A novel lysozyme mutation Phe57Ile associated with hereditary renal amyloidosis

BACKGROUND: Variant forms of lysozyme, a ubiquitous bacteriolytic enzyme, are known to lead to hereditary non-neuropathic renal amyloidosis and, so far, three different mutations of the lysozyme gene have been reported. In this study, we report a novel lysozyme variant, Phe57Ile, associated with renal amyloidosis in three patients in one Italian Canadian family. METHODS: The proband was a 52-year-old woman who developed renal failure at the age of 42 years. Renal biopsy demonstrated replacement of glomeruli by amyloid. Her younger sister and her younger daughter who underwent renal transplantation also had renal amyloidosis. The proband's older daughter and her niece were in good health. To elucidate pathogenesis of this hereditary renal amyloidosis, DNA analyses of the lysozyme gene, including single strand confirmation polymorphism, direct DNA sequence, and restriction fragment length polymorphism analyses, were performed. RESULTS: DNA analyses of the lysozyme gene revealed a T to A transversion at the first position of codon 57 of the lysozyme gene in the proband, her sister, and her affected and unaffected daughters, indicating a replacement of Phe by Ile at residue 57. In addition, DNA sequencing demonstrated a C to A transversion at the second position of codon 70, denoting a replacement of Thr by Asn at residue 70, in the proband's sister and her niece. Thus, the proband's sister is compound heterozygous for the Phe57Ile and Thr70Asn alleles. CONCLUSION: Distinctive clinical features in patients of this family are nephropathy due to renal amyloidosis. Our results indicate that the novel lysozyme variant Phe57Ile is associated with renal amyloidosis in this family. From our results, a clear relation between the Thr70Asn polymorphism and renal amyloidosis could not be demonstrated.     

Hereditary renal amyloidosis associated with variant lysozyme in a large English family.

BACKGROUND: Two kindreds with hereditary systemic amyloidosis caused by the first two mutations to be described in the human lysozyme gene were discovered recently and study of the variant lysozyme has been powerfully informative about mechanisms of amyloid fibrillogenesis. However, the clinical manifestations in these families, additional members of which have lately been identified, have not previously been reported in detail. METHODS: The proband presented with proteinuria aged 50 and a family history of amyloidosis, and underwent renal biopsy, whole-body serum amyloid P component (SAP) scintigraphy, and sequencing of the lysozyme gene. Her family history and the phenotype of hereditary lysozyme amyloidosis were thoroughly documented and compared with the presentation and natural history of all other known patients with this condition. RESULTS: The proband belonged to an extended English family other members of which were known to have hereditary lysozyme amyloidosis. Those with amyloid in previous generations presented with renal involvement, frequently developed complications due to gastrointestinal amyloid, and died before age 60. All amyloid deposits were composed of lysozyme and complete concordance was established between amyloid and heterozygosity for a point mutation in the lysozyme gene, encoding the previously reported Asp67His substitution in the mature protein. CONCLUSION: The phenotype, reported for the first time in this extended kindred, contrasts with that of an apparently unrelated family carrying the same mutation who presented with spontaneous hepatic haemorrhage and rupture, and with the manifestations in a family with the lysozyme Ile56Thr variant who presented with dermal petechiae before proceeding to fatal visceral amyloidosis. A remarkably wide spectrum of disease can be caused by the same amyloid fibril protein, although renal involvement predominates in all cases except those dying of hepatic rupture.     

Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene.

BACKGROUND: Although apolipoprotein A-II (apoA-II) associated amyloidosis has been described in the senescent accelerated mouse (SAM) model of aging, so far there has been no report of human apoA-II amyloidosis except for a recent report of renal amyloidosis resulting from a stop-codon to glycine mutation of apoA-II. The mechanisms of amyloid formation in human apoA-II amyloidosis are not clear. METHODS: A 46-year-old Caucasian male with proteinuria noted at 42 years of age was studied. Renal biopsy revealed amyloid deposition in glomeruli. DNA analysis of genes known to be associated with hereditary renal amyloidosis revealed no abnormalities. To elucidate the type of his amyloidosis, apoA-II gene and plasma apoA-II were examined. RESULTS: DNA analysis revealed heterozygosity for a G to C transversion at the second position of the stop-codon of apoA-II gene, suggesting a stop to serine substitution at codon 78. Western blot analysis and amino acid sequence analysis of the patient's plasma apoA-II showed both normal apoA-II and variant apoA-II with a 21-amino acid residue extension at the C-terminus. CONCLUSIONS: These results indicate that the patient's amyloid fibrils were derived from apoA-II and the amyloidogenesis is likely to be closely linked to the peptide extension at the C-terminus of variant apoA-II. The pathogenesis of human apoA-II amyloidosis is different from that of SAM.     

