was observed on semithin sections hence the tissue was not examined at ultrastructural level. A biopsy diagnosis of chronic active interstitial nephritis likely secondary to lithium toxicity was made. The presence of numerous cortical micro cysts and the focal global and segmental glomerulosclerosis (FSGS) were also attributed to lithium.

CASE PRESENTATION A 26-year-old Caucasian man with a history of viral myocarditis and subsequent heart transplant at age 13 underwent a kidney biopsy for rapidly deteriorating renal function. The patient’s baseline serum creatinine was 2.2–3.0 mg/dl (194–264 mmol/l) with 3þ albuminuria by dipstick, but had recently increased to 4.8 mg/dl (422 mmol/l) over a 5-month period. His immunosuppressive regimen included azathioprine, prednisone, and cyclosporine (CsA); the latter was changed to sirolimus 6 months before presentation without improvement in renal function. Treatment with sirolimus led to the development of acne, which was treated with a 5-month course of cephalexin. Empiric therapy with prednisone for presumed allergic interstitial nephritis was ineffective after 2 weeks of therapy. Past history was otherwise remarkable for hypertension and hyperlipidemia. Physical examination revealed a well-appearing man. His blood pressure was 156/96, heart rate was 92, and he was afebrile. His jugular venous pressure was not elevated and there was trace peripheral edema. The remainder of the examination was unremarkable. Laboratory values are shown in Table 1. The serological work-up for a secondary cause for his nephrotic-range proteinuria was negative. He subsequently underwent renal biopsy to guide therapy.

CASE PRESENTATION A 54-year-old Hispanic man with type 2 diabetes mellitus and hypertension was initially evaluated at another institution for difficulty voiding urine. He was found to have a serum creatinine of 7.1 mg/dl that had increased from his baseline of 1.0 mg/dl 2 years earlier. Renal ultrasound revealed bilateral hydronephrosis with hydroureter. In addition, he had significant enlargement of his prostate. Over the ensuing 4 months, he underwent three transurethral resections of his prostate for persistent symptoms. His serum creatinine plateaued at 3.8 mg/dl. He was referred to our institution for further evaluation and management of his persistent symptom of voiding difficulty and elevated creatinine. At our institution, a detailed history and physical examination was performed. His International Prostate Symptom Score (IPSS) was 35, suggesting severe lower urinary tract symptoms. He denied polyor oliguria, dysuria, fever, chills, and change in weight or appetite. His medications included NPH insulin and amlodipine. He denied tobacco, alcohol, and occupational chemical exposure, exposure to asbestos, tuberculosis, or use of over-the-counter medications. His family history was not significant. Physical examination revealed a wellappearing man with blood pressure of 126/80 mm Hg, body mass weight 34 kg/m. Jugular venous pressure was 9 cm H2O, lungs were clear to auscultation, cardiovascular exam revealed a displaced left ventricle apical impulse, the abdomen was obese, non-tender with no palpable kidneys, and prostate enlargement on digital rectal exam. Examination of the testicles was unremarkable. Extremities did not reveal edema or changes of chronic venous stasis. Normal dorsalis pedis pulses were present on palpation. Renal ultrasound revealed mild bilateral hydronephrosis and hydroureter. Urodynamic measurements showed no evidence of outlet obstruction. A trial of indwelling urinary catheter was without benefit. Magnetic resonance imaging of the abdomen showed fibrosed soft tissue in the retroperitoneum, narrowing of the inferior vena cava and hydronephrosis consistent with retroperitoneal fibrosis (Figure 1a). Serology revealed an elevated acute-phase reactants 126 mm/h, auto-antibodies 1:160 (speckled), and a positive anti-ribonucleo protein (anti-RNP) assay. Investigation for secondary causes was undertaken. Extensive drug history did not reveal any medications that could cause retroperitoneal fibrosis (e.g., methysergide, ergot derivatives, hydralazine, or b-blocker). There was no history of trauma, radiation, or malignancy. Purified protein derivative test was negative. Prostate-specific antigen was 1.1 mg/dl (within normal limits). Therefore, the diagnosis of idiopathic retroperitoneal fibrosis (IRF) was presumptively made.

