Volume 57, No. 1/2002(January)
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 Clinical Nephrology
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Review
Enzyme replacement therapy for Fabry disease, an inherited nephropathy
Abstract
R.J. Desnick, M. Banikazemi and M. Wasserstein
Department of Human Genetics, Mount Sinai School of Medicine of New York University, New York, NY, USA
Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme a-galactosidase A (a-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life. Recently identified “renal variants” who lack the classical disease manifestations of acroparesthesias, angiokeratoma, hypohidrosis, and characteristic corneal/lenticular opacities also develop renal failure. In contrast, “cardiac variants” who also lack the classical phenotype, develop proteinuria in adulthood, but survive a normal lifespan without developing renal failure. Here, we review the renal involvement and pathology in the classical, renal and cardiac variant phenotypes, and present highlights of the preclinical studies and clinical trials that demonstrated the safety and effectiveness of recombinant a-Gal A replacement for this inherited nephropathy.
Originals
Early progressive interstitial fibrosis in human renal allografts
Abstract
H. Abo-Zenah, S. Katsoudas, D. de Takats, J. Shortland, G. Wild, C.B. Brown and A.M. El Nahas
1Sheffield Kidney Institute, 2Histopathology,
and 3Immunology Departments, Northern General Hospital Trust, Sheffield, UK
Background: Early fibrosis has been described in renal allografts and implicated in the progression of chronic allograft nephropathy (CAN). The precise factors implicated in the initiation and progression of early allograft fibrosis remain uncertain. Patients and methods: We studied retrospectively 23 cadaveric renal allograft recipients over a 3-year period, who had paired renal biopsies (Bx) (at implantation and as clinically indicated) within 3 months of transplantation (Tx). Eight of them have progressed over an average period of 3.16 ± 0.83 years to CAN. Histological evaluation of interstitial fibrosis (IF) relied on point count analysis of Masson’s trichrome (MT) staining as well as immunostainable collagens III (iCol III) and IV (iCol IV). The severity of the IF scores was correlated with the clinical, biochemical and histological parameters. The nature and severity of the interstitial inflammatory infiltrate were also evaluated by immunofluorescence. In addition, patients were subdivided into those whose fibrosis progressed (> 50% increase in IF/iCol III; Group 1) and non-progressors (< 50% increase in fibrosis score; Group 2) in an attempt to determine discriminatory features. Results: In the whole group, there was a significant increase in the IF score, as estimated by MT staining and iCol III, from implantation to follow-up Bx (p = 0.0027 and p = 0.0088, respectively). The changes in iCol IV were not significant. Further, the increase in interstitial inflammatory infiltrate of total T lymphocytes, and not of macrophages, from implantation (modal category = 2) to follow-up (modal category = 0) was significant (p = 0.0121). The predictive value of such increase was significant (R2 = 0.617, p = 0.03). The donor’s age (R2 = 0.892, p = < 0.0001), death from cerebrovascular accident (CVA) (R2 = 0.822, p = 0.047), as well as recipient’s body weight (R2 = 0.892, p = 0.001), male gender (R2 = 0.687, p = 0.041) and elevated mean arterial pressure (MAP) (R2 = 0.892, p = < 0.0001) were all significant risk factors for early IF. Delayed graft function (DGF) proved to be a significant predictor of early IF (R2 = 0.822, p = 0.003) and became more significant in the presence of superimposed acute rejection (AR) (p = 0.0001). Proteinuria > 1 g/day (R2 = 0.882, p = 0.004) and hypertriglyceridemia > 2.25 mmol/l (R2 = 0.808, p = < 0.0001) were also associated with early IF. Of the implantation histological parameters, iCol III proved to be a highly significant predictor of early IF (R2 = 0.892, p = < 0.0001). Interestingly, the predictive value of iCol III for graft survival in terms of CAN was significant (Cox p = 0.088). Group 1 progressor patients (n = 10) were all males (p = 0.038) and received their kidneys from donors who died from CVAs in 90% of cases (p = 0.011). They had, compared to non-progressors, a lower cyclosporin A level (p = 0.047), a higher incidence of AR episodes (80% versus 54%), a higher serum creatinine at 10 days post-Tx (p = 0.005), a higher proteinuria (2.07 ± 3.89 g/l vs 0.96 ± 0.97 g/l, p = 0.041) and a higher serum triglyceride (2.48 ± 1.37 mmol/l vs 1.69 ± 0.81 mmol/l, p = 0.039) level. 8% of Group 1 patients had DGF compared to 30% in Group 2 (p = 0.023). Of note, the modal category of cytotoxic: helper T lymphocytes ratio was greater than 1 in Group 1 (2 : 1) patients and not in Group 2 (1 : 1). Conclusion: Implantation histology, and in particular iCol III, is a predictor of early IF in a subgroup of patients with DGF and AR. Additional risk factors include hypertension, proteinuria and hypertriglyceridemia especially in patients receiving kidneys from older donors who died of CVAs.
