Piero Ruggenenti

Progression, remission, regression of chronic renal diseases

The prevalence of chronic renal disease is increasing worldwide. Most chronic nephropathies lack a specific treatment and progress relentlessly to end-stage renal disease. However, research in animals and people has helped our understanding of the mechanisms of this progression and has indicated possible preventive methods. The notion of renoprotection is developing into a combined approach to renal diseases, the main measures being pharmacological control of blood pressure and reduction of proteinuria. Lowering of blood lipids, smoking cessation, and tight glucose control for diabetes also form part of the multimodal protocol for management of renal patients. With available treatments, dialysis can be postponed for many patients with chronic nephropathies, but the real goal has to be less dialysis-in other words remission of disease and regression of structural damage to the kidney. Experimental and clinical data lend support to the notion that less dialysis (and maybe none for some patients) is at least possible.

Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril : REIN follow-up trial

BACKGROUND The Ramipril Efficacy In Nephropathy (REIN) study found that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, ramipril safely reduced the rate of decline of the glomerular filtration rate (GFR) and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF), as compared with placebo plus conventional antihypertensive drugs at the same level of blood pressure control. At the end of the core study patients continued on or shifted to ramipril and were formally enrolled into the REIN follow-up study. METHODS 97 patients entered the follow-up study. Patients originally randomised to ramipril continued with the same daily dose (n=51), whereas those originally on placebo plus conventional antihypertensive drugs switched to ramipril after the first visit of the follow-up study (n=46). Ramipril (1.25 to 5.00 mg/day) and conventional antihypertensive therapy were targeted at achieving diastolic blood pressure under 90 mm Hg. The main efficacy variables were GFR decline and ESRF (need for dialysis). Analysis was by intention to treat. FINDINGS During the follow-up study the mean rate of GFR decline per month decreased from 0.44 (SD 0.54) mL/min per 1.73 m2 in the core study to 0.10 (0.50) mL/min per 1.73 m2 in patients originally randomised to ramipril (p=0.017), and from 0.81 (1.12) to 0.14 (0.87) mL/min per 1.73 m2 in those originally randomised to placebo plus conventional antihypertensive therapy (p=0.017). At the final visit, mean absolute GFR values were 12 mL/min per 1.73 m2 higher (33% better) in patients randomised to ramipril than in those assigned placebo (n=26 and 17, respectively: 35.5 [19.0] vs 23.8 [9.4] mL/min per 1.73 m2, p=0.01). 19 of the patients originally on ramipril versus 35 switched from placebo to ramipril progressed to ESRF (p=0.027) during the whole observation period; of these, six (8%) versus 14 (16%) reached that endpoint during the follow-up study; and the risk ratios were 1.86 (95% CI 1.07-3.26) over the whole observation period and 2.95 (1.13-7.68) during follow-up. Beyond follow-up at month 36, the incidence of ESRF was zero in patients originally randomised to ramipril but 30% in patients on placebo plus conventional antihypertensive therapy. INTERPRETATION In patients with chronic nephropathy and high risk of rapid progression to ESRF, ramipril reversed the tendency of GFR to decline with time. Moreover, a treatment period of sufficient duration (> or =36 months) eliminated the need for dialysis. Even patients previously treated with antihypertensive drugs other than angiotensin-converting-enzyme inhibitors benefited from shifting to ramipril.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Chronic Renal Diseases: Renoprotective Benefits of Renin–Angiotensin System Inhibition