tite. One day prior to admission, the patient saw her primary physician, who noted that she was moderately hypertensive, with a blood pressure of 140/80 mm Hg as compared to a blood pressure of 110/70 mm Hg at six weeks of gestation. He also noted 31 proteinuria on dipstick. A 24-hour urine collection contained 9 g of protein; the creatinine clearance was 102 mL/ min. Serum creatinine had risen to 1.6 mg/dL from 1.0 mg/dL earlier in the pregnancy. ANA was positive at 1:320. Following this visit, the patient developed vaginal bleeding and presented the next day to the emergency department at the Brigham and Women’s Hospital. In the emergency room, the patient had no active vaginal bleeding. The medical history was noteworthy for a diagnosis of rheumatoid arthritis, hypothyroidism with a multinodular goiter, and mitral valve prolapse. She was taking levothyroxine sodium (Synthroid), 0.05 mg daily. She reported having one CASE PRESENTATION sister with an unspecified autoimmune disorder. A 32-year-old woman was gravida 2, para 0, and had had Physical examination revealed a patient comfortable at rest. one spontaneous abortion. When she was 12 weeks pregnant, Her blood pressure was 138/78 mm Hg and she was afebrile. she presented to the emergency department at the Brigham Her weight was 182 pounds. Head and neck examination was and Women’s Hospital with new-onset nephrotic syndrome remarkable for facial edema. No lymphadenopathy was apparand systemic lupus erythematosus. Seven years earlier, she ent, and the joints and skin were normal. Cardiac examination had had swelling in the small joints of her upper and lower was normal. Lung examination revealed decreased breath extremities. At that time she was told that she had rheumatoid sounds one-half way up with dullness to percussion in the right arthritis. Hydroxychloroquine sulfate (Plaquenil) relieved her hemithorax. The abdominal examination revealed distension symptoms. After five years of treatment, the patient discontinued consistent with ascites. The uterus was not palpable. The extaking the Plaquenil, as she was concerned about becoming tremities showed 21 pitting edema bilaterally. Her calves were pregnant. She did very well after the medication was stopped. not tender. A pelvic examination did not reveal bleeding. Approximately two years before this admission, she became The O2 saturation was 98% while breathing room air. A pregnant. Other than a positive rapid plasma reagin, all antenachest radiograph revealed a right pleural effusion and right tal tests were in the normal range. At approximately eight chest wall subcutaneous emphysema. An ultrasound study weeks gestation, the patient had a spontaneous abortion. She demonstrated an intrauterine pregnancy at 12.5 weeks, ascites, underwent a dilatation and curettage because of hemorrhage and a right pleural effusion. A urinalysis showed a specific and was diagnosed with a septate uterus. The septum was hystergravity of 1.025; pH, 6.0; 31 protein; and 31 blood; the rest oscopically resected one year prior to the current admission. of the parameters were negative. Sediment examination The patient had been well until approximately eight weeks showed 25 to 30 white blood cells/high-power field and toointo her current pregnancy, when she developed facial, hand, numerous-to-count red blood cells/high-power field with 5 to and leg edema. The edema gradually worsened, with a 12 pound 7 coarse granular/degenerating cellular casts. The blood urea weight gain over the next four weeks. She also noted increasing nitrogen was 35 mg/dL and the serum creatinine was 1.6 mg/dL. shortness of breath, abdominal distension, and decreased appeElectrolytes were in the normal range. A complete blood count showed a hematocrit of 25.8%, white cell count of 1536/mm (normal, 4000–10,000/mm), and platelet count of 128,000/mm The Nephrology Forum is funded in part by grants from Amgen, (normal, 150,000–450,000/mm). Liver function tests were norIncorporated; Merck & Co. Incorporated; AstraZeneca LP; Dialysis mal. Her total protein was 3.3 g/dL (normal, 6.0 to 8.0 g/dL); Clinic, Incorporated; and R & D Laboratories. albumin, 1.4 g/dL (normal, 3.7 to 5.4 g/dL); calcium, 6.8 mg/dL

Kosmadakis et al. highlight the importance of pruritus in a hemodialysis cohort.1 It is not possible for us to critically comment on the data that Kosmadakis et al. provide as information on the assembly of the cohort and demographic and clinical characteristics of the population are not provided in detail. However, their estimate of the prevalence of pruritus in the dialysis population is similar in magnitude to other estimates published previously and discussed in our recent article.2 Kosmadakis et al. present data that 34% of patients in their cohort did not report change in the intensity of uremic pruritus during dialysis, whereas 48% reported uremic pruritus to be less intense and 18% reported worsening during dialysis. Overall, uremic pruritus intensity remained unchanged in 54% of the subjects in their cohort despite 36% of their patients receiving treatment with antihistamines, sedatives, and emollients. Although several studies have tested the efficacy of various therapies, including, ultraviolet B phototherapy,3, 4 high efficiency dialysis,5 gabapentin,6, 7 capsaicin,8 and naltrexone9, 10 for uremic pruritus, these studies have methodologic limitations. The letter by Kosmadakis et al. underscores the inadequacy of current therapeutic strategies for uremic pruritus. We believe that properly designed randomized trials to evaluate the benefit of improved metabolic control and/or pharmacologic interventions are warranted.

