Minimal Proteinuria Research Articles

Global dimensions of chronic kidney disease of unknown etiology (CKDu): a modern era environmental and/or occupational nephropathy?

Diabetes and hypertension are the predominant risk factors for chronic kidney disease (CKD) globally. Infectious diseases resulting in glomerulonephritis are also important in low-income countries [1, 2]. However, in the past two decades, a severe form of CKD has been reported in individuals without these risk factors. CKD of unknown etiology (CKDu) affects adults in their third to fifth decade and is often fatal due to disease progression and lack of dialysis or transplant options in the involved geographic areas. CKDu has been reported in Sri Lanka, several Central American countries, the state of Andhra Prakesh in India and the El-Minia Governorate in Egypt. The results of a joint Sri Lankan and World Health Organization (WHO) funded study focused on identification of risk factors for CKDu in Sri Lanka was recently published in this journal [3]. Subsequent correspondence, highlighting the range of risk factors under consideration, illustrates the complexity of this endeavor [4, 5]. Despite the comprehensive exposure assessment of Jayatilake and colleagues, and prior work in Sri Lanka and Central America, the name CKDu remains appropriate because the etiology is still unknown. Consideration of the similarities and differences in CKDu in the four regions in which it has been reported to date may be useful in the effort to determine causality and develop prevention strategies. Therefore, the table included in this manuscript compares and contrasts the currently available information on CKDu. Importantly, there is no global definition for this disease. Furthermore, levels of proteinuria and albuminuria tend to be low in Central America [6], however the case definition in Sri Lanka was based on persistent albuminuria defined as an albumin–creatinine ratio ≥30 mg/g in an initial urine sample and at a repeat visit [3]. Therefore, the data below utilize the criteria for CKDu of the authors in each publication. Given the limited information about CKDu in the affected areas, particularly in Andhra Pradesh and Egypt, it is not clear that the etiology of the kidney disease is the same in all locations. Different risk factors have been emphasized; altitude and occupational risks factors have received more attention in Central America whereas extensive chemical monitoring was recently reported in Sri Lanka [3]. Moreover, case ascertainment in Sri Lanka has relied much more on proteinuria whereas, in Central America, both urine dipstick and serum creatinine have been used in case identification. Data on magnitude remains extremely limited. However, as shown in the table, a number of similarities are present. The disease is characterized by substantial morbidity and mortality, resulting in death in young and middle aged adult patients, and absence of known causes of CKD such as diabetes and hypertension (or at least severe hypertension as the blood pressure inclusion criteria in the Sri Lankan study was less than 160/100 [3]). Men seem to be more at risk, at least for the most severe disease, and very poor rural areas are most affected with agricultural work being the dominant occupation. Poverty with lack of access to health care makes determining clinical characteristics of CKDu difficult. Even determining when the outbreaks actually started is challenging; CKDu may have been present for a significant period of time but not identified due to absence of diagnostic testing. Furthermore, many of these areas have recently seen a transition from earlier deaths from infectious diseases to deaths from non-communicable diseases in the setting of longer life spans which provides time for CKD to develop and progress. Few studies have reported on urinary findings in CKDu patients. However, in described clinical presentations, typical patients present with a bland urine sediment and minimal proteinuria (Table 1). Recent studies have measured levels of kidney early biological effect markers in urine [7, 8]. The results are consistent with proximal tubular damage and may be useful in future work to identify CKDu at earlier stages and to determine etiology. Information on renal pathology has also been very limited to date. The two studies reporting biopsy results from patients with CKDu in El Salvador both found interstitial fibrosis with varying degrees of tubular atrophy, essentially proportional to stage of CKD. Both series also reported non-specific glomerular damage. Whether this is secondary to a primary tubulointerstitial process or represents a primary glomerular disease or could be due to recurrent ischemia of the glomerular capillaries, such as from dehydration or concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), remains unknown. Wijkstrom et al. concluded that the biopsy results from Central America did not resemble any other common kidney disease [9]. Importantly, these findings are similar to those described in CKDu from Sri Lanka [10–12]. It would be very useful to have additional information on pathology, including at earlier stages of the disease process. Table 1 Comparisons of Key Characteristics Among Areas with Reported CKDu

Long-term outcome of childhood IgA nephropathy with minimal proteinuria.