Certain renal diseases seen in clinical practice, such as rapidly progressive glomerulonephritis, have a very rapid course that soon leads to irreversible end-stage renal failure caused by complete structural damage. These diseases, however, are rare. The more common nephropathies, which progress more slowly, still evolve to end-stage renal failure. Diabetes mellitus or hypertension can, in some patients, cause renal injury that progresses to renal failure and the need for kidney replacement therapy. The number of patients requiring kidney replacement therapy in 1997 was 304 083 in the United States, 175 988 in Japan, and 197 721 in Europe. The number of new patients entering kidney replacement programs has increased constantly in the past 10 years and will probably continue to increase. In the United States, 450 000 patients are expected to require treatment for end-stage renal disease by 2005 (1, 2). With so many patients involved, the costs of treatment will become extremely high and prohibitive, and not just for developing countries (3). Thus, efforts must be directed toward stopping renal diseases from progressing to end-stage renal failure. Methods We identified papers mentioned in this review by searching the MEDLINE database from 1966 to 2000. We selected the most relevant articles (original research and reviews) for this topic using the following individual or combined search terms: progressive chronic nephropathies, proteinuria, clinical trials, experimental models, renal function, ACE inhibitors, angiotensin II receptor blockers, blood pressure, lipid lowering agents, low protein diet, and smoke. Selected articles were published in the most recognized nephrology journals and in general medicine journals with the highest impact factor. The Progressive Nature of Renal Diseases In 1952, Robert Platt (4) reported that when 80% of the renal tissue was removed from rats, the remaining nephrons became hypertrophied as they assumed a volume of work that a normal kidney would never have to perform. This was interpreted as a possible adaptation to compensate for the effects of nephron loss; renal function then progressively deteriorated. In 1982, however, investigators at Brigham and Womens Hospital in Boston, Massachusetts, first presented the concept that progressive deterioration of renal function was the result of compensatory glomerular hemodynamic changes in response to nephron loss related to the original insult; the hemodynamic changes then caused relentless injury of the remaining intact nephrons (5, 6). In animal models, high intraglomerular capillary pressure impairs the size-selective function of the glomerular permeability barrier and causes protein ultrafiltration (7, 8). In 1986 (9), Bertani and colleagues suggested that proteins filtered through the glomerular capillary wall might have intrinsic renal toxicity and could contribute to the progression of renal damage. Consistent with these experimental observations was evidence that in humans with nephropathy, disease progressed more quickly when proteinuria was more severe (10-13). Even in normal conditions, proteins cross the glomerular capillary wall in large amounts and return to the blood by a transtubular mechanism involving proximal tubular cells (14, 15) (Figure 1). Abundant evidence from in vitro cell culture studies (16-18) and in vivo rat models of proteinuric renal disease (19-25) indicates that reabsorption of filtered proteins activates the proximal tubular epithelium. Biochemical events associated with tubular cell activation in response to protein stress include upregulation of the genes encoding vasoactive and inflammatory substances and synthesis of the corresponding protein products, such as endothelin-1 (16), monocyte chemoattractant protein (MCP-1) (17), and RANTES (regulated upon activation, normal T-cell expressed and secreted) (18, 26). Figure 1. Effect of increased glomerular permeability to proteins on progressive renal injury. TGF- Inflammatory and vasoactive substances formed in excessive amounts by proximal tubuli are secreted toward the basolateral compartment of the cell and give rise to an inflammatory reaction in the interstitium that consistently precedes renal scarring. These processes can be accelerated by cytokines released by tubular epithelial cells and by inflammatory cells that accumulate in the interstitium when proteinuria is present (27-31). Limiting Protein Traffic Prevents the Progression of Renal Disease in Animals In chronic proteinuric nephropathies, if the interstitial inflammatory reaction and the subsequent fibrosis were indeed a feature of protein overloading, limiting protein traffic or the biological effect of excessive tubular protein reabsorption should prevent or slow the progression of renal disease. This is precisely what happens in animals treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (Figure 2). In experimental diabetes, short- or long-term treatment