Originals
Type 2 angiotensin II receptor expression in human renal allografts: an association with chronic allograft nephropathy
Abstract
B.N. Becker, L.M. Jacobson, D.A. Hullett, N.A. Radke, T.D. Oberley, P.C. Brazy and A.D. Kirk
1Department of Medicine, Division of Nephrology, 2Department of Surgery, Division of Transplantation, 3Department of Pathology and Laboratory Medicine, University of Wisconsin, Department of Veterans Affairs Hospital, Madison, WI, and 4NIDDK-Navy Transplantation and Autoimmunity Branch, National Naval Medical Center, Bethesda, MD, USA
Aims: The renin-angiotensin system (RAS) has been implicated in renal fibrosis through activation of the type 1 angiotensin II (Ang II) receptor (AT1R). Whether the other predominant Ang II receptor, the type 2 Ang II receptor (AT2R), has a fibrotic or sparing role in adult human renal tissue is unknown. Materials and methods: We used the reverse-transcription polymerase chain reaction (RT-PCR) to assess intragraft AT2R mRNA expression in biopsy samples from 23 renal transplant recipients. Potential correlations between intragraft AT2R mRNA, matrix-modulating genes and histologic evidence of chronic rejection were assessed. Results: AT2R mRNA was confirmed by sequence analysis of the RT-PCR product. AT2R mRNA expression directly correlated with angiotensinogen (Spearman correlation coefficient (rs) 0.72; p = 0.0011) mRNA expression, and interestingly, AT2R mRNA inversely correlated with inflammatory gene expression in the biopsy samples. However, AT2R mRNA directly correlated with transforming growth factor-b (TGF-b) (rs 0.59; p = 0.044), matrix metalloproteinase-1 (MMP-1) (rs 0.83; p = 0.001), tissue inhibitor of metalloproteinase-2 (TIMP-2) (rs 0.74; p = 0.001) and TIMP-3 (rs 0.80; p = 0.001) mRNA expression. Moreover, AT2R mRNA and protein expression was significantly greater in the patients with biopsy-proven chronic allograft nephropathy (n = 9; p = 0.045 vs. no chronic allograft nephropathy and donor biopsy samples for mRNA analyses). Conclusions: These data demonstrate that AT2R mRNA is expressed in adult human renal tissue in the setting of renal transplantation. Its apparent association with matrix-modulating genes raises the hypothesis that AT2R mRNA expression may be linked with extracellular matrix regulation in the setting of chronic allograft nephropathy.
Originals
HLA matching for simultaneous pancreas- kidney transplantation in the United States: a multivariable analysis of the UNOS data
Abstract
M.J. Mancini, A.F. Connors Jr., X.-Q. Wang, S. Nock, C. Spencer, C. McCullough, P. Lobo and R. Isaacs
Departments of 1Medicine, 2Surgery, 3Sociology and 4Health Evaluation Sciences, The University of Virginia Health System, Charlottesville, Virginia, USA
Background: As the incidence of diabetic nephropathy increases, especially in minority populations, more simultaneous pancreas-kidney (SPK) transplants are being performed both in the United States and worldwide. The role of matching on SPK outcomes and organ allocation remains controversial. The purpose of this analysis was to determine the influence of HLA matching using currently employed criteria on 5-year SPK graft survival. Methods: We performed an analysis of all 3,316 SPK transplants performed in the United States reported to the United Network for Organ Sharing (UNOS) between December 31, 1988 and December 31, 1994. Kaplan-Meier unadjusted 1- and 5-year graft survival with log rank comparisons and Cox multivariable regression models that adjusted for 12 confounding variables were used to analyze the influence of HLA matching on outcomes. Results: Despite low-grade HLA or DR matching or high levels of common reactive groups (CREG) mismatching, 1- and 5-year allograft survival rates were 90% and 78% for kidney, and 85% and 75% for pancreas transplantation. Conclusions: SPK transplantation is associated with excellent outcomes independent of the level of HLA matching. These data support the hypothesis that SPK transplants need not be allocated based on matching criteria, thus minimizing organ ischemia time and promoting a more racially equitable allocation for SPKs in the US today.
