Chronic Tubulointerstitial Nephritis Research Articles

LEFT VENTRICULAR HYPERTROPHY

Cardiovascular system diseases are playing the outstanding role in the cause ofmorbidity and mortality in dialysis patients. Left ventricular hypertrophy is one of the universalstructural abnormalities in patients on regular dialysis. Objective: The target of the study wasto search out the frequency of left ventricular hypertrophy in end stage renal disease patientson maintenance hemodialysis. Study design: Single center case-series study. Setting:Department of Nephro-Urology, Liaquat University of Medical & Health Sciences Jamshoro.Period: Begin from 1st March, 2013 to 30th August 2013. Results: Total numbers of patientswere seventy three. Thirty three patients were male and 40 were female. Mean age of thepatients was 44.19 years. High blood pressure was the most typical cause of nephropathy thatis as certain in twenty 9(39.7%) cases pursue by Diabetes and Chronic Glomerulonephritis intwenty (27.4%) in each, renal stone in four (5.5%), unresolved acute renal failure four(5.5%)and Chronic Tubulointerstitial nephritis in two(2.7%) patients. Left ventricular hypertrophy wasascertained in nineteen (26%) patients. Conclusion: Our study concedes the high frequency ofleft ventricular hypertrophy in dialysis patients.

English

4 ORIGINAL PROF-2949 ABSTRACT… Cardiovascular system diseases are playing the outstanding role in the cause of morbidity and mortality in dialysis patients. Left ventricular hypertrophy is one of the universal structural abnormalities in patients on regular dialysis. Objective: The target of the study was to search out the frequency of left ventricular hypertrophy in end stage renal disease patients on maintenance hemodialysis. Study design: Single center case-series study. Setting: Department of Nephro-Urology, Liaquat University of Medical & Health Sciences Jamshoro. Period: Begin from 1 st March, 2013 to 30 th August 2013. Results: Total numbers of patients were seventy three. Thirty three patients were male and 40 were female. Mean age of the patients was 44.19 years. High blood pressure was the most typical cause of nephropathy that is as certain in twenty 9(39.7%) cases pursue by Diabetes and Chronic Glomerulonephritis in twenty (27.4%) in each, renal stone in four (5.5%), unresolved acute renal failure four(5.5%) and Chronic Tubulointerstitial nephritis in two(2.7%) patients. Left ventricular hypertrophy was ascertained in nineteen (26%) patients. Conclusion: Our study concedes the high frequency of left ventricular hypertrophy in dialysis patients.

Identification and Investigation of Mucin 1‐Mediated Kidney Disease

Establishing a causal link between genomic variation and pathology is the foundation of the successful application of genomics to clinical medicine. Whole genome sequencing (WGS) increases the resolution with which we can investigate the genome, but this increased resolution leads to an increase in the number of potentially damaging or disease causing variants identified. Consequently, WGS in the analysis of disease requires both bioinformatics approaches for efficient prioritization of variants as well as experimental evidence that demonstrates that the variant alters the function of the protein which directly contributes to the development of the disease phenotype(s). We have identified a family with an autosomal dominant chronic tubulointerstitial nephritis that presents insidiously between 20 and 60 years of age, leads to end stage renal disease, and subsequently requires dialysis and transplantation. By utilizing a WGS approach in affected members of this family, literature queries, and targeted gene analyses, we were able to identify a single base insertion in mucin 1 (MUC1) that segregated with the disease in this family, was absent in the general population, and was bioinformatically interesting. We are utilizing a mutant Muc1 rat model in an effort to confirm that MUC1‐dysfunction is causative in this phenotype, to more completely characterize this disease process, and to investigate potential treatment strategies with the hope that subsequent findings can, at least in part, be directly applied to patient care.Funding was provided by the NIH (award 5T32HL007852‐17) and an extramural donation.

Atazanavir nephrotoxicity.

