Proteinuria: detection and role in native renal disease progression

The presence of albuminuria or proteinuria constitutes a sign of kidney damage and, together with the estimation of glomerular filtration rate, is based on the evaluation of chronic kidney disease. Proteinuria is a strong marker for progression of chronic kidney disease, and it is also a marker of increased cardiovascular morbimortality.Filtration of albumin by the glomerulus is followed by tubular reabsorption, and thus, the resulting albuminuria reflects the combined contribution of these 2 processes. Dysfunction of both processes may result in increased excretion of albumin, and both glomerular injury and tubular impairment have been involved in the initial events leading to proteinuria.Independently of the underlying causes, chronic proteinuric glomerulopathies have in common the sustained or permanent loss of selectivity of the glomerular barrier to protein filtration. The integrity of the glomerular filtration barrier depends on its 3-layer structure (the endothelium, the glomerular basement membrane, and the podocytes). Increased intraglomerular hydraulic pressure or damage to glomerular filtration barrier may elicit glomerular or overload proteinuria. The mechanisms underlying glomerular disease are very variable and include infiltration of inflammatory cells, proliferation of glomerular cells, and malfunction of podocyte-associated molecules such as nephrin or podocin.Albumin is filtered by the glomeruli and reabsorbed by the proximal tubular cells by receptor-mediated endocytosis. Internalization by endocytosis is followed by transport into lysosomes for degradation. The multiligand receptors megalin and cubilin are responsible for the constitutive uptake in this mechanism. Albumin and its ligands induce expression of inflammatory and fibrogenic mediators resulting in inflammation and fibrosis resulting in the loss of renal function as a result of tubular proteinuria. TGF-β, which may be induced by albumin exposure, may also act in a feedback mechanism increasing albumin filtration and at the same time inhibiting megalin- and cubilin-mediated albumin endocytosis, leading to increased albuminuria.Urinary proteins themselves may elicit proinflammatory and profibrotic effects that directly contribute to chronic tubulointerstitial damage. Multiple pathways are involved, including induction of tubular chemokine expression, cytokines, monocyte chemotactic proteins, different growth factors, and complement activation, which lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis. This tubulointerstitial injury is one of the key factors that induce the renal damage progression.Therefore, high-grade proteinuria is an independent mediator of progressive kidney damage. Glomerular lesions and their effects on the renal tubules appear to provide a critical link between proteinuria and tubulointerstitial injury, although several other mechanisms have also been involved. Injury is transmitted to the interstitium favoring the self-destruction of nephrons and finally of the kidney structure.     

Albumin transport and processing by the proximal tubule: physiology and pathophysiology

PURPOSE OF REVIEW: Significant epidemiological and clinical trial evidence supports the association between increased urinary albumin excretion, cardiovascular events and renal failure. An increase in albumin excretion has traditionally been considered to reflect a 'glomerular' leak of protein; however, it is now recognized that significant tubular reabsorption of albumin occurs under physiological conditions that may be modified by genetic determinants, systemic disease and drug therapies. RECENT FINDINGS: The endocytosis of albumin by the proximal tubule is a highly regulated process depending on protein-protein interactions between several membrane proteins and scaffolding and regulatory molecules. The elucidation of these interactions is an ongoing research focus. There is also mounting evidence for a transcytotic pathway for retrieval of albumin from the tubular filtrate. The molecular basis for the role of albuminuria in both interstitial renal disease and cardiovascular pathology continues to be defined. The clinical implications of albuminuria due to a glomerular leak vs. reduced tubular reabsorption of albumin are, however, now under consideration. In particular, the prognostic implication of microalbuminuria induced by the more potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors is under study. SUMMARY: The currently defined mechanisms underpinning the tubular reabsorption of albumin, how these are modified by pathology and pharmacology, and the clinical implications are the subject of this review.     

