Incidence of analgesic nephropathy among patients undergoing renal replacement therapy in Czech republic and Slovak republic

BACKGROUND.: The occurrence of analgesic nephropathy (AN) among renal replacementtherapy patients in former Czechoslovakia is not known. Previoussurveys were not based on representative samples and lackeduniform criteria for diagnosing the disease. METHODS.: Incidence of AN in former Czechoslovakia was investigated inpatients commencing renal replacement therapy in 24 (1/3 ofall) dialysis centres from 1 January to 31 December 1992. Patientsshowing an unclear renal diagnosis (n=149) were investigatedwith an interview and renal imaging techniques. The diagnosisof AN was withheld or rejected on the base of recently publisheddiagnostic criteria demonstrating that a decreased renal massof both kidneys combined with bumpy contours and/or papillarycalcifications had a high performance for diagnosing AN (NephrolDial Transplant 1992; 7: 479–486). RESULTS.: Based on the renal imaging criteria, AN was diagnosed in 30of 328 registered patients, resulting in an AN incidence of9.1% while the EDTA data only mentioned an incidence of 4.8%(period 1986–1989). The products most commonly abusedwere analgesic mixtures containing two analgesic substancescombined with caffeine and/or codeine. CONCLUSIONS.: AN was found to be a common disease in the Czech and SlovakRepublics. The disease was diagnosed using reliable renal imagingcriteria.     

IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells

BACKGROUND: Sera of patients with IgA nephropathy (IgAN) contain circulating immune complexes (CIC) composed of galactose-deficient IgA1 complexed with antiglycan antibodies. The role of these CIC in the pathogenesis of IgAN is not known. METHODS: We studied how proliferation of cultured mesangial cells (MC) is affected by CIC prepared from sera of IgAN patients and healthy control subjects using size-exclusion chromatography. CIC-containing fractions were added to serum-starved MC in culture, and cell proliferation was measured using (3)H-thymidine incorporation. The results were confirmed by staining MC using an antibody against proliferating cell nuclear antigen. RESULTS: The incubation of starved MC with serum fractions with M(r) 800 to 900 kD, rich with galactose-deficient IgA1, stimulated proliferation, while fractions with smaller complexes were inhibitory. Furthermore, CIC-containing larger molecular mass fractions isolated from serum of an IgAN patient collected during an episode of macroscopic hematuria stimulated MC proliferation more than CIC obtained during a subsequent quiescent phase. To examine the role of IgA, we removed IgA1 from serum before fractionation. The resultant IgA1-depleted fractions were devoid of stimulatory IgA-CIC. Sera of IgAN patients were also fractionated after addition of desialylated galactose-deficient polymeric IgA1 to form additional immune complexes. Supplementation with a small quantity of this IgA1 increased cellular proliferation in assays using serum fractions of M(r)>/=800 to 900 kD; uncomplexed IgA1 did not affect MC proliferation significantly. In contrast, supplementation with a larger quantity of this IgA1 inhibited cellular proliferation in assays using serum fractions of M(r) 700 to 800 kD. CONCLUSION: Overall, these findings suggest that CIC containing aberrantly glycosylated IgA1 affect proliferation of MC in vitro and, thus, likely play a role in the pathogenesis of IgAN.     

Inhibitors of cyclic nucleotide phosphodiesterase isozymes type-III and type-IV suppress mitogenesis of rat mesangial cells.

We studied interactions between the mitogen-activated protein kinase (MAPK) signalling pathway and cAMP-protein kinase (PKA) signaling pathway in regulation of mitogenesis of mesangial cells (MC) determined by [3H]thymidine incorporation, with or without added EGF. Forskolin or dibutyryl cAMP strongly (by 60-70%) inhibited [3H]thymidine incorporation into MC. Cilostamide, lixazinone or cilostazol selective inhibitors of cAMP-phosphodiesterase (PDE) isozyme PDE-III, inhibited mitogenesis to similar extent as forskolin and DBcAMP and activated in situ PKA, but without detectable increase in cAMP levels. Cilostamide and cilostazol were more than three times more effective at inhibiting mesangial mitogenesis than rolipram and denbufylline, inhibitors of isozyme PDE-IV, even though PDE-IV was two times more abundant in MC than was PDE-III. On the other hand, when incubated with forskolin, rolipram-enhanced cAMP accumulation was far greater (10-100x) than with cilostamide. EGF increased MAPK activity (+300%); PDE isozyme inhibitors which suppressed mitogenesis also inhibited MAPK. PDE isozyme inhibitors also suppressed PDGF-stimulated MC proliferation. We conclude that cAMP inhibits the mitogen-dependent MAPK-signaling pathway probably by decreasing the activity of Raf-1 due to PKA-catalyzed phosphorylation. Further, we surmise that minor increase in the cAMP pool metabolized by PDE-III is intimately related to regulation of mesangial proliferation. Thus, PDE isozyme inhibitors have the potential to suppress MC proliferation by a focused effect upon signaling pathways.     