Atazanavir is commonly used as one of the key drugs in combination antiretroviral therapy for human immunodeficiency virus (HIV). However, atazanavir has the potential to yield its crystalline precipitation in urine and renal interstitial tissues, leading to crystalluria, urolithiasis, acute kidney injury (AKI) or chronic kidney disease (CKD). In epidemiological studies, atazanavir/ritonavir alone or in combination with tenofovir has been associated with increased risk of progression to CKD. However, renal biopsies were not provided in these studies. Case reports showing an association between atazanavir use and tubulointerstitial nephritis among HIV-infected individuals provide clues as to the potential causes of atazanavir nephrotoxicity. We now review atazanavir-related kidney disease including urolithiasis, renal dysfunction and interstitial nephritis and illustrate the review with a further case of atazanavir-associated kidney injury with sequential renal biopsies. There are two forms of atazanavir-associated tubulointerstitial nephritis: acute tubulointerstitial nephritis that may develop AKI rapidly (in weeks) after initiation of atazanavir, and chronic tubulointerstitial nephritis that may develop progressive CKD slowly (in years) with granuloma and intrarenal precipitation of atazanavir crystals as well as crystalluria. Caution should be exercised when prescribing atazanavir to patients at high risk of CKD, and therapy should be reevaluated if renal function deteriorates, especially associated with crystalluria and hematuria.

Assessment of intravenous adipose-derived allogeneic mesenchymal stem cells for the treatment of feline chronic kidney disease: a randomized, placebo-controlled clinical trial in eight cats.

Feline chronic kidney disease (CKD) is characterized by chronic tubulointerstitial nephritis, and inflammation contributes to the progression of renal fibrosis. Mesenchymal stem cells (MSCs) have demonstrated anti-inflammatory and antifibrotic effects in rodent CKD models. However, few randomized trials evaluating the effectiveness of MSC therapy for diseases in companion animals have been reported. The purpose of this study was to evaluate the effectiveness of allogeneic MSCs for the treatment of feline CKD using a randomized, placebo-controlled trial. MSCs were isolated from the cryopreserved adipose tissues of specific pathogen-free research cats and culture expanded. CKD cats were enrolled in a randomized, placebo-controlled, blinded one-way crossover clinical study. Four CKD cats were randomized to receive 2 × 10(6) MSCs/kg intravenously at 2, 4 and 6 weeks. Four CKD cats were randomized to receive placebo, with two cats crossing over to the MSC treatment group and one cat failing to complete the trial. Complete blood counts, chemistry and urinalysis were performed at weeks 0, 2, 4, 6 and 8. Glomerular filtration rate (GFR) via nuclear scintigraphy and urine protein:creatinine ratio (UPC) were determined at weeks 0 and 8. Six cats received three doses of allogeneic MSC culture expanded from cryopreserved adipose without adverse effects. No significant change in serum creatinine, blood urea nitrogen, potassium, phosphorus, GFR by nuclear scintigraphy, UPC or packed cell volume was seen in cats treated with MSCs. Individual changes in GFR were 12%, 8%, 8%, 2%, -13% and -67% in treated cats compared with 16%, 36% and 0% in placebo-treated cats. While administration of MSC culture expanded from cryopreserved adipose was not associated with adverse effects, significant improvement in renal function was not observed immediately after administration. Long-term follow-up is necessary to determine whether MSC administration affects disease progression in cats with CKD.

Immunolocalisation of alpha-smooth muscle actin and matrix metalloproteinase-9 in kidney of a dog with chronic tubulointerstitial nephritis

Chronic tubulointerstitial nephritis indicates tubular destruction and is evidenced by accumulation of interstitial fibroblasts, deposition of extracellular matrix, and loss of renal tubular epithelial cells. It is the most common form of kidney damage in older dogs. We reportd etection of alpha-smooth muscle actin (alpha-SMA) and matrix metalloproteinase-9 (MMP-9) in the kidney of a dog diagnosed with chronic tubulo-interstitial nephritis using immunohistochemistry. Alpha-SMA was detected in the interstitium, peri-glomerular and peri-tubular fibrotic areas and interstitial myofibroblasts while MMP-9 was detected in the peri-tubular and interstitial fibrotic areas as well as interstitial macrophagesin the kidney.