Factors causing variation in urinary N-nitrosamine levels in enterocystoplasties

OBJECTIVE: To evaluate changes in protein leakage in the glomerular filtration barrier, and in the ability of the tubule to reabsorb proteins during and after acute urinary retention (AUR). PATIENTS AND METHODS: Glomerular and tubular function was investigated in 24 men during AUR (mean age 68 years, mean retention time 31 h and mean retention volume 1140 mL) who were then followed for 6 months by measuring the urinary excretion of glomerular and tubular proteins, and the glomerular filtration rate (GFR). Retention was relieved by inserting a suprapubic catheter and the cause of retention treated one month later. No patient had a previous renal disease or diabetes. RESULTS: During AUR, and after 1 and 6 months, albuminuria was detected in 100%, 92% and 54% of patients, and increased excretion of alpha1-microglobulin in 52%, 36% and 58%, of IgG in 79%, 58% and 40%, and of IgG4 in 67%, 42% and 20%, respectively. The mean GFR was normal during retention and during the follow-up. CONCLUSION: AUR causes disturbances in both the glomerular filtration and tubular reabsorption of proteins. Albuminuria and increased excretion of IgG, IgG4 and alpha1-microglobulin occurred in most patients during AUR. After relieving retention, the albuminuria and elevated alpha1-microglobulin excretion persisted, indicating slight glomerular dysfunction and a permanent defect in the proximal tubule to reabsorb proteins. This could be caused partly by previous chronic obstruction. AUR should be relieved immediately and the basic cause treated effectively to prevent further deterioration of renal function.     

Time to abandon microalbuminuria?

The term microalbuminuria--a urinary albumin excretion (UAE) between 20 and 200 microg/min--has been introduced to identify subjects at increased risk of renal and cardiovascular disease. However, the relationship between albuminuria and risk is not restricted to the microalbuminuric range and extends to as low as 2-5 microg/min. On the contrary, the increase of UAE above 200 microg/min (macroalbuminuria) heralds the onset of proteinuria (urinary protein excretion above 0.5 g/24 h) and progressive renal and cardiovascular disease. Albuminuria is a component of the metabolic syndrome and may represent a marker of the increased risk of renal and cardiovascular disease associated with insulin resistance and endothelial dysfunction. Proteinuria is a sign of established kidney damage and plays a direct pathogenic role in the progression of renal and cardiovascular disease. Albuminuria reflects functional and potentially reversible abnormalities initiated by glomerular hyperfiltration, proteinuria, a size-selective dysfunction of the glomerular barrier normally associated with glomerular filtration rate (GFR) decline that may result in end-stage renal disease. Thus, the limit of 200 microg/min segregates patients with albuminuria or proteinuria who are at quite different risk. Among subjects with albuminuria, however, there is a continuous relationship between albumin excretion and risk and no lower bound between normal albuminuria and microalbuminuria can be identified that segregates subjects at different risk. Thus, the terms microalbuminuria and macroalbuminuria could be replaced by the concepts of albuminuria- and proteinuria-associated diseases. Future studies are needed to identify levels of albuminuria below which therapy is no longer beneficial.     

Renal tubular protein handling in experimental renal disease

Competitive inhibition of renal tubular transport occurs between low- and high-molecular-weight proteins following intravenous infusion, but this relationship is less clear following de novo glomerular or renal tubular injury. The present study evaluated renal lysozyme and albumin handling following renal tubular injury induced by both low- and high-dose mercuric chloride (0.5 and 2.0 mg/kg) and maleic acid (50 and 400 mg/kg), and following glomerular injury induced by puromycin aminonucleoside (5 mg/100 g) or Adriamycin (5 mg/kg). Subtle renal tubular injury induced only mild isolated albuminuria, while severe tubular injury caused dramatic lysozymuria and moderate albuminuria. However, increased filtration of albumin in these models of glomerular injury did not inhibit lysozyme transport.     

Influence of albumin infusion on the urinary excretion of beta2-microglobulin in patients with proteinuria