Some patients with childhood immunoglobulin A nephropathy (IgAN) progress to end-stage renal disease within 20 years, while others achieve spontaneous remission even without medication. Prognosis of IgAN with minimal proteinuria (MP-IgAN, <0.5 g/day/1.73 m(2)) at diagnosis seems to be generally good. However, the long-term outcome for patients with childhood MP-IgAN has not yet been determined. We retrospectively analyzed 385 children newly diagnosed with biopsy-proven IgAN between June 1976 and July 2009 whose renal biopsy specimens could be evaluated by the Oxford classification criteria. Of these 385 children with IgAN, 106 (27.5%) were diagnosed with MP-IgAN. We compared clinical and pathological findings between the 106 patients with MP-IgAN and the remaining 279 patients to elucidate the characteristics of MP-IgAN in children. Patients with MP-IgAN were identified through a school screening program (73.6%) or upon presentation with gross hematuria (26.4%). Patients with MP-IgAN had significantly milder pathological symptoms than those with IgAN. The most frequently used therapeutic regimes were angiotensin converting enzyme inhibitors (30.2%) and no therapy (36.8%). None of the patients with MP-IgAN reached stage III chronic kidney disease within 15 years after onset. Four patients with MP-IgAN (3.8 %) received immunosuppressive therapy during the course of the disease. Our results indicate that the outcome of patients with a diagnosis of childhood MP-IgAN is good, but that careful long-term observation is required.

G486(P) First successful paediatric hla incompatible renal transplantation in the united kingdom

Aims To report the successful outcome of HLA incompatible renal transplantation using plasmapheresis and intravenous immunoglobulin (on day –1) and quadruple immunosuppression with anti–thymocyte globulin (1.5 mg/kg day 1–4), corticosteroids, mycophenolate mofetil and tacrolimus (from day -7). Methods Six month follow–up data of 14–year old young lady who underwent living related ABO compatible (O into B) and HLA incompatible renal transplantation from her father (mismatch 0,1,1) for end-stage kidney disease on peritoneal dialysis secondary to congenital abnormalities of the kidney and urinary tract with bilateral renal dysplasia, recurrent urinary tract infections, bilateral vesico–ureteric reflux after left ureteric reimplantation and right nephrectomy. She had a previous failed renal transplantation at 11 years of age with primary non–function due to intra-renal thrombosis (no acute rejection or TMA) requiring transplant nephrectomy the day after transplantation with 95–100% calculated reaction frequency due to HLA antibodies, specific for mismatches HLA B7 and DQ8 against father with B cell positive (T cell negative) crossmatch which was reduced to negative with test plasma exchange and reduction in MFI from 16,200 to 6,480 and from 11,602 to 4,625 on the day prior to transplantation. She had no offers from the deceased donor waiting list or via the paired exchange scheme (NLDKSS). Results Successful renal transplant without further antibody removal or surgical complications with six month follow–up data with stable renal allograft function with eGFR of 60–96 mls/min/1.73m 2 , 12-hour trough tacrolimus and mycophenolate levels of 7.3 mcg/l and 3.0 mg/l respectively, controlled hypertension on one anti-hypertensive agent with minimal albuminuria (17.4 mg/mmol). Her DSA reduced to 4,691on day 2 but increased further to 23,772 to 38,630 during weeks 1 to 3 and have stabilised out at 21,246 to 22,168 (B7 and DQ8 of 8,407 and 13,761 respectively). She has had three percutaneous renal transplant biopsies at weeks 2, 7 and 11 without acute rejection or IFTA but moderate concentric fibrous intimal thickening of large muscular arteries and C4d deposition in peritubular capillaries and glomeruli. Conclusions This is the first paediatric HLA incompatible renal transplantation in UK and highlights that clinicians must consider this option in ESKD patients whose living donors have been excluded due to HLA incompatibility.