Hereditary systemic amyloidosis with renal involvement

Hereditary systemic amyloidosis is caused by deposition of genetically variant proteins as amyloid fibrils. The types that present with renal disease are usually associated with mutations in the genes for either apolipoprotein AI, apolipoprotein AII, lysozyme or fibrinogen A alpha-chain. These diseases are inherited in an autosomal dominant manner with variable penetrance, and can present clinically at any time from the teen years to old age, though usually in mid-adult life. Hereditary amyloidosis is uncommon, but its precise characterization has major implications for patient management and genetic counseling, and it has been an extremely valuable model for elucidating the pathogenesis of amyloid deposition generally. The amyloidogenic variant proteins associated with hereditary amyloidosis are less stable than their normal wild type counterparts and even under physiological conditions can populate partly unfolded states, involving loss of tertiary or higher order structure, which readily aggregate with retention of beta-sheet secondary structure into protofilaments and fibrils. The clinical phenotype of hereditary renal amyloid is non-specific and is readily misdiagnosed as acquired AL amyloidosis. Indeed, we have lately demonstrated that five percent of patients with apparent sporadic amyloid have hereditary fibrinogen A alpha-chain amyloidosis associated with the valine 526 variant. Penetrance of this particular mutation is extremely low in most families obscuring the genetic etiology, but the renal histology is very characteristic showing substantial accumulation of amyloid within enlarged glomeruli, but none in blood vessels or the interstitium. DNA analysis is now performed routinely in UK National Amyloidosis Centre in patients with systemic amyloidosis in whom AA or AL fibril type cannot be definitively verified.     

Successful Hepatorenal Transplantation in Hereditary Amyloidosis Caused by a Frame-Shift Mutation in Fibrinogen Aα-Chain Gene

Hereditary systemic amyloidosis comprises several autosomal dominant diseases caused by mutations in a number of plasma proteins, including the fibrinogen Aalpha-chain. Four mutations in the fibrinogen Aalpha-chain that are able to induce amyloidosis have been identified so far, the most common being the Glu526Val mutation. We have observed a family in which the father and his son reached end-stage renal failure because of renal amyloidosis induced by a frame-shift mutation in the fibrinogen Aalpha-chain gene producing a novel amyloid protein. Two kidney transplantations in the father and one in the son resulted in fast graft loss caused by recurrence of amyloid deposition. We then performed hepatorenal transplantation in the son. Three years later, liver and kidney functions are normal without recurrence of amyloid deposition. This case, together with three others with the Glu526Val mutation in the extensive literature, suggests that liver transplantation can cure hereditary fibrinogen amyloidosis, whatever the mutation may be.     

Infertility and hypergonadotropic hypogonadism as first evidence of hereditary apolipoprotein A-I amyloidosis

PURPOSE: We report that primary infertility and hypergonadotropic hypogonadism in young patients may be caused by testicular amyloidosis and it is associated with the presence of a mutation in the apoA-I gene, resulting in the replacement of proline for leucine at residue 75 of the protein. MATERIALS AND METHODS: Ten patients presenting with infertility, gynecomastia, decreased libido, erectile dysfunction or a family history of amyloidosis underwent clinical evaluation, hormone assays, semen analysis, ultrasonographic investigation of the testicles, testicular biopsy and DNA sequencing of the apoA-I gene. RESULTS: All patients showed azoospermia and 9 had increased testicular volume. Massive amyloid deposition was observed in all testicular biopsies and the apoA-I mutation of replacement of proline for leucine at residue 75 of the protein was noted. Five patients showed hypergonadotropic hypogonadism and 5 had normal testosterone values with high gonadotropin levels. CONCLUSIONS: Nonobstructive azoospermia and macro-orchidism with or without hypogonadism may be caused by hereditary apoA-I amyloidosis in young patients. Testicular amyloidosis can be the first manifestation of this systemic disease. Specific staining for amyloid deposits and genetic analysis of apoA-I mutations are recommended in young, infertile patients with macro-orchidism. Finally, surveillance in asymptomatic mutation carriers is suggested to evaluate the opportunity to implement sperm retrieval and start androgen replacement therapy when necessary.     

Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis

Apolipoprotein A-I amyloidosis is a rare, late-onset, autosomal dominant condition characterized by systemic deposition of amyloid in tissues, the major clinical problems being related to renal, hepatic, and cardiac involvement. Described is the clinical and histologic picture of renal involvement as a result of apolipoprotein A-I amyloidosis in five families of Italian ancestry. In all of the affected family members, the disease was caused by the Leu75Pro heterozygous mutation in exon 4 of apolipoprotein A-I gene, as demonstrated by direct sequencing and RFLP analysis. Immunohistochemistry confirmed that amyloid deposits were specifically stained with an anti-apolipoprotein A-I antibody. The clinical phenotype was mainly characterized by a variable combination of kidney and liver disturbance. The occurrence of renal involvement seemed to be almost universal, although its severity varied greatly ranging from subclinical organ damage to overt, slowly progressive renal dysfunction. The renal presentation was consistent with a tubulointerstitial disease, as suggested by the findings of defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria. Histology confirmed tubulointerstitial nephritis. Surprising, amyloid was restricted to nonglomerular regions and limited to the renal medulla. This location of apolipoprotein A-I amyloid differs sharply from other systemic amyloidoses that are mainly characterized by glomerular and vascular deposits. The tubulointerstitial nephritis as a result of hereditary apolipoprotein A-I amyloidosis is a rare disease and a challenging diagnosis to recognize. Patients who present with familial tubulointerstitial nephritis associated with liver disease require a high index of suspicion for apolipoprotein A-I amyloidosis.     

Clinical and biochemical outcome of hepatorenal transplantation for hereditary systemic amyloidosis associated with apolipoprotein AI Gly26Arg

BACKGROUND: Treatment of systemic amyloidosis comprises measures to support failing organ function coupled with attempts to reduce the supply of the respective amyloid fibril precursor protein. Orthotopic hepatic transplantation is effective in familial amyloid polyneuropathy associated with variant transthyretin, because this protein is produced almost exclusively in the liver. Hepatic transplantation has not been performed in hereditary apolipoprotein AI (apoAI) amyloidosis, and the liver's contribution to plasma apoAI levels has not been determined in vivo. METHODS: A 57-year-old Irish man with hereditary systemic amyloidosis associated with apoAI Gly26Arg, which had led to end-stage renal failure and progressive liver dysfunction, underwent hepatorenal transplantation. His outcome was followed clinically and his amyloid deposits were monitored with serum amyloid P component scintigraphy. The proportion of variant apoAI in the plasma was estimated by quantitative isoelectric focusing before and after liver transplantation. RESULTS: Plasma levels of variant apoAI decreased by 50% after liver transplantation, and the patient was asymptomatic 2 years after surgery. Subclinical amyloid deposits that were present in his spleen and heart preoperatively have regressed and stabilized respectively. CONCLUSIONS: Orthotopic liver transplantation substantially reduces the supply of the amyloid fibril precursor protein in hereditary apoAI amyloidosis, and the excellent outcome in this patient probably reflects the balance between deposition and turnover of amyloid having been altered in favor of the latter. These findings support the use of liver transplantation in patients with hereditary apoAI amyloidosis who develop hepatic dysfunction.     

Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg

Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg. BACKGROUND: Mutations in the gene for apolipoprotein AII (apoAII) have recently been found to cause hereditary renal amyloidosis. In each case amyloid deposition has been associated with a peptide extension at the carboxyl-terminus of apoAII, the result of mutations in the normal stop codon. METHODS: A Caucasian man who has had progressive renal dysfunction since age of 34 was found to have amyloidosis on renal biopsy at age 56. Echocardiogram showed mild intraventricular septal thickness and technetium-99m (99mTc)-pyrophosphate scintigraphy demonstrated uptake by cardiac muscle consistent with amyloid deposition in the myocardium. His father died of renal failure and his paternal half brother has renal dysfunction. RESULTS: DNA sequencing of the apoAII gene in the proband showed a T to C transition at the first position of the stop codon indicating replacement of the stop codon by l-arginine (Arg) at residue 78. Western analysis of the proband's plasma under reducing conditions using anti-apoAII revealed an extra band at approximately 10 kD in addition to the normal apoAII band at 8 kD. Western analysis of solubilized amyloid fibrils isolated from rectal biopsy tissue contained only the variant apoAII. CONCLUSION: These results indicate that the proband's amyloid fibrils are derived from apoAII and the amyloidogenesis is linked to the peptide extension at the carboxyl-terminus of variant apoAII. Of particular interest is that this novel apoAII variant may cause amyloid cardiomyopathy in addition to renal amyloid.     

Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks.

BACKGROUND: Among hereditary fevers characterized by recurrent attacks of fever and organ localized inflammation, familial Mediterranean fever (FMF), and tumour necrosis factor receptor superfamily 1A (TNFRSF1A) receptor associated periodic syndrome (TRAPS) are diseases with identified genes that can be associated with renal amyloidosis of the AA type. In this study we have characterized FMF and TRAPS genotypes in 38 unrelated patients suffering from amyloidosis AA and recurrent inflammatory attacks. METHODS: Mutations of the MEFV and TNFRSF1A genes, responsible respectively for FMF and TRAPS, were searched for by amplifying, using polymerase chain reaction (PCR), genomic DNA, and direct sequencing. RESULTS: Twenty-seven patients (71%) carried mutations in MEFV (22 patients with two mutations, two patients with a single mutation) or TNFRSF1A genes (three patients). Patients with MEFV mutations belonged to the classical at-risk ethnic group for FMF: Sephardic Jews, Turks, Armenians, and Arabs from the Maghreb. The main genotype encountered was M694V/M694V (19/22), one Turkish patient was M680I/M680I, and two Arab patients from the Maghreb were M694I/M694I. We found three Caucasian patients with the C55S, C70Y, R92Q mutations in the TNFRSF1A gene. CONCLUSIONS: In this series we observed that FMF is the main cause of AA amyloidosis in Sephardic Jews and Turks. MEFV and TNFRSF1A mutations were found in only 6 of 14 Arab patients from the Maghreb. We found three families (one Caucasian and two from Maghreb) with AA amyloidosis without MEFV or TNFRSF1A mutations, suggesting that other genetic cause(s) exist(s). The characterization of mutations in MEFV and TNFRSF1A is important for the therapeutic behaviour of AA amyloidosis associated with inherited recurrent fever.     

A Case Report of AA Amyloidosis Associated With Familial Periodic Fever Syndrome Diagnosed After Kidney Transplantation: Never Say Never

Recurrent or “de novo” AA amyloidosis in the renal allograft is rarely described. We describe a case of severe nephrotic syndrome in a recipient of a kidney graft with a previous diagnosis of polycystic nephropathy caused by AA amyloidosis diagnosed only after the renal transplantation. The disease was possibly a tumor necrosis factor receptor–associated periodic syndrome (TRAPS). TRAPS is a rare hereditary inflammatory disease never reported to the best of our knowledge, as a de novo diagnosis in the transplantation setting. Biopsy of the renal graft, indicated for the onset of heavy proteinuria, and genetic investigation provided the clues for diagnosis.     

Medullary amyloidosis associated with apolipoprotein A-IV deposition

Amyloidosis is caused by extracellular deposition of proteins in an insoluble manner within tissues. In hereditary forms of amyloidosis, transthyretin, fibrinogen A-α, lysozyme, gelsolin, apolipoprotein A-I, and A-II accumulate in the tissue plaques. Here we describe a 52-year-old man with no family history of renal disease who presented with increased urinary frequency, gradual loss of renal function but no significant proteinuria. Renal biopsy found large amounts of amyloid restricted to the medulla with no involvement of glomeruli or vessels. Immunohistochemical analysis for transthyretin or serum amyloid A and tests for an underlying monoclonal gammopathy were negative. Although initially suspected to be amyloid light chain amyloidosis, laser microdissection and mass spectrometry showed that the amyloid was composed of large amounts of apolipoprotein A-IV. This was based on mass spectrometry studies that showed 100, 96, and 73 spectra in three microdissected samples that matched to apolipoprotein A-IV with 100% probability. DNA analyses detected three sequence variants representing common polymorphisms of the apolipoprotein A-IV gene. Thus, in this case, apolipoprotein A-IV deposition and renal involvement appear to be restricted to the medulla. A high degree of suspicion is required for the diagnosis of apolipoprotein A-IV amyloidosis as it may be missed if a renal biopsy consists only of cortex.     

Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid

Transthyretin-derived amyloidosis (ATTR) amyloidosis is the third most prevalent amyloid type in surgical pathology and may occur as a hereditary disease with germline mutations in the TTR gene or as senile systemic amyloidosis (SSA) without mutations. Distinction between hereditary ATTR amyloidosis and SSA is of central importance, as the former necessitates genetic counseling and can be treated by liver transplantation. However, little is known about the prevalence of hereditary ATTR amyloidosis in surgical pathology specimens. We have examined the distribution of hereditary ATTR amyloidosis and SSA in a consecutive series of surgical pathology specimens with histologically and immunohistochemically confirmed ATTR amyloid. Thirty-three consecutive patients were retrieved from the Amyloid Registry of the Charité University Hospital. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue or patient blood and examined by DNA sequencing. ATTR amyloid was found in the gastrointestinal tract, endomyocardium, peripheral nerve, carpal tunnel ligament, synovia, breast, and testicle. Amyloid fibrils were present as interstitial and vascular deposits, as evidenced by Congo red staining. TTR gene mutations were detected in 12 of 30 patients, with p.Val30Met being the most prevalent (5 patients). Furthermore, 2 novel mutations (p.Asp39Val and p.Glu54Asp) were found. In patients carrying a mutation, ATTR amyloid was found in the gastrointestinal tract, myocardium, nerve, and testicles. To conclude, the hereditary form of ATTR amyloid seems to be more common in elderly patients than previously thought. It is, therefore, important to genetically test every patient when diagnosing ATTR amyloidosis.     

Renal Transplantation in Systemic Amyloidosis—Importance of Amyloid Fibril Type and Precursor Protein Abundance

Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty‐nine percent of patients with end‐stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A‐I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post‐RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history.     

Hereditary amyloidosis with progressive peripheral neuropathy associated with apolipoprotein AI Gly26Arg: outcome of hepatorenal transplantation.

Liver transplantation (LT) has been reported in only 1 patient with hereditary variant apolipoprotein AI (apoAI) amyloidosis and was associated with a 50% decrease in production of variant apoAI. The potential for this to benefit clinical manifestations of apoAI amyloidosis such as peripheral neuropathy has not been determined. A 59-yr-old Irish-born male with hereditary systemic amyloidosis associated with apoAI Gly26Arg, which was suspected to be the cause of a progressive peripheral neuropathy, along with end-stage renal failure and hepatic dysfunction, underwent hepatorenal transplantation. Evaluation of his clinical outcome included serial neurological examinations and nerve conduction studies. The proportion of variant apoAI in the plasma was estimated before and after LT. Hepatorenal transplantation was successful, with the plasma concentration of variant apoAI decreasing by over 50% after transplantation and this was associated with progressive resolution of the patient's neuropathic symptoms and a significant and sustained improvement in electrophysiological parameters. In conclusion, liver transplantation reduces production of the amyloid fibril precursor protein to a degree that can facilitate net regression of amyloid deposits, which may aid recovery of end-organ damage such as that seen in peripheral neuropathy.     

14例Fabry病肾损害的临床、病理及基因突变特点的分析

目的 探讨Fabry病肾损害的临床病理及α-半乳糖苷酶A(α-Gal A)基因(GLA 基因)突变的特点.方法 回顾性分析14例Fabry病患者的临床、肾脏病理及GLA基因突变等特点.结果 Fabry病肾损害在肾活检患者中检出率为0.074％,平均确诊年龄(30.57±9.32)岁,男∶女=2.5∶1.尿蛋白量中位数为1.71 g/24 h[(0.32～ 4.71)g/24 h].5例有血尿,4例有肾功能受损,肾外受累的表现以血管角质瘤最多见(10/14),其次为心脏病变(6/14).经典型患者9例,迟发型5例,其中6例有肾脏病家族史.肾脏病理光镜下可见明显的肾小球细胞空泡变性,部分患者可见硬化的肾小球.电镜下2例女性患者为部分足细胞内有髓磷脂样小体形成,其余病例所有足细胞内均可见髓磷脂样小体.4例测定α-Gal A活性的先证者均低于正常值.12例先证者进行了GLA基因突变分析,11例发现有GLA基因突变.3个新突变为碱基插入或缺失突变,临床表型均为经典型Fabry病.大多数迟发型患者携带的基因突变位于酶结构的包埋区或部分包埋区(3/11).在已证实的GLA基因突变中,携带I91T、R112H、Q312H的先证者主要表现为“迟发型”;携带W162X、F169S、S201F、N272K及L310R的先证者均表现为“经典型”.结论 本组Fabry病肾损害患者占肾活检的0.074％,常伴有血管角质瘤及心脏受累,且不同的GLA基因突变可能与患者的表型密切相关.     

Redistribution of connexin43 expression in glomerular podocytes predicts poor renal prognosis in patients with type 2 diabetes and overt nephropathy.