Originals
Biocompatible membranes do not promote graft recovery following cadaveric renal transplantation
Abstract
Y.M. Woo, A.-M. Craig, B.B. King, B.J.R. Junor, M.A. McMillan, J.D. Briggs and R.S.C. Rodger
1Renal Unit, Western Infirmary, Glasgow, Scotland, and
2Renal Unit, Nelson Hospital, Nelson, New Zealand
Background: Controversy surrounds the role of biocompatible membrane dialyzers in treatment of acute renal failure. Studies that have shown a benefit have involved critically ill patients where renal recovery and patient mortality are influenced by other comorbid disease. The aim of the present work is to clarify this issue in a more homogeneous population of patients with acute renal failure following cadaveric renal transplantation. Methods: All patients with delayed graft function between January 1996 and February 1998 were randomized to receive either a biocompatible (BCM, polysulfone) membrane or bioincompatible (BICM, cuprophane) membrane for dialysis until onset of graft function. Results: Forty-one patients were randomized, 23 to receive BCM and 18 BICM. Five patients (2 BCM, 3 BICM; p = NS) with primary non-function of graft were excluded from analysis, leaving 36 cases of acute tubular necrosis (ATN). Patient and donor characteristics were similar in both groups. The BCM group had significantly longer periods of dialysis dependency compared to the BICM group (14 vs 10 days; p = 0.03). There was a tendency towards higher serum creatinine levels in the short term in the BCM group (318 vs 164 mmol/l at 1 month (p = 0.1), 190 vs 169 mmol/l at latest visit (p = 0.07)) and a greater number of acute rejection episodes in the BCM group (3.7 vs 1.7 episodes per 100 days of dialysis dependency, p = 0.1). With an intention-to-treat analysis of all 41 patients originally randomized, there was no significant difference in time to graft recovery between the 2 groups (p = 0.18). Conclusions: In the setting of ARF post-transplantation, we have found no evidence to support the use of biocompatible membranes for dialysis. Rather, our study provides argument against a large benefit for the use of BCM in the recovery of ARF, as suggested by earlier studies.
Originals
Resistive index in chronic nephropathies: predictive value of renal outcome
Abstract
G. Splendiani, C. Parolini, L. Fortunato, A. Sturniolo and S. Costanzi
Department of Nephrology, Tor Vergata University of Rome, Italy
The study of renovascular resistances by color Doppler ultrasound has become a useful diagnostic resource for nephrologists. In recent nephrological literature, many papers deal with the correlations between resistive index, anatomo-pathological patterns and renal function. Aims: In our study, we have tried to discover if resistive index represents a prognostic index of progressive renal failure. Material and methods: To this purpose we compared renal resistive index and blood creatinine obtained from 28 nephropathic patients at their first control, with blood creatinine values after a 3-year follow-up period. Using a linear regression test, we found a strong correlation between the initial value of resistive index and the value of creatinine variation (p = 0.006). Results: All of the patients with normal resistive index at the beginning maintained a stable renal function. Conversely, the patients with high resistive index at their first control showed a progressive renal failure. Conclusion: Our study shows the reliability of resistive index in the prognostic evaluation of renal outcome.
Originals
Racial differences in parathyroid hormone levels in patients with secondary hyperparathyroidism
Abstract
B.P. Sawaya, M.-C. Monier-Faugere, P.Ratanapanichkich, R. Butros, P.J. Wedlund and P.Fanti
1Division of Nephrology, Bone and Mineral Metabolism and 2College of Pharmacy, University of Kentucky, Lexington, KY, USA
Aim: African-Americans (AA) with normal renal function have higher parathyroid hormone (PTH) levels than Caucasians (C). This difference was also noted in cross-sectional studies of patients on dialysis. In this study, we evaluated patients with end-stage renal disease who have just began dialysis and who were not receiving any vitamin D therapy. Methods: A total of 363 patients were recruited (C: 260; AA: 103). All patients had serum calcium, phosphorus, alkaline phosphatase and intact PTH (iPTH) levels measured within 3 months of initiating dialysis. Results: Serum PTH levels were significantly higher in AA vs. C (383 ± 33 vs. 246 ± 19, p < 0.001). This difference was present despite similar calcium, phosphorus and alkaline phosphatase levels between the 2 groups and regardless of gender or diabetes status. However, PTH levels in patients younger than 47 years of age were similar in both groups. Conclusion: PTH levels in ESRD patients over 47 years of age are higher in AA compared to C. The difference is, in part, due to an age-dependent reduction in PTH seen only in C. Further studies are needed to understand the mechanisms of these racial differences and to verify whether they mirror similar alterations at the level of the end-organ tissue.