Clinicopathological Features and Outcomes of IgA Nephropathy with Hematuria and/or Minimal Proteinuria

Background/Aims: Information regarding the clinical and histological prognostic factors of IgA nephropathy (IgAN) is mostly derived from patients in whom diagnostic renal biopsies were performed because their proteinuria levels were higher than 1-2 g/d. The clinicopathological features and outcomes of IgAN patients presenting with normal blood pressure, normal renal function, hematuria and minimal or no proteinuria are not well described. We therefore conducted a study of the clinicopathological features and outcomes in IgAN patients with these characteristics. Methods: The clinical, laboratory, and pathological manifestations and long-term outcomes of all IgAN patients with the above-mentioned characteristics were collected. The relationships between renal pathology, injury, long-term outcomes and clinical factors were studied, and the risk factors of IgAN were analyzed using multivariate logistic regression. Results: Of all of the renal biopsy cases, IgAN with the above features accounted for 8.9%. Among these patients, 67.2% (253) showed simultaneous hematuria and proteinuria, 23.1% (87) showed only hematuria, and 9.7% (36) showed only proteinuria. Additionally, 33.8% (127) patients showed macroscopic hematuria and 65.1% (245) had a prodromal infection. Regarding renal pathological changes, 45.5% (171) of the patients were unexpectedly classified as Grade II to IV (Hass classification). Proteinuria at the time of renal biopsy was an independent predictor of more severe renal pathological injury. After a median follow-up of 75 months, 61 (16.2%) patients experienced adverse events. Among these patients, 28 (7.45%) exhibited hypertension, 22 (5.85%) presented proteinuria levels >1 g/24 h, and 11 (2.9%) developed impaired renal function. Conclusions: Severe renal histological injury may be observed in some IgAN patients with benign clinical characteristics. Proteinuria is an independent predictor of severe renal pathological injury in IgAN patients with mild proteinuria. More severe pathological injury (> Grade II, Hass classification) are predictors of poor prognosis.

Clinicopathologic analysis of isolated hematuria in child/adolescent and adult patients.

To our knowledge, no in-depth clinicopathologic study of isolated hematuria (IH) is currently available. To address this gap, we analyzed the clinicopathologic features of IH as it manifests in child/adolescent and adult patients. The clinical data and pathological types of 543 IH patients who underwent renal pathological examinations from January 2005 to June 2010 were retrospectively analyzed. Clinical manifestations differed among the age groups: children/adolescents exhibited the highest percentage of mesangial proliferative glomerulonephritis (41.78%), whereas adults showed the highest percentage of immunoglobulin A nephropathy (IgAN) (52.39%). In addition, the percentage of IH patients who were classified according to clinical pathology differed from that of patients who were classified according to renal pathological type. Patients with IgAN who were found to have minimal proteinuria had more severe IH. For IH patients, especially those with a small amount of proteinuria, renal biopsy should be performed as early as possible in order to develop a long-term treatment plan and prognosis evaluation.

Antibody-mediated vascular rejection of kidney allograft: characterization of different kidney allograft rejection phenotypes via histology, C4d deposition and donor-specific antibodies

Antibody-mediated vascular rejection of kidney allograft: characterization of different kidney allograft rejection phenotypes via histology, C4d deposition and donor-specific antibodies

Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways.

MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously and evaluated the therapeutic potential of these anti-miR-21 oligonucleotides in chronic kidney disease. In a murine model of Alport nephropathy, miR-21 silencing did not produce any adverse effects and resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, compared with vehicle-treated mice. miR-21 silencing dramatically improved survival of Alport mice and reduced histological end points, including glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti-miR-21 enhanced PPARα/retinoid X receptor (PPARα/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondrial ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-β-induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPARα/RXR activity and improved mitochondrial function. Together, these results demonstrate that inhibition of miR-21 represents a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy.

