John J. Curtis

Rapid Loss of Vertebral Mineral Density after Renal Transplantation

BACKGROUND Osteopenia is a major complication of renal transplantation. Immunosuppressive regimens including cyclosporine, which permit the use of lower doses of glucocorticoids, may reduce glucocorticoid-induced osteopenia. METHODS We prospectively studied the magnitude, distribution, and mechanism of bone loss in 20 adults who received renal allografts from living related donors, who had good renal function, and who were treated with azathioprine, cyclosporine, and low doses of prednisone. We measured serum biochemical markers of bone metabolism, determined the bone mineral density of the second, third, and fourth lumbar vertebrae and the shaft of the radius, and analyzed the histomorphometric features of iliac bone at the time of transplantation and six months later. Measurements of vertebral mineral density were repeated 18 months after transplantation in 17 of the patients. RESULTS After transplantation, the mean serum concentrations of parathyroid hormone, phosphorus, and alkaline phosphatase decreased and the serum calcitriol concentration increased. The mean (+/- SD) bone mineral density of the vertebrae had decreased 6.8 +/- 5.6 percent 6 months after transplantation (P less than 0.05) and 8.8 +/- 7.0 percent 18 months after transplantation. In contrast, the bone mineral density of the radius had increased six months after transplantation (P less than 0.05). The histomorphometric studies showed that the rate of bone formation decreased from 50.5 +/- 44.8 to 23.1 +/- 13.8 microns3 per square micrometer per year (P less than 0.05), and the formation period lengthened from 70 +/- 42 to 146 +/- 144 days (P less than 0.05). Consequently, the amount of bone replaced during a remodeling cycle diminished. CONCLUSIONS Osteopenia associated with renal transplantation remains a problem in the cyclosporine era. The loss of vertebral bone in our subjects was due to an imbalance in bone remodeling consistent with a toxic effect of glucocorticoids.

Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients.

Experimental studies have shown that antilymphocyte globulin combined with transfusion of donor-specific bone marrow cells can induce partial tolerance to allograft tissue. We have adapted these protocols to clinical use and present the results of 57 cadaveric renal allograft recipients who received Minnesota ALG followed by the transfusion of cryopreserved donor-specific bone marrow. A group of 54 patients received the contralateral kidney and similar immunosuppression without the marrow transfusion and serve as controls. Both groups received quadruple immunosuppression with MALG, cyclosporin, azathioprine, and prednisone. In the bone marrow group, after a 10-14 day induction course of ALG, cryopreserved marrow was transfused on the seventh day after the last dose of ALG. The median follow-up in both groups is 16 months, (range 2.5-33 months). Six grafts have been lost in the bone marrow group, (three rejections, 2 deaths [Cr 2.0, 2.3], 1 recurrent disease). In the control group 16 grafts have been lost (13 rejections, 3 deaths [Cr 1.7, 2.5, 3.0]). Five patients in the control group have biopsy-proved chronic rejection compared to one in the bone marrow group. 17 patients in the bone marrow group have been tapered off the prednisone, and three of these patients have had mild late rejection episodes without graft loss. The two groups were compared for differences in the number of rejection episodes, estimated renal plasma flow, glomerular filtration rate, and urine protein. No differences were found. The allograft survival of the bone marrow group was significantly greater (P less than .01) than the control group. The graft survival rates for the bone marrow group at 12 and 18 months were 90% (confidence limits [CL] 85-94) and 85% (CL 78-90), respectively. In the the control group the 12 and 18 month allograft survival rates were 71% (CL 63-78) and 67% (CL 58-74), respectively. The survival in the control group was similar to our overall transplant experience with quadruple therapy. Mixed lymphocyte culture analysis shows a trend to diminished donor-specific responsiveness in the bone marrow group. The use of cryopreserved donor-specific bone marrow is associated with improved allograft survival in cadaveric kidney allograft recipients. However, a more effective induction protocol is needed to reduce the overall number of rejection episodes.