with enalapril or the angiotensin II receptor blocker losartan reduced proteinuria and conferred protection (32, 33). Use of ACE inhibitors reduced proteinuria and limited progressive deterioration of renal function in other models of renal disease, including spontaneous proteinuria in aging male Munich Wistar Fromter/Ztm rats (34) and rats with passive Heymann nephritis (35), an experimental model that mimics membranous nephropathy in humans. Figure 2. Limiting protein traffic prevents progression of renal disease in animals. MWF/Ztm P In a recent study of rats with Heymann nephritis and severe proteinuria, simultaneous blocking of angiotensin II and endothelin-1 activity by an ACE inhibitor, together with an endothelin type A receptor antagonist, was more renoprotective than either drug alone (36). Thus, in animals, limiting protein excretion and the resulting activation of tubular epithelial cells is instrumental in protecting the kidney from further damage. From Animal Experiments to Designing a Clinical Study Clinical studies and clinicopathologic correlations in patients with progressive proteinuric nephropathies indicate that the observations in experimental models are relevant to understanding human disease (37). Among several baseline measures, proteinuria was a strong and independent predictor of renal outcome in a series of 840 patients with nondiabetic renal disease entering the Modification of Diet in Renal Disease (MDRD) study (38) and in 409 patients with type 1 diabetes and nephropathy (39). Moreover, in patients with nephroangiosclerosis (40), the onset of de novo proteinuria after years of stable renal function indicated subsequent decline in renal function. Minimal-change disease seems to be an exception to the rule that interstitial infiltrates develop with time in proteinuric glomerulopathies. This type of disease is the only example of a human proteinuric nephropathy in which a substantial percentage of patients consistently respond to steroids. Thus, periods of elevated protein excretion are relatively limited in minimal-change disease and may be inadequate to generate injury (41). Patients with this disease who have only a few relapses are protected from progressive renal damage (42), whereas those who initially responded to glucocorticoid therapy but then have frequent relapses tend to develop focal glomerulosclerosis (43-46). In patients with permanent proteinuria and nephrotic syndrome caused by minimal-change disease that is resistant to treatment, renal function inevitably deteriorates with time (47). The few patients who have undergone repeated renal biopsies show interstitial inflammation and fibrosis, with an increasing number of sclerotic glomeruli over time (48). Primary tubulointerstitial nephritis also appears to be indolent with regard to progression to end-stage renal disease, despite the hypothetical relationship between the degree of interstitial damage and the rate of renal function decline (49). This may occur because during the early stages of interstitial nephritis, tubular functional abnormalities are more pronounced than is the decline in glomerular filtration rate (GFR). At the time of the initial insult, injury is limited to segmental loci of the tubulointerstitial areas, with almost all glomeruli structurally and functionally intact; thus, renal functional reserve is completely preserved (50). Glomerular abnormalities arise only in advanced stages of primary tubulointerstitial nephritis; they are a consequence of adaptive alterations to glomeruli or of the injurious effects of tubulointerstitial processes. In such circumstances, excess protein leakage from glomeruli into the tubular lumen and the resulting reabsorption of excess proteins by proximal tubular cells may have additional interstitial damaging effects, which accelerate the progression of renal disease. The pivotal role of enhanced protein traffic as a predictor of end-stage renal disease and its impact on renal outcome are clearly illustrated by the Ramipril Efficacy in Nephropathy (REIN) study. This study formally investigated whether excessive ultrafiltration of proteins influenced the progression of renal disease and whether an ACE inhibitor (ramipril) was superior to placebo and other antihypertensive drugs in reducing proteinuria, limiting the decline in GFR, and preventing end-stage renal disease in patients with and without hypertension; blood pressure was controlled at similar levels in both treatment groups (51). The REIN study is a randomized, double-blind, placebo-controlled, multicenter clinical trial in 352 nondiabetic patients with clinical proteinuria ( 1 g/24 hours). Patients were randomly assigned to receive ramipril or conventional antihypertensive therapy to maintain diastolic blood pressure at 90 mm Hg or less. A prestratification strategy recognized two levels of proteinuria (stratum 1: >1 and <3 g/24 hours; stratum 2: 3 g/24 hours) in patients randomly a