Multiple kidney cysts in thin basement membrane disease with proteinuria and kidney function impairment.

BackgroundSome patients with thin basement membrane disease (TBMD) develop proteinuria, hypertension and different degrees of CKD, besides the persistent microhaematuria characteristic of the disease. Little is known about factors associated with this unfavourable outcome.MethodsWe reviewed clinical, pathological and radiological features of 32 patients with biopsy-proven TBMD. Patients were divided in two groups: those with persistent normal kidney function and negative or minimal proteinuria (n = 16) and those with persistent proteinuria >0.5 g/day (n = 16).ResultsPatients with proteinuria had a worse kidney function at baseline than those with negative proteinuria. Global or segmental glomerulosclerosis, together with interstitial fibrosis, was found in 37% of patients with proteinuria. All proteinuric patients were treated with renin–angiotensin system blockers. At the end of follow-up (198 months in proteinuric patients and 210 months in patients with negative proteinuria) the prevalence of hypertension was 68% in proteinuric patients (12% at baseline), compared with 12 and 6%, respectively, in non-proteinuric patients. A slow decline of renal function was observed in proteinuric patients, although no patient developed end-stage kidney disease. Ultrasound studies showed bilateral kidney cysts in nine patients (56%) with proteinuria. Cysts were bilateral and countless in six patients, and bilateral but with a limited number of cysts in the three remaining patients. No cysts were found in patients with negative proteinuria.ConclusionsSome patients with TBMD develop hypertension, proteinuria and CKD. Multiple bilateral kidney cysts were found in a majority (56%) of these patients. Further studies are needed to investigate the pathogenesis and the influence on long-term outcome of this TBMD-associated multiple kidney cysts.

Does tonsillectomy have a role in the treatment of patients with immunoglobulin A nephropathy?

Immunoglobulin A nephropathy (IgAN) is an immune-complex mediated glomerulonephritis characterized by deposition of polymeric IgA (mainly IgA1) in the mesangium of the kidney [1]. It is the most common form of primary glomerulonephritis worldwide and is prevalent among all ages and racial demographics [2]. Its pathogenesis has been under investigation for the last several decades and one of the key players is the aberrant glycosylation pattern of IgA1. There is now convincing evidence that the hinge region of IgA1 heavy chain has defective glycosylation with a reduction in the galactose and or sialic acid residues [3]. As a result, the N-acetylgalactosamine in the IgA1 hinge region is exposed and recognized by IgG antibodies. This in turn leads to formation of IgG-IgA immune complexes and their deposition in the mesangium and renal injury that subsequently ensues [4–7]. It should be noted that aberrantly glycosylated IgA1 can also be seen in circulation in normal subjects following an immune response triggered by exposure to mucosal antigens such as food, bacteria or viruses. Thus, other factors, including genetic predisposition, are likely to influence the pathogenesis of IgAN [8]. The renal outcomes of IgAN vary significantly between individuals ranging from minimal proteinuria and stable renal function to development of end-stage renal disease (ESRD) in up to 50% of the cases [9]. Markers of poor prognosis include impaired kidney function at presentation, hypertension and persistent proteinuria >1 g/day in adults, and 0.5 g/day in children [10–12]. In addition, the recent Oxford classification has identified MEST (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis) as an independent renal biopsy indicator of poor renal outcome [13]. Treatments aiming to block the angiotensin II system, the use of corticosteroids, either alone or in combination with cytotoxic medications have been used in patients with IgAN with variable success [14–18]. In some patients, renal disease progresses despite treatment and thus a search for additional forms of therapy have been carried out including the use of tonsillectomy. What is the rationale behind performing tonsillectomy in patients with IgA nephropathy? First, recurrent tonsillitis is the most common extrarenal clinical manifestation in IgAN and there is a clear recognition that in some patients episodes of macroscopic hematuria and proteinuria are often associated with tonsillitis (synpharyngitic hematuria) [19, 20]. In fact, studies have shown that episodes of macroscopic hematuria can be reduced following tonsillectomy [21, 22]. Second, tonsils provide the first line of defense against inhaled pathogens. The foreign antigens, particularly bacterial polysaccharides, activate the Toll-like receptors (TLRs) of the cells of innate immunity, which ultimately results in activation of tonsillar B-cells and production of immunoglobulins particularly polymeric IgA1. Third, tonsils from patients with IgAN have an increased number of polymeric IgA1 compared with controls [23]. Forth, the polymeric IgA1 deposited in the kidney are, in part, of tonsillar origin. This was based on the evidence that IgA1 eluted from the mesangium of patients with IgAN specifically bound the nuclear regions of tonsillar cells obtained from the same patient and the binding was completely inhibited by the addition of antihuman IgA sera [24]. Fifth, abnormal IgAsecreting cells which predominantly produce polymeric IgA1 are found in the tonsillar tissue of patients with IgAN in contrast to IgG-secreting cells that predominate in tonsils of patients without IgAN [20, 25–27]. Taken together, it has been postulated that chronic tonsillitis in a susceptible patient may lead to increased production of aberrantly glycosylated IgA1, formation of IgG-IgA immune complexes and their deposition in the glomeruli triggering an inflammatory response [28]. As such, tonsillectomy has been suggested as a possible treatment modality in patients with IgAN. Several retrospective studies have evaluated the efficacy of tonsillectomy in treatment of IgAN with conflicting results as shown in Table 1 [21, 22, 29– 35]. Most of the studies, however, are from an era prior to IN F O C U S