Enteric-Coated Mycophenolate Sodium can be Safely Administered in Maintenance Renal Transplant Patients: Results of a 1-Year Study

With the objective of enhancing upper gastrointestinal (GI) tolerability, enteric‐coated mycophenolate sodium (EC‐MPS, myfortic®, Novartis Pharma AG, Basel, Switzerland) has been developed. This double‐blinded, 12‐month study investigated whether renal transplant patients taking mycophenolate mofetil (MMF) can be safely converted to EC‐MPS. Stable kidney transplant patients were randomized to receive EC‐MPS (720 mg b.i.d.; n = 159) or continue receiving MMF (1000 mg b.i.d.; n = 163). The incidence of GI adverse events (AEs) was similar at 3 months (primary endpoint: EC‐MPS 26.4%; MMF 20.9%; p = NS) and at 12 months (EC‐MPS 29.6%; MMF 24.5%; p = NS). The increase from baseline in mean GI AE severity score, adjusted for duration, tended to be lower in EC‐MPS patients (3 months: 0.15 vs. 0.20; 12 months: 0.23 vs. 0.47; p = NS). Neutropenia (<1500 cells/mm3) within the first 3 months (coprimary endpoint) was low in both groups (EC‐MPS 0.6%; MMF 3.1%; p = NS). Although the overall incidence of infections was similar, the number of serious infections was significantly lower in EC‐MPS patients (8.8% vs. 16.0%; p < 0.05). Similar rates of efficacy failure (EC‐MPS 2.5%; MMF 6.1%; p = NS), biopsy‐proven acute rejection (EC‐MPS 1.3%; MMF 3.1%; p = NS) and biopsy‐proven chronic rejection (EC‐MPS 3.8%; MMF 4.9%; p = NS) were observed in both groups. In conclusion, renal maintenance patients can be converted from MMF to EC‐MPS without compromising the safety and efficacy profile associated with MMF.

Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent

PURPOSE Physicians increasingly prescribe cyclosporine as an immunosuppressive agent for both organ-transplant and non-organ-transplant recipients. Investigators have reported a high incidence of drug-induced hypertension even when clinical nephrotoxicity was not present. We wanted to determine the reason. PATIENTS AND METHODS A comparison was made of hypertension in 15 cyclosporine-treated transplant recipients with that in a similar group of 15 azathioprine-treated transplant recipients. RESULTS Hypertension in the cyclosporine group responded differently from that seen in the azathioprine group and from previously described forms of post-transplantation hypertension. Hypertensive cyclosporine-treated patients show a sodium acquisitive renal state that responds to sodium restriction. Unlike rat models, which suggest cyclosporine-induced stimulation of the renin-angiotensin system, or previous forms of post-transplant hypertension in humans, plasma renin levels were not elevated and blood pressure did not respond to a test dose of captopril. CONCLUSION Hypertension in cyclosporine-treated patients is an iatrogenic form of hypertension that may be associated with an early, subtle, renal defect in sodium excretion, a genesis of hypertension that is consistent with Guytons view of essential hypertension.

Inhibition of Angiotensin-Converting Enzyme in Renal-Transplant Recipients with Hypertension

HYPERTENSION has a high prevalence among recipients of renal allografts.1 , 2 Such post-transplantation hypertension may contribute3 , 4 to the high mortality from atherosclerotic vascular disease ...

Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study.

Background. Everolimus and cyclosporine (CsA) exhibit synergistic immunosuppressive activity when used in combination. We explored the use of everolimus with a CsA-sparing strategy in de novo renal-transplant recipients. Methods. A phase II, randomized, open-label 3-year study was performed in 111 patients to compare the efficacy and tolerability of everolimus (3 mg/day) in combination with basiliximab, steroids, and either full-dose Neoral (FDN) or reduced-dose Neoral (RDN) (CsA trough levels 125–250 ng/mL and 50–100 ng/mL, respectively). Efficacy failure (biopsy-proven acute rejection, death, graft loss, or loss to follow-up), safety, and renal function were evaluated at 6, 12, and 36 months. A protocol amendment allowed further reduction of CsA exposure after 12 months. Results. Efficacy failure was significantly higher in FDN than in the RDN group at 6 (15.1% vs. 3.4%; P=0.046), 12 (28.3% vs. 8.6%; P=0.012), and 36 (35.8% vs. 17.2%; P=0.032) months. Mean creatinine clearance was higher in the RDN group at 6 (59.7 mL/min vs. 51.1 mL/min; P=0.009), 12 (60.9 mL/min vs. 53.5 mL/min; P=0.007), and 36 (56.6 mL/min vs. 51.7 mL/min; P=0.436) months. Discontinuations and serious adverse events were more frequent in the FDN group. Reduction of CsA exposure for 6 months during the amendment improved renal function in the FDN group. Conclusions. In de novo renal-transplant recipients, the regimen of everolimus plus RDN was well tolerated, with low efficacy failure and better renal function in comparison with everolimus plus FDN.