Tubulointerstitial Nephritis Caused by Peritubular Capillaritis Accompanied by Cryoglobulinemia

A 73-year-old man with fever, renal insufficiency, and purpura was referred to our hospital to be evaluated for renal insufficiency. Renal biopsy revealed acute and chronic tubulointerstitial nephritis with no laboratory findings of sarcoidosis or connective tissue disease. Low C4 levels and elevation of rheumatoid factors suggested cryoglobulinemia, which was confirmed with quantitative analysis. CD34 staining of kidney tissue revealed peritubular capillaritis. Antineutrophil cytoplasmic antibodies were negative. The etiology of peritubular capillaritis was not clear in our patient; however, it might be associated with cryoglobulinemia because we cannot find any other diseases that could have induced the peritubular capillaritis.

Granulomatous Interstitial Nephritis as the Presenting Manifestation of Crohn’s Disease: A Case Report and Review of Literature

Introduction: Extraintestinal manifestations are reported in 6-47% of patients with IBD and may be diagnosed before, concurrently. or after the diagnosis of IBD. We hereby report an unusual presentation of granulomatous interstitial nephritis preceding the GI manifestations of Crohn’s disease. Case Report: A 17-year-old male with history of obesity and attention deficit hyperactivity disorder on dextroamphetamine presented with new onset of acute kidney injury with creatinine (Cr) level of 4.5 mg/dL. After an extensive negative blood work, renal biopsy was performed, which revealed marked chronic granulomatous tubulointerstitial nephritis. Further work-up for granulomatous disease (chest CT) was negative. Prednisone was initiated for presumed autoimmune process and the serum Cr improved to 2-3 mg/dL. Six months later, the patient developed chronic watery, non-bloody diarrhea. Colonoscopy with terminal ileal biopsy showed active enteritis with granulomatous inflammation consistent with Crohn’s disease. Azathioprine and prednisone were initiated with modest response. Infliximab was then started and his diarrhea resolved. His renal function was restored back to baseline. Unfortunately, he was lost to follow-up and did not receive infliximab. His serum Cr worsened to 9.2 mg/dL. Infliximab was promptly reinstituted and his Cr again improved to his baseline. However, his renal function gradually deteriorated and he eventually needed renal transplant after 5 years from the initial diagnosis. Discussion: To our knowledge, this is the first case of Crohn’s with renal involvement preceding GI symptom. Table 1 summarizes a total of 9 previously reported patients with granulomatous tubulointerstitial nephritis related to Crohn’s disease. All the cases progressed to chronic kidney disease; 2 with end stage renal disease. Eight cases initially presented with GI manifestations; 1 with both diarrhea and renal failure. In conclusion, granulomatous interstitial nephritis associated with Crohn’s disease usually portends a poor prognosis. It is important for clinicians to promptly recognize it as a possible extraintestinal manifestation of Crohn’s disease, as this condition often demands early aggressive treatment with immunomodulators.Table 1

Mononuclear phagocyte accumulation in visceral tissue in HIV encephalitis: evidence for increased monocyte/macrophage trafficking and altered differentiation.

The invasion of circulating monocytes/macrophages (MΦ)s from the peripheral blood into the central nervous system (CNS) appears to play an important role in the pathogenesis of HIV dementia (HIV-D), the most severe form of HIV-associated neurocognitive disorders (HAND), often confirmed histologically as HIV encephalitis (HIVE). In order to determine if trafficking of monocytes/MΦs is exclusive to the CNS or if it also occurs in organs outside of the brain, we have focused our investigation on visceral tissues of patients with HIVE. Liver, lymph node, spleen, and kidney autopsy tissues from the same HIVE cases investigated in earlier studies were examined by immunohistochemistry for the presence of CD14, CD16, CD68, Ki-67, and HIV-1 p24 expression. Here, we report a statistically significant increase in accumulation of MΦs in kidney, spleen, and lymph node tissues in specimens from patients with HIVE. In liver, we did not observe a significant increase in parenchymal macrophage accumulation, although perivascular macrophage accumulation was consistently observed with nodular lesions in 4 of 5 HIVE cases. We also observed an absence of CD14 expression on splenic MΦs in HIVE cases, which may implicate the spleen as a potential source of increased plasma soluble CD14 in HIV infection. HIV-1 p24 expression was observed in liver, lymph node and spleen but not kidney. Interestingly, renal pathology suggestive of chronic tubulointerstitial nephritis (possibly due to chronic pyelonephritis), including tubulointerstitial scarring, chronic interstitial inflammation and focal global glomerulosclerosis, without evidence of HIV-associated nephropathy (HIVAN), was seen in four of eight HIVE cases. Focal segmental and global glomerulosclerosis with tubular dilatation and prominent interstitial inflammation, consistent with HIVAN, was observed in two of the eight cases. Abundant cells expressing monocyte/MΦ cell surface markers, CD14 and CD68, were also CD16(+) and found surrounding dilated tubules and adjacent to areas of glomerulosclerosis. The finding of co-morbid HIVE and renal pathology characterized by prominent interstitial inflammation may suggest a common mechanism involving the invasion of activated monocytes/MΦs from circulation. Monocyte/MΦ invasion of visceral tissues may play an important role in the immune dysfunction as well as comorbidity in AIDS and may, therefore, provide a high value target for the design of therapeutic strategies.