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Efficacy and Safety of Abatacept in Lupus Nephritis: A Twelve‐Month, Randomized, Double‐Blind Study

To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids. This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period. There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an ∼20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment. Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.

FRI0287 Proliferative nephritis forms in sle patients with minimal proteinuria and high sledai

BackgroundACR and EULAR guidelines recommend performing renal biopsy in every SLE patient with proteinuria above 0,5g/24h. Some patients show an active urine analysis with dysmorphic erythrocytes but proteinuria < 0,5g/24h.ObjectivesTo...

Treatment of Early Immunoglobulin A Nephropathy by Angiotensin-converting Enzyme Inhibitor

BackgroundThe treatment of immunoglobulin A (IgA) nephropathy with normal renal function and minimal proteinuria is unknown. MethodsWe randomly assigned 60 patients with IgA nephropathy, proteinuria <0.5 g/day, normal blood pressure and renal function to ramipril 2.5 mg daily or no treatment. Patients were followed for 5 years for the development of hypertension, proteinuria, or impaired renal function. ResultsThe blood pressure of the treatment group was marginally lower than the control group throughout the study period. At 60 months, the event-free survival was marginally higher for the treatment group as compared with the control group (81.1% vs 70.5%, P=.27). The proteinuria-free survival was similar at 82.9% and 79.3% for the treatment and control groups, respectively (P=.6); hypertension-free survival was 86.4% and 79.3% (P=.2). After 60 months of follow-up, the estimated glomerular filtration rate (GFR) was 108.1±29.0 mL/min/1.73 m2 for the treatment group and 105.7±17.7 mL/min/1.73 m2 for the control group (P=.7), but the difference was not statistically significant. None of the patients developed impaired renal function. The rate of GFR decline was similar between the treatment and control groups (−0.39±2.57 vs −0.59±1.63 mL/min/1.73 m2 per year, respectively, P=.7). In general, the study medication was well tolerated. Two patients needed to stop prematurely because of cough and dizziness. ConclusionFor early IgA nephropathy patients with minimal proteinuria, normal blood pressure, and normal renal function, treatment with 2.5 mg/daily of ramipril for 5 years does not offer any benefit.