Transplant Renal Artery Stenosis

Transplant renal artery stenosis (TRAS) is a recognized, potentially curable cause of posttransplant arterial hypertension, allograft dysfunction, and graft loss. It usually occurs 3 mo to 2 yr after transplantation, but early or later presentations are not uncommon. The prevalence ranges widely from 1 to 23% in different series, reflecting the heterogeneous criteria used to establish the diagnosis, the different manner of preservation of the graft, and surgical expertise. Reported cases are progressively increasing in parallel with the use of non-invasive investigation procedures, such as Doppler ultrasonography and magnetic resonance (MR) angiography, that arouse the suspicion of the disease even in less symptomatic cases. However, definitive diagnosis of hemodynamically significant stenosis rests on the use of invasive angiographic techniques. Percutaneous transluminal angioplasty (PTA) is the treatment of choice and restores kidney perfusion in 60 to 90% of cases. The risk of re-stenosis, the major drawback of the procedure, is prevented by the use of expandable endoprostheses. Surgery is indicated for stenoses that cannot be treated by PTA or that recur after it. Doppler ultrasonography is the procedure of choice to evaluate graft perfusion before and after revascularization.

Rituximab for idiopathic membranous nephropathy

Treatments for idiopathic membranous nephropathy, a common cause of nephrotic syndrome, can be very toxic. In view of the pathogenic potential of B cells in this disease, we studied the effects of four weekly infusions of rituximab (375 mg/m(2)-- the monoclonal antibody to B-cell antigen CD20--in eight patients who had idiopathic membranous nephropathy with persistent nephrotic syndrome. At weeks 4 and 20, urinary protein decreased from mean (SE) 8.6 g/24 h (1.4) to 3.8 (0.8) and 3.7 (0.9), respectively (p<0.0001). At week 20, albuminuria and albumin fractional clearance decreased by 70% and 65%, and serum albumin increased by 31%. CD20 B lymphocytes fell below normal ranges up to study end. The short-term risk-benefit profile of rituximab seems more favourable to that of any other immunosuppressive drug used to treat idiopathic membranous nephropathy.

Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes

abstract Objective: To evaluate whether the protein:creatinine ratio in spot morning urine samples is a reliable indicator of 24 hour urinary protein excretion and predicts the rate of decline of glomerular filtration rate and progression to end stage renal failure in non-diabetic patients with chronic nephropathy. Design: Cross sectional correlation between the ratio and urinary protein excretion rate. Univariate and multivariate analysis of baseline predictors, including the ratio and 24 hour urinary protein, of decline in glomerular filtration rate and end stage renal failure in the long term. Setting: Research centre in Italy. Subjects: 177 non-diabetic outpatients with chronic renal disease screened for participation in the ramipril efficacy in nephropathy study. Main outcome measures: Rate of decline in filtration rate evaluated by repeated measurements of unlabelled iohexol plasma clearance and rate of progression to renal failure. Results: Protein:creatinine ratio was significantly correlated with absolute and log transformed 24 hour urinary protein values (P=0.0001 and P<0.0001, respectively.) Ratios also had high predictive value for rate of decline of the glomerular filtration rate (univariate P=0.0003, multivariate P=0.004) and end stage renal failure (P=0.002 and P=0.04). Baseline protein:creatinine ratios and rate of decline of the glomerular filtration rate were also significantly correlated (P<0.0005). In the lowest third of the protein:creatinine ratio (<1.7) there was 3% renal failure compared with 21.2% in the highest third (>2.7) (P<0.05). Conclusions: Protein:creatinine ratio in spot morning urine samples is a precise indicator of proteinuria and a reliable predictor of progression of disease in non-diabetic patients with chronic nephropathies and represents a simple and inexpensive procedure in establishing severity of renal disease and prognosis. Key messages The protein:creatinine ratio measured in spot morning urine samples is a simple and reliable indicator of 24 hour urinary protein excretion rate and can therefore be used to quantify proteinuria without the need for timed urine collection Spot morning urinary protein:creatinine ratio is the strongest baseline predictor of progression of renal disease in non-diabetic patients with chronic nephropathies Compared with 24 hour urinary protein excretion rate, the spot morning ratio is an even more reliable predictor of decline in glomerular filtration rate and progression to end stage renal failure and represents a simple and inexpensive procedure in the determination of severity of renal disease and prognosis