A case of Non-compaction of Left Ventricle Coexistent with Juvenile Nephronophthisis. Is this Another Presentation of Ciliopathy?

Nephronophthisis is a chronic tubulo-interstitial nephritis which can progress to end-stage renal disease. Juvenile nephronophthisis is the most common type of nephronophthisis, which accounts for 5-10% of the cases of pediatric end stage renal diseases. Left ventricular non-compaction (LVNC), a rare form of cardiomyopathy, is the result of intrauterine arrest of compaction of the endomyocardial morphogenesis. Clinical manifestations of LVNC range from asymptomatic child to a progressive deterioration in the cardiac function, congestive heart failure, arrhythmias, systemic thromboembolism and sudden cardiac death. This report presents a case of juvenile nephronophthisis with LVNC. A 15-year-old boy was referred to our nephrology outpatient clinic with a 6-month history of non-specific complaints such as lethargy, anorexia, polydipsia, polyuria, and pallor. Abdominal sonography showed a generalized increase in the parenchymal echo of kidneys. Renal biopsy was performed for him which showed nephronophthisis. Echocardiography was done and revealed LVNC. He was discharged with training for careful follow-up. Our reported case had nephronophthisis and LVNC. To the best of our knowledge, there is no report of this combination in the literature. This suggests that LVNC may be another presentation of cilia involvement. The clinical coexistence of LVNC and nephronophthisis could guide us to better localize and discover the underlying genetic mutations and the role of ciliopathies in various human diseases; Therefore, further research with a special focus on potential common derangement of cilia and protein products in these diseases is recommended. Keywords: Juvenile nephronophthisis; Isolated Noncompaction of the Ventricular Myocardium; Ciliary Motility Disorders

Renal allograft pyelonephritis and fungemia due to Candida krusei.

A 61-year-old female was admitted for fever and acute renal failure 6 weeks after receiving a kidney transplant. Her past medical history was notable for CKD stage 5 due to chronic idiopathic tubulointerstitial nephritis. This was diagnosed in 1998 when she presented with an elevated creatinine, sterile pyuria and proteinuria, and underwent native kidney biopsy confirming the diagnosis. She was initially treated with corticosteroids and remained on 5 mg daily of prednisone up until the date of her pre-emptive living related kidney transplant. She had a low-risk immunologic profile with a negative T and B cell crossmatch prior to transplant. Per our center protocol, she received basiliximab for induction, and was maintained on tacrolimus, mycophenolate and prednisone for immunosuppression, with trough FK506 levels ranging between 8 and 12 ng/mL. She was discharged on a standard antimicrobial prophylaxis regimen of trimethoprimsulfamethoxazole and valacyclovir and had a nadir serum creatinine of 1.2 mg/dL following her transplant. Her post-operative course was uneventful until her presentation to the hospital, when she complained of fevers, nausea and vomiting. Her physical examination and

Chronic tubulo-interstitial nephritis in common variable immunodeficiency: A rare association

Common variable immunodeficiency (CVID) is characterized by reduced serum immunoglobulin levels and repeated serious bacterial infections involving different organ systems. Chronic kidney disease (CKD) is an uncommon association with CVID. Chronic tubulo-interstitial nephritis in a case of CVID that progressed to CKD is distinctly rare.