BACKGROUND: Significance of podocyte injury in the progression of diabetic nephropathy is not well-understood. In this study, we examined whether alteration of gap junction protein connexin43 (Cx43) expression in podocytes is associated with the progression of overt diabetic nephropathy. METHODS: We recruited 29 type 2 diabetic patients with overt nephropathy who underwent renal biopsy. Nephrectomized kidney samples obtained from seven subjects with localized neoplasm and biopsy specimens from five patients diagnosed as minor glomerular abnormalities were used as controls. Cx43 staining on paraffin-embedded kidney sections were studied by immunohistochemistry. RESULTS: In controls, Cx43 was expressed at podocytes in a linear pattern along the glomerular basement membrane. In contrast, downregulation and loss of uniformly linear staining of Cx43 (Cx43 heterogeneity) in podocytes were observed in diabetic nephropathy. Cx43 intensity correlated with current renal function (R = 0.647, P < 0.005), whereas the magnitude of Cx43 heterogeneity correlated well with the degree of future decline in renal function (R = -0.705, P < 0.001). CONCLUSIONS: Alteration of Cx43 expression in podocytes was closely associated with the progression of overt diabetic nephropathy. These results indicate that change in Cx43 expression at podocytes represents a progressive stage in overt diabetic nephropathy and that it may be a convenient way to predict future decline in renal function.     

IgA nephropathy associated with psoriasis vulgaris: a contribution to the entity of 'psoriatic nephropathy'

BACKGROUND: It is generally accepted that there is no higher prevalence of renal disease in psoriatic patients, except in the case of secondary renal amyloidosis in psoriatic arthropathy. Contrary to this, however, some authors suggest that kidney diseases in psoriasis vulgaris may be more common and they presume the existence of 'psoriatic nephropathy'. METHOD: We report a case of IgA nephropathy in a patient with psoriasis vulgaris as a contribution to the ongoing discussion concerning this entity of 'psoriatic nephropathy'. RESULT: A 62-year-old man with a history of psoriasis vulgaris, without evidence of psoriatic arthropathy, was admitted to hospital for nephrotic proteinuria 6.74 g/day and a moderate decrease of glomerular filtration rate with a serum creatinine level of 213 micromol/L and creatinine clearance of 0.95 ml/s. Kidney biopsy revealed IgA nephropathy with vascular nephrosclerosis and tubulointerstitial nephritis. After 1 month of treatment with prednisone 1 mg/kg/day, proteinuria decreased to 2.45 g/day, and skin lesions almost completely resolved. CONCLUSION: About 10 cases of IgA nephropathy associated with psoriasis are referred to in the literature. We report an-other interesting case of IgA nephropathy in a psoriatic patient, as a contribution to the discussion regarding the hypothetical conception of 'psoriatic nephropathy'. We recommend routine urinalysis, careful examination of kidney function and a wider application of renal biopsy in psoriatic patients.     

Renal manifestations of a mutation in the uromodulin (Tamm Horsfall protein) gene

Background:Uromodulin (Tamm Horsfall glycoprotein) is the most abundant protein found in normal human urine. Its function has yet to be determined. Identifying mutations in the uromodulin gene may be helpful in understanding the function of uromodulin. There has been 1 report of 4 families suffering from mutations in the uromodulin gene, resulting in the autosomal dominant transmission of hypouricosuric hyperuricemia and chronic renal failure. This case report describes another family with similar clinical manifestations.Methods:A family was identified with clinical characteristics of hypouricosuric hyperuricemia and renal failure occurring in a mother and daughter. Clinical characteristics were identified, and laboratory studies were obtained in the proband and the proband's daughter. A genetic analysis was performed to evaluate for mutations in the uromodulin gene.Results:The proband suffered from hyperuricemia at an early age and progressive renal failure with end-stage renal disease developing at age 49 years. The proband's daughter suffered from hyperuricemia, a reduced fractional excretion of uric acid, and mild renal insufficiency. A g.2105G > A mutation in exon 4 of the uromodulin gene resulting in a substitution of tyrosine for cysteine was identified in both the proband and the proband's daughter. The clinical characteristics were similar to those of other patients suffering from uromodulin mutations and to those of patients suffering from medullary cystic kidney disease type 2 and familial juvenile hyperuricemic nephropathy.Conclusion:Uromodulin associated kidney disease results in hyperuricemia and renal failure. The specific uromodulin mutation found in this family is consistent with the hypothesis that mutations disrupt highly conserved cysteine residues in the uromodulin protein. Potential mechanisms for these pathologic changes are discussed. The authors would appreciate referral of other families for screening for mutations.