YMK Farag, GP Bayliss and AK Singh Renal Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA and Renal Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA Correspondence: AK Singh, Renal Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. E-mail: asingh@partners.org

Cytokine gene expression in the MRL/lpr model of lupus nephritis. The murine MRL/lpr model of lupus nephritis is characterized by a systemic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signaling Fas antigen gene which causes accelerated autoimmune disease in MRL/lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr/lpr mice. The role of cytokines in autoimmune pathogenesis and its relationship with the lpr mutation remains poorly understood. In this study we utilized a RNase protection assay to quantitatively and simultaneously examine the expression of 10 different cytokine genes, namely IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-γ, TNF-α, and TNF-β in kidney, spleen, liver, and lymph nodes obtained from pre-diseased and diseased lupus-prone MRL/lpr, pre-diseased MRL/+ + and C57BL/6-lpr mice, as well as healthy non-autoimmune C57BL/6 and Balb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1β gene up-regulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-α and IFN-γ genes was also observed in lymph nodes, and less consistently, in the spleen, and kidneys derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+ + or normal non-autoimmune control mice. Furthermore, a modest increase in the expression of both IL-1β and IFN-γ message was observed in lymphoid organs of pre-diseased MRL/lpr and C51BL/6-lpr mice compared with MRL/+ + and C57BL/6 controls, respectively. Increased IL-1β gene expression was associated with the presence of the lpr mutation, was observed during the prediseased stage, and increased during active disease in both male and female mice. In summary, these results demonstrate that generalized up-regulation of IL-1β gene expression, in concert with a more limited up-regulation of both TNF-α and IFN-γ expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-accelerating effect of the lpr mutation.

A subgroup of hemodialysis patients experience high serum ferritin and low tansferrin saturation for reasons not clearly understood. Here we determined the economic impact of administering sodium ferric gluconate complex to patients with serum ferritin levels higher than 500 ng/ml and a transferrin saturation less than 25% based on the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study and its extension, DRIVE II. A cost effectiveness model was developed, consistent with the DRIVE studies, using decision analysis with a 12-week time horizon. The primary effectiveness measure was the mean hemoglobin increase in the intent to treat patient groups comparing epoetin with or without sodium ferric gluconate complex. Costs were computed using projected 2007 US Medicare reimbursements for the treatments and for serious adverse events, with the effectiveness factored by the increase in hemoglobin. The net savings for sodium ferric gluconate complex plus epoetin treatment was $1390 compared to epoetin alone for each g/dl hemoglobin increase over 12 weeks of study. Sensitivity analyses were performed to test the impact of change in the variables (using medians or means and actual 2005 or projected 2007 Medicare reimbursements) and these affirmed the robustness of the model. Our study shows that treatment of patients with high ferritin and low transferrin saturation levels, as defined in DRIVE, with sodium ferric gluconate complex and epoetin resulted in significant savings compared to epoetin alone.

A 30-year-old Caucasian male on chronic hemodialysis presents with a 4-day history of right flank pain accompanied by fever, nausea, and anorexia. On physical examination, he had a heart rate of 100 beats per minute and a blood pressure of 147/95 mm Hg. The abdomen was soft. There was no tenderness or guarding over the allograft, and lymph nodes were not enlarged. His remaining examination was unremarkable. Blood and urine cultures were negative. The patient had undergone ultrasonographic examination of the allograft every year since 1998 with evidence of simple cysts in the parenchyma (Figure la) and a persistent fluid collection adjacent to the lower pole representing a lymphocele. A CT scan of the abdomen showed two sub-centimeter low-density lesions within the enlarged right transplanted kidney, suspicious for an infectious or neoplastic process. A persistent and stable right lower quadrant lymphocele was also present. Aspiration of the lymphocele yielded sterile fluid without evidence of infection. A transplant nephrectomy was performed.

Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USACASE PRESENTATIONA 60-year-old white Latino female with a clinical diagnosisof diabetes mellitus (diagnosed in 1993) and hypertensionwas referred to the chronic kidney disease clinic atBrigham and Women’s Hospital for the evaluation of acutekidney injury; serum creatinine had increased from abaseline of 0.9 to 1.5mg/dl in a 11-week period. She wasasymptomatic at the time of presentation. Her pastmedical history included a total abdominal hysterectomywith bilateral salpingo oophorectomy and uppervaginectomy for high-grade squamous intraepitheliallesion of the cervix, 11 weeks prior to presentation. Threeweeks prior to presentation (8 weeks after surgery) andwithin a week of each other, she was evaluated for twoconsecutive episodes of acute onset of chest pain withpulmonary edema in the setting of severe hypertension.Both episodes had blood pressures in excess of190–200mmHg systolic that resolved with intravenousdiuretics. Cardiovascular workup revealed no evidence ofischemic heart disease. Additionally, renal evaluationincluded magnetic resonance angiography with andwithout gadolinium, which did not reveal renal arterystenosis. However, serum creatinine peaked at 1.9 mg/dlimmediately after surgical procedure and remainedelevated at 1.5mg/dl throughout the course of her currentpresentation (corresponding to a glomerular filtration rateof 33ml/min per 1.73m

CASE PRESENTATION A 76-year-old white male with hypertension, progressive renal insufficiency, and proteinuria of unclear etiology was admitted for renal biopsy in June 2005. His kidney disease had steadily progressed over the past 3 years. On admission, he complained of fatigue with increased daytime somnolence, loss of appetite, weight loss, and increased itching. There was no nausea, vomiting, or other uremic symptoms. Review of systems revealed mild cold intolerance, complaints of occasional mild non-exertional chest pains lasting minutes, and bilateral knee pain. There were no neurologic symptoms. His past medical history was notable for gout, glaucoma, arthritis, hypertension, and chronic kidney disease. There was no history of any invasive vascular procedure, use of radio-contrast agent, or treatment with anticoagulant or thrombolytic agents. He had been taking amlodipine, hydrochlorothiazide, enalapril, and atorvastatin before admission. He was a nonsmoker and not a current alcohol user. On examination, he was a well-oriented alert elderly male, his peripheral pulse rate was 57 beats/minute regular in rate and rhythm, and his blood pressure was 153/ 77 mm Hg. His lower extremities were well perfused with no ischemic or gangrenous lesions. There was no livedo reticularis and no muscle tenderness. He did not have peripheral edema. Laboratory investigations (Table 1) revealed a white blood cell count of 5.86 K/μl, with a normal differential count and no evidence of eosinophilia. His blood urea nitrogen was 53 mg/dl, serum creatinine 4.4 mg/dl, and an estimated glomerular filtration rate was 14ml/min/ 1.73 m 2 . Urine dipstick showed a urine albumin of 3 +, and the sediment revealed 2-3 white blood cells and 0-1 red blood cell/high power field. Spot protein/creatinine ratio was 4.7 mg/g of creatinine. Chest X-ray revealed cardiomegaly with a tortuous atherosclerotic aorta.

Over a discussion about my project, Screening and Early Evaluation of Kidney Disease, or SEEK, a colleague questioned me on whether involvement in research and educational initiatives in the developing world added value. Would it make a difference to my career? Why not let the local academic people in India do the work and instead focus my time in the United States?

Attaf and Torres suggest that we inappropriately use the term 'biosimilar' to describe Wepox in our paper on pure red cell aplasia. They suggest that using the term 'biosimilar' to describe Wepox might be confusing in the European Union.1 Further, Attaf and Torres suggest that clinical efficacy and safety studies and postmarketing surveillance should be used to differentiate a biosimilar from a follow-on biologic. Attaf and Torres argue that as Wepox has not undergone the aforenamed studies it cannot be described as a biosimilar to epoetin-. We humbly disagree. To our knowledge, the terms 'biosimilar' and 'follow-on biologics' are used interchangeably. Consequently, we believe this is simply an issue of semantics.2, 3 Indeed, the European Agency for the Evaluation of Medicinal Products (EMEA) has taken the position that biosimilar medicines are follow-on versions of original biological medicines.3 At this point, it is not possible for us to critically comment on the postmarketing surveillance infrastructure adopted by Wokhardt India (the manufacturers of Wepox) and whether it adheres to EMEA guidelines. Although we agree that the EMEA has been more enlightened than the US Food and Drug Administration in addressing the issues related to biosimilars,4 especially with respect to epoetin biosimilars, undergoing EMEA regulatory approval should not be a prerequisite for an noninnovator epoetin molecule to be considered a biosimilar. We believe that 'the process is product' concept for biologics remains a matter of controversy. The key message is that agents considered as either biosimilars or follow-on biologics should be regarded as essentially different from the innovator biologic by virtue of subtle differences in the manufacturing and/or purification process. These agents must undergo formal regulatory approval and they should be marketed in the context of a strong pharmacovigilance infrastructure. In this regard, the EMEA has provided a well-thought-out process for regulatory approval, and the European Union, like the United States, has robust pharmacovigilance in place.