Chronic kidney disease of unknown etiology in agricultural communities.

In recent years, Central America, Egypt, India and Sri Lanka have reported a high prevalence of chronic kidney disease of unknown etiology in agricultural communities, predominantly among male farmworkers. This essay examines the disease's case definitions, epidemiology (disease burden, demographics, associated risk factors) and causal hypotheses, by reviewing published findings from El Salvador, Nicaragua, Costa Rica, Sri Lanka, Egypt and India. The range of confirmed chronic kidney disease prevalence was 17.9%-21.1%. Prevalence of reduced glomerular filtration (<60 mL/min/1.73 m2 body surface area) based on a single serum creatinine measurement was 0%-67% men and 0%-57% women. Prevalence was generally higher in male farmworkers aged 20-50 years, and varied by community economic activity and altitude. Cause was unknown in 57.4%-66.7% of patients. The dominant histopathological diagnosis was chronic tubulointerstitial nephritis. Associations were reported with agricultural work, agrochemical exposure, dehydration, hypertension, homemade alcohol use and family history of chronic kidney disease. There is no strong evidence for a single cause, and multiple environmental, occupational and social factors are probably involved. Further etiological research is needed, plus interventions to reduce preventable risk factors.

P-022 Renal Disease Associated with Crohnʼs Disease, Mesalamine and Infliximab

15 year old female with 5 year history of Crohn's Disease (CD) ileocolitis developed increasing serum creatinine concentrations over a 6 month period. She was steroid and mesalamine (50 mg/kg/day) dependant for 1 year after diagnosis of CD prompting addition of Remicade therapy at 5 mg/kg/dose every 8 weeks. Relapsing disease continued and dose of Remiade was increased to 10 mg/kg every 8 weeks 2 years post diagnosis. Interval of administration was gradually shortened to every 4 weeks by 3 years post diagnosis. Symptoms stabilized on this regimen. However, ESR increased to 50–60 for the 6 months period (4.5–5 yrs post CD diagnosis) prior to renal disease recognition. No urinary tract symptoms noted, Creatinine 1.22 mg/dL, Creatinine Clearance 53 mL/min/1.73 m2, ANA 1:320. No other serum immune abnormalities detected. Renal Biopsy revealed active chronic tubulointerstitial nephritis, mesangioproliferative immune complex glomerulopathy with focal global glomerulosclerosis. Discontinuation of Remicade and mesalamine led to rapid decrease in ESR to 11, and gradual decrease over the next year in serum creatinine to range of 0.99–1.07 mg/dL and rise in creatinine clearance to 68 mL/min/1.73 m2 which although improved continues to be compatible with quiescent chronic renal disease stage 2. Biweekly Humira 40 mg/dose was initiated 3 months after discontinuing pentasa and Remicade. Differential diagnoses of renal disease incriminate: CD, mesalamine, infliximab or autoimmune disease and or combination of these processes. Clinical History recounted above. Clinical History recounted above. Included in abstract.

Patient With IgG Heavy Chain Disease Presents With Parathyroid Hormone-Related Peptide Mediated Hypercalcemia