Most filtered proteins are reabsorbed by the renal proximal tubule by a mechanism that involves binding to the brush border membrane and endocytosis. Under normal conditions the low-molecular-weight protein beta2-microglobulin (beta2M), which is used to detect tubular injury, is reabsorbed almost completely. However, in proteinuric patients an increased urinary excretion of beta2M may not simply reflect tubular damage but might also result from a decreased tubular reabsorption due to competitive mechanisms. To examine the magnitude of such an effect we have studied the renal effects of albumin infusion (40 g in 2 h of a 20% solution) in 10 patients with a glomerular disease and proteinuria >3.5 g/24 h. Before, during and after albumin infusion the GFR (inulin clearance), RPF (PAH clearance), blood pressure and the urinary excretion of albumin, IgG, transferrin and beta2M were measured. Albumin infusion resulted in a slight decrease of the GFR (72 +/- 11 ml/min before and 67 +/- 10 ml/min after infusion), an increase of the RPF (379 +/- 66 ml/min before and 445 +/- 83 ml/min after), a decrease of the filtration fraction (0.20 before and 0.17 after), and hemodilution. After infusion the urinary excretion of albumin increased from 4.5 +/- 0.7 to 8.4 +/- 1.6 mg/min (p < 0.05). The urinary excretion of IgG and transferrin increased, probably reflecting a change in glomerular size-selectivity. In contrast, the urinary excretion of beta2M did not change significantly (baseline 12 +/- 5 microg/min, end 13 +/- 6 microg/min, percentage change 16.8 +/- 11%). To correct for changes in tubular load we calculated the fractional reabsorption of beta2M. The initial rise in albuminuria during infusion did not affect fractional tubular reabsorption (Delta%: 0. 72 +/- 0.52%, median 0.005%). In the period after infusion a slight decrease was noted (median -0.33%, p < 0.01). A decrease in the fractional reabsorption was particularly observed in patients with pre-existing tubular damage. In conclusion: infusion of albumin in proteinuric patients has no clinically relevant effect on the tubular reabsorption of beta2M. Therefore, beta2M is useful as a parameter to detect tubular injury and alterations in tubular handling of proteins in patients with proteinuria and glomerular diseases.     

The contribution of hypoxia to postischemic renal dysfunction

Renal ischemia is a multifactorial insult consisting of both hypoxia and stagnation of blood flow. This study compared the renal response with hypoxia alone versus ischemia (hypoxia and stagnation of flow). Isolated rat kidneys were perfused at 90 to 110 mm Hg and 37 degrees C with an asanguinous modified Krebs' buffer. Perfusate flow rate, vascular resistance, urine flow rate, glomerular filtration rate (GFR), percent sodium reabsorption, and oxygen consumption were measured. Five groups were examined: 10-minute hypoxia (HYP10), 30-minute hypoxia (HYP30), 10-minute ischemia (ISC10), 30-minute ischemia (ISC30), and time-matched controls. HYP10 resulted in isolated tubular dysfunction, as evidenced by an increase in urine flow rate and a decrease in percent sodium reabsorption. ISC10 caused decreased GFR, oliguria, and more severe tubular dysfunction. The pattern of glomerular and tubular dysfunction after HYP30 was similar to that after ISC30. Glomerular dysfunction was associated with a decrease in perfusate flow rate and an increase in vascular resistance only after ISC30. This suggests that the decrease in GFR seen with postischemic renal dysfunction is not a primary result of decreased flow. Furthermore, hypoxia does not account for the entire reduction in renal function after ischemia of similar duration. The more severe dysfunction after ischemia may be a consequence of the stagnation of renal flow (anaerobic waste product accumulation and inadequate nutrient supply).     

Oxygen free radical mediated renal dysfunction

Postischemic renal dysfunction (PIRD) is characterized by a reduction in glomerular filtration and tubular reabsorption of solute. The relative contribution of oxygen free radicals (OFRs) generated during reperfusion remains unclear. This study characterized the renal response to OFRs--independent of an ischemic insult. Isolated rat kidneys were perfused at 37 degrees C and 90-100 mm Hg with a modified Krebs' buffer. Hypoxanthine (25 mumole) and xanthine oxidase (1 unit) were combined and infused proximal to the kidney. There was a 50% increase in vascular resistance. This was accompanied by a 30% reduction in perfusate flow rate and a 70% reduction in glomerular filtration rate. There was also a significant reduction in urine flow rate and oxygen consumption. The percentage reabsorption of filtered water and sodium by the renal tubules was not diminished, however. This pattern was not observed when the xanthine oxidase was inactivated or when the perfusate was pretreated with superoxide dismutase (250 units/ml) and catalase (500 units/ml). The generation of OFRs, independent of an ischemic insult, causes a decrease in glomerular filtration out of proportion to the decrease in renal flow similar to that observed with PIRD. OFRs may contribute to the hemodynamic and glomerular alterations seen with PIRD. Factors other than OFRs, probably associated with ischemia, must be responsible for the tubular dysfunction.     