Surgical therapy for persistent hypertension after renal transplantation.

SUMMARY The presence of the original diseased native kidneys in renal allograft recipients is associated with an increased prevalence of persisting post-transplant hypertension. In 9 of 10 such transplant patients bilateral nephrectomy of these native kidneys, performed at least 1 year after successful transplantation of a renal allograft, resulted in improved blood pressure control. Although these 10 patients had higher peripheral plasma renin activity (PRA) than normotensive patients (5.9 ± 1.3 ng/ml/hr versus 1.5 ± 0.3 mg/ml/hr), selective renal vein renin measurements did not consistently demonstrate higher renin concentrations from the native kidneys. Removal of the original kidneys was beneficial even in some patients who had stenosis of the allograft artery demonstrated by arteriography.

Brief Communication: Glomerulonephritis in Patients with Hepatitis C Cirrhosis Undergoing Liver Transplantation

Context We do not know why some patients infected with hepatitis C virus (HCV) develop renal failure after liver transplantation. Contribution This case series describes 30 patients who had kidney biopsies during liver engraftment for HCV-induced cirrhosis. Twenty-five had immune-complex glomerulonephritis. Of these, 10 had normal serum creatinine levels, urinalysis results, and urinary protein excretion and none had blood or kidney cryoglobulins. Cautions Investigators did not study clinical outcomes after transplantation. Implications Clinically silent immune-complex glomerulonephritis occurs in patients with end-stage HCV-induced cirrhosis. We do not yet know whether it can lead to renal failure after liver transplantation. The Editors Chronic infection with hepatitis C virus (HCV) substantially impacts health care in the United States; currently, it affects approximately 2.7 million persons (1, 2). Accompanying extrahepatic syndromes may include glomerulonephritis (3, 4). Transplantation is a life-saving procedure for patients with end-stage cirrhosis; this disease accounts for 30% to 50% of the liver transplant surgeries performed annually in the United States. Compared with HCV-negative transplant recipients, HCV-positive recipients have an increased risk for renal failure after engraftment (5), perhaps because of glomerular renal disease. However, it is unclear whether such disease is present at engraftment or develops later. We performed the current study to determine whether HCV-infected patients have substantial renal injury at liver transplantation. Methods Patients From January 2004 through June 2005, 48 HCV antibodypositive adults underwent deceased-donor liver transplantation at the University of Alabama at Birmingham. We enrolled all 37 patients who provided written informed consent and met the following inclusion criteria: age older than 18 years; positive results for HCV antibody on second-generation enzyme-linked immunosorbent assay; circulating HCV RNA; and cirrhosis documented by history, liver biopsy, or abdominal imaging. Patients were excluded if they had previous organ transplantation, concomitant renal transplantation, ABO-incompatible liver, or seropositivity for hepatitis B virus or HIV. The Institutional Review Board for Human Use at the University of Alabama at Birmingham approved this study. Study Procedures Within 6 months of expected liver transplantation, medical history was recorded, physical examination was performed, and blood and urine samples were collected. Blood studies included serum creatinine and albumin, blood urea nitrogen, cryoglobulins (University of Alabama Hospital laboratory [6], assay repeated 9 days later), rheumatoid factor (Behring RapiTex RF slide latex agglutination, Newark, New Jersey), complement component 3 (C3) and complement component 4 (C4) (nephelometry assay, Beckman Array 360 Protein System, Beckman Instruments, Fullerton, California), 50% hemolytic complement (CH50) assay (University of Alabama Hospital laboratory) (7), HCV RNA by polymerase chain reaction (Cobas TaqMan HCV test, Roche Diagnostics, Branchburg, New Jersey), and HCV genotype (GeneAmp 9700 thermal cycler, Applied Biosystems, Foster City, California). Clean-catch urine samples were collected for all patients except the 2 with hepatorenal syndrome, who had indwelling bladder catheters. We defined elevated serum creatinine level as at least 124 mol/L (1.4 mg/dL) in men or at least 115 mol/L (1.3 mg/dL) in women, pathologic proteinuria as urine protein of at least 1+ on dipstick urinalysis or a urinary proteincreatinine ratio greater than 0.3, and hematuria as urine blood of at least 1+ on dipstick urinalysis or more than 2 erythrocytes per high-power field in a resuspended sediment. During liver transplantation, a kidney biopsy specimen was obtained with a Bard Max-Core Disposable Biopsy Instrument (Bard, Covington, Georgia) after reperfusion of the hepatic allograft if there was no clinical coagulopathy. Two-micron sections were processed for routine light microscopy. Direct immunofluorescence studies used polyclonal antibodies for IgA, IgG, IgM, and C3 and C1q components of complement. One-micron sections were used for ultrastructural studies. Role of the Funding Source Roche Pharmaceuticals, Inc., provided funding for this study. The authors independently designed, wrote, and conducted the study; collected and analyzed the data; and prepared and approved the manuscript. Results Patients Renal