Originals
The usefulness of F-18 deoxyglucose wholebody positron emission tomography (PET) for re-staging of renal cell cancer
Abstract
A. Safaei, R. Figlin, C.K. Hoh, D.H. Silverman, M. Seltzer, M.E. Phelps and J. Czernin
1Ahmanson Biological Imaging Clinic/Nuclear Medicine, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, 2Department of Medicine, UCLA School of Medicine, Los Angeles, CA, 3Department of Nuclear Medicine, UCSD School of Medicine, San Diego, CA, USA
Purpose: The use of whole-body PET for re-staging of renal cell carcinoma has not been investigated. The aim of the current study was to examine the diagnostic accuracy and clinical usefulness of whole-body PET imaging for re-staging of renal cell cancer. Patients and methods: Clinical PET was performed for re-staging in 36 patients with advanced renal cell cancer. Written reports of imaging studies (including CT, MRI, US, plain film and bone scan), patient history, and extensive chart notes were used to define the clinical stage before PET (pre-PET stage). The written PET report was used to define the clinical stage after PET (PET stage). Reports were used to determine the accuracy of PET for re-staging renal cell cancer and for defining biopsy proven lesions. Clinical parameters and biopsy proven lesions served as reference for the accuracy of PET for re-staging renal cell cancer. Results: PET classified the clinical stage correctly in 32/36 patients (89%) and was incorrect in 4/36 (11%) (sensitivity and specificity: 87% and 100%). In 20 patients, 25 suspicious lesions were biopsied within 3.2 ± 6.7 months of the PET study. Of these, 17 were malignant and 8 were benign. PET correctly classified 21/25 (84%) of the biopsied lesions (sensitivity and specificity: 88% and 75%). Conclusion: PET re-stages renal cell cancer with a diagnostic accuracy of 89%. Its diagnostic accuracy for classifying biopsy proven anatomic lesions as malignant or benign was 84%. These findings suggest that PET is useful in characterizing anatomic lesions of unknown significance in patients with renal cell cancer.
Case reports
Nephrotic IgA nephropathy<br /> associated with disseminated tuberculosis
Abstract
N. Matsuzawa, K. Nakabayashi, T. Nagasawa and Y. Nakamoto
1First Department of Internal Medicine, Kyorin University School of Medicine, and 2Department of Internal Medicine, Kichijyouji Asahi Hospital, Tokyo, Japan
A 35-year-old woman who had been suffering from ascites more than 3 months after the delivery of her first baby, developed generalized edema, pyrexia, pleural effusion, and right lower abdominal pain. The laboratory data revealed 5.6 g of 24-hour urinary protein, increased ESR and CRP, a positive skin test for tuberculosis, and a positive culture for tuberculous bacilli from pleural effusion. A renal biopsy showed mild proliferative glomerulonephritis, IgA and C3 depositions along the capillary loop, in the mesangium and also in the focal tubular basement membrane, and scattered membranolysis of the glomerular basement membrane in addition to paramesangial and intramembranous electron-dense deposits. A positive culture of tuberculous bacilli led anti-tuberculous drugs resulted in the complete disappearance of proteinuria, inflammation, and various organ manifestations. As far as we know, the association of tuberculosis with glomerulonephritis is an uncommon occurrence. In addition to describing this case, we also discussed the role of tuberculosis in the pathogenesis of glomerulonephritis, and reviewed the pertinent literature.
Case reports
Association of parvovirus B19 infection with acute glomerulonephritis in healthy adults: case report and review of the literature
Abstract
Y. Mori, H. Yamashita, Y. Umeda,Y.U. Uchiyama-Tanaka, A. Nose,N. Kishimoto, Y. Kijima, T. Nagata,M. Mori, H. Matsubara, H. Yoshida and T. Iwasaka
1Department of Medicine II, Kansai Medical University, Osaka, and
2Department of Clinical Laboratory Medicine, Fukui Medical University,
Fukui, Japan
An otherwise healthy 20-year-old woman presented with an erythematous rash on her face as well as arthralgia and anemia. She also had systemic edema, proteinuria and hypertension. Laboratory data on admission showed hypocomplementemia, human parvovirus B19 (HPV) DNA and both immunoglobulin (Ig) M and IgG antibodies to HPV in her serum. Renal biopsy specimens showed features of endocapillary glomerulonephritis under light microscopy. Electron microscopy showed massive subendothelial electron-dense deposits. No cause was probable other than immune complex-mediated glomerulonephritis associated with HPV infection. In a review of this and similar cases reported in the literature, several characteristic features come to light: female dominance, onset in the second or third decade of life, hypocomplementemia, histologic renal endocapillary and/or mesangioproliferative glomerulonephritis with subendothelial deposits and spontaneous recovery.