Immunoglobulin A and renal diseases

Immunoglobulin A (IgA) is a dominant immunoglobulin of the mucosal surfaces, but it is also present in plasma. In men and in hominoid primates it occurs in two subclasses: IgA1 and IgA2. Circulating IgA is mostly IgA1 monomer, secretory IgA is mostly dimer or tetramer with varying content of IgA1 and IgA2 on individual mucosal surfaces. Its main physiological function is a defence of the mucosal surfaces against infection. It binds either specifically to bacterial antigens or through its O-linked glycosidic chains, it binds to the lectins of bacterial cells and thus protects mucosal surfaces against bacterial adhesion and infection. On each of its heavy chain, IgA1 has at least two N-glycosidically bound oligosaccharides and 3 to 5 O-linked side-chains. The occurrence of O-glycosidically bound glycans on other circulating immunoglobulins is rare. An aberrant composition of these glycans may be an antigenic determinant for naturally occurring circulating antibodies. The resulting IgA-containing immune complexes, which are deposited in the glomeruli, may be the cause of IgA nephropathy. IgA glomerular deposits are also frequently present in many other primary and systemic glomerulonephritides.     

Wegener's granulomatosis with bilateral necrotizing scleritis,polyarthritis and renal failure efficiently treated with immunosuppressive therapy

Summary A case report of a female patient with Wegener's granulomatosis is presented. After an initial involvement of the upper respiratory tract in the form of a sinusitis, there followed a severe necrotizing bilateral scleritis necessitating the enucleation of the left eye ball. Renal involvement developed as late as 24 months after the onset of the disease and led to renal failure within three months. Throughout the duration of her disease, the patient had joint symptoms in the form of episodes of migratory nondeforming polyarthritis. The administration of corticosteroids alone in daily doses up to 60 mg prednisone failed to control the progression of the disease, while immunosuppressive therapy with cyclophosphamide combined with methylprednisolone pulse therapy and haemodialysis resulted in a marked improvement of renal function and in the subsidence of the ocular and articular symptoms.     

Initial single-center experience with sirolimus after lung transplantation

BACKGROUND: Standard immunosuppression after lung transplantation includes calcineurin inhibitors, mycophenolate mofetil, and steroids. Long-term survivors of lung transplantation are often confronted with chronic kidney disease, by definition related to the intake of calcineurin inhibitors. Sirolimus has been increasingly proposed as an alternative immunosuppressive agent due to its absence of nephrotoxicity, which could be used in selected patients. METHODS: We prospectively administered sirolimus as an alternative to calcineurin inhibitors in 10 lung transplantation recipients with persistent drug nephrotoxicity. They were switched from tacrolimus to sirolimus. Four patients also had bronchiolitis obliterans syndrome. The conversion scheme consisted of an immediate stop of tacrolimus and an 6 to 8-mg loading dose of sirolimus, followed by 4 mg/d. After 5 days, the sirolimus dose was adjusted to maintain trough levels between 12 and 18 ng/mL or 6 and 12 ng/mL for combined sirolimus and tacrolimus. Patients were monitored for renal and graft function as well as clinical status. RESULTS: A significant decrease in creatinine was observed after 1 week of treatment (P = .011). Azotemia decreased after 1 month, remaining stable (P < .01). Pulmonary function tests did not show significant modification from before sirolimus, inception in patients with or without bronchiolitis obliterans syndrome. There were seven infections. One patient died of complications related to bronchiolitis obliterans. CONCLUSION: Sirolimus was a useful alternative immunosuppressant, allowing significant tacrolimus withdrawal in transplant recipients with renal impairment. Sirolimus administration allowed recovery of renal function with low morbidity; it was useful for rescue of chronic renal impairment after lung transplantation.     

Evaluation of diagnostic criteria for analgesic nephropathy in patients with end-stage renal failure: results of the ANNE study

It was found that in Belgium, renal imaging techniques, demonstratinga decreased renal mass of both kidneys combined with eitherbumpy contours or papillary calcifications, were the only methodsto reliably diagnose analgesic nephropathy (AN) in patientswith end-stage renal failure. However, these criteria were selectedin an area with a high prevalence of this disease (15.6% ofthe dialysis population at December 1990). To evaluate the criteriaselected to diagnose AN in populations with lower or unknownprevalences of AN, the Analgesic Nephropathy Network of Europe(ANNE) was formed, consisting of 23 dialysis units from 14 Europeancountries and Brazil. During 1991–1992, 598 new patientswith equivocal diagnosis of renal disease (excluding biopsy-provenglomerulonephritis, polycystic disease, diabetic nephropathyand other systemic diseases) and who began renal replacementtherapy in the ANNE centres were evaluated by a short questionnaireand two renal imaging techniques: sonography and either tomographyor computed tomography (CT) scan. A comparison of 82 abusers(daily use of analgesic mixtures for at least 5 years) and 495controls corroborated the excellent diagnostic performance ofthe renal imaging techniques for AN. We recommend the use ofthese renal imaging criteria in all patients without a clearrenal diagnosis in order to obtain a more reliable insight intothe magnitude of the AN problem in different countries.     