biopsy was not performed in 7 patients because of ongoing coagulopathy (n= 6) or inadequate tissue (n= 1); these patients were excluded from further analysis. Of the 20 men and 10 women in the analysis, 25 were white, 4 were African American, and 1 was Hispanic. Mean age at transplantation was 53 years (SD, 8); ages ranged from 41 to 73 years. Twelve patients had a history of hypertension, and 6 had diabetes mellitus. Thirteen patients had received interferon- therapy for at least 3 months, but none had resolution of viremia. Two participants with the hepatorenal syndrome at engraftment required continuous low-flow hemodialysis. Laboratory Data The mean interval between pretransplantation laboratory testing and surgery was 21 days (SD, 47), ranging from 0 to 192 days. Mean Model for End-stage Liver Disease score, including the exemption for hepatoma, was 25 (SD, 6); the range was 16 to 40. Thirteen patients had a normal renal laboratory profile (normal serum creatinine level, no pathologic proteinuria, and no hematuria) (Table 1). Mean serum creatinine level in 28 patients without the hepatorenal syndrome was 112 mol/L (SD, 46) (1.27 mg/dL [SD, 0.52]); values ranged from 44 to 265 mol/L (0.5 to 3.0 mg/dL). Mean HCV RNA viral load was 320000 IU/mL (SD, 440000); genotype was type 1 in 23 of 28 patients tested. Cryoglobulinemia was not detected in the 20 patients tested. Level of C3 was low in 18 of 24 patients, C4 level was low in 7 of 24 patients, and CH50 level was low in 18 of 23 patients. Results of tests for rheumatoid factor were positive in 10 of 24 patients. Table 1. Baseline Demographic and Clinical Characteristics and Renal Biopsy Findings of the 30 Patients, Grouped by Renal Biopsy Diagnosis Renal Biopsy With 1 exception, biopsy specimens contained 10 to 40 (mean, 22) glomeruli. Global glomerulosclerosis was relatively mild; 4 specimens showed more than 20% obsolete glomeruli. Three specimens contained a single segmental sclerotic lesion, and 1 specimen contained 2. Twenty-nine kidney biopsy specimens showed mesangial proliferation by light microscopy with immunofluorescence staining for immunoglobulins, complement, or both (Table 1). However, 4 of these specimens had no deposits by electron microscopy: One showed focal segmental glomerulosclerosis, and 3 were diagnosed as minor glomerular abnormalities in the absence of well-defined, electron-dense deposits. The 1 specimen that appeared normal on immunofluorescence and electron microscopy contained only 3 glomeruli. No specimen showed features of cryoglobulins. Twelve specimens were classified as membranoproliferative glomerulonephritis (MPGN) type 1 but did not show lobular accentuation and marked endocapillary hypercellularity, both of which are common in idiopathic MPGN type 1. Instead, mild to moderate mesangial hypercellularity was observed, with focal duplication of glomerular basement membranes. Another unusual feature was the pattern of immunofluorescence staining. Ten specimens showed staining for all reagents; 1 lacked staining for only IgA and another for only C3. Electron microscopy demonstrated mesangial interposition with subendothelial and mesangial deposits. Three specimens contained occasional subepithelial deposits. Thirteen other biopsy specimens showed an immune-complex glomerulonephritis of 2 patterns. Seven exhibited IgA nephropathy; none had mesangial interposition, but 4 had subendothelial deposits. Six other specimens demonstrated mesangial glomerulonephritis with proliferation of mesangial cells and variable increases in mesangial matrix without mesangial interposition. Immunofluorescence staining for IgA was less intense than that for IgG or IgM; electron microscopy confirmed mesangial deposits. Correlation of Renal Biopsy Findings with Clinical and Laboratory Data Age, ethnicity, and sex appeared similar among the patients grouped by histologic diagnosis. Frequency of diabetes mellitus, hypertension, previous alcohol use, hepatocellular carcinoma, HCV genotype, treatment with interferon-, and viral load did not differ substantially among groups. Levels of C3, C4, and CH50 tended to be lower in patients with MPGN type 1. Eighteen patients had no evidence of renal injury by urinary testing, including 15 with immune-complex glomerulonephritis; of these, 10 had a normal serum creatinine level and, thus, a normal renal laboratory profile (Figure). Patients with MPGN type 1 were most likely to have a clinical renal abnormality (Tables 1 and 2). Figure. Features of glomeruli in a kidney biopsy specimen from a 49-year-old white man with mesangial glomerulonephritis. A B C D E F Table 2. Pretransplantation Laboratory Characteristics of 25 Patients with Hepatitis C Infection and Immune-Complex Glomerulonephritis at Liver Transplantation Discussion An immune-complex glomerulonephritis, characterized by IgA deposits and some mesangial hypercellularity, was very common in patients with end-stage cirrhosis due to chronic HCV infection. Three types of disease were observed: MPGN type 1, IgA nephropathy, and mesangial glomerulonephritis. These distinctive patterns were not associated with any demographic variable tested. The immunoglobulin staining in MPGN type 1 differed from that in patients with idiopathic MPGN; IgA was much more frequent (8). Cryoglobulins, often found in HCV-infected patients with MPGN (9), were not detected, even in rheumatoid factorpositive patients with urinary abnormalities. Subendothelial depos

