Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics.

BACKGROUND: Hypertensive nephrosclerosis is the presumed underlying cause in many end-stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. OBJECTIVE: To evaluate and improve the diagnostic process for nephrosclerosis patients. METHODS: We included adults from the population-based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988-2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve-based methods of optimal cut-offs were used to improve clinical nephrosclerosis criteria. RESULTS: Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney-related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy-verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (<0.75 g d-1 ), systolic blood pressure (>155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false-positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk-tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. CONCLUSION: Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment.

Banff 07 classification of renal allograft pathology: updates and future directions.

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23-29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero-time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti-score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated 'v' lesion and incorporation of omics-technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

Chronic myeloid leukemia-associated membranoproliferative glomerulonephritis that responded to imatinib mesylate therapy.

There is no known clinical association between chronic myelogenous leukemia (CML) and membranoproliferative glomerulonephritis (MPGN). We present a patient who was followed in the renal clinic for proteinuria of unknown etiology (3.2 g/24 h) and normal renal function who was diagnosed with CML as well as MPGN and acute renal failure at the same time. The patient's renal function and proteinuria improved when his CML was treated with imatinib mesylate, suggesting that CML either caused or exacerbated existing MGPN. To the best of our knowledge, this is the first reported case of MPGN associated with CML that improved with imatinib mesylate therapy.

Thin Glomerular Basement Membrane in a Kidney Transplant of an Alport's Syndrome Patient: A Case Report.

Alport syndrome (AS) and thin basement membrane lesions are caused by various mutations in type IV collagen genes. Although AS is considered a rare disease, thin basement membrane is a frequent pattern, especially in families with a history of persistent hematuria. We report a patient with a diagnosis of AS who developed end-stage kidney disease (ESKD) and received a kidney transplant from a living unrelated donor. The graft biopsy specimen surprisingly showed a pattern of thin basement membranes.

Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition.

BACKGROUND: Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by N(omega)-nitro-L-arginine methyl ester (L-NAME). METHODS AND RESULTS: We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1-deficient (PAI-1(-/-)) and wild-type (WT) male mice (N=6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141+/-3 mm Hg in WT animals versus 112+/-4 mm Hg in PAI-1(-/-) mice (P<0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME-treated WT mice (P<0.01 versus PAI-1(-/-) mice). Cardiac type I collagen mRNA expression was greater in control (P<0.01) and L-NAME-treated PAI-1(-/-) (P<0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. CONCLUSIONS: These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.

The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis.

Regardless of the primary cause, progressive renal deterioration with sclerosis is a hallmark of many renal diseases. Several studies have shown the superiority of angiotensin-converting enzyme inhibitors compared with other antihypertensive agents in providing protection from progressive renal deterioration. Furthermore, animal studies have shown that angiotensin II antagonists in excess of antihypertensive doses can also ameliorate or reverse glomerulosclerosis, leading to the hypothesis that angiotensin II has nonhemodynamic effects that mediate the renoprotective effects shown in these investigations. Although historically angiotensin II has been associated with salt and fluid homeostasis, recent data show that angiotensin II induces cell growth and matrix accumulation in glomerular cells. Plasminogen activator inhibitor-1 has been shown to be the major inhibitor of tissue plasminogen activator and urokinase-like plasminogen activator, with potentially important effects not only on thrombosis/fibrinolysis, but also on matrix degradation because of the proteolytic actions of these substances. Angiotensin II has been shown to influence the actions of plasminogen activator inhibitor-1 and, consequently, its thrombotic and sclerotic effects. Various studies, both in vitro and in vivo, have shown that direct hemodynamic actions, modulation of endothelial injury, and growth factor actions also may be important in the development of sclerosis. These factors can be directly modulated by angiotensin II inhibition. Sclerosis may even be reversed when therapies augment matrix degradation processes, both by directly increasing proteolytic activity and by downregulating inhibitors of matrix degradation. These observations indicate that angiotensin II is important in fibrotic as well as thrombotic renal injuries that lead to progressive renal disease and also in the development of therapies such as specific angiotensin receptor antagonists to prevent or reverse these conditions.

Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease.