BackgroundMultiple myeloma is associated with excessive tumor-induced, osteoclast-mediated bone destruction. Hypercalcemia remains the most frequent metabolic complication of myeloma in patients, and excessive osteolysis plays a major contributory role in its pathogenesis. Hypercalcemia caused by increased blood levels of PTHrP have been found in patients with solid tumors and are uncommon in patients with hematologic malignancies including multiple myeloma. Here we present a unique case of a rare variant of multiple myeloma, IgG heavy chain disease, presenting with PTHrP associated hypercalcemia. MethodsA retrospective chart review of one patient from 2011-2013 including clinical history, laboratory data, imaging, and pathology was performed. ResultsA 60 year old female with past medical history of stage IIA Hodgkin's lymphoma diagnosed in 1992, treated with total nodal radiation with recurrence in 1997 treated with 6 cycles of ABVD achieving complete remission. The patient was found to have hypercalcemia (11.0 mg/dL) and renal failure (1.29 mg/dL) in March 2011. Hypercalcemia workup revealed suppressed PTH (<3 pg/ml), elevated ionized calcium (6.1 mg/dL) elevated parathyroid related peptide (38pg/ml), normal vitamin D and ACE levels. Serum protein electrophoresis (SPEP) showed M-spike of 0.9 g/dL. Immunofixation electrophoresis (IFE) demonstrated an IgG monoclonal immunoglobulin without a corresponding light chain (figure 1). Free serum kappa and lamda light chains were within normal limits. Serum IgG was elevated (4678 mg/dL), normal IgA (127 mg/dL) and low IgM (39mg/dL). Also, Beta-2 microglobulin was elevated (14.3 mg/L). The patient was seen by hematology for monoclonal gammopathy and hypercalcemia and a solid tumor work up was recommended given that the most common the mechanism of hypercalcemia for multiple myeloma is osteoclast-driven and not PTHrP related. CT chest/abdomen/pelvis, bone scan, bone survey, mammography, pelvis ultrasound were negative. Bone marrow biopsy was performed November 2011 showing 10% plasma cells (PC) by CD138, non clonal by kappa/lambda. Patient was placed on zolendonic acid for hypercalcemia and her renal function and hypercalcemia continued to worsen over a period of months. A kidney biopsy was performed in April, 2012 and revealed acute and chronic tubulointerstitial nephritis with secondary glomerulosclerosis and mild interstitial fibrosis and tubular atrophy suggestive of sarcoidosis and the patient was placed on a course of prednisone with transient improvement in calcium and renal function. The patient presented in emergency room in April 2013 with altered mental status. She was found to have hypercalcemia (12.0 mg/dL), renal failure (1.55 mg/dL),). SPEP revealed M-spike 0.64 g/dl. IFE displayed a broad band of IgG heavy chain, without associated light chains and severe depression of the non-monoclonal IgG. Serum immunoglobulins demonstrated elevated IgG (2110 mg/dL), normal IgA (46 mg/dL) and decreased IgM (<21 mg/dL). Bone marrow biopsy showed 5% PCs (figure 2), non clonal by kappa/lambda- but exclusive for IgG by IHC, without any staining for IgA or IgM (figure 3). Cytogenetics were normal. Based on the constellation of findings and similarity to prior workup the patient was diagnosed with IgG heavy chain disease and therapy with cytoxan, dexamethasone, bortezomib was initiated. Calcium levels improved and she has recovered clinically; she is currently completing her second cycle of therapy. We plan to follow PTHrP levels along with routine paraprotein assessments. [Display omitted] [Display omitted] [Display omitted] ConclusionsPTHrP mediated hypercalcemia is rare in patients with multiple myeloma and the main mechanism of hypercalcemia in multiple myeloma is osteoclast-mediated bone destruction. This is the first reported case of IgG heavy chain disease presenting with PTHrP related hypercalcemia. Another critical point related to this case, is that kappa/lambda staining, the primary mechanism of determining plasma cell clonality, is not useful in exclusively heavy chain disease- and can, in such cases, obscure the diagnosis of this plasma cell malignancy. Disclosures:No relevant conflicts of interest to declare.

Nephrotoxizität und Langzeitbehandlung mit Lithium

With particular focus on clinical, pathophysiologic and epidemiologic aspects this systematic review article presents the available data on nephrotoxic effects of a long-term treatment with lithium. Lithium may lead to tubular dysfunction (LITD = nephrogenic diabetes insipidus, hyperchloremic metabolic acidosis, increased natriuresis) and lithium-induced nephropathy (LIN) with reduced glomerular filtration rate (GFR). The histopathologic finding of LIN is chronic tubulo-interstitial nephritis. LITD frequently presents with polydipsia/-uria and reduced urine osmolality, while LIN features a wide clinical spectrum ranging from clinically asymptomatic presentations with reduced GFR to end-stage renal failure. LIN seems to feature slow progression and is significantly less frequent than LITD. Regular monitoring of renal function is indispensable for patients treated with lithium. Patients with reduced GFR under treatment with lithium should always be presented to a nephrologist. Currently, there are no guidelines for the handling of patients with LIN and ongoing treatment with lithium. Thus, regarding continuation of lithium-treatment an individual benefit/risk assessment is necessary.