Hemodialysis Without Anticoagulation

Heparin is usually employed as an anticoagulant during routine hemodialysis. In patients at high risk of bleeding, however, use of heparin significantly increases their morbidity and, presumably, mortality. Over 1 year, we performed 156 hemodialysis procedures successfully without heparin in the transplant dialysis unit. Twenty-eight patients were included in the study; 23 patients had received renal transplants and five patients were in the mouth dental extraction, and parathyroidectomy). Only one of these patients had a coagulopathy. No dialysis procedure produced or aggravated bleeding. Conversely, a coagulopathy was not induced or worsened by dialysis without heparin. A significant complication, defined as complete clotting of the artificial kidney with or without clotting in the lines, occurred in eight dialyses (5.13% of the total) and resulted in an average blood loss of 150 ml. Partial clotting of the dialyzer did not interrupt the procedure and occurred nine times (5.8% of the total). These results compare favorably with previously documented complications from low-dose and regional heparin.

Clinical Documentation of End-Stage Renal Disease Due to Hypertension

Hypertensive end-stage renal disease (ESRD) purportedly accounts for 25% of new ESRD patients each year in the United States, but remains poorly understood. Clinical features include normal renal function at diagnosis of hypertension, family history of hypertension, left ventricular hypertrophy, and minimal proteinuria. We evaluated clinical and historic data documenting the diagnosis of hypertensive ESRD in 43 patients with ESRD attributed to hypertension who were referred to our center for renal transplantation. Hypertensive ESRD patients were more likely to be black patients with left ventricular hypertrophy compared with our overall population. Few of the hypertensive ESRD patients had undergone kidney biopsy, none of whom had classic features of benign nephrosclerosis. Less than 5% of patients had hypertension documented at any time with normal renal function. Based on our review, it is clearly possible that the number of patients reaching dialysis and transplantation with renal failure attributed to hypertensive ESRD may be overestimated.