Kidney, Pancreas and Islet Transplant Options for Patients with Diabetic Nephropathy

Recent progress in surgery and immunosuppression has expanded the “transplant menu” for patients with diabetic nephropathy which is now including: Kidney Transplantation from a Deceased Donor (DDKT) or a Living Donor (LDKT), Simultaneous Pancreas Kidney (SPK), Pancreas Transplantation Alone (PTA), Pancreas after Kidney (PAK) and Islet transplantation. As pre-emptive transplantation presents a clear survival advantage over dialysis, all diabetic patients with chronic kidney disease (CKD) should be referred for early evaluation by a transplant center. For type 1 diabetes mellitus (T1DM) patients, LDKT and SPK transplantation offer superior and approximately equivalent long-term patient and allograft survival. PAK transplant rates tend to decline due to surgical and immunological complications, but it may still be considered for well selected candidates with preserved kidney allograft function. For type 2 diabetes mellitus (T2DM) patients, not only LDKT, but even DDKT are superior to dialysis. SPK transplantation should be offered only in selected cases with special metabolic characteristics similar to T1DM. PTA should be considered only for selected cases of T1DM with well preserved renal function (eGFR>80 ml/min/1.73 m2 and minimal proteinuria), as it may a cause of rapid deterioration of renal function. Islet transplantation should still be considered as an experimental procedure for T1DM, and has no place in patients with advanced CKD, but it may be applied in already immunosuppressed patients following KT. However, the best transplant option for patients with diabetic nephropathy therapy should always be individualized, taking under consideration the patients’ preferences and expectations, their overall medical condition and the transplant center’s experience with all these procedures.

Double-positive Goodpasture′s syndrome with concomitant active pulmonary tuberculosis

Anti-glomerular basement membrane (anti-GBM) disease usually presents as rapidly progressive glomerulonephritis, and, when accompanied with pulmonary hemorrhage, it is called Goodpasture's syndrome. Anti-neutrophilic cytoplasmic antibodies (ANCA) may co-exist with anti-GBM antibodies. In most of these "double positive" cases, ANCA is specific for myeloperoxidase (p-ANCA). We report a rare case of a critically ill patient c-ANCA-associated double-positive Goodpasture's syndrome with concomitant tuberculosis that was successfully treated with immunosuppression, plasmapheresis and anti-tuberculous therapy (ATT). A 32-year-old gentleman with a 15 pack-year smoking history presented with massive hemoptysis, respiratory failure and oliguria. Laboratory investigation revealed anemia, elevated creatinine and active urinary sediment. Chest X-ray revealed bilateral pulmonary infiltrates. Broad-spectrum antibiotics and intravenous corticosteroids were started. Bronchoscopy showed alveolar hemorrhage and smears from bronchial lavage from both lungs were positive for acid fast bacillus (AFB). Vasculitis work-up revealed high titers of c-ANCA and anti-GBM antibodies. Kidney biopsy revealed crescents in >50% glomeruli on light microscopy. Immunofluorescence showed linear deposition of IgG and C3. The patient received pulse methylprednisone for three days followed by oral prednisone and ATT. In addition, he also underwent nine sessions of plasmapheresis. Oral Cyclophosphamide was added on Day 10. The patient showed remarkable recovery as his lung fields cleared and his kidney function got stabilized. Cyclophosphamide was continued for three months and then switched to azathioprine. At six months, the creatinine is 1.2 mg/dL, with minimal proteinuria and a normal chest X-ray. To the best of our knowledge, this is the only reported case of double-positive Goodpasture's syndrome (c-ANCA and anti GBM) with active tuberculosis treated successfully.

Acute interstitial nephritis due to proton pump inhibitors

Proton pump inhibitors (PPI) are commonly prescribed for dyspepsia and acid peptic disease. Acute interstitial nephritis (AIN) is an uncommon though important side-effect of these classes of drugs. We describe four cases: three females and one male. PPIs implicated were pantoprazole in two, omeprazole and esomeprazole in one each. AIN developed after an average period of 4 weeks of drug therapy. The symptoms were vomiting, loin pain, and oliguria. Minimal proteinuria with pyuria were seen and the mean serum creatinine was 4.95 ± 4 mg/dl. Two patients required hemodialysis. Renal biopsy showed interstitial mononuclear, plasma cell and eosinophilic infiltrates in all cases. PPI was stopped and steroids were started in all. Renal recovery was total in two and partial in two. A high index of suspicion is required to diagnose PPI induced AIN. Renal biopsy for confirmation followed up by prompt steroid therapy results in renal functional improvement.