Evaluation of Urinary Biomarkers for the Prognosis of Drug-associated Chronic Tubulointerstitial Nephritis

BackgroundThe efficacy of urinary biomarkers for predicting adverse clinical outcomes in drug-induced chronic tubulointerstitial nephritis (D-CTIN) has not been well described. MethodsA total of 54 patients with D-CTIN were prospectively followed-up in this study. The urinary excretion of α1-microglobulin and transforming growth factor-β1 and the activity of urinary N-acetyl-β-d-glucosaminidase (NAG) and matrix metalloproteinases (MMPs) 2 and 9 at baseline were measured. Changes in the estimated glomerular filtration rate (GFR) over a period of 11 to 54months (median, 38months) of follow-up were recorded. The efficacy of urinary biomarkers for differentiating patients with various outcomes was tested. Ten patients with IgA nephropathy and 20 healthy volunteers were enrolled as controls. ResultsThe areas under the receiver operating characteristic curve for urinary NAG, MMP-9, MMP-2 and α1-microglobulin for predicting deterioration of the estimated GFR were 0.879, 0.867, 0.735 and 0.709, respectively (P<0.05 for all). Partial regression coefficient results demonstrated that urinary NAG (P=0.02), MMP-2 (P=0.046) and MMP-9 (P=0.041) were inversely correlated with the rate of GFR decline. ConclusionsUrinary NAG, MMP-2 and MMP-9 may be considered as possible candidates for forecasting the progression rate of D-CTIN.

CLINICAL CASE OF NEPHROPATHY CAUSED BY THE RECEPTION OF THE AGRIMONIA EUPATORIA

The article describes the clinical observation of toxic chronic tubulointerstitial nephritis due to prolonged use of herbal drug Agrimonia Eupatoria. The toxic effects of A.Eupatoria more associated not with specific toxicants, and the presence of a large number of coumarin glycosides and its metabolites. Earlier in the literature descriptions of nephrotoxicity A.Eupatoria ordinary does not. In conducting the study of the morphological characteristics were described tubulopathy, characterized by a pronounced hydropic dystrophy tubular epithelium up to vacuolization, weak and small focal diffuse interstitial fibrosis. Special attention in the clinical picture itself drawn the progressive increase in proteinuria, hypertension due to lower filtration function of the kidney and renal tubular dysfunction. Key words: toxic nephropathy, Agrimony ordinary, Agrimonia Eupatoria, coumarin, phytotoxins

Tubulointerstitial nephritis and cancer chemotherapy: update on a neglected clinical entity

Cancer patients are particularly vulnerable to drug-induced kidney injury during their chemotherapy. Whereas the direct nephrotoxic effects of these drugs are well recognized, that of tubulointerstitial nephritis (TIN) is less well known, underdiagnosed and often reported only as a functional tubular disorder. The diagnosis of acute TIN is important because of its insidious onset with tubular dysfunction, its potential reversibility if detected early and the possibility of its response to steroid treatment. We performed a literature review (44 cases) and reviewed our institutional biopsy register (12 cases) of patients on cancer chemotherapy with documented TIN. Biopsies were considered in three groups: acute TIN, chronic TIN and acute on chronic TIN. The outcomes that were evaluated were recovery of kidney function, development of chronic kidney disease and onset of end-stage renal disease (ESRD). Ifosfamide, BCG, tyrosine kinase inhibitors and premetrexed were the most commonly implicated drugs. Ifosfamide and premetrexed were associated with worst outcomes. Recovery of kidney function was better in acute TIN (ATIN) (29%) with fewer progressing to ESRD (12.9%) than with chronic TIN (7.6% recovery, 15.3% ESRD). Steroid use appeared to favorably alter outcomes in ATIN (40% recovery) compared with conservative treatment (18.75% recovery). Peak serum creatinine, age, gender and type of malignancy did not influence outcomes. As a potentially reversible lesion that can respond to withdrawal of the suspected agent, and in some cases to a short course of steroid therapy, it is important to consider ATIN in the differential diagnosis of all cases of acute kidney injury in cancer patients on chemotherapy.

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.