Increased tubular proliferation as an adaptive response to glomerular albuminuria

Renal tubular atrophy accompanies many proteinuric renal diseases, suggesting that glomerular proteinuria injures the tubules. However, local or systemic inflammation and filtration of abnormal proteins known to directly injure tubules are also present in many of these diseases and animal models; therefore, whether glomerular proteinuria directly causes tubular injury is unknown. Here, we examined the renal response to proteinuria induced by selective podocyte loss. We generated mice that express the diphtheria toxin receptor exclusively in podocytes, allowing reproducible dose-dependent, specific ablation of podocytes by administering diphtheria toxin. Ablation of <20% of podocytes resulted in profound albuminuria that resolved over 1-2 weeks after the re-establishment of normal podocyte morphology. Immediately after the onset of albuminuria, proximal tubule cells underwent a transient burst of proliferation without evidence of tubular damage or increased apoptosis, resulting in an increase in total tubular cell numbers. The proliferative response coincided with detection of the growth factor Gas6 in the urine and phosphorylation of the Gas6 receptor Axl in the apical membrane of renal tubular cells. In contrast, ablation of >40% of podocytes led to progressive glomerulosclerosis, profound tubular injury, and renal failure. These data suggest that glomerular proteinuria in the absence of severe structural glomerular injury activates tubular proliferation, potentially as an adaptive response to minimize the loss of filtered proteins.     

Renal sodium and water handling in hypothyroid patients: the role of renal insufficiency

The mechanism responsible for renal tubular abnormalities in sodium and water excretion in hypothyroid patients is poorly understood. To evaluate the possible contribution of the reduced glomerular filtration rate of hypothyroidism to these abnormalities, tubular function in hypothyroid patients was compared with that in patients with chronic renal failure and in normal subjects. The lithium clearance method and oral water loading were used to evaluate parameters of tubular sodium and water handling, respectively. The hypothyroid and the chronic renal failure patients were selected to have similar reductions in glomerular filtration rate. As compared to the normal subjects, the hypothyroid and chronic renal failure patients had a decrease in proximal sodium reabsorption and an increase in distal sodium reabsorption. The changes in tubular handling of sodium were not different in the hypothyroid and the chronic renal failure patients. Maximal urinary flow rate and free water clearances were similarly reduced in the hypothyroid patients and the chronic renal failure patients. For all subjects studied, proximal sodium reabsorption and maximal urinary volume were directly correlated with the glomerular filtration rate, and distal nephron sodium reabsorption was proportionate to delivery of sodium from the proximal tubule. The results suggest that the abnormalities in tubular sodium and water handling in hypothyroid patients are comparable to those present in other patients with a similar degree of renal insufficiency. Thus, the tubular abnormalities in hypothyroidism may be a consequence of the associated decrease in glomerular filtration rate.     

Urinary excretion of alpha 2 mu-globulin and albumin by adult male rats following treatment with nephrotoxic agents

Nephrotoxic agents such as puromycin aminonucleoside (PAN) and sodium maleate (MAL) have been used to induce experimental glomerular proteinuria and tubular disease, respectively. Current studies show that PAN caused a massive loss of albumin in the urine while not affecting the excretion of the smaller, sex-dependent alpha 2 mu-globulin. On the other hand, MAL which inhibits the reabsorption of proteins, increased the loss of both alpha 2 mu and albumin. Both nephrotoxic agents increased the excretion of albumin when administered to female rats. MAL-induced proteinuria was used as a direct measure of the renal load for alpha 2 mu and albumin. Renal loads and excretion of alpha 2 mu and albumin were measured in male rats maintained on 0, 20, and 50% casein diets. On the protein-free diet, the excretion of both alpha 2 mu and albumin was reduced (less than 1 mg daily); their renal loads were almost totally reabsorbed. On a 50% casein diet the reabsorption of alpha 2 mu was reduced from a normal of 60% to 10% of the renal load. Thus the high protein diet increased the excretion of alpha 2 mu while having little effect on the excretion of albumin. We suggest that dietary protein exerts two levels of control on the excretion of protein in the urine of the adult male rat. Protein-deficient diets stimulate the general reabsorption of proteins thereby minimizing the excretion of alpha 2 mu and albumin. High protein diets appear to reduce selectively the reabsorption of alpha 2 mu-globulin, thereby increasing its excretion in the urine.     