Rituximab in Idiopathic Membranous Nephropathy: A One-Year Prospective Study

Currently available monoclonal antibodies against the B cell surface antigen CD20 have been employed to explore whether specific inhibition of B cells may help improve the outcome of idiopathic membranous nephropathy (IMN) and may avoid the side effects of steroids and immunosuppressants. This prospective, observational study evaluated the 1-yr outcome of eight IMN patients with persistent (>6 mo) urinary protein excretion > 3.5 g/24 h given four weekly infusions of the anti-CD20 antibody rituximab (375 mg/m(2)). At 3 and 12 mo, proteinuria significantly decreased from mean (+/- SD) 8.6 +/- 4.2 to 4.3 +/- 3.3 (-51%, P < 0.005) and 3.0 +/- 2.5 (-66%, P < 0.005) g/24 h, albumin fractional clearance from 2.3 +/- 2.1 to 1.2 +/- 1.7 (-47%, P < 0.05) and 0.5 +/- 0.6 (-76%, P < 0.003), and serum albumin concentration increased from 2.7 +/- 0.5 to 3.1 +/- 0.3 (+21%, P < 0.05) and 3.5 +/- 0.4 (+41%, P < 0.05) mg/dl. At 12 mo, proteinuria decreased to < or =0.5 g/24 h or < or =3.5 g/24 h in two and three patients, respectively. Proteinuria decreased in the remaining patients by 74%, 44%, and 41%, respectively. Body weight, diastolic BP, and serum cholesterol progressively decreased in parallel with an improvement of edema in all patients. Renal function stabilized (Delta1/creatinine: +0.002 +/- 0.007). CD20 B lymphocytes fell below normal ranges up to study-end. No patient had major drug-related events or major changes in other laboratory parameters. Rituximab thus promotes sustained disease remission in patients otherwise predicted to progress to ESRD, and it is safe. The long-term risk/benefit profile of this novel, disease-specific approach seems much more favorable to that of commonly employed immunosuppressive drugs.

Sodium Intake, ACE Inhibition, and Progression to ESRD

High sodium intake limits the antihypertensive and antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors in patients with CKD; however, whether dietary sodium also associates with progression to ESRD is unknown. We conducted a post hoc analysis of the first and second Ramipril Efficacy in Nephropathy trials to evaluate the association of sodium intake with proteinuria and progression to ESRD among 500 CKD patients without diabetes who were treated with ramipril (5 mg/d) and monitored with serial 24-hour urinary sodium and creatinine measurements. Urinary sodium/creatinine excretion defined low (<100 mEq/g), medium (100 to <200 mEq/g), and high (≥200 mEq/g) sodium intake. During a follow-up of >4.25 years, 92 individuals (18.4%) developed ESRD. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 (95% confidence interval [95% CI], 3.8-9.7), 7.9 (95% CI, 6.1-10.2), and 18.2 (95% CI, 11.3-29.3) per 100 patient-years, respectively (P<0.001). Patients with high dietary sodium exhibited a blunted antiproteinuric effect of ACE inhibition despite similar BP among groups. Each 100-mEq/g increase in urinary sodium/creatinine excretion associated with a 1.61-fold (95% CI, 1.15-2.24) higher risk for ESRD; adjusting for baseline proteinuria attenuated this association to 1.38-fold (95% CI, 0.95-2.00). This association was independent from BP but was lost after adjusting for changes in proteinuria. In summary, among patients with CKD but without diabetes, high dietary salt (>14 g daily) seems to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for ESRD, independent of BP control.

The RAAS in the pathogenesis and treatment of diabetic nephropathy

Angiotensin II and other components of the renin–angiotensin–aldosterone system (RAAS) have a central role in the pathogenesis and progression of diabetic renal disease. A study in patients with type 1 diabetes and overt nephropathy found that RAAS inhibition with angiotensin-converting-enzyme (ACE) inhibitors was associated with a reduced risk of progression to end-stage renal disease and mortality compared with non-RAAS-inhibiting drugs. Blood-pressure control was similar between groups and proteinuria reduction was responsible for a large part of the renoprotective and cardioprotective effect. ACE inhibitors can also prevent microalbuminuria in patients with type 2 diabetes who are hypertensive and normoalbuminuric; in addition, ACE inhibitors are cardioprotective even in the early stages of diabetic renal disease. Angiotensin-II-receptor blockers (ARBs) are renoprotective (but not cardioprotective) in patients with type 2 diabetes and overt nephropathy or microalbuminuria. Studies have evaluated the renoprotective effect of other RAAS inhibitors, such as aldosterone antagonists and renin inhibitors, administered either alone or in combination with ACE inhibitors or ARBs. An important task for the future will be identifying which combination of agents achieves the best renoprotection (and cardioprotection) at the lowest cost. Such findings will have major implications, particularly in settings where money and facilities are limited and in settings where renal replacement therapy is not available and the prevention of kidney failure is life saving.