An elevated uric acid level is associated with cardiovascular disease. Hyperuricemia is predictive for the development of both hypertension and coronary artery disease; it is increased in patients with hypertension, and, when present in hypertension, an elevated uric acid level is associated with increased cardiovascular morbidity and mortality. Serum uric acid level should be measured in patients at risk for coronary artery disease because it carries prognostic information. Hyperuricemia is caused by decreased renal excretion. In this article, we suggest that this may be mediated by intrarenal ischemia with lactate generation and the inhibition of the secretion of urate by the anion-exchange transport system. The possibility that hyperuricemia directly contributes to cardiovascular or renal disease needs to be reconsidered. Although hyperuricemia is associated with a number of cardiovascular or renal risk factors, several studies have found uric acid level to be independently associated with increased mortality by multivariate analysis. If hyperuricemia is directly toxic, the most likely site is the kidney. Chronic hyperuricemia is strongly associated with chronic tubulointerstitial disease, and many of these patients have decreased renal function. Although it is possible that the hyperuricemia could simply be the consequence of the renal disease, further studies are necessary to rule out a pathogenic role for uric acid in the development of renal disease and salt-dependent hypertension.

Two patients with ring chromosome 15 syndrome.

We report on 2 patients (3 1/2 year-old-male and 6-year-old female) with the ring 15 chromosome syndrome and speech delays and review 25 cases from the literature. The main characteristics of this syndrome include growth retardation (100%), variable mental retardation (95%), microcephaly (88%), hypertelorism (46%), and triangular facies (42%). Other frequent findings include delayed bone age (75%), brachydactyly (44%), speech delay (39%), frontal bossing (36%), anomalous ears (30%), café-au-lait spots (30%), cryptorchidism (30%), and cardiac abnormalities (30%). The average age at diagnosis was 8.1 years. The average maternal and paternal age at the time of birth was 28 and 31 years, respectively.

Role of angiotensin II in glomerular injury.

The components of the renin-angiotensin system (RAS) in progressive renal disease have been extensively investigated, indicating multiple actions beyond hemodynamic and salt/water homeostasis. Studies in various human diseases and in animal models have shown that angiotensin (Ang) I-converting enzyme inhibitors (ACEI) are superior to other antihypertensive agents in protecting the kidney against progressive deterioration, even in conditions without systemic hypertension. These findings suggest that Ang II has nonhemodynamic effects in progressive renal disease. Interactions of the RAS with aldosterone and bradykinin may have impact on both blood pressure and tissue injury. The RAS is now recognized to be linked to induction of plasminogen activator inhibitor-1 (PAI-1) likely via both the type 1 (AT1) and type 4 (AT4) receptors, thus, promoting both thrombosis and fibrosis. A role of angiotensin in the regulation of immune injury and inflammation has also been identified. Polymorphisms of genes relevant to the RAS appear to affect the risk and course of cardiovascular and renal diseases and response to treatment. The beneficial effect on renal fibrosis of inhibiting the RAS likely reflects the central role that angiotensin has in regulating renal function and structure by its multifaceted actions. This article will focus on the role of the RAS in glomerular injury.

Evaluation of the Coulter S-Plus IV three-part differential as a screening tool in a tertiary care hospital.

The Coulter S-Plus IV separates leukocytes in peripheral blood by volume analysis into granulocytes, lymphocytes, and mononuclear cell fractions, the so-called three-part differential (3PD). White blood cell (WBC) counts, hemoglobin concentrations, platelet counts, 3PDs, and histograms were compared with smear differentials on 3,861 samples, including samples from oncology patients, to determine the predictive value of the Coulter parameters in detecting smear abnormalities. Results showed good correlation between the 3PD and smear differential for granulocytes and lymphocytes (correlation coefficients were 0.883 and 0.868, respectively) and poor correlation for mononuclear cells (0.492). No histogram region flag indicators were observed in the following samples: 15 of 40 samples with greater than or 1% blasts; 105 of 183 with greater than or 1 nucleated red blood cell (NRBC) per 100 WBCs; 65 of 113 with monocytosis greater than 1,600/microL (1.6 X 10(9)/L); 425 of 548 with greater than 2,000 bands/microL (2.0 X 10(9)/L); 84 of 112 with eosinophilia greater than 600/microL (0.6 X 10(9)L); and 88 of 149 with greater than 2% immature granulocytes. All samples with greater than 5% blasts were indicated by region flags and abnormal histograms. Oncology patient data were analyzed, yielding similar results. The authors established guidelines for using the Coulter 3PD data in their tertiary care laboratory to select samples that require smear evaluation.

Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases.

The development and progression of sclerosis is determined by complex interactions of many mechanisms, including direct hemodynamic actions, modulation of glomerular cell injury, and growth factor actions. The interplay of these factors determines the balance of cell growth and proliferation versus cell death by necrosis or apoptosis, and the balance of matrix accumulation versus degradation. Sclerosis may even be reversed when therapies inhibit these mechanisms and augment matrix degradation processes, both by directly increasing proteolytic activity and by down-regulating inhibitors of matrix degradation. We will focus in this review on the roles of glomerular hemodynamics and growth in the progression of renal diseases.

Mechanisms in nephrosclerosis and hypertension-beyond hemodynamics.

These studies support that global glomerulosclerosis is a key lesion in human hypertensive nephrosclerosis, and cannot be simply explained by worse vascular sclerosis caused by higher blood pressure. Possible pathogenetic mechanisms include genetic susceptibility, accelerated aging and a primary microvascular disease. The potential importance of the renin angiotensin system in glomerular sclerosis is underscored by the effectiveness of therapies that aim to inhibit its manifold actions, including induction of plasminogen activator inhibitor-1 (PAI-1). Further, regression of existing glomerulosclerosis, including age-related renal and vascular sclerosis, can be achieved in various experimental settings by high dose angiotensin inhibiton, and is linked to inhibition of PAI-1. Ongoing studies will establish which of these provocative findings from animal models are relevant to human diseases, and may lead to optimal therapies to forestall progression and perhaps even induce regression of sclerosis.

Postinfectious glomerulonephritis: Is there a role for steroids?

The role of steroids in treatment of postinfectious glomerulonephritis (PIGN) has been controversial. The reason for such controversy is the risk of infection relapse associated with steroid therapy. Steroids may have a place in the treatment of resistant cases where renal function does not improve despite aggressive antibiotic therapy as well as in patients with crescentic form of PIGN. We report a case of a 39 year-old Caucasian man who was diagnosed with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia resulting in acute IgA dominant PIGN that failed to respond to antibiotic treatment alone, but responded significantly to steroids in addition to antibiotics. This anecdotal experience suggests that steroids could be considered in conjunction with antibiotic therapy for the treatment of refractory cases of PIGN or crescentic form of PIGN. More studies with long-term follow-up of patients treated with steroids in addition to antimicrobial agents are required to quantify the risk of infection relapse with steroid therapy.

PPAR-gamma agonist protects podocytes from injury.

Podocyte injury and loss contribute to progressive glomerulosclerosis. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear hormone receptor, which we have found to be increased in podocytes in a variety of kidney diseases. It is not known if PPAR-gamma contributes to renal injury or if it serves as a countermeasure to limit renal injury during disease progression. We tested these possibilities utilizing the puromycin aminonucleoside (PAN) model of renal injury in immortalized mouse podocytes. The cultured podocytes expressed PPAR-gamma mRNA at baseline but this was decreased by PAN. Pioglitazone, a pharmacologic agonist of PPAR-gamma, increased both PPAR-gamma mRNA and activity in injured podocytes, as assessed by a reporter plasmid assay. Further, pioglitazone significantly decreased PAN-induced podocyte apoptosis and necrosis while restoring podocyte differentiation. The PPAR-gamma agonist significantly restored expression of the cyclin-dependent kinase inhibitor p27 and the antiapoptotic molecule Bcl-xL while significantly decreasing proapoptotic caspase-3 activity. Pioglitazone tended to decrease PAN-induced transforming growth factor-beta (TGF-beta) mRNA expression. Our study shows that PPAR-gamma is normally expressed by podocytes and its activation is protective against PAN-induced apoptosis and necrosis. We postulate that this protective effect may be mediated in part by effects on p27 and TGF-beta expression.