Dense deposit nephropathy: a peculiar variant of glomerulonephritis or a distinct disease entity (author's transl)]

In four renal biopsies of two patients with chronic glomerulonephritis (GN), the so-called dense deposit nephropathy (NDD) was diagnosed by means of light, electron, and immunofluorescence microscopy. In routine paraffin sections the picture approached that of the membrano-proliferative GN. In semithin sections (toluidine blue, periodic acid-Ag-methenamine) and especially in the ultrastructure there appeared extensive confluent deposits of a very dense substance, infiltrating the lamina densa of glomerular capillaries, basal membranes of both Bowman's capsules and tubules, and arteriolar walls. In this localization, a non-diffuse "psdudolinear" deposition of beta1c was detected, whereas antisera to main Ig-fractions and fibrin(ogen) were not fixed. In a biopsy performed six years later, a concentration of dense depositis towards the mesangial area and a partial regeneration of basal membranes were observed. In a part of dense deposits there appeared vacuolization, primarily in tubular and arteriolar basal membranes. In glomeruli, focal IgM deposits were apparent at an advanced stage. NDD apparently is a sequel of a particular metabolic (immune?) process, afflicting solely the renal membranous system and distinctly dns known at present. The noncharacteristic clinical presentation resembles chronic. GN, is very protracted, lengthy, and relatively benigh, with a chance of functional and possible even morphological remission.     

Urinary transforming growth factor-β1 in children with obstructive uropathy

Aim: Obstructive uropathies (OU) in childhood constitute one of the major causes of chronic renal insufficiency. Transforming growth factor‐β1 (TGF‐β1) is considered to be the major fibrogenic growth factor. The aim of the present study was to investigate urinary TGF‐β1 levels in children with obstructive and non‐obstructive uropathies (NOU). Methods: This study involved 19 children with OU, 11 children with non‐obstructive hydronephrosis and 21 healthy children. Urinary TGF‐β1, proteinuria, microalbuminuria and urinary α1‐microglobulin were measured, and renal function was assesed. The results were statistically analyzed. Results: Mean urinary TGF‐β1 concentrations in patients with OU were significantly higher than those with NOU (4.14 ± 0.67 creatinine vs 1.80 ± 0.24 pg/mmol creatinine, P < 0.05) and healthy controls (1.66 ± 0.28 pg/mmol creatinine, P < 0.05). Positive correlations of urinary TGF‐β1 concentrations with proteinuria (r = 0.87, P < 0.0001) and urinary α1‐microglobulin (r = 0.82, P = 0.0002) were found in patients with OU. Conclusion: Children with OU have higher urinary TGF‐β1 than children with NOU. Urinary TGF‐β1 may be a useful non‐invasive tool for the differential diagnosis between OU and NOU in children. A positive correlation of TGF‐β1 with markers of renal tissue damage in patients with OU was found.     

Chronic nephropathies and disorders of renal function--is it sufficiently diagnosed in patients hospitalised on department of internal medicine and cardiology?

We have found out that nephropathies and renal dysfunctions are diagnosed insufficiently. At the same time, it has been observed that patients are sent to nephrology out-patient clinics too late. The aim of our study was to identify how nephropathy and renal dysfunction are diagnosed and how these diagnoses are recorded in diagnostic summary of hospital discharge report in patients hospitalized in department of internal medicine and cardiology of a big teaching hospital. Also, we studied the incidence of risk diseases (arterial hypertension and diabetes mellitus) and serious cardiovascular complications in individual stages of renal dysfunction. We analysed 325 medical records of patients hospitalized and discharged in the course of one month. Renal dysfunction was classified according to Kidney Disease Outcomes Quality Initiative. Glomerulal filtration rate was calculated via simplified Levey's formula. Nephropathy and renal dysfunction were diagnosed, and properly recorded in diagnostic summary, only in 5 % of patients in the Stage I of renal dysfunction (Stage II = 2%, Stage III = 28%, Stage IV = 88% and Stage V = 88%). The incidence of risk diseases and cardiovascular complications increased linearly with progression of renal insufficiency. The results of our study prove that nephropathy and renal dysfunction are diagnosed insufficiently, particularly in early stages when it is still possible to use targeted therapy and early control of specific complications of renal insufficiency.