Urine excretion of protein HC in proteinuric glomerular diseases correlates to urine IgG but not to albuminuria.

BACKGROUND: Proteinuric glomerular diseases often are associated with tubulointerstitial injury, which imposes on the progression of renal failure. Tubular damage is partly referable to toxic effects on the tubular epithelial cells induced by filtered plasma proteins. Patients with nonselective proteinuria, that is, increased urine excretion of high-molecular-weight plasma proteins such as IgG in comparison to albumin, often have poor renal outcome. The present observational study examined correlations between the degree of tubular damage, measured by urine concentration of protein HC, and the levels of urine IgG and albuminuria. METHODS: Measurements of urine concentrations of IgG, albumin, and protein HC were performed in 56 proteinuric patients (33 males and 23 females) with nondiabetic glomerular diseases at the time of the diagnostic renal biopsy and at a mean of 49 follow-up months. RESULTS: A highly significant correlation between the urine IgG excretion and the urine protein HC concentration was found both at the start and at the end of the observational time (r = 0.74 and 0.65, respectively, P < 0.001). Furthermore, alterations in the urinary excretion of the two proteins in single patients correlated significantly to each other (r = 0.84, P < 0.001). The correlation between the degree of albuminuria and the protein HC excretion was significant at the time of kidney biopsy, but ceased to exist during the follow-up time. Stepwise linear regression analysis showed that in comparison with the creatinine clearance and albuminuria, only the changes in urinary IgG excretion were related to the corresponding changes in urinary protein HC excretion (r = 0.84 and r2 = 0.7, P < 0.001). CONCLUSION: The findings of the study suggest that the urinary protein HC concentration correlates to the degree of IgG-uria but not to the degree of albuminuria during the course of proteinuric glomerular disease. Whether this correlation is to be explained by an intrinsic toxic effect on tubular cells executed by IgG or perhaps by some other high molecular weight proteins, needs to be investigated further. However, the results contribute to the understanding of the poor renal survival in patients with glomerular diseases and nonselective proteinuria.     

Estimation of ifosfamide/cisplatinum-induced renal toxicity by urinary protein analysis

Ifosfamide (IFO) chemotherapy has been reported to result in deToni-Debré-Fanconi syndrome in a minority of patients only, but evaluation of tubular transport capacities has identified a substantial number of patients as having subclinical tubular dysfunction. After completion of combination chemotherapy employing IFO (n=37) or IFO plus cisplatinum (CPL) (n=27), glomerular and tubular function was assessed in 64 patients by the urinary excretion of transferrin, IgG, albumin, ₁-microglobulin (A1M) andN-acetyl--d-glucosaminidase. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was performed in 21 patients. The determination of urinary marker proteins was compared with the glomerular filtration rate, the fractional phosphate and percent amino acid reabsorption. A reduced glomerular filtration rate was observed in 9.8% of patients. Tubular dysfunction was frequent, with a predominance of renal amino acid (57%) and A1M (48%) loss. IFO-mediated renal toxicity was dose dependent. CPL treatment resulted in significant enhancement of tubular toxicity induced by IFO, whereas concomitant gentamicin therapy did not affect tubular function. Measurement of urinary protein cannot replace other tests for tubular dysfunction in IFO-treated patients, because the spectrum of IFO-induced nephrotoxicity includes dysfunction of different and independent transport mechanisms of the proximal tubular system. Increased urinary A1M excretion is an important indicator of impaired tubular protein reabsorption.     

The role of albuminuria in the follow-up of HIV-infected pediatric patients

Background

In HIV-infected adults, elevated albumin has been associated with increased inflammatory activity, HIV-related nephropathy, and type 2 diabetes. Data on albuminuria in HIV-infected children are very scarce, and guidelines do not include routine determination of urinary albumin/creatinine ratio in this population.

Methods

We performed a cross-sectional study in a cohort of HIV-infected pediatric patients. Urinary protein/creatinine and albumin/creatinine ratios and hematuria were determined from at least three morning urine samples, and glomerular filtration rate (GFR) was estimated from creatinine levels. Persistent renal damage was defined according to the presence of at least two sequentially abnormal values in one of the parameters. The relationship between renal damage, HIV-related variables, and metabolic comorbidities (dyslipidemia, fat redistribution, glucose intolerance, hypertension) was investigated.