Collapsing FSGS Post Non Renal Solid Organ Transplantation

Introduction: Collapsing focal and segmental glomerulosclerosis (cFSGS) is a rare and aggressive form of FSGS. It occurs in a variety of clinical settings and is usually associated with a heavy proteinuria and very poor renal outcome. We describe the clinical and histological characteristics of 10 cases of cFSGS occurring at our institution after non-renal solid organ transplantation. Methods: We performed a retrospective review of all cases of biopsy proven cFSGS occurring post non-renal solid organ transplantation at our institution. Results are given as mean ±SEM. Results: We identified 10 cases of cFSGS post non-renal solid organ transplantation occurring over the last 20 years at our institution. 5 cases occurred post heart transplantation, 3 cases post combined heart and lung transplantation, 1 case post liver transplantation and 1 post lung transplantation. Two patients were female, the rest (8) were male. All had well preserved renal function and minimal proteinuria prior to transplantation. 3/10 of the patients had been smokers prior to transplantation, 5/10 patients had developed diabetes post transplantation and 7/10 were being treated for hypertension at the time of renal biopsy. 9/10 patients were treated with a calcineurin inhibitor (CNI) based immunosuppressive regimen post transplantation and 1/10 was treated with an everolimus based immunosuppressive regimen without CNI. The mean age of patients at the time of renal biopsy was 44±4.73. Mean time in years between transplantation and renal biopsy was 8.1±1.81. Mean serum creatinine at the time of biopsy was 261±30μmol/L. Mean proteinuria at the time of renal biopsy was 6.6±1.35g/24hours and mean serum albumin at the time of biopsy was 31.1±1.88g/L. On biopsy the mean percentage of glomeruli with global sclerosis was 45±7%. Remaining glomeruli showed changes constant with cFSGS. All biopsies showed moderate to severe interstitial fibrosis and atrophy, mostly in a striped pattern consistent with chronic CNI nephrotoxicity. At diagnosis many patients were converted to non-CNI based immunosuppressive regimens. Despite this all but 1 patient progressed to end-stage renal failure (ESRF) within a mean of 20±8.3 months of diagnosis. The only patient not to progress to ESRF has had only 4 months follow-up. Conclusion: cFSGS is a rare complication occurring late post non-renal solid organ transplantation. It occurs in the setting of prolonged exposure to CNIs and in association with other vascular risk factors. It presents with heavy proteinuria and moderate degrees of renal failure. The prognosis, as with most forms of FSGS, is almost universally poor. Late amendment to immunosuppressive therapy, in particular withdrawal of CNIs has little effect on the progression of disease which is characterised by chronic and irreversible biopsy changes. Close monitoring of renal parameters in the post transplant period, particularly regular monitoring for the onset of proteinuria may allow earlier detection of the lesion and improve outcome with earlier changes to immunosuppressive regimens.

Collapsing FSGS Post Non Renal Solid Organ Transplantation

Introduction: Collapsing focal and segmental glomerulosclerosis (cFSGS) is a rare and aggressive form of FSGS. It occurs in a variety of clinical settings and is usually associated with a heavy proteinuria and very poor renal outcome. We describe the clinical and histological characteristics of 10 cases of cFSGS occurring at our institution after non-renal solid organ transplantation. Methods: We performed a retrospective review of all cases of biopsy proven cFSGS occurring post non-renal solid organ transplantation at our institution. Results are given as mean ±SEM. Results: We identified 10 cases of cFSGS post non-renal solid organ transplantation occurring over the last 20 years at our institution. 5 cases occurred post heart transplantation, 3 cases post combined heart and lung transplantation, 1 case post liver transplantation and 1 post lung transplantation. Two patients were female, the rest (8) were male. All had well preserved renal function and minimal proteinuria prior to transplantation. 3/10 of the patients had been smokers prior to transplantation, 5/10 patients had developed diabetes post transplantation and 7/10 were being treated for hypertension at the time of renal biopsy. 9/10 patients were treated with a calcineurin inhibitor (CNI) based immunosuppressive regimen post transplantation and 1/10 was treated with an everolimus based immunosuppressive regimen without CNI. The mean age of patients at the time of renal biopsy was 44±4.73. Mean time in years between transplantation and renal biopsy was 8.1±1.81. Mean serum creatinine at the time of biopsy was 261±30μmol/L. Mean proteinuria at the time of renal biopsy was 6.6±1.35g/24hours and mean serum albumin at the time of biopsy was 31.1±1.88g/L. On biopsy the mean percentage of glomeruli with global sclerosis was 45±7%. Remaining glomeruli showed changes constant with cFSGS. All biopsies showed moderate to severe interstitial fibrosis and atrophy, mostly in a striped pattern consistent with chronic CNI nephrotoxicity. At diagnosis many patients were converted to non-CNI based immunosuppressive regimens. Despite this all but 1 patient progressed to end-stage renal failure (ESRF) within a mean of 20±8.3 months of diagnosis. The only patient not to progress to ESRF has had only 4 months follow-up. Conclusion: cFSGS is a rare complication occurring late post non-renal solid organ transplantation. It occurs in the setting of prolonged exposure to CNIs and in association with other vascular risk factors. It presents with heavy proteinuria and moderate degrees of renal failure. The prognosis, as with most forms of FSGS, is almost universally poor. Late amendment to immunosuppressive therapy, in particular withdrawal of CNIs has little effect on the progression of disease which is characterised by chronic and irreversible biopsy changes. Close monitoring of renal parameters in the post transplant period, particularly regular monitoring for the onset of proteinuria may allow earlier detection of the lesion and improve outcome with earlier changes to immunosuppressive regimens.

How Benign Is IgA Nephropathy with Minimal Proteinuria?

nosis and treatment. 2,3 The natural history of IgAN can range from clinically silent urinary abnormalities and preserved renal function over many decades to ESRD. Progression to ESRD occurs in 10%–50% of patients, usually developing slowly over 20 years. 4,5 Ten-year renal survival rates (62%–98%) are also highly variable. 6,7 In regions where renal biopsies are routinely performed for isolated urinary abnormalities (microscopic hematuria, minimal proteinuria ,0.5 g/d), the incidence of IgAN is higher, and the estimates of renal survival are affected by lead-time bias. A more fully informed understanding of the natural history of IgAN across its entire clinical and histologic spectrum could assist clinicians in assessing prognosis and implementing treatment. Muchhasbeenlearnedoverthelast20–30yearsregarding risk stratification of IgAN. 3 Clinical parameters that correlate with increased risk of progression of disease include proteinuria .1 g/d, hypertension, and reduced GFR. The impact of these variables on prognosis is strengthened when they are followed over time. In contrast to other glomerular diseases, proteinuria in IgAN at an excretion rate of even 0.5–1.0 g/d is associated with risk of ESRD. 3

Non-nephronal hematuria misdiagnosed as C1q nephropathy: Look before you leap

A 19-year-old male presented with persistent macroscopic hematuria for last 3 months. On initial evaluation, he was found to have minimal proteinuria, normal renal function, and normal complement with negative lupus serology. Light microscopy, immunofluorescence and electron microscopy of renal tissue confirmed the presence of C1q nephropathy. Because of poor response to immunosuppressive agent (prednisolone and mycophenolate mofetil), passage of urinary clot once and vexing persistent macroscopic hematuria, alternative diagnosis was considered. Cystourethroscopy showed urethritis of prostatic urethra. Immunosuppressives were stopped and doxycycline started to which hematuria responded dramatically. This case report illustrates that hematuria in this patient was because of undiagnosed urethritis rather than incidental C1q nephropathy.