Case reports
A unique renal lesion in common variable immunodeficiency: a case report
Abstract
C. Stigant, D. Sapir, J. Sweet, G.Downey and J. Bargman
1Nephrology Fellow, University of Toronto, 2Staff Pathologist,
Toronto General Hospital, 3Faculty of Medicine, University of Toronto, Division of Nephrology, Toronto General Hospital, University Health Network, Toronto
This article reports the case of a 33-year-old woman with common variable immunodeficiency (CVI) who developed renal failure 17 years after diagnosis and initiation of treatment with monthly IVIG. A renal biopsy revealed mesangial and paramesangial immune complex deposition and interstitial granulomatous infiltration. Renal function improved with oral corticosteroids, but did not return to normal. Decreasing the dose of IVIG had no effect on renal function. Immune dysfunction can be associated with both granulomatous disease and immune complex glomerulonephritis, or the latter may be related to chronic infection or immunoglobulin use. This is the first report of concomitant glomerular-tubulointerstitial lesions in this immunodeficiency syndrome. Renal function should be closely followed in patients with CVI.
Case reports
Carcinoid tumor and membranous glomerulonephritis: coincidence or malignancy-associated glomerulonephritis?
Abstract
C. Luyckx, B. Van Damme,Y. Vanrenterghem and B. Maes
1Department of Nephrology, and 2Department of Pathology, University Hospital Gasthuisberg, Leuven, Belgium
Membranous glomerulonephritis is known to be associated with malignancies. A 43-year-old man with a history of chronic renal insufficiency secondary to 20-year-old membranous glomerulonephritis was operated on for an infrarenal aneurysm. During surgical intervention, multiple nodular liver lesions were detected. Histologic examination of these lesions showed metastases of a carcinoid tumor. Despite extensive examination, the primary tumor site could not be detected. The patient remained asymptomatic 3 years postoperatively without any treatment for carcinoid tumor. This clinical report is the second case of a membranous glomerulonephritis associated with a carcinoid tumor. Whether the association is merely a coincidence or a real malignancy-related glomerulopathy remains unclear. Because survival of 23 years after the onset of symptoms of carcinoid tumor has occurred, it is possible that our patient already had an asymptomatic carcinoid tumor at the time the diagnosis of membranous glomerulonephritis was made. Comparison with other paraneoplastic glomerulonephritis as well as diagnosis of a carcinoid tumor in renal insufficiency are discussed.
Case reports
Severe hyponatremia as the presenting feature of clinically non-functional pituitary adenoma with hypopituitarism
Abstract
S.-H. Lin, Y.-H. Hung and Y.-F. Lin
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
Hyponatremia can result from a wide range of causes. While hyponatremia is known to occur in patients with hypopituitarism, severe hyponatremia occurring as the presenting feature of hypopituitarism is very rare. We present two cases in which severe hyponatremia developed with weakness, light-headedness and seizure. The hyponatremia in these 2 cases mimicked the laboratory diagnostic criteria of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). However, the hormone studies displayed hypopituitarism. Hyponatremia was completely corrected after administering a supplement of prednisolone and L-thyroxine. Computerized tomography of the brain revealed an adenoma of the pituitary gland. These two cases illustrate that severe hyponatremia may be the presenting feature of clinically non-functional pituitary adenoma with hypopituitarism, which should be kept in mind in the differential diagnosis of hyponatremia mimicking SIADH.
Letters to the Editor
Hypokalemic rhabdomyolysis aggravated by diuretics complicating Conn?s syndrome without acute renal failure
Letters to the Editor
Biological evolution of renal osteodystrophy after decreasing dialysate calcium from 1.75 to 1.6 mmol/l
Abstract
G. Jean, C. Chazot and B. Charra
Letters to the Editor
Spurious hyperchloremia and cerebellar ataxia: clue to suggest chronic bromvalerylurea intoxication
Abstract
C.-F. Su, C.-C. Wu, J.-C Yeh and S-H Lin