Results

Symptom-free renal damage was observed in 13 of 68 patients (19.1 %) and mainly consisted of persistent proteinuria (17.6 %); glomerular proteinuria was twice as prevalent as tubular proteinuria. GFR were normal in all cases. No relationship between renal markers and HIV-related variables or metabolic comorbidities was observed.

Conclusions

Mild proteinuria affected approximately one fifth of patients in our cohort. The determination of albuminuria allowed the differentiation between glomerular and tubular proteinuria, although no relationship with metabolic comorbidities was observed.     

The kidney, a cardiovascular risk marker, and a new target for therapy

Both reduced filtration power and increased excretion of albumin in the urine are powerful markers for renal and cardiovascular progressive function loss. These risk markers indicate the risk above and beyond the conventional existing risk markers/factors. The risk is substantial, because both reduced filtration and microalbuminuria are highly prevalent in the general population, matching in prevalence with the most well-known risk factor, hypertension. Therapeutic interventions to preserve renal and cardiovascular function, such as with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, are highly effective, particularly in those patients that have reduced filtration power. In addition, short-term reduction of albuminuria that follows the renin-angiotensin-aldosterone-system intervention appears to be predictive of long-term cardiovascular and renal protection. In conclusion, estimated glomerular filtration rate as well as albumin excretion in the urine are powerful predictors for cardiovascular and renal outcome and should be used as such. Intervention and prevention could be aimed at not only at reducing conventional risk markers, but also at reducing albuminuria.     

Effect of lipid reduction on the progression of renal disease: a meta-analysis

BACKGROUND: It has been proposed that hyperlipidemia contributes to the progression of renal disease. A large trial has not been performed; however, a number of small, controlled trials have been reported. We examined the effects of antilipemic agents on glomerular filtration rate and proteinuria or albuminuria in patients with renal disease. METHODS: We used Medline, abstracts from scientific meetings, and bibliographies from recent reviews and scientific reports to locate pertinent studies. Thirteen prospective controlled trials examining the effects of antilipemic agents on renal function, proteinuria, or albuminuria were included. Studies were published as full reports or abstracts and were at least three months in duration. For five of the studies, individual patient data were obtained. Other summary data were independently extracted from the published reports by two investigators and included study quality, subject characteristics, cause of renal disease, change in serum cholesterol, blood pressure, glomerular filtration rate, proteinuria, and albuminuria. RESULTS: There was a lower rate of decline in glomerular filtration rate with treatment compared with controls (treated controls, 0.156 mL/min/month; 95% CI, 0.026 to 0. 285 mL/min/month, P = 0.008). The study results were statistically homogeneous, and in a regression analysis, the effect of treatment on glomerular filtration rate did not correlate with study quality, the percentage change in cholesterol, the type of lipid-lowering agent, or the cause of renal disease. However, longer follow-up correlated with the amount of improvement in glomerular filtration rate from treatment (P = 0.007). There was a tendency for a favorable effect of treatment on protein or albumin excretion [Ln (treatment) - Ln (control) = -0.248, 95% CI, -0.562 to 0.064, P = 0. 077]. However, these results were statistically heterogeneous between studies (P < 0.001). No obvious explanation for this heterogeneity was apparent in a regression analysis examining potential reasons for differences in study results. CONCLUSIONS: Lipid reduction may preserve glomerular filtration rate and may decrease proteinuria in patients with renal disease.     

Endothelial-Podocyte Crosstalk: The Missing Link Between Endothelial Dysfunction and Albuminuria in Diabetes

Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, most people with diabetic nephropathy will never develop ESRD but will instead die of cardiovascular (CV) disease (CVD). The first evidence of kidney injury in diabetes is often microalbuminuria, itself also an independent risk marker for CVD. Although the two processes are closely associated, the recent failure of antialbuminuric therapies to affect CV outcomes has encouraged a reconsideration of how albuminuria may occur in diabetes and how increased urinary albumin excretion may be indicative of CV risk. The relationship between CVD and urinary albumin content (even within the normal range) is widely considered to reflect the common underlying pathology of endothelial dysfunction. At the same time, recent years have witnessed a growing appreciation that diabetic albuminuria commonly arises from damage to glomerular podocytes, specialized epithelial cells acting as the final barrier to macromolecular flow into the urinary filtrate. These superficially discordant paradigms can be assimilated by the emerging concept of endothelial-podocyte crosstalk across the glomerular filtration barrier, whereby the actions of one type of cell may profoundly influence the function of the other. The bidirectional nature of this paracrine network is illustrated by the actions of the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor-2 and activated protein C systems, among others. Identification of novel mediators of endothelial-podocyte crosstalk may lead to the development of more effective treatments for diabetic nephropathy and its sequelae.Even though it is the most common cause of end-stage renal disease (ESRD) worldwide, most people with diabetic nephropathy will never reach the stage of requiring dialysis or a kidney transplant but will instead die of cardiovascular (CV) disease (CVD). Often, the earliest indicator of kidney damage in diabetes is the abnormal passage of the protein albumin into the urinary filtrate, which is widely considered to reflect underlying endothelial dysfunction and is itself an independent predictor of CVD. Despite their well-recognized association, the manner in which endothelial dysfunction may result in albuminuria is incompletely understood. The passage of albumin into the urine is normally impeded by a three-layered glomerular filtration barrier composed of fenestrated glomerular endothelial cells lining the capillary loops, interdigitating podocytes lining the urinary space, and an interpositioned glomerular basement membrane (Fig. 1A–C). Recent evidence indicates that paracrine communication between the fenestrated endothelium and podocytes plays a critical role in maintaining filtration barrier integrity and that this communication may be disrupted by hyperglycemia and its associated hemodynamic and metabolic perturbations leading to albumin leakage. Here, we consider the roles of the superficially competing paradigms of endothelial dysfunction and podocyte injury in diabetic nephropathy and how these phenomena can be reconciled by the emerging concept of endothelial-podocyte crosstalk.Open in a separate windowFIG. 1.A: Scanning electron micrograph illustrating the fenestrated glomerular endothelium. B: Scanning electron micrograph illustrating interdigitating podocyte foot processes wrapped around the glomerular capillary wall. C: Transmission electron micrograph showing the structure of the glomerular filtration barrier composed of fenestrated endothelium, glomerular basement membrane, and interdigitating podocytes bridged by a molecular slit diaphragm. D: Transmission electron micrograph of the glomerular filtration barrier from a diabetic endothelial NO synthase–deficient mouse showing podocyte foot process effacement in the presence of normal glomerular endothelial fenestrations and ultrastructure.     

Renal handling of albumin: A critical review of basic concepts and perspective

Biochemical and physiological processes that underlie the mechanism of albuminuria are completely reassessed in this article in view of recent discoveries that filtered proteins undergo rapid degradation during renal passage and the resulting excreted peptide fragments are not detected by conventional urine protein assays. This means that filtered protein and/or albumin levels in urine have been seriously underestimated. The concept that albuminuria is a result of changes in glomerular permeability is questioned in light of these findings and also in terms of a critical examination of charge selectivity, shunts, or large-pore formation and hemodynamic effects. The glomerulus appears to function merely in terms of size selectivity alone, and for albumin, this does not change significantly in disease states. Intensive albumin processing by a living kidney occurs through cellular processes distal to the glomerular basement membrane. Failure of this cellular processing primarily leads to albuminuria. This review brings together recent data about urinary albumin clearance and current knowledge of receptors known to process albumin in both health and disease states. We conclude with a discussion of topical and controversial issues associated with the proposed new understanding of renal handling of albumin. © 2002 by the National Kidney Foundation, Inc.     

Renal creatinine handling in very old patients with chronic renal disease

Abstract  

Renal creatinine handling is basically the result of its glomerular filtration and proximal tubular secretion. However, creatinine reabsorption has been documented in certain conditions, such as premature babies, newborns, and healthy elderly people. Additionally, it is known that there is an increase in the proportion of secreted creatinine in chronic renal disease. In this paper, we report our studies on the characteristic reabsorption pattern of creatinine in the elderly with chronic renal disease.     

Glomerular hyperfiltration and the salt paradox in early [corrected] type 1 diabetes mellitus: a tubulo-centric view

Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a "tubulo-centric" view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease.